2014 Florey Annual Report

THE FLOREY ANNUAL REPORT 2014

THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

FLOREY INSTITUTE OF NEUROSCIENCE AND MENTAL HEALTH Parkville campus

Find us online

30 Royal Parade Parkville VIC 3052 Australia

florey.edu.au

T +61 3 9035 6789

facebook.com/TheFlorey twitter.com/TheFlorey

ABN: 92 124 762 027 Howard Florey laboratories Gate 11, Royal Parade University of Melbourne Victoria 3010, Australia Austin campus Melbourne Brain Centre 245 Burgundy Street Heidelberg Victoria 3084, Australia

OUR MISSION To improve lives through brain research

OUR VISION To create significant knowledge about the brain

T +61 3 9035 7000

OUR VALUES Generate scientific knowledge to improve global health Innovate and problem-solve Work together with integrity Share our discoveries with our supporters and partners

Cover Image: Professor Ingrid Scheffer AO has had a long- standing interest in childhood epilepsy, identifying the first “epilepsy gene” in 1995. Since then, she and her collaborators have discovered around half of the 40 or so genes involved in causing epilepsy.

Acknowledgements Project manager: Amanda Place Text: Anne Crawford, Amanda Place and Rita Alampi Design: Iris Shum and Stephen Wood at Blueboat Design Photography: Mark Chew Proofreading: Margit Simondson, Rachel Smith, Jane Standish, Anna Marcon Published May 2015 A summary of highlights from this Annual Report is available in print from Margit via email: margit.simondson@florey.edu.au or call +61 3 8344 9679.

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TABLE OF CONTENTS

“

As you get older, whether or not you’re a scientist, it’s exciting to understand what being human is. As a scientist, I’ve had a peculiar privilege in being able to see some aspects of life through chemistry.

Maybe of all the things that fascinate me most, it’s to be able to look at the chemistry of ageing and in our case, we’ve opened up the field of metals and their role in human disease. We increasingly understand how much of ageing is actually related to good old-fashioned chemistry.

That is mind-blowing sometimes.

” Professor Ashley Bush, heads the Florey Institute’s Oxidation Biology Unit, researching Alzheimer’s disease and other neurological disorders of Ageing.

In 2014, Professor Bush won the Victoria Prize for Science and Innovation in Life Sciences.

Our mission, vision and values

1

Introducing Dr Jennifer Walz

63

About us

4

Schizophrenia - The relentless quest to find answers

64

Why do we study the brain?

6

Mental Health

66

Florey in a flash

8

Clinical Discovery Unit

69

Chairman’s & Director’s report

10

Psychotropic Drug Advisory Service

70

Chief Operating Officer’s report

12

Victorian Brain Bank Network

71

Written in Blood - Biomarkers for Alzheimer’s Disease

14

Multiple sclerosis

72

A Star on the Rise - Alexander Eastwood

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Neurodegeneration

78

Game Changers - The Future of Neuroscience

18

Drug targets in sight

82

The Two of Us - Prof Ashley Bush & Dr Ya Hui Hung

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Neuropeptides

84

Foundation Council Chairman’s report

22

Slipping from Stroke into Dementia

90

Board of Directors

24

Stroke

92

Neuroscience Trials Australia Division

30

Systems Neurophysiology

100

Equality in Science report

34

Florey Governors

105

Divison Heads

36

Board Committees and Foundation Council

106

Brain Development and Regeneration

40

Faculty & Senior Positions

107

Chasing a cure for Motor Neurone Disease

44

Our Donors

108

Cognitive Neuroscience

46

Publications

112

Four Key Ways to Improve your Brain Health

52

Our People

134

Epilepsy

54

Financial Statements

140

Imaging

60

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

ABOUT US

THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

ADDICTION ALZHEIMER’S DISEASE CARDIOVASCULAR DISEASE MENTAL ILLNESS EPILEPSY

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he Florey Institute of Neuroscience and Mental Health is one of the largest and most highly respected brain research centres in the world.

Neuroscience is an area of medical research attracting enormous attention as our understanding of the brain rapidly evolves.

Internationally, populations are ageing and there is a sense of urgency to find causes, treatments and cures for conditions affecting the brain and mind. There is an urgent imperative to address these conditions to avoid suffering and to contain healthrelated expenditure.

The Florey provides scientists and students with world-class facilities and the opportunity to improve people’s lives through brain research and, ultimately, to influence global wellbeing and health economics.

By the end of 2014, the Florey employed 482 staff, and worked with 157 postgraduate students throughout the year.

The Florey continues to be a world-leader in developing and applying imaging technology, and research into genetics, stroke rehabilitation, epidemiological studies, psychotic illnesses and neurodegenerative diseases.

HUNTINGTON’S DISEASE MOTOR NEURONE DISEASE MULTIPLE SCLEROSIS PARKINSON’S DISEASE STROKE SUDDEN INFANT DEATH SYNDROME TRAUMATIC BRAIN AND SPINAL CORD INJURY

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WHY DO WE STUDY THE BRAIN?

“While much of the human body has been analysed and its machinations largely understood, the brain is still an enormous mystery waiting to be unravelled.

The knowledge gained over the next 20 years, I believe, is set to be utterly fascinating and will transform the human condition.

We are at a crucial time in neuroscience with our understanding accelerating at a cracking pace.

We are learning how the brain is vulnerable to addiction, how it stores and retrieves information, how it influences our appetite, heart function and breathing. We are delving down and isolating amino acids which may contribute to depression and asking whether particles of iron contribute to dementia. These are just a few of the many life-changing projects underway at the Florey.

As President Barack Obama recently declared, the neuroscience revolution has begun.”

Professor Geoffrey Donnan AO Director The Florey Institute of Neuroscience and Mental Health MBBS MD FRACP FRCP (Edin)

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“

We flew into 2014 with much gusto and kept the pace cracking all year. The expansion of two major projects of national significance grew in momentum. The Victorian Stroke Telemedicine program was expanded to more hospitals around the state.

We won an NHMRC grant to further evaluate the economics of the program, fostering further collaboration between the Florey, Monash and Deakin universities.

The Australian Stroke Clinical Registry is expanding across Victoria. As custodian for this registry, the Florey is driving national clinical improvement in stroke care across Australia.

We also contributed to the successful NHMRC Centre for Research Excellence in Stroke Rehabilitation, so watch this space.

” Associate Professor Dominique Cadilhac, Head, Public Health, Stroke division.

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

FLOREY IN A FLASH

Florey outreach The Florey hosts regular events at its Parkville campus, involving school children and members of the general public. Our researchers and medical practitioners share their knowledge of the brain in a variety of ways.

STUDENTS ADULTS

Citations

Outreach

Scientific publications published over the 10 years, 2004-2014.

The number of Florey publications for 2014.

Cumulative citations, 2004- 2014.

Average citation per publication, 2004-2014.

Argentina | Australia | Austria | Belgium | Brazil | Canada | Chile | China | England | Finland | France | Germany | Hong Kong | Hungary | Ireland | Israel | Italy | Japan | Malaysia | Northern Ireland | Norway | Netherlands | New Zealand | Philippines | South Korea | Scotland | Singapore | Spain | Sweden | Switzerland | Taiwan | UK | USA | Wales

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ADMINISTRATIVE AND SCIENTIFIC SUPPORT STAFF

RESEARCHERS

COUNTRIES REPRESENTED BY OUR STAFF AND STUDENTS

POSTGRADUATE STUDENTS

from 24 schools learned about the life of a neuroscientist.

YEAR 12 STUDENTS

visited to learn about mental illness.

Research highlights

Alzheimers disease: Global players against a global scourge

Our team

ALL STAFF

visited to attend lectures about various diseases of the brain and our quest to improve lives through improved treatments and cures.

In 2014 alone, Florey researchers published 47 papers on Alzheimer’s disease and other dementias, which were cited 121 times by other researchers.

These papers included classifying new real-time imaging agents for dementia proteins, using blood-based markers to predict Alzheimer’s protein deposition in patients’ brains, and looked at the levels of that protein in patient blood samples to accurately predict changes in patients’ mental abilities.

Severe epilepsy: small brain lesions Neuroimaging is helping to explain why epilepsy can involve intellectual disability.

Widespread abnormal electrical activity occurs, even when patients are not seizing.

In some patients we have located a small brain lesion.

After surgical removal, the abnormal activity is eliminated and the patients are seizure free.

Stroke by the numbers: Save a minute, save a day 87% of the 12 million strokes worldwide are caused by a blocked vessel in the brain, causing hundreds of thousands of brain cells to die.

Every minute that can be saved before the clot is ‘busted’, can save up to 1.8 days of disability-free life meaning 15 minutes saved on the average 70 minute wait for treatment could equate to an extra month of healthy life.

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The last 12 months saw the retirement from the Board of Laureate Professor Colin Masters and Professor Graeme Jackson. We acknowledge them for their enormous contribution over the years as we have successfully amalgamated the Mental Health Research Institute and the Brain Research Institute with the Florey. Both are dynamic investigators who contribute significantly to global research of the brain. Professor Masters is a world leader in Alzheimer’s research. His work over the last 35 years has been widely acknowledged as having had a major influence on our understanding of amyloid plaques. He continues the search for novel therapeutic strategies to combat this terrible disease. Professor Jackson is a neurologist and leader of a research team dedicated to curing epilepsy. His work in MRI technology has changed international practice and has led to improved understanding of the disease and more sophisticated surgical outcomes for some of the most serious forms of epilepsy.

Most recently, we accepted the resignation from the Florey Board of Professor Anne Kelso AO, who has become the chief executive officer of the National Health and Medical Research Council.

This significant position, at the centre of national research funding and policy, is perfectly suited to this very wise and strategic professional. We wish Anne well in this new endeavour at a time of great change in the sector.

From a national perspective, 2014 was a year dominated by political campaigning for fairer federal funding through the proposed Medical Research Future Fund. The Florey has been cautious when commenting on funding sources but, rather, we have emphasised our strong support for the $20 billion initiative. There is no doubt it will be an absolute game changer for medical research in this country. It would provide a stable environment for Australian scientists who currently live year to year with the uncertainty around the likelihood of being able to continue their research.

It is well documented that the incidence of diseases of the brain and mind is continuing to grow, placing a huge burden on healthcare costs. During 2014, the Florey developed a long-term strategic approach to address this looming crisis by designing four key ‘working models’ for disease intervention. We aim to deliver major advances by 2035, improving lives so individuals across the nation can work, feel well and be unimpeded by diseases that can be avoided, treated or cured.

We aim to:

Chairman’s & Director’s Report

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he Florey’s past year has been packed with scientific activity. There have been great advances in our knowledge of the brain - both at the laboratory bench and in the hospital setting.

Our superb facilities continue to provide new opportunities to collaborate – for colleagues within the buildings and with those who come from overseas to work as members of the world’s third most-cited neuroscience facility. It is heartening to witness casual scientific connections being made and robust discussions taking place in corridors and hubs.

The scientists have been publishing in high-ranking journals on a range of diseases from Alzheimer’s to autism. You will read about some of these in this report.

Outside of research, the Florey has taken great strides forward in terms of our financial security.

Our budget situation has stabilised, and in 2015 the investment earnings on our investments of over $25 million is solely being applied to support and grow research for the future of the institute.

Whilst modest deficits are planned for the foreseeable future, the focus now is on the medium term in order to grow the Florey’s endowment so as to sustain our science in perpetuity.

Once again, we have experienced overwhelming support from the community. Diseases of the brain and mind touch the lives of so many people and we have appreciated the passionate interest shown in our work. The scientists are invigorated by the opportunity to share their research – through the media, at public lectures and as part of our school program. We are so grateful for donations, bequests and financial support for fellowships which we direct to our important science initiatives. Our community fundraisers have exceeded all expectations this year by contributing significantly to the Florey through a range of innovative fundraising initiatives. We thank them most sincerely.

ҩҩ Diminish the scourge of dementia

ҩҩ Prevent stroke and limit its impact when it does occur

ҩҩ Reduce the incidence and devastation caused by mental illness ҩҩ Identify and help those genetically prone to epilepsy.

We believe this comprehensive program has the capacity to enable 175,000 people per annum to participate in the workforce. This translates to individuals living more independent lives, with less reliance on the health system and a capacity to contribute to the economy. We are on the brink of an exciting new era.

Finally, we would like to take this opportunity to thank our dedicated researchers and clinical partners who work together over many years to deliver discoveries. You are working for the good of humanity, improving lives and ensuring that children born today will enjoy healthier lives, free of some of the neurological conditions we face today. With National Health and Medical Research funding static, there has never been a more testing time to be a medical researcher in Australia.

Thank you again to our dedicated and generous supporters. Please enjoy reading this report and know you have helped make discoveries happen.

Mr Harold Mitchell AC, Chairman

Professor Geoffrey Donnan AO, Scientific Director

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“

COMPANY SECRETARY REPORT

As a young scientist, I felt a real need to make a positive contribution to society and eventually I found my niche in genetic epilepsy.

Report from the Company Secretary, Peter Plecher

Research by Professors Sam Berkovic and Ingrid Scheffer - who would become my most important and closest collaborators - helped me realise that genetic epilepsies demanded an urgent clinical response and a paradigm shift in our understanding of the fundamental causes of this “sacred” disease. We are trying to change the lives of children and adults with genetic epilepsy by discovering how genetic mutations lead to seizures and by developing new drugs and therapies to improve lives.

uring 2014 the Florey entered a new era. With the 2012 amalgamation, the completion of the building project and the collapse of the group structure behind us, management is focused on the Florey’s prosperous future.

We are absolutely committed to building tightly managed operations in order to support our mission, to improve lives through brain research.

During 2014 the restructuring and streamlining of internal operations has enabled management to focus on extracting the best value for the Florey on every dollar spent, whilst at the same time improving service and support to researchers. New systems, automation and reporting have been implemented to make internal operations easier for researchers, and this will continue throughout 2015, particularly with regard to the Human Resources function.

Additionally arrangements with third parties have either been re-negotiated or not renewed, such as building agreements and information technology, in order to ensure internal operations are fully funded.

In recent years our Corporate Services department has operated multi-million dollar deficits. Corporate Services is budgeting a surplus for 2015. This will mean that all monies contributed to the Florey’s endowment will be used to directly fund vital world class research. The tremendous work of the Board via the Finance and Investment Committee, the Commercialisation Committee and the Audit Committee has been instrumental in this regard and is greatly appreciated.

The management team has also commenced implementing a framework for the long term financial sustainability of the Florey, including the adequate co-funding of all researchers as a matter of policy and practice. A big thanks to all those who have contributed to the Florey’s on-going success and I look forward to providing an even brighter report in 2016.

Mr Peter Plecher, Company Secretary

” Professor Steven Petrou, Deputy Director and Head, Division of Epilepsy, Ion channels and Disease.

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

WRITTEN IN BLOOD Biomarkers for Alzheimer’s disease

DEMENTIA IS THE THIRD LEADING CAUSE OF DEATH IN AUSTRALIA AND CURRENTLY THERE IS NO CURE FOR THE DISEASE. BIOLOGICAL INDICATORS OF ALZHEIMER’S DISEASE OCCUR UP TO 15 YEARS BEFORE CLINICAL SYMPTOMS SHOW. BY 2060, SPENDING ON DEMENTIA IS SET TO OUTSTRIP THAT OF ANY OTHER HEALTH CONDITION AND WILL REPRESENT AROUND 11% OF HEALTH AND RESIDENTIAL AGED CARE SECTOR SPENDING. Dr Noel Faux ‘s work has been selected by the National Health and Medical Research Council as one of the nation’s ten most promising for 2014.

D

ementia. It’s a collection of diseases that strike fear into the hearts of many, but we’ve barely scratched the surface to understanding it.

Our methods for staving off and treating dementia have been increasing very slowly despite intense international focus.

But according to Dr Noel Faux from the Florey Institute of Neuroscience and Mental Health, one of the main issues with dementia is that by the time a clinical diagnosis is made, a huge amount of brain damage has already occurred. And the damage caused by this progressive disease is not reversible.

The race is on to develop an inexpensive test that will enable far earlier diagnoses of dementia. As with most diseases, the earlier the diagnosis the sooner treatment can begin and the better the chance of a good outcome. Making the test affordable is also important as it will allow greater numbers of people to access it and act on the results.

Dr Faux is in the thick of this race and is using data from the ongoing Australian Imaging Biomarker and Lifestyle Study (AIBL), which began in 2006, to support his research into the most common form of dementia, Alzheimer’s disease.

“AIBL is a large scale population-based observational study with over 700 cognitively healthy participants, over 100 participants with mild cognitive impairment and over 200 participants with Alzheimer’s disease,” Noel explains.

“Using blood-based measurements from AIBL, we were able to identify two useful signatures. One was able to distinguish people with Alzheimer’s disease from cognitively healthy individuals. The other signature was able to distinguish people who have a biomarker identifiable through brain imaging from those who do not.”

Analysing blood avoids the need for expensive imaging and cerebrospinal fluid analyses, which are currently used.

Potential distress and pain are also minimised using this method.

Other researchers have adapted the research approach Noel used to identify blood-based signatures for several other diseases and conditions such as schizophrenia and Parkinson’s disease.

Looking back, it’s apparent that Noel was well-placed for his line of research with his background in computer science and PhD in bioinformatics.

“During my PhD studies, I became very interested in neuroscience and how

I could apply my bioinformatics knowledge to help understand neurodegenerative diseases and, in the instance of Alzheimer’s disease, how we could identify people at high risk of developing Alzheimer’s disease before clinical symptoms show,” he says.

With nearly 1 million Australians expected to be diagnosed with dementia by 2050, Noel’s research could not have come at a better time. Needless to say, the hopes of the nation hang on significant breakthroughs in dementia – and Noel could be just the person to deliver one of them.

TEAM MEMBERS

Professor Colin Masters Professor Ashley Bush Professor Christopher Rowe Dr Victor Villemagne Professor Ralph Martins Dr Justin Bedo Dr Samantha Burnham Dr James Doecke Dr Simon Laws Dr Kathryn Ellis AIBL research team AFFILIATION

Australian Biomarker Imaging and Lifestyle (AIBL) study of ageing CSIRO.

NEXT STEPS Having designed two useful blood biomarkers through his research, Noel’s next steps will be to validate these results with the AIBL cohort, international volunteers and those with other neurodegenerative diseases (to ensure disease specificity). From there, Noel and his colleagues will develop a prototype test that will be administered in a healthcare setting.

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A Star on the Rise Alexander Eastwood

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lexander Eastwood is off to Oxford University on a coveted Rhodes Scholarship. The Florey will miss this extraordinary young man’s contribution to our research. We wish him well for what is sure to be a great career.

Alexander Eastwood was determined to become a secondary school teacher when he was in the final year of his science degree at the University of Melbourne.

A STAR ON THE RISE Alexander Eastwood

Passionate about education, Alexander was a Campus Ambassador for Teach for Australia, an organisation that recruits outstanding young graduates and other professionals to work in disadvantaged schools. He previously campaigned on educational and youth matters.

But a third-year lecture in neuroscience offered by the Florey’s Dr Emma Burrows changed his mind – and the course of his life. The lecture was about the emerging fields of environmental enrichment and neuroplasticity.

“It was a career changer,” says Alexander.

“Emma was among the most engaging lecturers I had ever had.”

Alexander approached the scientist after the lecture, and she later invited him to do research experience in the Neural Plasticity laboratory, led by Professor Anthony Hannan.

The following year he jumped at the chance to study an Honours year researching autism spectrum disorder with Emma and Anthony as his supervisors.

“I’d always had an interest in autism – two of my cousins have the condition.

“We were interested in how it developed in a mouse model and also, in better understanding how mice communicate.

We looked at the high-pitched sounds produced when males ‘sing’ to females.

“We were collaborating with researchers from other faculties and unexpectedly learnt that mice also yodel and growl!”

For Alex, it was an enjoyable yet intense year and his project was an overall success.

The researchers found that mice with the

mutation similar to that in some humans with autism used a completely different set of calls to those without it.

“The project provides interesting and novel findings and is a roadmap for future research,” says Alexander.

Tony Hannan describes Alexander as bright and motivated.

“He has exceptional promise as a neuroscience researcher – he’s meticulous, curious, he reads all the literature and picks up the techniques really quickly. He has all the makings of a really exceptional scientist.”

At the end of the year Alexander was awarded a Rhodes Scholarship to complete a Masters and PhD at the University of Oxford.

The honour was the latest in a long string of awards and scholarships, including Dux of school in 2008 and Bendigo Youth Citizen of the Year in 2010. He’s an allrounder, active in sport, debating, theatre and volunteering, including working on environmental causes.

“The Florey is an incredible launching pad – it’s stimulating, social and cosmopolitan.”

He is continuing autism research with Emma and Tony, working towards a publication before he leaves for England in September - and hopes to collaborate with them while at Oxford.

And beyond his PhD? “Ideally, I’ll join the global effort to better understand autism and help improve the lives of people with the condition.”

“Teaching is something I’ll come back to but I need to chase this interest for now.”

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

“But it’s already begun.”

The Florey is linked into the Obama BRAIN Initiative, and large initiatives in the European Union, among other projects.

GAME CHANGERS The future of neuroscience

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euroscience is attracting massive community interest as we discover remarkable facts about this elusive organ, hidden away behind our bony skulls. There is still a lot to reveal – and the Florey’s Dr Henry De Aizpurua is helping to steer our scientists to new frontiers.

Pictured: Dr Henry De Aizpurua is a deputy director at the Florey and manages business development.

Dr Henry De Aizpurua is a deputy director at the Florey and the man responsible for its business development.

During his 15 years at the Institute, he has witnessed an explosion in knowledge about neuroscience.

He’s seen the Florey evolve to bring together the bulk of neuroscience expertise in Melbourne and become by far the largest independent brain research institute in Australia.

He’s watched it grow in global relevance to become among the top three or four leading neuroscience institutes in the world.

And, he says, there’s more to come – much more.

Henry says the Florey will be active in several neuroscientific frontiers in the next 20 years.

The first will involve mapping the connectivity of the brain. The aim?

To create a 3D map of the brain known as a “connectome”.

“This has the ability, when achieved, to help us understand the brain and the consequences of damage and repairs to it,” he says.

“There’s a huge amount of excitement about where we could go with this.”

Creating a connectome would be like the advent of the human genome, which revolutionised medicine more than a decade ago.

Like the genome, building a connectome would be a huge, global effort of “staggering complexity and requiring massive investment”, he says.

“It will probably require the invention of tools and systems we don’t have right now. It’s enormously multidisciplinary – engineers, IT specialists, imagers, basic cellular scientists, clinicians, will all have to be part of big programs in that area.”

Another ambition of the Florey is to nail down safe and effective treatment for at least one of the most common neurological diseases – within the next decade.

“Any institution that sees itself as globally relevant wants to do this. We aim to develop a powerful treatment that is broadly applicable to the community at large – possibly for Parkinson’s or Alzheimer’s, depending on our progress in the next few years.

“Work at the Florey on all the diseases we research is being driven at a frenetic pace but often in medicine serendipity is the thing that gets you across the line.”

“It’s an achievable ambition.”

A breakthrough with one disease could also lead to lessons and shortcuts in developing treatments for other diseases, he says.

“Medicine always shows you that there are lessons to be learnt and shortcuts to be understood as you unravel one Gordian knot of a disease and flow through to other pathologies. You can’t guarantee that but the history of medicine shows that, as in infectious diseases.”

Florey scientists are ready to tackle another frontier – the development of a simple, safe biomarker for early detection of neurological disease.

“It’s super important because fewer of us are going to die from heart attacks or tumours – they’re already becoming manageable diseases – and so we’re going to have a population living to an age that biology hasn’t actually been programmed to plan for.

“We want to identify those people in the community who are susceptible to early progression into chronic degenerative disease. Then we will offer them interventions that avoid the catastrophic collapse of the cognitive neuro functions, their mental health or their physical ability to navigate daily life.

“Right now we’re relying on big clunky expensive tools like MRI and PET (molecular imaging devices) but we need to refine medications and other treatments so we can offer simple, safe, cheap effective tools for people around the world.”

Brain maintenance is a third theme demanding attention of Florey scientists and one offering an opportunity for a partnership with the public, says Henry.

“Thirty or 40 years ago, it was thought the brain was static and its development set in concrete once you hit puberty. Now, of course, we know it can be moulded, shaped, exercised and driven. It’s the concept of the plastic brain.”

“Maintain the brain” is the catchcry but it is ultimately up to the public to make the lifestyle choices to do this, he says. The Florey has an obligation to educate the community.

“It’s a bit like the public education campaigns to quit smoking,” Henry says.

“The concept of maintaining brain health is going to explode over the next decade. People will begin to understand the direct benefits of healthy lifestyles so they maintain brain health.

“The baby boomers and the Gen-Xers are better educated than any generation before them. They have an enormous interest in maintaining brain health – and they will be empowered to do something about it.”

Establishing partnerships with clinical psychologists, commercial organisations that develop brain training tools and the media, (the Florey has already has a strong link with the ABC’s Active Memory), is going to be pivotal in giving the public the information it needs and in rolling out brain activity tools developed by cognitive neuroscientists.

“And at the end of the day, it will be use it or lose it.”

The final frontier is developing the ability for the brain to regenerate itself.

“Now that is a long way off,” Henry says, “because the whole area of cellular regeneration is still finding its feet.

“But there’s a huge amount of fantastic stem cell biology and regenerative medicine happening at the Florey.

Eventually good quality medicine and research is going to deliver approaches to regenerate various parts of the body and the brain as well, which will give patients and their doctors a new set of options as they approach particular problems with their brain health.”

Henry says he is buoyed by the possibilities for neuroscience in the next two decades.

“The brain is the most complex, the least understood major organ in the body. The opportunity for exploration and discovery, for new insights and interventions, are just all there.

“The Florey is, aspires to be, and will be, a global leader in delivering some of these life-changing opportunities.”

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

The Two of Us Prof Ashley Bush & Dr Ya Hui Hung

THE TWO OF US Prof Ashley Bush & Dr Ya Hui Hung

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rofessor Ashley Bush heads the Florey Institute’s Oxidation Biology Unit, researching Alzheimer’s disease and other neurological disorders. He’s a psychiatrist and basic researcher. Senior researcher Ya Hui Hung is investigating a rare, genetic and fatal disease called NiemannPick Type C (NP-C) that is also known as ‘childhood Alzheimer’s’. The two researchers hope this work will lead to drugs to treat young people afflicted with the condition, and that it will have implications for a cure for Alzheimer’s, too.

PROFESSOR ASHLEY BUSH I met Ya Hui when I was recruiting staff after returning from Harvard University in 2005. My main work has been on the role of metals in brain diseases and we know this has something to do with Alzheimer’s disease. I thought Ya Hui was very bright and recruited her to do a post-doc.

For the first few years she investigated whether there was a relationship between copper and cholesterol. In 2010 I was approached by a lady called Chris Hempel, whose twin daughters have NP-C, who’d set up a foundation in the US to encourage study of it. It was such a heart-rending story, I found it hard not to engage. Chris’s girls are 11 years of age and have lost the capacity to walk and speak as they have advanced dementia. Ya Hui was very moved by the story as well. She’s got a big heart. Once she saw what this disease was, it made the science seem very real.

Her mission is to find drugs that can reduce the accumulation of cholesterol, and help correct the loss of function that occurs in NP-C. Ya Hui’s very smart and an excellent scientist but is modest and self-effacing.

She gets disappointed in herself very easily. I mentor her about her career and try to keep her optimistic. It’s a tough world trying to be a career scientist in Australia.

A couple of times she thought she’d have to give it away and I did what I could to keep her going.

We’re both music buffs. A common friend has an orchestra and we found ourselves in the same recording studio once, surprised to see each other outside work!

Pictured: Professor Ashley Bush and Doctor Ya Hui Hung.

I insisted that Ya Hui present her findings at an international conference in Greece in 2012. She was terrified so I got her trained by a coach, an actor from Neighbours.

She did a great job. I think that was the watershed for her; when she blossomed into a mature scientist. She went on to become our public face for this research.

She must be the leading scientist on NP-C in Australia.

DOCTOR YA HUI HUNG When Chris Hempel contacted Ashley in 2010, she brought to us a question: is there something you can do to help my daughters?

Driven by Chris’s personal quest, we looked at the metal changes in NP-C disease patient skin cells, in blood samples and post-mortem brain cells. We published a paper last year that reported widespread metal changes in NP-C disease. This finding gives us confidence that by altering metal levels we may be able to treat NP-C. We’re learning amazing things from talking to patients and their families, too.

I’m a softie! It’s really heart-breaking to see these children suffering, and see their parents’ lives so affected by the disease too. Hopefully our drug screen will result in a treatment to help patients.

Ashley’s really good when I’ve got questions; his door is always open. He’s very knowledgeable, a lateral thinker, and he’s always encouraging and very supportive. I often thank him for putting up with it when I say ‘I can’t do this any more!’. He’s a great boss and mentor. He lightens things up – he says ‘everything’s a lazy afternoon’s work’!

He’s very determined and persistent in pursuing science. I’ve learned from him to never give up.

If you would like to help this research to continue, please contact the Florey on 1800 063 693

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FOUNDATION COUNCIL CHAIRMAN’S REPORT Report from the Foundation Council Chairman, Ross Oakley OAM

THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

cabinets. We definitely need more Australians to declare their belief in an act of public generosity and to help create a groundswell of funding support for medical research. Those behind new and innovative initiatives need to step up publicly and share their belief in philanthropic generosity. As we have seen in the United States, the impact can last a century or more.

In 2014 the Florey Foundation and its Council included Chairman Trevor Clark, Julian Clarke, Graeme Kelly, Ross Oakley and Stephen Spargo. Ex officio members were Geoffrey Donnan, Henry De Aizpurua and Ross Johnstone. We are very grateful to these individuals who have contributed to the organisations with their expertise.

COMMUNITY SUPPORT

THANK YOU TO OUR SUPPORTERS FROM THE FLOREY’S FOUNDATION COUNCIL. A CHANGING WORLD The Federal Government’s National Health and Medical Research Council (NHMRC) has traditionally been the major provider of funds for medical research. It is a highly competitive arena under the constant pressure of funding constraints and increasing demand. In 2014, the success rate of scientists across Australia for NHMRC grants was the lowest since the current selection process was adopted 15 years ago. While there is great excitement and hope about the proposed Medical Research Future Fund, it remains exactly that: a fund in the future.

In the face of the changing models of government funding, the Florey’s capacity to fundraise has become increasingly important.

Thanks to the generosity of many individuals and organisations, the Foundation had a productive year. We have seen good growth in our philanthropic income and the support we have received has been crucial to our research programs and our ability to recruit and retain the best researchers.

Philanthropic contributions have purchased some of the latest research technologies and equipment, thus playing a vital role in our work to identify methods of early diagnosis and to develop effective treatments for illnesses that affect the brain.

We are heartened by the growth in our income from donations. In 2014 we raised $3.88 million from private donors and philanthropists, community fundraisers, trusts and foundations, and bequests. We feel tremendously privileged to receive support from the many individuals who respond to our appeal letters during the year. These gifts, small and large, come from across Australia and are crucial to our achievements. We thank all our donors for their loyal support.

As part of this program we are fortunate to attract funds from philanthropic trusts and foundations that enable research projects which are focussed on exciting new findings to get underway and become established. They also allow us to purchase the latest technologies that can accelerate the progress of research or provide new insights into the illnesses we study. They often fund work being done by promising young scientists as they establish their research programs.

This year has seen a great many people sweating for the Florey, fundraising in the City2Sea, the Melbourne Marathon, and Surf Coast Century. Some people were running for the first time and others were regular supporters who used this opportunity to keep fit and raise money and awareness at the same time.

And there were others who did something a bit more out of the ordinary, like Kingsley Just who broke the world record for consecutive spins in a plane. That was a hair-raising day. Not only did he beat the world record, he did 600 more rolls to reach a staggering 987 rolls altogether.

This was all to raise money for research that may one day help his son Kaelen who has a rare genetic condition which is a variant of Acrodermatitis Enteropathica.

Andrew and Claire Heenan have also been great supporters in the face of tragedy. Andrew, with the support of Claire, set off from Perth on a 4000km solo cycle trip across Australia to the NSW Central Coast. Before his journey Andrew shared a thought with his supporters: “I lost my son Ben after a long battle with mental illness. Despite being surrounded by a loving family and intensive treatment from a team of mental health professionals Ben could no longer cope with his illness and took his own life. Ben’s death was a complete tragedy for our family”.

Rather than feel helpless, Andrew and Claire saw the value in investing in mental health research and decided to help the Florey in its quest to improve treatments for those suffering mental illnesses.

The support of people like these families, and the individuals running their own fundraising activities, is invaluable in funding research into illnesses of the brain. We appreciate their bravery, determination and commitment to help us find answers.

In addition to these individuals, it is important to also recognise the wonderful, ongoing support we receive from voluntary groups in the community such as One in Five, River’s Gift, and Cure MND, all of whom work tirelessly to raise funds to support our research. These Florey champions are motivated by tragedy and determination to help others who might one day face an illness of the brain or mind. We are so grateful for their vision and generosity.

I would also like to acknowledge the wonderful work being done by the fundraising, media and marketing teams who work tirelessly across a wide range of activities to raise funds to support our scientists while keeping the community up-to-date with the research we are doing.

Many trusts and foundations were established decades ago by forward thinking philanthropists.

Today, it is heartening to see new foundations being established by generous individuals and families who see the importance of medical research and share our vision for a healthier community. The Dowd Foundation was a new donor to the Florey this year, providing a threeyear fellowship to support Associate Professor Chris Reid and his work on epilepsy whilst The Finkel Foundation gave its support to annual scholarships for three promising young scientists.

While the act of philanthropy is yet to penetrate deeply within Australia, it is a discussion that is occurring increasingly around family dinner tables, conference rooms and parliamentary

Council Chairman, Ross Oakley OAM

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

BOARD OF DIRECTORS

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BOARD OF DIRECTORS PROFESSOR GEOFFREY A DONNAN AO

MR ROB GERRAND

Florey Director MBBS MD FRACP FRCP (Edin)

BA, FAICD

Director of The Florey Institute of Neuroscience and Mental Health, Professor Geoffrey Donnan was previously Director of the National Stroke Research Institute and subsequently the Florey Neuroscience Institutes. He is also Professor of Neurology at the University of Melbourne. His research interest is clinical stroke management and was co-founder of the Australian Stroke Trials Network. He is Past-President of the World Stroke Organisation. He received the American Stroke Association William Feinberg Award for Excellence in Clinical Stroke Research in 2007, the Swedish Karolinska Institute Award for Excellence in Stroke Research and the World Stroke Organization Leadership in Stroke Medicine Award in 2012 and the European Stroke Congress Wepfer Award for stroke research in 2014.

MR HAROLD MITCHELL AC

PROFESSOR JAMES ANGUS AO

Chairman

FAA BSc PhD

Mr Harold Mitchell is the founder of Mitchell & Partners and until August 2013 was the Executive Chairman of Aegis Media Australia and New Zealand. Mitchell & Partners is the largest media and communication group in Australia, with growing presence in New Zealand and across the Asia-Pacific region. Mr Mitchell holds a large number of community roles including Chairman of the Melbourne Symphony Orchestra; Chairman of TVS, University of Western Sydney’s television service for Greater Sydney; Chairman of Arts Exhibitions Australia; Chairman Free TV Australia; Vice President of Tennis Australia; Director of New York Philharmonic, and Director of Crown Ltd. He has also been Chairman of CARE Australia; Chairman of the National Gallery Australia; Chairman of the National Gallery Australia; President of the Melbourne International Festival of Arts; President of the Museums Board of Victoria and a Board member of the Opera Australia Council. Mr Mitchell was appointed Companion of the Order of Australia in 2010 for eminent service to the community through leadership and philanthropic endeavours in the fields of art, health and education and as a supporter of humanitarian aid in Timor-Leste and Indigenous communities. In 2013 Mr Mitchell was awarded the Victorian of the Year.

James Angus is former Dean of the Faculty of Medicine, Dentistry and Health Science at the University of Melbourne. He is also a Fellow and former Member of Council at the Australian Academy of Science. He is currently Professor of Pharmacology at the University of Melbourne, a Director of The Peter MacCallum Cancer Institute and Chairs the Victorian Clinical Training Council. Professor Angus is the Vice Chancellor’s nominee for appointment in accordance with the Constitution and was previously a non-executive Director of The Mental Health Research Institute (appointed 2003). He was appointed an Officer of The Order of Australia in 2010 for distinguished service to biomedical research, particularly in the fields of pharmacology and cardiovascular disease, as a leading academic and medical educator, and as a contributor to a range of advisory boards and professional organisations, both nationally and internationally.

Mr Gerrand is Chairman of Healthy Parks Healthy People Global Ltd and Wheretonext.biz Pty Ltd, a Director of Melbourne Primary Care Network Ltd and The Dax Centre, and is an AICD Director Nexus Chairman. He heads the marketing and communications consultancy Gerrand & Associates, is a consulting partner with SenateSHJ and was General Manager of Group Public Affairs at ANZ Bank. Previous board appointments include Chairman of Parks Victoria and Director of Alfred Health, the Financial Planning Association of Australia, the Koorie Heritage Trust and the Melbourne Convention and Marketing Bureau. He was the Founding President of the Monash Alumni Association, and was appointed Adjunct Professor at Deakin University. He is a published author.

MR CRAIG DRUMMOND

PROFESSOR ANNE KELSO AO

B.Comm (Melb) ACA SFFIN

BSc (Hons) Ph D (Melb)

Craig joined the National Australia Bank in November 2013 as Group Executive, Finance & Strategy and appointed Chairman of JB Were Board in July 2014. Prior to joining NAB, Craig spent four years as Chief Executive and Country Head of Bank of America Merrill Lynch Australia. Prior to that, Craig joined Goldman Sachs JB Were in 1986 and held various roles including Chief Operating Officer, Chief Executive Officer and Executive Chairman. Craig is a Board member of The Geelong Football Club and a member of The Ian Potter Foundation Finance Committee. Craig is a Senior Fellow of FINSIA and a Chartered Accountant.

Professor Anne Kelso is Director of the WHO Collaborating Centre for Reference and Research on Influenza at Melbourne Health. She is also an honorary professorial fellow at the University of Melbourne where she undertakes research on immunity to influenza. She is currently a member of the Board of Trustees of the International Society for Influenza and Other Respiratory Virus Diseases, and a number of committees advising the WHO and the Australian Government on influenza. Professor Anne Kelso has recently been appointed the Chief Executive Officer of the National Health and Medical Research Council (NHMRC).

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MR MARK JONES

MR ANDREW STRIPP

MR STEPHEN SPARGO AM

MR ANDREW ABERCROMBIE

BA (Hons) (Sheff) MBA (MBS)

MSc (Clinical Psychol) BBSc (Hons)

LLB LLM

BEc LLb MBA (IMD)

Mr Mark Jones is the Ethics and Independence Partner and the Chief Operating Officer of the Risk Management Group at KPMG. He also provides professional services in the areas of corporate governance and internal audit. Mr Jones is a Fellow of both the Institute of Chartered Accountants in England and Wales, and the Institute of Chartered Accountants in Australia, and is a member of both CPA Australia and the Australian Institute of Company Directors.

Andrew Stripp is the Deputy Chief Executive Officer and Chief Operating Officer at Alfred Health where he has worked for 10 years in various roles. He has worked across various settings in the health sector and Victorian State Government including Director Mental Health and has undertaken service and strategic reviews for a range of organizations across Australia.

Mr Stephen Spargo is a Partner practising in the Banking and Finance Practice Group of Allens. He is a director of Asia Society AustralAsia Centre, Chairman of The Royal Agricultural Society of Victoria Limited, a Vice-President of the Melbourne Cricket Club, Vice-President of Golf Victoria and a director of the Committee for the Economic Development of Australia.

Andrew Abercrombie is the founding Director of FlexiGroup Limited (FXL) and remains on the FlexiGroup Board continuing to work with the CEO and management team. FXL is a now a top 150 company on the ASX. Formerly a commercial lawyer, he oversees a broad range of commercial interests. He is the Regional Chairman of the World Presidents’ Organisation and continues to participate in international education programs in various roles. Formerly a member of one of Victoria’s Alpine Resort Management Boards, he is also a Director of the Menzies Research Centre, the Melbourne Zoo Foundation and Treasurer of the Liberal Party of Australia (Victorian Division).

MRS JENNIFER LABOURNE

DR BRENDAN MURPHY

EMERITUS PROFESSOR ANDREA HULL AO

BBus, FCPA

MBBS PhD FRACP FAICD

Jennifer Labourne is the Director of Finance & Business Services at Colac Area Health for the past 5 years. She was previously a partner at Ernst & Young, Deputy Chair of Health Purchasing Victoria, Director of Parks Victoria and has been involved on various committees of the Australian Society of Certified Practicing Accountants (CPA).

Dr Brendan Murphy was appointed Chief Executive Officer of Austin Health in January 2005. Prior to that he was Professor/ Director of Nephrology and Chief Medical Officer at St. Vincent’s Health. He is President of the Victorian Hospitals Industry Association and is also a Director of the Olivia Newton-John Cancer Research Institute and a Professorial Fellow with the title of Professor at Melbourne University.

BA Dip Ed (Univ of Sydney) MBA (MBS, Univ of Melb) Hon Doc (Univ of Melb) FAICD FAIM Professor Andrea Hull has had a distinguished career in CEO and executive roles, and also as a non-executive Board member in government and not-for-profit organisations. She is an Emeritus Professor at the University of Melbourne, and is Chair of ABC Advisory Council, Deputy Chair of the Breast Cancer Network of Australia and former Deputy Chair of the National Museum of Australia. She is also a Board member of The Melbourne Forum, and The Melbourne Prize. Professor Hull has undertaken numerous international and national assignments, and served on many international, federal and state bodies to advance the integration of economic, social and cultural agendas.

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ACCESS TO: CLINICAL NETWORKS, KOLS AND SITES

Phase I

NEUROSCIENCE TRIALS AUSTRALIA

Pharmaceutical and Biotechnology industry

Feasibility Project Management Monitoring

Phase II

Government granting bodies

Phase III

Collaborative groups

Data Management and Biostatistics

Phase IV

Investigator-initiated studies (local and International)

Medical safety and report writing Regulatory

Key services provided by Neurosciences Trials Australia to various stakeholders.

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euroscience Trials Australia is a niche, not-for-profit, contract research organisation within The Florey Institute of Neuroscience and Mental Health. It offers an Australian approach to global clients seeking economical, smart and timely neuroscientific clinical research.

The services provided include study feasibility, project management, monitoring of studies to global regulatory standards, safety reporting throughout the clinical trial, data management and biostatistics and report writing. The relationship with services provided and key stakeholders are outlines in the following diagram.

Neuroscience Trials Australia is co-chaired by two of Australia’s most experienced clinicians and medical researchers, Professors Geoffrey Donnan and Stephen Davis.

The General Manager, Dr Tina Soulis, oversees all personnel and projects as well as driving business strategy and objectives. To date, the business has grown, on average, 39 per cent each year and continues to provide a sustainable, highly experienced environment for bringing clincial trials to Australian patients.

“Many of the projects we undertake at Neuroscience Trials Australia assess new ways of treating strokes and their effects. Our trials involve developing new drug treatments as well as new devices.”

The team’s areas of expertise include stroke and strokerelated conditions, multiple sclerosis, epilepsy, Parkinson’s disease, spinal cord injuries, Huntington’s disease, neurosurgery, pain, neuromuscular disease, mental illness and migraine. The team has strategic alliances with many therapeutic disease groups and can provide access to key opinion leaders, sites and clinical trial expertise through a range of tailored services. Staff have global management experience in all phases (I to IV), of clinical research.

Dr Tina Soulis

The division continues to expand and has a healthy pipeline of new and ongoing projects with multiple trials in various neuroscience therapeutic areas being conducted at any one time. These projects consist of investigator initiated studies as well as those initiated by commercial interests. Outlined, next, are examples of the many projects underway.

Mechanically retrieving clots that occur during strokes: the EXTEND-IA study Stroke is Australia’s second biggest killer after coronary heart disease and a leading cause of disability. According to the National Stroke Foundation, one in six people will have a stroke in their lifetime. The total financial costs of stroke in Australia are estimated to be $5 billion (2012 figures).

A stroke occurs when a clot blocks one of the blood vessels to the brain. This causes poor blood supply and lack of oxygen to the brain tissue. If blood supply is not restored to the brain there is permanent brain damage. Currently there is only one treatment for stroke caused by a blocked blood vessel. This treatment is a medicine called tissue plasminogen activator (t-PA). t-PA works by dissolving the clot that is blocking blood supply to part of the brain and has been proven to reduce disability after stroke. However, tPA does not always succeed in opening the blocked artery and it should be given within the first 4.5 hours after stroke.

The aim of the EXTEND-IA study was to test whether mechanical clot retrieval (using a device called Solitaire) after standard intravenous tPA is more effective in opening the blocked blood vessel and improving recovery from stroke than just tPA alone.

This cutting edge multi-centre study examined the effectiveness of one of the latest clot retrieval devices available globally, the Solitaire FR clot retrieval device.

Results were published in the New England Journal of Medicine with concurrent presentation at the International Stroke Conference in Nashville, USA. It was found that early intraarterial clot retrieval, in addition to giving tPA, improved neurological recovery and functional outcome.

Neuroscience Trials Australia was the program manager and was responsible for setting up the project, the data management systems and project management for this successful trial.

Stem cell hope for Parkinson’s disease patients A therapy for Parkinson’s disease from International Stem Cell Corp. is expected to get imminent approval for testing in Australia.

The US-based publicly traded company has grown neural stem cells, which can mature into cells making the neurotransmitter dopamine, deficient in Parkinson’s. The company plans to implant these stem cells into the brains of Parkinson’s patients, restoring dopamine production and normal movement in the patients.

The trial will be the first test of therapy with the company’s cells, derived from unfertilised, or parthenogenetic, human egg cells. The cells, which in theory can produce nearly all types of cells found in the body, are grown into neural stem cells. These cells will be implanted and mature in place. The trial will primarily assess safety, but also look for evidence of efficacy.

International Stem Cell Corp. chose Australia for its first trial because its regulatory agency is more “interactive” than the U.S. Food and Drug Administration.

Neuroscience Trials Australia has assisted the company with all required submissions and interactions with the Australian Therapeutics Goods administration utilising the Clinical Trial Exemption (CTX) scheme. In addition, Neuroscience Trials Australia will be responsible for the project management of the entire trial process, including project management, importation of study stem cells and data management processes.

Ground-breaking Alzheimer disease treatments Anavex Life Sciences Corp. is a US-based publicly traded biopharmaceutical company dedicated to the development of novel drug candidates to treat Alzheimer’s disease, other Central Nervous System (CNS) diseases, and various types of cancer.

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Anavex’s lead drug candidate, ANAVEX 2-73, is currently in a Phase 2a clinical trial for Alzheimer’s disease in an Australian-only trial that is being managed by Neuroscience Trials Australia.

Neuroscience Trials Australia is the program manager and is responsible for setting up the project, project and data management systems as well as sourcing and labelling of the study drug.

ANAVEX 2-73 is an orally available drug candidate that targets sigma-1 and muscarinic receptors and successfully completed Phase 1 with a clean data profile. Preclinical studies demonstrated its potential to halt and/or reverse the course of Alzheimer’s disease.

Making spinal cord injury less traumatic: the ICED (Immediate Cooling and Emergency Decompression) pilot, safety and feasibility studies Neuroscience Trials Australia is fortunate to play a leading role in this ground breaking set of studies. Our team is involved in setting up project and data management of a unique program which aims to address and change the way that patients who have a spinal cord injury are treated.

With its adaptive design, the aim of this trial is to objectively measure all possible effects of the drug in patients, which serves to optimally design and reduce the risk for future pivotal trials. There is an urgent, unmet need in Alzheimer’s disease, with a new case developing every 67 seconds and 5.2 million Americans currently diagnosed.

The main focus of the project is to offer urgent decompression of the injury as close as possible to the time of occurrence.

The current multicentre Phase 2a adaptive clinical trial will enrol at least 32 mild to moderate Alzheimer’s patients and they will be able to receive the study drug for up to 26 weeks.

The primary objective of the trial is to evaluate the maximum tolerated dose of ANAVEX 2-73 in these patients. Additional trial objectives include dose response, bioavailability, cognitive efficacy and the relationship of ANAVEX 2-73 as an add-on therapy to donepezil, the current standard of care.

The main causes of traumatic spinal cord injuries (SCI) are road trauma, falls and water related accidents with most spinal cord injuries occurring to men under the age of 35. This type of injury impacts the majority of people at the prime of their lives and it is thought that Australia alone currently has 10,000 people living with spinal cord injury.

Innovative new treatment hope for neuromuscular disorders Flex Pharma is a US-based biopharmaceutical company dedicated to creating innovative, novel treatments for neuromuscular disorders.

Pictured: Dr Tina Soulis General Manager Neuroscience Trials Australia.

Neuroscience Trials Australia will manage several clinical trials that will assess a new treatment as a solution for people suffering from nocturnal leg cramps, as well as muscle cramping and spasms resulting from a broad range of neuromuscular disorders, such as multiple sclerosis.

Stopping bleeding during stroke: the STOP-AUST study

Flex Pharma’s proprietary treatment is based on research showing that cramps are caused by excessive firing of alphamotor neurons in the spinal cord that control muscle contraction. The treatment is designed to stop the firing of the neurons by topically stimulating the transient receptor potential (TRP) ion channels located in the gastrointestinal tract. Physical properties of the TRP activators largely limit their action to sensory neurons in the mouth, esophagus and stomach, with minimal concentrations reaching the bloodstream and, consequently, fewer potential systemic side effects.

Previous studies have demonstrated that Flex Pharma’s treatment reduced electrically induced muscle cramps within 15 minutes, and its effect lasted between six and eight hours compared to subjects taking a vehicle control. When data from the three studies were aggregated, the treatment showed a statistically significant overall treatment effect, reducing cramp intensity by three-fold compared to subjects taking a vehicle control (ANOVA, p<0.0001).

Some types of strokes involve bleeding in the brain. This is called an intracerebral haemorrhage and can be seen on brain scans as a spot. Growth of the haemorrhage is common. It is known to be harmful because it increases mental and physical disability and the chances of death.

There are currently no known effective medications to reduce or prevent haemorrhage growth.

Tranexamic acid is a medication that is known to reduce bleeding in other diseases and therefore it is thought that it may reduce bleeding also in intracerebral haemorrhage.

Although tranexamic acid is approved by the Therapeutic Goods Administration of Australia to reduce blood loss and the need to give extra blood in patients undergoing heart or joint surgery, it is not approved to treat intracerebral haemorrhage.

The purpose of this research project is to evaluate if the medication tranexamic acid reduces the growth of intracerebral haemorrhage.

The project is an international collaboration, with approximately 12 centres in Australia and Finland currently participating. Eighteen participants are currently enrolled.

The total cost of spinal cord injury in Australia is estimated to be $2 billion annually which includes costs to patients and their families. If just 10 per cent of carers were able to return to the workforce because their family member with a disability had appropriate personal support, there would be a $3 billion boost into the economy.

Even more disheartening, physical injury to the spinal cord results not just from the initial impact, but also from compression of the spinal cord as a consequence of the displaced vertebra.

A multi-centre clinical trial of immediate cooling followed by emergency decompression (ICED) in patients with cervical SCIs is proposed. The current project aims to conduct the pilot as well as safety and feasibility studies necessary before commencing this trial. The contemporary timing of decompression is currently being established in key Australian states and areas of delay identified.

Treatment protocols will then be streamlined and the feasibility of decompression within the 18h window established.

Because hypothermia is being initiated by paramedics, it is important that entry neurological assessment is carried out in the field prior to initiation of therapy. A key study is therefore to establish the reliability and validity of paramedic L3 and S1 motor and sensory scores in acute cervical SCI. Once these studies have been performed, it will be possible to proceed to a feasibility and safety study of immediate cooling followed by emergency decompression.

Getting to the POINT of the matter-The (POINT) Trial: Platelet-Oriented Inhibition in New TIA and minor ischemic stroke Transient ischemic attack (TIA) is a transient episode of neurological dysfunction. TIAs are common events with an estimated 250,000-350,000 occurring each year in the US alone, an incidence about 30 to 40 per cent that of stroke. Rapid recovery is a defining characteristic of TIA and distinguishes it from a complete stroke.

This Phase III multi-centre trial will involve 4,150 participants from 250 centres around the world with either a confirmed high-risk TIA or a minor stroke. Treatment will be within 12 hours of symptom onset with either clopidogrel or placebo. This multi-centered clinical trial is sponsored by the University of California, San Francisco and funded by the National Institute of Neurological Disorders and Stroke in the US. The purpose of the study is to determine whether clopidogrel is effective in improving survival free from major ischemic vascular events (ischemic stroke, myocardial infarction, and ischemic vascular death) at 90 days when initiated within 12 hours of TIA or minor ischemic stroke onset in patients who are already receiving aspirin.

Recruitment into the trial across all sites is currently at 45% or 2632 participants to date.

Neuroscience Trials Australia is responsible for setting up the trial and complete project management across 10 sites throughout Australia and New Zealand.

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A FAIR WORKPLACE FOR ALL The Florey forges ahead

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t the Florey we are committed to harnessing the full complement of talent within the organisation. We believe that supporting and promoting diversity will help accelerate scientific discovery and cures. The Equality in Science Committee (EqIS) collaborates to create conditions in which diverse people can both operate to their full potential and also work together cohesively. This committee has broad representation from professional and academic staff of the Florey to ensure relevant equity and staff development issues are canvassed. Our working groups tackled important issues across the institute and this year’s report celebrates many achievements.

THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

A highlight of the communications group was the successful Women in Neuroscience “Wikibomb” or Wikipedia edit-a-thon, led by Dr Michele Veldsman and Dr Katherine Jackman, pictured left. In partnership with Wikimedia Australia, women and men from the Florey and beyond came together to create Wikipedia pages to profile the achievements of prominent Australian women who have worked or are currently working in neuroscience.

The aim? To overcome the poor representation of this group. On the day, the 20 participants created 20 new pages. Amongst these was one dedicated to the achievements of our own Professor Ingrid Scheffer who has won several awards for her ground-breaking achievements in the genetics of epilepsy, including the 2014 Prime Minister’s Prize for Science.

The parenting group continued to work on issues important to staff with young families. A key achievement in 2014 was the creation of two family-friendly workspaces (parenting rooms) at each campus of the Florey. This is in addition to supporting new policies to help increase flexible work practices such as family-friendly meeting times, flexible working hours and part-time positions. The familyfriendly workspaces will allow scientists with young children to bring them to work when necessary, meet with colleagues or conduct other business in an environment that is safe for children.

At the policy level we continue to work to gain more equitable representation of our female scientists on committees across the Institute. We recognise that diversity in committees can change conversations and that opportunities to participate in decision-making groups builds skills and confidence. We have also been working to increase transparency of committee appointments to ensure that everyone at the Florey gets a chance to contribute to the life and culture of the organisation.

The value of mentoring is often underappreciated by scientists, yet mentoring can create enormous opportunities for growth for both the mentee and the mentor. In 2014 we relaunched our mentoring program with a view to creating an even stronger culture of mentorship for Florey staff.

Another exciting development this year was our successful partnership with the Baker Foundation, supported by Kerry Kornhauser from Women in Rotary, to develop a new Women in Science Fellowship. Following an unusual selection process which considered both the quality and potential impact of the candidate’s science (judged relative to opportunity), and their ability to communicate their science to a lay audience, we selected Dr Despina Ganella as the preferred Florey candidate for this award.

An application for the Fellowship was then made to the Baker Foundation Board and we were delighted to have the Fellowship approved in December. This three-year fellowship will support Despina as she works to find new treatments for young people suffering from anxiety disorders.

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“To be the best at research and translation by providing an environment that allows more women to lead and excel.”

Parkville hub - collective vision

Further progress was made with Women in Science Parkville Precinct (WISPP) collaboration throughout 2014. The Florey acts as the backbone (support) organisation for the collaboration of some 4000 researchers in the Parkville hub. Following a number of meetings, stakeholder interviews and workshops, we created the collective vision for the group: “To be the best at research and translation by providing an environment that allows more women to lead and excel.” We launched the initiative in November, which now includes researchers from some the largest medical research institutes in Australia: The Florey, Walter and Eliza Hall Institute (WEHI), Peter Mac, Murdoch Children’s Research Institute and the Doherty Institute.

The work of the group will continue with the support of funds from the Trust Company Australia as we move to develop agreed ways of measuring institute performance and achievements. The challenge of supporting more women to excel in science and the work of our WiSPP initiative was highlighted across the ABC network in late 2014.

It has been an extremely successful year for the EqIS committee and we thank the efforts of our committee and our very active subgroup members who have helped to develop and implement policies and practices that encourage diversity at all levels of our Institute. We’d also like to thank supporters from outside the organisation for their donations to the Women in Science corpus. At the end of year function we were delighted to have a young male scientist say “your committee is really helping to change the culture of the Florey for the better.” That kind of feedback is deeply gratifying and motivating.

We will continue to find new ways of building equity for all into the fabric of our Institute.

Pictured: Dr Michele Veldsman and Dr Kath Jackman.

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PROFESSOR ANDREW LAWRENCE Behavioural Neuroscience Professor Lawrence is the Co-Division Head of Behavioural Neuroscience, running the Addiction Neuroscience laboratory.

His primary research interest is in the development of robust animal models of drug-seeking, drug-taking and drug-induced neural adaptation. In addition, his group uses these models to define new potential therapeutic targets for drug and alcohol abuse disorders. He has published over 180 original articles and reviews. Professor Lawrence is currently Senior Editor of The British Journal of Pharmacology and also sits on the editorial boards of Neurochemical Research, the Journal of Pharmacological Sciences & Addiction Biology. In 2009, Professor Lawrence was awarded the Australian Neuroscience Society medallion for services to the society.

In his spare time, Andrew is a keen cyclist and a surf life guard.

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DR AMY BRODTMANN

PROFESSOR GRAEME JACKSON

PROFESSOR ALAN CONNELLY

Behavioural Neuroscience

Epilepsy and Imaging

Imaging

Dr Amy Brodtmann is Co-Division Head of Behavioural Neuroscience, consultant neurologist at Austin Health and Director of the Eastern Cognitive Disorders clinic, Eastern Health, Box Hill Hospital. She is a past recipient of a National Health and Medical Research Council Australian Training Research Fellowship, and previous National Brain School Co-ordinator for the Australian and New Zealand Association of Neurologists.

She sits on the editorial board of Neurology, the research board of Alzheimer’s Australia Victoria, and is the founding director of the Australian Frontotemporal Dementia Association. Her research focuses on imaging correlates of cognitive decline in stroke, the neural basis of neglect, and the diagnosis and management of focal onset dementias.

Professor Graeme Jackson is the Deputy Director of the Florey, a practising clinical neurologist specialising in epilepsy at the Austin Hospital, and a Professorial Fellow of the University of Melbourne.

He is recognised as an expert and world authority in understanding brain function and structure using new MR technologies, particularly as they apply to understanding and treating epilepsy. The National Health and Medical Research Council of Australia (NHMRC) awarded him the Outstanding Achievement Award for research excellence.

Professor Alan Connelly is an NHMRC Principal Research Fellow.

He is the Co-Division Head of the Imaging Division, and Head of the Advanced MRI Development group. He also heads the MRI imaging Facility at the Florey Austin (including two research-only 3T MRI scanners) and the Florey Parkville Small Animal Imaging Facility. Prof Connelly is a development MRI physicist whose work has encompassed a range of MR methods, with current focus primarily on diffusion and perfusion MRI and their application to the investigation of epilepsy, stroke, and cognitive function. His group is internationally recognised as leaders in the field of diffusion MRI fibre tractography, and has developed novel methods to characterise the complex white matter fibre connections in the brain. He has published widely in magnetic resonance, general scientific, and neuroscientific journals, and is a member of the editorial board of Epilepsia.

PROFESSOR SEONG-SENG TAN

PROFESSOR STEVEN PETROU

LAUREATE PROFESSOR COLIN MASTERS

Brain Development and Regeneration

Epilepsy

Mental Health

Professor Tan is the Head of the Division of Brain Development and Regeneration, NH&MRC Senior Principal Research Fellow, and Adjunct Professor at the Melbourne Neuroscience at The University of Melbourne, and University of Queensland Brain Institute. He is interested in understanding how the brain is assembled during development, and what mechanisms protect brain cells from death following brain injury such as trauma and stroke. Professor Tan has published over 100 papers and was awarded the Amgen Australia Medical Research Award (1997). He is on the Editorial Boards of the Journal of Neuroscience (USA) and Experimental Neurology.

Professor Tan is a keen swimmer and a member of the Brighton Icebergers. He recently gave a TEDX Brisbane talk on “Why women have different brains.”

Professor Petrou is the Co-Division Head of the Division of Epilepsy, and heads the Laboratory of Ion Channels and Human Disease, a multidisciplinary team of researchers with a focus on revealing fundamental mechanisms of disease genesis in the central nervous system. Current major areas of investigation centre on the development and characterisation of genetically engineered mouse models for the study of human familial epilepsy. He works closely with industry and has several patents for his discoveries. In addition, he is the Deputy Director of the Centre for Neural Engineering at University of Melbourne, serves on the editorial board of the Journal Neurobiology of Disease and the Basic Science Committee for the International League Against Epilepsy and is Editor of the Australian and New Zealand Society for Neuroscience.

Professor Colin Masters is the Head of the Division of Mental Health, a Fellow of the Royal College of Pathologists, the Royal Australian College of Pathologists and the Australian Academy of Science.

Professor Masters is a world leader in Alzheimer’s disease research.

His research helped to isolate and characterise elements of the primary pathway causing Alzheimer’s disease. This discovery has been important in defining the mechanisms that contribute to the nerve cell degeneration which is the main feature of Alzheimer’s disease. His findings are now the subject of intense world-wide research for diagnosis and drug discovery. Professor Masters has also won many national and international prizes and awards.

DIVISION HEADS

DIVISION HEADS

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

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PROFESSOR TREVOR KILPATRICK

PROFESSOR ROSS BATHGATE

ASSOCIATE PROFESSOR DAVID W HOWELLS

Multiple Sclerosis

Neuropeptides

Stroke

Trevor Kilpatrick leads the MS Division at the Florey Institute of Neuroscience and Mental Health and is a neurologist and Head of the MS Unit at the Royal Melbourne Hospital, in addition to being a Professor of Neurology and Director of the Melbourne Neuroscience Institute at The University of Melbourne. His research interests include the neurobiology of multiple sclerosis, neural precursor cell biology and the study of genetic and environmental factors that contribute to MS as well as the translation of basic research discoveries to the clinic.

Professor Kilpatrick has been the recipient of the Sunderland Award (1994), AMRAD Postdoctoral Award (1995), inaugural Leonard Cox Award (2000), Bethlehem Griffiths Research Foundation Award for Medical Research (2004), the Australian Museum’s Jamie Callachor Eureka Prize for Medical Research (2008), the Stephen C. Reingold Research Award by the US MS National Multiple Sclerosis Society (2010) and in 2013 Professor Kilpatrick was awarded the Bethlehem Griffiths Research Foundation Medal for outstanding leadership in medical research.

Professor Ross Bathgate is the Head of the Division of Neuropeptides, an NHMRC Senior Research Fellow (Level B) and an Honorary Professorial Fellow in the Department of Biochemistry and Molecular Biology at the University of Melbourne. His work focuses on understanding the interactions of peptide ligands with their G protein-coupled receptor (GPCR) targets for the development of peptidebased drugs and utilizing structure based drug design to develop novel therapeutics. One of the peptide targets his lab is investigating is the peptide hormone relaxin which has recently completed a successful Phase III clinical trial for the treatment of acute heart failure. He works closely with Novartis who are conducting the clinical trial on relaxin as well as a number of other pharmaceutical companies interested in the clinical potential of drugs targeting peptide GPCRs. He currently serves on the editorial boards of Molecular and Cellular Endocrinology, Frontiers in Molecular and Structural Endocrinology and Journal of Pharmacological Sciences.

Associate Professor David Howells is the Co-Division Head of the Division of Stroke and began his career investigating the biochemical and genetic basis of dopamine and serotonin deficits in children.

He went on to describe a new population of dopaminergic neurons, demonstrated that BDNF depletion can cause parkinsonism and that Parkinson’s disease patients are deficient in BDNF. His other research interest is in stroke: his studies of neuroprotection in stroke have led to improved modelling of stroke in animals, the development of new methods of imaging, and development of systematic review and analysis as tools for rigorously evaluating basic science literature. The latter have led three leading stroke journals to publish guidelines for Good Laboratory Practice.

PROFESSOR PHILIP BEART

PROFESSOR JULIE BERNHARDT

PROFESSOR ROBIN MCALLEN

Neurodegeneration

Stroke

Systems Neurophysiology

Professor Philip Beart (PhD ANU, DSc Melbourne) has been a NH&MRC Research Fellow for 30 years and is currently Professorial Fellow in the Florey and Adjunct Professor in Pharmacology, University of Melbourne.

He worked at Cambridge and Harvard Universities, before holding positions at the Austin Hospital and Monash University. Professor Beart has published >200 papers, served on numerous editorial boards and has diverse involvements in learned societies. Awards include the Bethlehem Griffiths Medal (2010), the Lawrie Austin Lectureship of the Australian Neuroscience Society (2009) and in pharmacology the Michael Rand Medal (2009). He has trained numerous honours and post-graduate students. He has a long-term commitment to promoting medical research, particularly neuroscience, in the wider community, and has provided extensive service to the NH&MRC. Professor Beart is currently Chair of the Scientific Promotions Committee and past President of the International Society for Neurochemistry (2011-13).

Professor Julie Bernhardt is the Co-Division Head of the Division of Stroke and leads the AVERT Early Intervention Research Program, which includes a multidisciplinary team of researchers committed to the development and testing of new, rehabilitation interventions that can reduce the burden of stroke related disability. AVERT, the largest, international, acute stroke rehabilitation trial ever conducted, sits at the core of the program. Advancing understanding of how exercisebased interventions alter bone, muscle and brain function after stroke is another aim of the program. Julie’s clinical career has been devoted to working with people with stroke and other neurological diseases. As a strong proponent of evidence-based care, another key theme within her program is the synthesis and translation of evidence into practice. Julie sits on the Board of the National Stroke Foundation and on a number of national and international stroke advisory groups.

Professor Robin McAllen is the Co-Division Head of the Division of Systems Neurophysiology and a NHMRC Principal Research Fellow.

He trained in Physiology in London and Birmingham and in Medicine at Birmingham (UK) before moving to the Florey in 1988. He is a neurophysiologist with an interest in the central nervous regulation on cardiovascular and autonomic functions, and has published extensively of this topic. More recently he has collaborated with Florey colleagues in neuroimaging experiments that aim to translate lessons learned from animal studies to the human brain. He currently serves on the editorial board of the American Journal of Physiology, is a section editor for Clinical and Experimental Pharmacology and Physiology, and is a member of the Faculty of 1000.

DIVISION HEADS

DIVISION HEADS

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PROFESSOR RICHARD MACDONELL Systems Neurophysiology Professor Richard Macdonell is Director of Neurology at Austin Health, a Co-Division Head of Systems Neurophysiology and an Honorary Professorial Fellow. He trained in Neurology and Clinical Neurophysiology at Austin Health, Massachusetts General and the London Hospitals and has been in charge of the Neurophysiology and Neuroimmunology services at Austin Health since 1991. His research interests include multiple sclerosis, peripheral nerve and muscle disorders and using transcranial magnetic stimulation to study the pathophysiology of epilepsy.

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

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BRAIN DEVELOPMENT AND REGENERATION Leader: Professor Seong-Seng Tan

A QUICK SNAPSHOT

Our group is interested in the self-defence mechanisms that operate in the brain when something goes wrong. This may take the form of degenerative disease (Parkinson’s, Alzheimer’s) or cancer (brain tumours) due to gene mutations and ageing. As a result, mutant or toxic proteins accumulate in brain cells, causing them to degenerate or proliferate.

We have been working with one system of self-defence called protein ubiquitination which allows harmful proteins in brain cells to be removed and in the process, halt or reverse the disease process. We are particularly interested in finding how to accelerate beneficial ubiquitination in neurones using the Nedd4/Ndfip1 proteins. Our studies so far demonstrate that these proteins can halt cell death following injury and stroke, and slow down the division of brain cancer cells.

RESEARCH HIGHLIGHT

AN IDEA LIKELY TO CHANGE LIVES BY 2035

We have made some progress in understanding how the natural brain protein Ndfip1 is capable of improving the survival of brain cells in stress environments which occur in traumatic brain injury and stroke. We have shown that artificially increasing the concentrations of Ndfip1 in brain cells can protect against metal poisoning. We found that Ndfip1 concentrations in human post-mortem brains is strongly correlated with neurones affected by Parkinson’s disease. In animal models, we have shown that Ndfip1 is increased in surviving neurones after stroke. To study the consequences of removing Ndfip1 from neurones, we have deleted the Ndfip1 gene by mouse knockout technology.

These animals demonstrate a greater sensitivity to brain damage from stroke, compared to normal animals that still carry the Ndfip1 gene.

We are working on using natural body transport vesicles called exosomes. We have discovered a way to load useful proteins into exosomes to bolster the survival of neurones under stress following injury. These exosomes can also be loaded with anti-cancer proteins to treated brain cancer.

We have found that Ndfip1 protects brain cells from death by hijacking an anti-cancer brain protein called PTEN. This protein is normally utilized as a defensive mechanism against tumour formation in brain cells. We found that after brain injury, this mechanism is activated to bolster the longevity of brain cells. The implication of this discovery exposes the PTEN anti-cancer pathway for therapeutic manipulation. In a separate discovery, we found that the anti-cancer protein PTEN can be secreted by cells and be carried in micro vesicles for transport to other cells. The secreted PTEN can then be internalised by recipient cells for physiological benefit, for example, for slowing down the proliferation of cancerous cells.

This discovery opens up new ways of administering anticancer PTEN for the control of brain tumours.

OUR LAB

Our mission is to translate discoveries from our laboratory to help patients with brain diseases. Our experiments make use of a variety of modern techniques to study how brain cells are able to resist death in a hostile environment.

Our experiments are framed around hypotheses that may be answerable using novel tools developed by our team.

These tools include creation of new mouse strains with inserted genes, molecular cloning of brain genes and manipulation of brain proteins. We have a democratic team structure, where every scientist including students and technicians all have an equal voice.

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The Brain Development team: Choo-Peng Goh, Ley-Hian Low, Anh Doan, Yijia Li, Jason Howitt, Seong-Seng Tan, Sophia Mah, Ulrich Putz, Yuh-Lit Chow, Michelle Tang, Ulrich Sterzenbach. Absent: Joanne Britto, Hui Xuan Ng, Ean Phing Lee.

BRAIN DEVELOPMENT GROUP Leader: Joanne Britto

In order for brain cells in the adult brain to function properly, it is important that they are first found in the correct locations. Failure of brain cells to migrate to their destinations is a frequent cause of many developmental disorders such as autism and schizophrenia.

For many years, our group has performed experiments to understand how brain cells are able to correctly migrate to their final positions.

microscope. The information from these studies allows us to pinpoint which types of interneurones are most at risk when something goes wrong. Our work has showed that different interneurones destined for different layers have separate rules for movement, dispelling previous notions that all interneurones behave alike.

Research highlights for 2014

We recently focussed on a class of brain cells called interneurones.

Although they are in the minority, this class of neurones controls much of our mental processing and sensory experience.

Therefore studying the behaviour of interneurones holds the key to understanding a number of developmental brain disorders.

Previously, we showed that interneurones are capable of migrating vast distances to reach their final positions in highly specific addresses. Over the last year, we have been tracking the migration of these neurones, using genetic mice engineered to paint brain cells with artificial colours. This technology allows us to follow the movements of different interneurone classes under a laser

Ndfip1 controls cell proliferation by driving PTEN into the cell nucleus. Work performed by Jason Howitt and published in Journal of Molecular Cell Biology

Binding of PTEN to Ndfip1 in the cell can be visualized by protein fluorescence – work by PhD student Yijia Li and published on the cover of Traffic.

Brain trauma directs the survival protein PTEN in to the cell nucleus to keep neurons alive. Work by Choo-Peng Goh (published in Experimental Neurology) shows that this process requires Ndfip1.

We have found that Ndfip1 protects brain cells from death by hijacking an anti- cancer brain protein called PTEN.

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SENIOR STAFF

• Seong-Seng Tan • Joanne Britto • Jason Howitt • Ulrich Putz • Ley-Hian Low • Choo-Peng Gohr •

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

BRAIN SURVIVAL GROUP EDITORIAL POSITIONS Leader: Jason Howitt

When the brain is injured, such as in an accident or in stroke, the main area of the brain injury is not recoverable due to massive bleeding and swelling. However, what is not commonly known is that dying brain cells (called neurones) can transmit death signals from the injured area into surrounding healthy tissues, this ripple effect causes death of neighbouring brain cells in large numbers. Right now, there is no drug treatment to reduce the rate of brain death after trauma. Therefore medical strategies to prevent neurones from succumbing to trauma-induced death is an unmet need.

Research highlights for 2014

Our brain survival team has identified a survival protein in human brain cells called Ndfip1. This survival protein is present in human brains following road trauma, and Ndfipi1 is massively increased in surviving cells, indicating its role as a protective agent.

Ndfip1 behaves like a bar-coding tool by putting a mark on harmful proteins that are produced during injury. These bar-coded harmful proteins are then recognised by the waste disposal system called ubiquitination in the neurone for removal.

This protein is also able to wake up a survival mechanism in brain cells using cancer pathways in neurones without causing tumours, taking advantage of the survival mechanisms that cancer cells are famous for.

We have also discovered that Ndfip1 is an important defender against metal accumulation in brain cells. This is important for degenerative brain diseases such as Parkinson’s and Alzheimer’s disease.

We showed that post-mortem brains from Parkinson’s disease contain deficient levels of Ndfip1. This deficiency is associated with increased iron accumulation in diseased brain cells. This work opens up the manipulation of Ndfip1 as a way of controlling onset and progress of Parkinson’s disease.

BRAIN COMMUNICATION GROUP Leader: Ulrich Putz

This group is interested in studying ways of using natural vesicles called exosomes to behave as cargo systems. This comes on top of our discovery that the anti-cancer protein PTEN is exported by cells in exosomes, and the anti-cancer protein can be transferred into other cells with anti-cancer consequences. This group is excited to use this technology to try and target anti-cancer protein PTEN into brain tumour cells to arrest the disease.

Research highlights for 2014

Over the last year, we have identified a peptide that can be used to coat exosomes so that they specifically recognise and target brain tumour cells. In cell culture experiments, we showed that brain tumour cells with mutations in the epidermal growth factor receptor are targeted by our engineered exosomes.

Realising the need for accurate and effective delivery of exosomes, we have invested our resources to understand how to more effectively transfer exosomes into recipient cells. We have discovered that centrifugation using special conditions and special media can increase the uptake of exosomes by recipient cells.

SEONG-SENG TAN

ҩҩ Experimental Neurology (USA) ҩҩ Journal of Anatomy (UK) ҩҩ Journal of Cell Biology (Korea) ҩҩ Frontiers in Neuroscience MAJOR NATIONAL AND INTERNATIONAL CONFERENCES 2014 INVITED SPEAKER

ҩҩ Asian-Pacific Society Neurochemistry, Kaohsiung, Taiwan.

August 2014. “Role of Ndfip1 during brain development.” ҩҩ Brain Disorders Institute, Beijing Capital Medical University, Beijing, China. August 2014. “Potential use of PTEN for therapy in gliomas.” ҩҩ Japan Neuroscience Society Annual Meeting, Yokohama. September 2014. “How PTEN can save neurones from death following stroke and brain injury.” ҩҩ Invited Speaker, TEDx Brisbane, October 2014. “Why women have different brains.”

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“

The process of discovery is the most exciting, intellectually stimulating and challenging of activities. The painstaking and arduous work culminates in the pleasure of finding something new that no-one has known or understood before.

When this is applied to medical research then there is the added reward that it may improve the lives and reduce the suffering of people with illness. I am determined to discover better treatments for schizophrenia and related disorders and develop markers to better diagnose and manage people with these illnesses.

” Associate Professor Suresh Sundram, head, Molecular psychopharmacology laboratory and Northern Psychiatry Research Centre.

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

CHASING A CURE FOR MOTOR NEURONE DISEASE

Brad Turner has a strong ally. Ian Davis, a medico living with MND, is driving a highprofile campaign to raise awareness and funds for research into a cure for the disease.

Dr Bradley Turner

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t’s no secret that funding for medical research is critically short. So it was a ‘dream come true’ when the Florey’s Dr Brad Turner spoke to a community group and unwittingly attracted the attention of a ‘scout’ who would radically change his future – and hopefully the lives of people living with motor neurone disease.

Dr Bradley Turner is renowned for his community outreach activities and his relentless quest to cure motor neurone disease (MND). As the head of the Florey’s MND group, Brad was recently speaking to an Inner Wheel Club in Pakenham 70km south east of Melbourne.

Brad enthusiastically described his work to the group, outlining a project he believed promised great hope for a new treatment.

This alerted Rotary Pakenham and a short time later, a phone call arrived from a trustee of a philanthropic foundation, recommending he submit a research proposal as quickly as possible.

A few days later, Brad was told he would receive $3 million over five years, thanks to the Stafford Fox Medical Research Foundation, a fund that does not accept requests but, rather, seeks worthy projects and invites applications.

“This could change the course of MND. Until now, I haven’t had the funding to achieve it. It is truly, utterly amazing,” Brad says.

It is a relentless disease, with nerves controlling movement (motor neurones) degenerating and rapidly wasting muscles.

It strips away the independence of people living with it, who lose their ability to walk, feed themselves, talk and breathe. The average lifespan from diagnosis is 27 months.

So the need to find effective treatment is urgent, Brad says.

Children born with the condition are missing a gene and become weak at six months and die within two years. Significantly, Brad found the gene was also missing in MND mice and in tissue from patients.

Brad says the MND patients he talks to are heartened by the findings and particularly by a graph showing the prolonged lifespan of the mice.

He experimented by putting the gene back in the MND mice – with dramatic results: the lifespan of the mice increased by two months. MND mice usually only live for four months.

The process of replacing the gene also measurably saved motor neurones.

“When people are diagnosed with MND they know precisely what it is, they know the course it will take and that they often have no or little hope. Part of their hope comes from the knowledge that people in lab coats are beavering away working on their disease, passionately, and as a fulltime commitment – and that actually lifts their spirits.”

“The sad thing about MND is that by the time people are diagnosed with it, 50 per cent of motor neurones are gone so that they are already at crisis point,” he says.

“We want to prolong a person’s lifespan and save their motor neurones – they are the two key objectives for an effective treatment.”

“Conventionally, a clinical trial can take 10 to 15 years to happen but in the case of MND it can be sooner due to accelerated approval and fast track status of promising drug candidates. Within five years we could potentially have something.”

Dr Bradley Turner

The grant will allow Brad and his team to fast-track some significant findings they made last year, using a form of gene therapy to substantially increase the lifespan of MND mice.

For the next phase of research, Brad and his team will collaborate with Flinders University scientists using a specially devised tool – a gene therapy – to deliver the SMA gene to motor neurones in the brains of mice.

The research builds on previous work Brad has done at Oxford University, looking at a gene involved in a childhood form of MND called Spinal Muscular Atrophy (SMA).

He says that once the team has demonstrated that the tool brings about the same effect in the mice – a two-month increase in survival – they will adapt it to a clinical trial in humans.

Brad will continue to share his work with the public – going out to speak to interest groups and hosting an annual “Ask the Expert” day when patients and their families hear talks and see demonstrations of lab techniques.

“They love it!” he says, “and they ask some impressive questions.”

The 36-year-old has researched MND for more than a decade and has succumbed to the Ice Bucket Challenge four times.

“When I first read about MND, I thought ‘it’s tragic and terminal’.

Then I thought ‘I need to help solve this.’ I tell people that I have a lifelong commitment to work on this disease.”

“The Florey’s a great place to work. It has prestige. It’s unique. I don’t know of many places that are working on so many neurological disorders under the one roof.

That means great collaboration.”

“At the start of my PhD, people would ask ‘is there going to be a cure’ and I’d say I wasn’t sure. Now I tell people that it’s not a matter of ‘if’ but ‘when’. An effective treatment or cure is on the horizon.”

Ian was in his early thirties, engaged to be married to his now wife Mel, and researching childhood leukaemia as a lab researcher when he was diagnosed with MND – but only after recognising the symptoms himself. Since then Ian has made the most of his limited time.

He has been skydiving, has been on stage in a wheelchair with Pearl Jam (his favourite band), and completed an epic tandem bike ride from Brisbane to Sydney, raising money for MND research.

Last year he and Mel became parents to baby Archie. Ian has inspired public figures including cricketer Shane Watson, Masterchef winner Julie Goodwin, and Australian Open champion Serena Williams to speak out about the cause and to donate to it. He says medical research into MND is “absolutely crucial” because there is so little that can be done for people living with the disease.

TO DONATE, PLEASE VISIT FLOREY.EDU.AU

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

ADDICTION NEUROSCIENCE GROUP

COGNITIVE NEUROSCIENCE

Leader: Andrew Lawrence

Leaders: Professor Andrew Lawrence and Dr Amy Brodtmann

A QUICK SNAPSHOT

The Division of Behavioural Neuroscience focuses on the use and development of animal models that reflect aspects of human disorders such as addiction, anxiety, depression, schizophrenia, autism and neurodegenerative conditions such as Huntington’s disease. The Cognitive Neuroscience group additionally studies cognitive disorders caused by diseases such as stroke (cerebrovascular disease), Alzheimer’s disease and other dementias from a clinical perspective.

RESEARCH HIGHLIGHT

RESEARCH OVERVIEW

There have been a number of highlights within the Division during 2014. A long-term collaboration between Professor Andrew Lawrence and Professor Alon Chen (Max Planck Institute, Munich) came to fruition with the finding that CRF1 receptors within the ventral tegmental area are critically implicated in both cue- and stress-induced relapse to cocaine-seeking.

This study was performed predominantly by a PhD student, Nicola Chen, and published in the prestigious Journal of Neuroscience.

2014 saw the Division strengthened by the addition of new laboratory heads, Dr Jhodie Duncan and Dr Jess Nithianantharajah. Moreover, 2014 was a highly successful year for the Division in terms of competitive grants. Dr Nithianantharajah was awarded an ARC Future Fellowship and Dr Jee Hyun Kim was awarded a Career Development Fellowship from the NHMRC; Professors Andrew Lawrence and Tony Hannan were both awarded two NHMRC project grants each; Dr Nithianantharajah received an NHMRC New Investigator project grant and Dr Kim received an ARC Discovery project. Dr Heather Madsen returned from her postdoctoral training in France to join the Developmental Psychobiology lab. Dr Despina Ganella won a highly competitive Baker Fellowship. Dr Kim won a Victoria Young Tall Poppy Award. In 2014 Professor Lawrence was appointed President of the Asian-Pacific Society for Neurochemistry (APSN).

SENIOR STAFF

• Professor Andrew Lawrence • Associate Professor Anthony Hannan • Associate Professor John Drago • Dr Amy Brodtmann • Associate Professor David Darby Dr Jhodie Duncan • Dr Jess Nithianantharajah • Dr Jee Hyun Kim •

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We also continued with our longstanding project on mGlu5 receptors.

The process of behavioural extinction is a form of inhibitory learning that can help to protect against relapse. Dr Christina Perry and Ms Felicia Reid are currently assessing the role of mGlu5 signalling in the extinction of drug cues and contexts. This is potentially translatable by using mGlu5 positive modulators to enhance the rehabilitation of addicts undergoing behavioural therapy.

Another project involves examining the link between salt appetite and opiate addiction. In collaboration with Professors Derek Denton and Michael McKinley, we have shown that opioid receptor antagonists that are used clinically to treat alcohol and heroin addicts reduce salt appetite. More intriguingly opiate dependent mice show an exaggerated salt appetite compared to normal mice.

We are now in the process of establishing where in the brain this regulation occurs. Professor Andrew Lawrence received an NHMRC project grant to pursue these studies.

COGNITIVE NEUROSCIENCE GROUP Leader: Amy Brodtmann

AN IDEA LIKELY TO CHANGE LIVES BY 2035

We showed that CRF1 receptors within the ventral tegmental area are critically implicated in both cue- and stress-induced relapse to cocaine-seeking.

The Addiction Neuroscience Group studies how alcohol and other drugs change the brain’s chemistry, structure and function. During 2014 we made a number of important findings, many of which are still being actively pursued. As part of her PhD, Hanna Kastman continues to unravel the circuitry implicated in stress-induced relapse to alcohol-seeking. In addition, she has also demonstrated for the first time that the neuropeptide, relaxin-3, interacts with both orexin and CRF to regulate relapse-like behaviour. This project has been expanded with the recruitment of two new PhD students (Sarah Sulaiman Ch’ng and Leigh Walker) plus an overseas placement student (Jan Koeleman). Together, these students are interrogating how and where in the brain these peptide systems interact to regulate reward-seeking. In parallel to this, Nicola Chen (co-supervised by Professor Andrew Lawrence & Dr Jee Hyun Kim) showed that CRF1 receptors within the ventral tegmental area are critically implicated in both cue- and stress-induced relapse to cocaine-seeking. Her studies are now concentrating on aversive learning paradigms. In 2014 Professor Andrew Lawrence was awarded an NHMRC project grant to continue these important studies.

By 2035, dementia will be a rare and treatable disease.

Patients admitted with stroke will receive dementia risk stratification and be treated with therapies that will recover all functions, including cognition. People at risk of Alzheimer’s disease will be identified via online testing or following a sentinel risk event, and treated prior to the development of brain atrophy.

We are a clinically-based research group examining the cognitive trajectories of patients. These include patients with stroke and dementia, using advanced imaging techniques in concert with novel testing paradigms developed by our team members. This also includes charting cognition in community dwelling healthy participants, via Associate Professor Darby’s online testing, which now includes over 1500 people.

Cognitive disorders can develop from a range of brain diseases, including stroke, Alzheimer’s disease, and other less well known dementias such as frontotemporal dementia. In 2013, there were 44.4 million people living with dementia; this number will increase to 135 million by 2050. Dementia care is estimated to cost $698 billion per year: one per cent of global GDP. 2014 was a productive year for the Cognitive Neuroscience group.

The international significance of the Cognition and Neocortical Volume After Stroke (CANVAS) study continued to grow, with conference proceedings and the strengthening of important collaborations with groups in Germany and the United States. The CANVAS project is an NHMRC study where we aim to establish whether stroke patients have increased atrophy (reductions in brain volume) in the first three years post-stroke compared to control subjects, perhaps answering whether stroke can be associated with neurodegenerative mechanisms. This NHMRC-funded project continues to be assisted by help from the Sidney and Fiona Myer Family Foundation.

Funding from the Mason Foundation was utilised to develop and compare imaging techniques in patients with dementia, and with half

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the patients recruited for this Florey-Royal Melbourne project, and the final patients booked for the first three months of 2015. Support from the Collie Trust allowed us to recruit a new post-doctoral research fellow in 2014, Dr Michele Veldsman, who been enormously productive, publishing an influential review paper in Human Brain Mapping on the challenges of functional imaging in stroke populations.

After Associate Professor Darby launched a study, more than 1500 people logged-in monthly for online cognitive testing. This study was covered by many of the major newspapers nationally, and was a feature on national television. He launched a similar project in Brazil, and is working with a long-term collaborator in Oxford, Professor Kia Nobre, with a large community of volunteers based in the UK. Dr Brodtmann continued her appointment with the Wicking Strategic Panel, a position which, along with her appointments to the Australian Frontotemporal Dementia Association and Alzheimer’s Australia – Victoria Dementia Research Grants committee and panel will allow her to lobby and advocate for people with cognitive disorders.

She was involved with organisation of a very successful Wicking Symposium. She developed further productive collaborations with Monash University’s Professor John McNeil and the Florey’s Lachlan Thompson, with two new successful NHMRC project grants in 2014 with these colleagues.

NEURAL PLASTICITY GROUP Leader: Anthony Hannan

Many neurological and psychiatric disorders, including schizophrenia and autism spectrum disorders (ASD), involve abnormal development of the brain. We are interested in the mechanisms whereby specific genes regulate maturation of the brain and are dynamically regulated by interaction with the environment in conditions like ASD and schizophrenia.

Autism spectrum disorders affect approximately one per cent of children. Dr Emma Burrows has discovered abnormalities of social interaction and communication in a mouse model of ASD carrying a human gene mutation. Ongoing investigations focus on identifying key molecules and cellular changes involved in ASD and testing new therapeutic approaches in this model. With collaborators at the University of Melbourne, we have new evidence that both the central and peripheral nervous system is disrupted in these mice, contributing to a broad array of ASD symptoms.

Schizophrenia is another neurodevelopmental disorder involving a complex combination of genetic and environmental factors which disrupt normal maturation and function of the brain. Using a mouse model of schizophrenia, Dr Emma Burrows has shown that enhanced mental and physical activity can ameliorate cognitive deficits and other behavioural symptoms and benefit specific areas of the brain.

Identifying molecules modulated by environmental stimulation has paved the way for future development of new therapeutic approaches. Furthermore, Dr Burrows and graduate student Faith Lamont have been the first researchers in Australia to generate data using our new automated touchscreen tests (which are directly translatable to human neuropsychological test batteries). They have identified specific aspects of cognitive dysfunction and are testing a therapeutic intervention in this model of schizophrenia.

Huntington’s disease (HD) is an inherited single-gene abnormality that involves a triad of psychiatric symptoms (e.g. depression), cognitive deficits (culminating in dementia) and a movement disorder. Dr Terence Pang, along with PhD student Xin Du, discovered an abnormal stress response associated with depression-like behaviours (which respond to antidepressants) in the mouse model of HD and identified key molecules involved in the disease, the response to environmental stimuli and the increased vulnerability of females. The effects of a major environmental factor, stress, on HD has been explored by Dr Thibault Renoir and a PhD student (Christina Mo) who demonstrated for the first time that stress can accelerate the onset of HD, in particular the cognitive deficits (modelling dementia). These findings will have

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

implications not only for HD, but for depression and dementia in the wider community. Further study of gene-environment interactions and experience-dependent changes in the nervous system may lead to new therapeutic approaches for HD and other brain disorders.

Another PhD student, Dean Wright, with Dr Renoir and Melbourne collaborators, has discovered a new treatment for HD, and shown that it works via mitochondria, the cellular ‘batteries’ that provide energy. Furthermore, their findings have implications not only for HD, but depression in the wider community.

These findings contributed to an NHMRC Project Grant won by Professor Hannan, Dr Nithianantharajah, Dr Renoir, in collaboration with the University of Melbourne. Furthermore, another new NHMRC Project Grant exploring the effects of paternal lifestyle on the mental health of offspring was won by Professor Hannan, Dr Pang and a collaborator from University of Queensland.

DEVELOPMENTAL PSYCHOBIOLOGY GROUP Leader: Jee Hyun Kim

Our vision is to understand the role of memory and forgetting across development in mental disorders, namely anxiety and substance abuse. We believe the key to finding effective treatments lies in how we remember and forget emotionally significant events formed at various stages of our development. A number of important discoveries have been made in 2014. Dr Despina Ganella showed that disruption of the communication between brain regions during inhibitory learning can permanently reduce the strength of a fear memory during adulthood. In collaboration with Melbourne Neuropsychiatry Center, she also showed in humans that childhood maltreatment was significantly associated with accelerated rate of growth in pituitary gland volume across adolescence in females but not males.

Dr Despina Ganella and Dr Heather Madsen, with PhD students Isabel Zbkuvic and Sophia Lukinga demonstrated that the popular bipolar medication, Aripiprazole, can lead to changes in dopamine signalling in the prefrontal cortex during inhibitory learning in adolescent animals. This finding explains why Aripiprazole may enhance inhibitory learning and reduce relapse in anxiety and drug seeking. Dr Heather Madsen is using transgenic mice that show green florescence in dopamine receptor 1 (D1) or D2, and PhD student Isabel Zbkuvic is measuring changes in D1/D2 mRNA profile across adolescence to understand the mechanisms behind adolescent vulnerability to anxiety and addiction.

Lastly, PhD student Nicola Chen discovered that reduction of corticotropin releasing factor 1 receptor in the ventral tegmental area leads to a stronger fear memory formation in mice, which suggests reductions in the stress signalling during learning may be beneficial.

INHALANT ABUSE LABORATORY Dr. Jhodie Duncan

The abuse of inhaled chemical vapours to produce self-intoxication is a significant concern, especially among adolescent and Indigenous populations. In 2014 Dr Jhodie Duncan and Mr Alec Dick published work demonstrating that exposure to inhalants during adolescence results in specific impairments in aspects of instrumental learning, without altering motor function and spatial learning. Our data suggest that exposure to inhalants affects corticostriatal processes specifically and does not involve global toxicity to white matter pathways in the brain as was originally thought.

Using this model we have also shown that exposure to inhalants during adolescence results in long-term metabolic dysfunction. This includes altering dietary preference and glycemic control. This novel finding suggests that adolescent inhalant abuse may increase the risk of adult onset disorders such as diabetes and has significant implications for our understanding of the long-term consequences, especially in Indigenous populations where there is a high degree

of overlap between inhalant abuse and nutrition related illness. The next step in our studies is to determine the underlying mechanisms, including both changes to central or peripheral mediated processes that drive the adverse outcomes observed in human abusers.

THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

ANDREW LAWRENCE EDITORIAL POSITIONS

SYNAPSE BIOLOGY AND COGNITION GROUP Jess Nithianantharajah

2014 saw the addition of the Synapse Biology and Cognition laboratory to the Division of Behavioural Neuroscience led by Dr. Jess Nithianantharajah, who was recruited back to Melbourne after six years in the UK (Cambridge and Edinburgh). Dr. Nithianantharajah was awarded a highly competitive Australian Research Council Future Fellowship in 2014, the only application out of 150 successful proposals awarded under the theme of Neurosciences.

Sensory information from the environment is ultimately processed at the level of synapses, the connection between neurons that form the most fundamental information-processing units in the nervous system. A central research focus of the lab is to understand the role of synaptic genes in cognition and disease.

Vertebrate synapses contain a large yet intricately organised signalling complex of proteins encompassing neurotransmitter receptors, scaffold proteins and cell adhesion proteins. In recent years, human genetic studies have increasingly highlighted that disruption of over 200 genes that encode postsynaptic proteins result in over 130 brain diseases. While it is accepted that postsynaptic proteins are fundamental for synaptic function, plasticity and thus behaviour, very little is actually known about the impact of postsynaptic gene mutations in regulating complex cognition and higher order processing.

Moreover, modelling the complex cognitive processes that are routinely assessed in the clinical setting has been challenging in animal models. Towards bridging the gap between mouse and human cognitive testing, the lab is employing novel behavioural technologies such as the recently developed rodent touchscreens as an innovative tool for dissecting higher cognitive functions in rodents. Dr. Nithianantharajah, along with PhD student Rebecca Norris, is beginning to investigate how a family of cell adhesion proteins (neuroligins) are involved in complex cognitive behaviours.

This is of particular interest as human mutations in neuroligins have been reported in autism spectrum disorders and schizophrenia.

The group is also developing novel touchscreen tests for mice to be able to further model and probe distinct cognitive capacities that are clinically relevant.

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ҩҩ The British Journal of Pharmacology, Senior Editor ҩҩ Neurochemical Research, Associate Editor ҩҩ The Journal of Pharmacological Sciences, Associate Editor ҩҩ Addiction Biology, Editorial board member ҩҩ The Open Neuropsychopharmacology Journal, Editorial board member ҩҩ ISRN Addiction, Editorial board member MAJOR NATIONAL AND INTERNATIONAL CONFERENCES 2014 INVITED SPEAKER

ҩҩ Japanese Pharmacological Society Annual Conference. Invited symposium speaker “Relaxin-3 Regulates Stress-Induced AlcoholSeeking in Rats”. Sendai, Japan. ҩҩ 3rd Asia-Pacific Society for Alcohol and Addiction Research Conference. Plenary Lecture “Ascending Relaxin-3 systems regulate stress-induced reinstatement of alcohol-seeking”. Shanghai, China ҩҩ 12th Conference of Asia-Pacific Society for Neurochemistry (APSN). Symposium speaker “mGlu5 & extinction of drug-seeking”, Kaohsiung, Taiwan. ҩҩ Joint Scientific Conference of The Hong Kong Society of Neurosciences and HK Biophysical Society. Plenary lecture “Neuropeptides & Reward-Seeking”. ҩҩ 8th International Meeting on Metabotropic Glutamate Receptors, Sicily, Italy – invited symposium speaker “mGlu5 Receptors and Extinction of Drug-Seeking”.

ҩҩ 16th International Society of Addiction Medicine Annual Meeting, Yokohama, Japan - invited symposium speaker “Neuropeptides as therapeutic targets for drug-seeking”. ҩҩ 2nd International Anniversary KBRI Symposium, Korea Brain Research Institute Daegu, Korea – invited speaker. ҩҩ ANS Annual Conference in Adelaide, invited symposium speaker “The many faces of the orexin system” ҩҩ ASCEPT-MPGPCR Meeting, invited speaker “Peptides & RewardSeeking”, Melbourne.

OTHER ACADEMIC INVITATIONS

ҩҩ Cass Memorial Lecture, Dundee University Medical Research Institute. ҩҩ Faculty member, APSN Advanced School in neurochemistry, Center for Translational Research in Biomedical Research, Chang Gung Memorial Hospital, Kaohsiung, Taiwan. ҩҩ President, Asian-Pacific Society for Neurochemistry (APSN). ҩҩ Member scientific programming committee International Society for Neurochemistry (ISN) conference in Cairns, Australia. ҩҩ Ambassador for the 2016 CINP World Congress of Neuropsychopharmacology, Seoul, Korea.

AMY BRODTMANN EDITORIAL POSITIONS

ҩҩ Neurology, Editorial Board Member, vascular division ҩҩ International Journal of Stroke, Co-Section Editor MAJOR NATIONAL AND INTERNATIONAL CONFERENCES 2014

ҩҩ Neuropsychiatry Neurobehavioural Meeting, Frontotemporal Dementia Update, Melbourne. ҩҩ Public Lecture Florey: Stroke and Dementia. ҩҩ FTD support group: Update from the International FTD Meeting, Vancouver.

INVITED SPEAKER

ҩҩ Hypertension and Dementia, World Congress of Neurology, Melbourne.

OTHER ACADEMIC INVITATIONS

TERENCE PANG

DESPINA GANELLA

MAJOR NATIONAL AND INTERNATIONAL CONFERENCES 2014

MAJOR NATIONAL AND INTERNATIONAL CONFERENCES 2014

INVITED SPEAKER

INVITED SPEAKER

ҩҩ Invited Symposium Speaker, ‘Behavioral manipulation and alcohol misuse’, 37th Annual Research Society on Alcoholism (RSA) Scientific Meeting and 17th Congress of the International Society for Biological Research on Alcoholism (ISBRA), Bellevue, Washington, USA.

ҩҩ Neurology Trainee lectures: Frontal lobe syndromes; Memory and H.M.

ҩҩ “The partial agonist of the dopamine receptor 2, Aripiprazole, facilitates extinction in adolescent rats.” The 12th meeting of APSN. Kaohsiung, Taiwan.

THIBAULT RENOIR EDITORIAL POSITIONS

ҩҩ Frontiers in Neuropharmacology, Associate Editor

MAJOR NATIONAL AND INTERNATIONAL CONFERENCES 2014 INVITED SPEAKER

ҩҩ Invited Symposium Speaker, Society for Mental Health Research (SMHR; formerly known as ASPR), Adelaide.

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

EDITORIAL POSITIONS

MAJOR NATIONAL AND INTERNATIONAL CONFERENCES 2014 INVITED SPEAKER

ҩҩ Integrative Center for Learning and Memory, Brain Research Institute, UCLA, USA. ҩҩ Invited Symposium Introduction and Discussant, ‘Behavioral manipulation and alcohol misuse’, 37th Annual Research Society on Alcoholism (RSA) Scientific Meeting and 17th Congress of the International Society for Biological Research on Alcoholism (ISBRA), Bellevue, Washington, USA. ҩҩ Invited Lecturer, European Molecular Biology (EMBL) PhD Course, ANU, Canberra. ҩҩ Invited Speaker, 12th International Conference on Cognitive Neuroscience (ICON) satellite meeting, ‘Mission MMN Workshop’, Newcastle. ҩҩ Symposium Speaker, 12th International Conference on Cognitive Neuroscience (ICON), Brisbane.

ҩҩ Invited Keynote Speaker, ‘The neurobiology of environmental enrichment and experience-dependent plasticity in animal models of mental illness’, Society for Mental Health Research (SMHR; formerly known as ASPR), Adelaide. ҩҩ Invited Speaker, SMHR Symposium, ‘Lifestyle approaches to mental health: The role of physical activity’, Adelaide. ҩҩ Invited Keynote Speaker, National Huntington’s Conference, UWA, Perth.

OTHER ACADEMIC INVITATIONS

ҩҩ Member, National Committee for Brain and Mind, Australian Academy of Science. ҩҩ State Representative for Victoria and Tasmania, National Association of Research Fellows (NARF). ҩҩ Scientific Committee Member, 12th International Conference on Cognitive Neuroscience (ICON). ҩҩ Scientific Committee Member, 5th International Congress on Neurology and Epidemiology (ICNE). ҩҩ Monash Clinical Imaging Neuroscience, Monash Biomedical Imaging, Monash University – Invited lecture. ҩҩ Leaders in Science Seminar, Garvan Institute of Medical Research, Sydney. ҩҩ Stroke Division Seminar Series, Melbourne Brain Centre, Austin Campus.

JEE HYUN KIM EDITORIAL POSITIONS

ҩҩ Frontiers in Behavioral Neuroscience, Review Editor ҩҩ International Scholarly Research Network: Neuroscience, Associate Editor ҩҩ Neurotransmitter, Associate Editor ҩҩ Pharmacology Research & Perspectives, Associate Editor MAJOR NATIONAL AND INTERNATIONAL CONFERENCES 2014 INVITED SPEAKER

ҩҩ “Adolescent sensitivity to cocaine-associated cues: a dopamine story”. 2014 Annual Pavlovian Society Meeting. Seattle, USA.

ҩҩ “Extinction of fear and drug-seeking during adolescence.” 37th Annual meeting of the Japan Neuroscience Society (JNS). Yokohama, Japan. ҩҩ “Extinction of fear and drug-seeking during adolescence.” The 12th meeting of the Asian-Pacific Society for Neurochemistry (APSN).

Kaohsiung, Taiwan.

JHODIE DUNCAN EDITORIAL POSITIONS

ҩҩ Journal of Reward Deficiency Syndrome, Associate Editor ҩҩ Brain Pathology, Editorial board member ҩҩ Neurochemical Research, Editorial board member MAJOR NATIONAL AND INTERNATIONAL CONFERENCES 2014 INVITED SPEAKER

ҩҩ “Glue sniffing sucks! The long-term consequences of inhalant abuse during adolescence on the brain and body” Department of Neuroscience Research, Strathclyde University, Glasgow, Scotland, UK.

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JESS NITHIANANTHARAJAH

ANTHONY HANNAN ҩҩ Journal of Huntington’s Disease, Associate Editor ҩҩ European Journal of Neuroscience, Scientific Review Associate ҩҩ CNS & Neurological Disorders - Drug Targets, Editorial board member ҩҩ Neural Plasticity, Editorial board member ҩҩ Neuroscience Letters, Associate Editor ҩҩ Frontiers in Neuropharmacology, Review Editor ҩҩ Neuroepidemiology, Editorial board member

THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

OTHER ACADEMIC INVITATIONS

ҩҩ Department of Psychology, Korea University, Seoul, South Korea – Invited lecture. ҩҩ RIKEN Brain Science Institute, Tokyo, Japan – Invited lecture. ҩҩ School of Psychology, Australian Catholic University, Melbourne, Australia – Invited lecture. ҩҩ School of Medical Sciences, The University of Sydney, Sydney, Australia – Invited lecture. ҩҩ Department of Cell Biology and Neuroscience, Sapienza University of Rome, Italy – Invited lecture. ҩҩ Academy of Sciences of the Czech Republic, Prague, Czech Repulic. – Invited lecture. ҩҩ 12th meeting of Asian-Pacific Society for Neurochemistry, Kaohsiung, Taiwan - Symposium Chair. ҩҩ International Society for Developmental Psychobiology – Board Member.

INVITED SPEAKER

ҩҩ Neuropsychiatric diseases Symposium, Monash Institute of Pharmaceutical Sciences, Melbourne Australia ҩҩ Centre for Neural Engineering, University of Melbourne, Australia ҩҩ National Institute on Alcohol Abuse and Alcoholism, Rockville USA.

EXTERNAL COLLABORATIONS FOR ADDICTION NEUROSCIENCE GROUP

EXTERNAL COLLABORATIONS FOR COGNITIVE NEUROSCIENCE GROUP

Professor Alon Chen (Weizmann Institute, Israel), Professor Jian-Hui Liang (NIDD, Beijing, China), Professor Bernard Balleine (University of Sydney), Professor Peter Kalivas (MUSC, USA), Professor Rainer Spanagel (ZIMH, Germany), Professor Caroline Rae (UNSW), Professor Sarah Dunlop (UWA), Assoc Professor Peter Dodd (UQ), Dr Kevin Pfleger (UWA), Dr Amir Rezvani (Duke, USA), Dr. Masa Funada (National Institute of Mental Health, Kohnodai, Japan), Dr. Tim Bredy (The Queensland Brain Institute), Dr. Zane Andrews (Monash), Professor Dan Lubman (Turning Point / Monash), Professor Michael Cowley (Monash), Professor Danny Winder (Vanderbilt, USA).

AMY BRODTMANN Dr Marina Boccardi and Dr Giovanni Frisoni, LENITEM, Fatebenefratelli, IRCSS, Brescia, Italy, Dr Marco Catani, King’s College, London, UK, Dr Charles DeCarli, University of California Davis, USA, Professor Trish Desmond, Royal Melbourne Hospital, Dr Martin Dichgins, Institute for Stroke and Dementia Research (ISD), Ludwig-Maximilians-University, Munich, Professor Vladimir Hachinski, Case Western University, London, Ontario, Canada, Professor John Hodges (FRONTIER, Sydney, Cambridge), Dr Tobias Loetscher (Flinders University, Adelaide), Professor Terence O’Brien, Royal Melbourne Hospital, Professor John McNeil, Monash University.

EXTERNAL COLLABORATIONS FOR INHALANT ABUSE LABORATORY

EXTERNAL COLLABORATIONS FOR DEVELOPMENTAL PSYCHOBIOLOGY GROUP

Professor Andrew Lawrence (Florey), Professor Bernard Balleine (University of Sydney), Professor Caroline Rae (UNSW), Dr. Masa Funada (National Institute of Mental Health, Kohnodai, Japan), Dr. Tim Bredy (The Queensland Brain Institute), Dr. Zane Andrews (Monash), Professor Dan Lubman (Turning Point / Monash), Mr. David Wright and Dr. Leigh Johnston (Florey and Melb. Uni), Dr. Joseph Nicolazzo (Monash University), Dr. Michael Mathai (Vic. Uni), Dr Sarah MacLean (Turning Point Alcohol and Drug Center, Melb), Associate Professor Sheree Cairney (Menzie’s and Flinders Uni), Deanne Skelly (Uni Melb), Professor Hannah Kinney and Dr. David Paterson (Harvard Medical School/ Children’s Hospital Boston), Prof. Roger Byard (Uni Adelaide), Drs. Marianne Garland, Michael Myers, William P. Fifer, and Raymond Stark (Primate Center and Departments of Pediatrics and Psychiatry, Columbia University College of Physicians and Surgeons, New York).

Professor Steven Collins (The University of Melbourne); Professor Antonio Paolini (RMIT); Professor Terry Speed (Walter and Eliza Hall Institute); Dr Sarah Whittle (Melbourne Neuropsychiatry Center).

MAJOR NATIONAL AND INTERNATIONAL CONFERENCES 2014 ҩҩ International Conference on Cognitive Neuroscience (ICON), Brisbane Australia (Chair of workshop) ҩҩ Evolution Symposium, Victorian Department of Environment and Primary Industries, Melbourne Australia

DAVID DARBY Professor Kia Nobre, Oxford University,UK, Dr Moacir Silva Neto, Brasilia, Brazil.

EXTERNAL COLLABORATIONS FOR SYNAPSE BIOLOGY AND COGNITION GROUP

ҩҩ “Glue sniffing sucks! The long-term consequences of inhalant abuse during adolescence on the brain and body” Department of Pharmacology, The University Of Melbourne, Vic., Aust. ҩҩ “Why glue sniffing sucks! The long-term consequences of inhalant abuse during adolescence on the brain and body” Monash Institute of Medical Research –Prince Henry’s Institute, Vic., Aust.

Prof. Seth Grant (Edinburgh University), Dr. Noboru Komiyama (Edinburgh University), Prof. Timothy Bussey (Cambridge University), Dr. Lisa Saksida (Cambridge University), Dr. Max Kopanitsa (Synome, Cambridge), Dr. Andrew McKechanie (Patrick Wild Centre, Edinburgh University), Dr. Mandy Johnston (Royal Edinburgh Hospital), Prof. Douglas Blackwood (Royal Edinburgh Hospital), Prof. Chris Pantelis (Melbourne Neuropsychiatry), Prof.

Arthur Christopoulos (Monash Institute of Pharmaceutical Sciences), Dr. Chris Langmead (Monash Institute of Pharmaceutical Sciences).

2014 STUDENTS: PhD: • Nicola Chen • Alec Dick • Rose Chesworth • Hanna Kastman • Andrew Walker • Danay Baker-Andresen • Isabel Zbukvic

• Sophia Luikinga• Christina Mo • Annabel Short • Dean Wright • Jake Rogers • Shlomo Yushuren • Sarah Sulaiman Ch’ng • Leigh Walker • Jirawoot Srisontiyakul • Fiona Bright (Adelaide) • Rebecca Norris • Matthew Poole • Kirrily Rogers • Karen Borschmann (primary supervisor Julie Bernhardt) • MASTERS: • Shawn Tan • Faith Lamont • Emma Giles • Felicia Reid • Katherine Beringer • HONOURS: • Rosa Heller • Ashleigh Qama • Katherine Drummond • Johnny Park •

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

Four key ways to improve your brain health

By Professor Anthony Hannan

It’s time we all focused more on this most important organ, to improve brain health throughout our lives.

cardiovascular system, as well as the immune system, that impact on the nervous system.

FIRST: STAY PHYSICALLY ACTIVE

FOURTH: DON’T STRESS TOO MUCH!

This is an obvious idea, however not everyone realises that physical activity is not only good for the body, it also boosts brain health.

Seldom do we need the stress response (“fight or flight”) that protected cave dwellers thousands of years ago.

There are many ways this could occur, as the brain and body are in constant, dynamic communication. Muscles release beneficial molecules that reach the brain, and exercise also stimulates the heart and other body systems which can beneficially impact the brain. Enhanced physical activity may stimulate the generation of new brain cells and connections.

Evidence is growing that such healthy lifestyle choices may help protect against Alzheimer’s, depression and other brain disorders.

FOUR KEY WAYS TO IMPROVE YOUR BRAIN HEALTH

Pictured: Professor Anthony Hannan, head of the Florey’s Neural Plasticity lab.

By Professor Anthony Hannan

T

he human brain is the most extraordinary and complex object in the known universe, a kilogram and a half of soft tissue that, at its peak, leaves computers behind with its endless capacity for problem solving, innovation and invention.

If the body is a “temple”, then surely the brain must be the “high altar” as it generates all of our thoughts, feelings and movements. Indeed, it is fundamental to all of our conscious experience.

Brain diseases such as Huntington’s, Alzheimer’s and other forms of dementia demonstrate how devastating it is when the brain degenerates, dragging the mind and its many wonderful capacities down with it.

SECOND: STAY MENTALLY ACTIVE Two cardinal rules of brain plasticity are “use it or lose it” and “neurones that fire together wire together”. People who maintain higher levels of cognitive activity may, in fact, be protected from Alzheimer’s and other forms of dementia.

Cognitive stimulation may help build a “brain reserve” to protect from, and compensate for, the brain ageing. So what mentally stimulating activities could you do? Each individual will know what cognitively challenges and interests them and making positive lifestyle choices that can be maintained for months and years are more likely to lead to long-term benefits.

THIRD: EAT A HEALTHY DIET Did you realise a balanced nutritious diet is good for your brain?

Excessive chronic stress may be toxic for the brain which is loaded with sensitive “stress receptors.”

Stress-reducing strategies such as “mindfulness” and meditation are increasingly popular. Other lifestyle choices, such as a good diet, plenty of physical activity, as well as healthy sleep patterns, may also contribute to resilience.

TAKE-HOME MESSAGE The phrase “mens sana in corpore sano” (a sound mind in a sound body) is thousands of years old, so the concept is clearly not new. The good news is that we can all do something to improve the health of our brains and bodies.

Each of us is dealt a genetic deck of cards at conception that we can do nothing about. Through development and adulthood, our genes interact constantly with environmental factors to regulate how our brains and bodies function, as well as dysfunction when they put us at risk of specific diseases.

With a positive mental attitude supporting a healthy lifestyle, we may be able to maintain soundness of body and mind for as long as possible. And hopefully, brain research at the Florey and elsewhere will deliver new treatments for devastating disorders such as Alzheimer’s disease and other forms of dementia.

Most of the nutrients from food circulate through your brain via the bloodstream.

So a healthy diet can directly improve the health of brain cells and may even slow down brain ageing.

What’s more, by improving body health, the brain may benefit via the heart and

Courtesy: TheConversation.com

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

EPILEPSY Leaders: Professor Graeme Jackson and Professor Steve Petrou

THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

EPILEPSY – ION CHANNELS AND HUMAN DISEASE

NEUROIMAGING

Leader: Steve Petrou

Leader: Graeme Jackson

Our research focuses on understanding the pathology of ion channel disorders, in particular epilepsy, using in vitro and in vivo models to reveal opportunities for developing novel therapies. We use a multidisciplinary approach spanning ion channel biophysics, mouse transgenesis, genetic analysis, computational modeling and in vitro and in vivo electrophysiology.

Research highlights for 2014

A QUICK SNAPSHOT

The Florey Epilepsy Division is a world-leading centre for epilepsy research. The division has major groups at both the Florey’s Austin and Parkville campus. The group studies mechanisms that cause epilepsy from cells to the function of the whole brain. We use technologies including advanced MRI and cutting edge cellular physiology techniques to allow us to understand genetic and acquired mechanisms that give rise to epilepsy. Together with our colleagues from The University of Melbourne and across Australia, we are working towards finding a cure for epilepsy.

RESEARCH HIGHLIGHTS

AN IDEA LIKELY TO CHANGE LIVES BY 2035

Our neuroimaging studies of epilepsy, including Lennox-Gastaut Syndrome, a particularly severe form of epilepsy, are helping to explain why epilepsy can be associated with intellectual disability.

Abnormal electrical activity has been detected in the brains of patients with this syndrome. It occurs frequently, even when the patients are not having a seizure and the activity is widespread, involving many of the brain’s major functional networks, and is therefore likely disrupting normal cognition. Yet in some patients with these symptoms we have located a small brain lesion. After surgical removal of the lesion, the widespread abnormal activity is eliminated and the patients are seizure-free.

We have shown that abnormal activity involving much of the brain can be triggered by a small focal brain lesion. We have also shown that if such a lesion can be found and surgically removed, seizures can be stopped. We will continue to help drive neuroimaging advances and we hope in coming years this will enable us to routinely locate all such lesions, providing many more epilepsy patients a surgical option to stop their seizures.

In 2014 we have accelerated our efforts towards delivering precision medicine outcomes in genetic epilepsy. We showed that quinidine, a drug related to the quinine of tonic water, is effective in controlling the function of an aberrant gene in a severe epilepsy.

Subsequent clinical trials showed efficacy of this treatment paving the way for disease mechanism specific therapies – the backbone of precision medicine approaches.

We continued to seek to find markers of the disease state in epilepsy, from fundamental biophysical changes in ion channel function, to structure of neurones and brains studied with light microscopy and MRI. This year alone contributed to the characterisation of four different epilepsy genes.

These markers of the disease state are critical for accurate diagnosis, but even more importantly can be used to track the efficacy of new therapeutics emerging from our disease mechanism targeted drug programs. We have fully embraced state-of-theart optical imaging approaches for structure and function of neurones to enhance our ability to tease out disease mechanisms.

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Research highlights for 2014

This group undertakes activities across both the Imaging Division and the Epilepsy Division and has published over 50 peer reviewed papers in 2014. This is a reflection of its origins as an advanced imaging centre with methods development and application to the problems of epilepsy. Through the use of cutting-edge MRI methods such as functional connectivity, tractography, simultaneous electroencephalography and functional MRI (EEG/fMRI) and other advanced imaging, we continue to achieve greater understanding of epilepsy mechanisms. The new knowledge is rapidly translated to improved patient care through the Victorian Epilepsy Centre’s comprehensive epilepsy program at the Austin Hospital in Heidelberg, and through Epilepsy Melbourne, which integrates centres across University of Melbourne teaching hospitals.

This group is primarily based at the Austin campus of the Florey.

Our basic work is to understand brain development and function, particularly the disturbances in distributed networks that underlie epileptic disorders. We are using EEG/fMRI, advanced diffusion techniques including tractography, functional connectivity and network analysis to investigate the underlying brain mechanisms responsible for the clinical symptoms. This is done in a translational environment that is immediately relevant to patient care.

In addition to the obvious symptomatology of epilepsy (i.e. seizures) cognition, memory and language disturbances are key cognitive areas affected by the disease. For example, we recently studied language in a group of patients with focal epilepsy, some with and some without reading difficulty, in an attempt to identify brain regions that may have disturbed function. We imaged the brain using functional MRI in the patients and also in healthy control subjects.

MAIN AREAS OF RESEARCH

ҩҩ Epilepsy genetics

“

With the recent advances in genetics and technology it is now possible to devise and deliver therapies based specifically on the fundamental disease mechanism in individual patients.”

”

ҩҩ Epilepsy imaging

ҩҩ Human brain structure and function ҩҩ Functional modelling of gene mutations in epilepsy

A

ҩҩ Multimodal imaging in epilepsy disease models

B

ҩҩ Purinergic signalling SENIOR STAFF

EPILEPSY IMAGING • Professor Graeme Jackson (Division Head) • Dr David Abbott • Associate Professor Peter Brotchie • Dr Patrick Carney • Associate Professor Paul McCrory • Dr Saul Mullen • Professor Ingrid Scheffer • ION CHANNELS AND EPILEPSY LAB • Professor Steve Petrou • Dr Alison Clarke • Dr Carol Milligan • Dr Elena Gazina • Dr Kay Richards • Dr Robert Richardson • Dr Verena Wimmer • SYNAPTIC PHYSIOLOGY • Dr Christopher Reid • Dr Marie Phillips • PURINERGIC SIGNALLING • Dr Ben Gu • Professor James Wiley •

A: mouse somatosensory cortex.

B: part of the hippocampus and overlying cortex.

Investigating subtle changes in the neuronal anatomy of the cortex in epilepsy. Red: neurones stained with an antibody against the neuronal marker NeuN. Blue: staining for the inhibitory neurotransmitter GABA, showing inhibitory neurones. Green: an inhibitory subclass of neurones identified by staining against the calciumbinding protein parvalbumin.

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

We discovered a functional abnormality in the left frontal region of the brain in patients with and without reading difficulties, and a further functional abnormality specific to the reading difficulty group localized to right temporo-occipital cortex—a region previously implicated in lexicosemantic processing (figure 3). Our observations suggest a failure of left hemisphere specialisation among focal epilepsy patients with reading difficulties, perhaps arising from abnormalities in brain development.

THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

to remove unwanted noise from functional MRI data. The algorithm, called “SOCK”, is an objective and fully automated procedure. An example of its effectiveness in a simultaneous EEG-fMRI study of Rolandic epilepsy is shown in figure 4. SOCK increases power to detect real effects in functional neuroimaging, providing a more complete picture of the brain networks of interest.

Brain activity during performance of a language task (thinking of words beginning with a given letter). Three brain slices are shown for each subject group, with significant activity associated with the task overlayed in colour (increases in warm colours, decreases in blue). Top row: healthy controls. Second row: focal epilepsy patients without reading difficulty. Bottom row: Focal epilepsy patients with reading difficulty.

Relative to healthy controls, both patient groups showed reduced activation in left inferior frontal cortex. However the reading difficulty group also exhibited greater activation in the right temporooccipital cortex (see dashed ellipse), indicating a failure of normal specialisation to the left hemisphere in this region. Adapted from Tailby C, Weintrob DL, Saling MM, Fitzgerald C, Jackson GD. Reading difficulty is associated with failure to lateralize temporooccipital function. Epilepsia.

2014;55(5):746-753.

CONTROL

The epilepsy imaging group is also developing new neuroimaging analysis methods to improve sensitivity to detect abnormal brain activity. For example, we have developed a novel processing method

MEAN LI = 0.62

EPILEPSY RD

Generalized paroxysmal fast activity detected on EEG is simultaneously imaged with fMRI to obtain spatial activation maps. The average activity of six subjects is shown here in colour overlayed on an anatomical template. Despite the common pattern of widespread activity, each subject has a different type and location of brain lesion. Adapted from Archer JS, Warren AEL, Stagnitti MR, Masterton RAJ, Abbott DF and Jackson GD, Lennox-Gastaut Syndrome and Phenotype: Secondary network epilepsies. Epilepsia 55(8):1245-54 (2014).

EPILEPSY NO-RD

MEAN LI = 0.82

MEAN LI = 0.47

Preoperative and postoperative EEG studies in 38-year-old man with Lennox-Gastaut Syndrome, a lesion, and intractable seizures since childhood. Prior to resection of a left frontal cortical dysplasia (arrowed), the patient had daily tonic seizures. Preoperative interictal EEG showed bursts of slow spike-and-wave (SSW) and generalized paroxysmal fast activity (PFA). Day 3 postoperative EEG shows persistence of SSW, whereas day 30 EEG shows complete normalization, consistent with a winding down of the epileptic process. The patient is 2 years seizure-free, consistent with LGS being a potentially reversible “secondary network epilepsy”. Adapted from Archer JS, Warren AEL, Stagnitti MR, Masterton RAJ, Abbott DF and Jackson GD, Lennox-Gastaut Syndrome and Phenotype: Secondary network epilepsies. Epilepsia 55(8):1245-54 (2014).

Brain activation associated with abnormal epileptic activity in an individual is shown in colour at two slice positions. The images on the left were created using conventional analysis, whilst the images on the right were created after noise-filtering with SOCK. The plots underneath are the associated estimates of the time-course of signal change. The shape of the time-course after applying SOCK is qualitatively smoother (less noisy), however the most dramatic improvement is evident in the spatial maps.

Arrows in green point to areas of increased activation in expected regions when SOCK is employed. From Bhaganagarapu K, Jackson GD, Abbott DF. Frontiers in Neuroscience 8(285):1-9 (2014).

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EPILEPSY – ION CHANNELS AND HUMAN DISEASE EDITORIAL POSITIONS

ҩҩ Neurobiology of Disease ҩҩ PLOS Genetics

MAJOR NATIONAL AND INTERNATIONAL CONFERENCES 2014

ҩҩ Mechanism of proton modulation of neuronal excitability.

International Biophysics Congress. Brisbane, Australia. ҩҩ Functional correlates of severity in Alternating Hemiplegia of Childhood. 3rd International Meeting of the AHC in Amsterdam September. ҩҩ Epilepsy Society of Australia. Microstructure and networks ҩҩ Translational opportunities in genetic epilepsies: Are we there yet?

Duke University. USA. ҩҩ Clear thinking in epilepsy: CLARITY imaging of short and long range neuronal networks. Hertie Institute, University of Tubingen. ҩҩ Direct and emergent pathologies reveal therapeutic opportunities in EIMFS and Dravet. Hertie Institute, University of Tubingen. ҩҩ pH modulation of neuronal excitability in epilepsy. Hertie Institute, University of Tubingen. ҩҩ Translational opportunities in the genetic epilepsies: Something old, something new, something borrowed, something blue. Aikenhead medical research week. St Vincent’s Hospital. ҩҩ Precision therapeutics in epilepsy. Epilepsy Genetics in the Era of Precision Medicine, San Francisco, USA. ҩҩ Translational opportunities in the epileptic encephalopathies. Hertie Institute, University of Tubingen. ҩҩ Mechanisms of pH modulation of neuronal function, Epilepsy Research Retreat, Yarra Valley Lodge. ҩҩ Biophysical consequences of SCN2A pathology in Epileptic Encephalopathies, Epilepsy Research Retreat, Yarra Valley Lodge. ҩҩ University of Newcastle, NSW. September. ҩҩ Multi-modal approaches to understand brain functions. Interactive Brain Function Workshop, Monash University. ҩҩ Modulation of neural excitability in health and disease. Pain Program Grant Retreat. University of Queensland. ҩҩ CLARITY imaging in genetic epilepsy models. Epilepsy retreat, Austin Hospital. ҩҩ Novel peptide therapy in Dravet Syndrome. Dravet round table meeting. Seattle, USA. ҩҩ Challenges and opportunities in delivering precision therapies in genetic epilepsy. The Epi4k annual meeting. Seattle, USA. ҩҩ Modulation of neural excitability in health and disease. Pain Program Grant Retreat. University of Queensland. ҩҩ CLARITY imaging in genetic epilepsy models. Epilepsy retreat, Austin Hospital. ҩҩ Novel peptide therapy in Dravet Syndrome. Dravet round table meeting. Seattle, USA. ҩҩ Challenges and opportunities in delivering precision therapies in genetic epilepsy. The Epi4k annual meeting. Seattle, USA EPILEPSY - NEUROIMAGING EDITORIAL POSITIONS

ҩҩ Annals of Neurology – Ingrid Scheffer ҩҩ Epileptic Disorders - Ingrid Scheffer ҩҩ Frontiers in Neurology – David Abbott, Patrick Carney, David Vaughan, Graeme Jackson

ҩҩ Frontiers in Neuroscience – David Abbott, Patrick Carney, David Vaughan, Graeme Jackson ҩҩ Journal of Neuroimaging – Graeme Jackson ҩҩ Progress in Epileptic Disorders series - Ingrid Scheffer MAJOR NATIONAL AND INTERNATIONAL CONFERENCES 2014

ҩҩ Invited speaker: “Malformations of cortical development” Center for Integrative Brain Research Seattle Children’s Research Institute Seattle, 9th Dec 2014. ҩҩ Plenary speaker: “From the bedside to the bench and back” 3rd annual National Health and Medical Research symposium Parkville Melbourne 13th November 2014. ҩҩ Chair: UCB Educational meeting: Management of epilepsy in women across the life cycle. Melbourne, 28th August 2014. ҩҩ Invited speaker & Co-chair: “Structural MRI; visual inspection versus automated assessment” 10th Asian & Oceanian Epilepsy Congress, Singapore 7th August 2014. ҩҩ Featured Speaker: “The near future of imaging in epilepsy”, Third International Epilepsy Research Center Symposium, Newport Beach, California 21st Feb 2014. ҩҩ Plenary lecture: “EEG-fMRI in Epilepsy”, EEG-fMRI turns 21, Kiel, Germany 8th June 2014. ҩҩ Keynote lecture: “Finding epilepsy networks in functional magnetic resonance imaging of the human brain” and participation in the mathematics Study Group Workshop (SGW 2014), Kyushu University, Fukuoka, Japan & University of Tokyo, Tokyo, Japan. 30th July – 5th August 2014. ҩҩ Invited seminar, “Data-driven artefact removal and analysis of fMRI and simultaneous EEG-fMRI”, Advanced Brain Signal Processing, RIKEN Brain Science Institute, Wako, Japan. 6th August 2014. ҩҩ Presentation: “Age-related structural changes to the human visual pathway determined using in vivo clinical imaging techniques”.

Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), Denver, Colorado, USA (May 3-7, 2015). ҩҩ Presentations: 20th Annual Meeting of the Organization for Human Brain Mapping, Hamburg, Germany, June 2014. ҩҩ Presentations: 12th International Conference on Cognitive Neuroscience, Brisbane, Australia. July 27-31, 2014. ҩҩ Presentations: 68th American Epilepsy Society annual meeting, Seattle, WA, USA, December 2014. ҩҩ Presentations: Section for Magnetic Resonance Technologists (SMRT) 23rd Annual Meeting, Milan 10-11th May 2014. ҩҩ Presentations: Joint Annual Meeting ISMRM-ESMRMB, Milan, Italy, 10-16 May 2014. ҩҩ Presentation (Best Scientific Poster 2014): Australia & New Zealand Spinal Cord Society (ANZSCoS), Auckland, New Zealand, 19 – 21 November 2014. ҩҩ Invited talk: “Mild head injury and flying”, Aviation Medical Society of Australia Annual Meeting, Melbourne 19 July 2014. ҩҩ Invited Lecture: “Concussion issues for medical staff”, AFL Medical Education Seminar, 24 June 2014. ҩҩ Keynote: IOC Injury Prevention and Athlete Health meeting, Monaco, 8-12 April 2014. ҩҩ Invited Lectures: “What’s new in concussion – the Zurich consensus” and “The difficult concussion patient”, IOC Advanced Team Physician Course. Mandelieu, France 12-13 April 2014. ҩҩ Invited Lecture: “Concussion in sport”, Aspetar Hospital Scientific Research Meeting, Doha, Qatar 7-14 March 2014. ҩҩ Invited Lecture: “Concussion and Medico-legal issues”, NRL CEO annual meeting, Auckland, New Zealand. 14 February 2014. ҩҩ Invited Lecture: “Chronic Traumatic Encephalopathy”, Australasian Neuroscience Society Annual Scientific Meeting, Adelaide January 2014.

THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

ҩҩ Invited Lecture: “Genetic testing in epilepsy: the key to precision medicine”, Dravet Syndrome Foundation Affiliate Meeting, Seattle, USA, 6 December 2014. ҩҩ Invited Lecture: “Dravet syndrome – where does the ketogenic diet sit in practice”, Global symposium for the dietary therapies for epilepsy and other neurological disorders. Liverpool, UK, 7-10 October 2014. ҩҩ Invited Chair: “Translation to the clinic”, Epilepsy Genetics in the new era of Precision Medicine. San Francisco, US, 29-30 September 2014. ҩҩ Invited Lecture: “KCNQ2 encephalopathy: an emerging disease within the epileptic encephalopathies.” KCNQ2 summit, Denver, US, 20 Septermber 2014.

EXTERNAL COLLABORATIONS FOR EPILEPSY IMAGING GROUP Ann & Robert H. Lurie Children’s Hospital of Chicago, USA, Austin Health, Melbourne, Boston Children’s Hospital & Harvard Medical School, Boston, USA, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Columbia University, NY, USA, Department of Molecular Genetics and Cytogenetics, Women’s and Children’s Hospital, North Adelaide, South Australia., Foothills Medical Centre, Canada, Harvard Medical School, Boston, USA, Hôpital Necker Enfants Malades, Paris, INSERM, Marseilles, France, Monash University, Melbourne, Murdoch Children’s Research Institute, Melbourne, New York University School of Medicine, USA, Northwestern University Feinberg School of Medicine, USA, Royal Children’s Hospital, Melbourne, Royal Hospital for Sick Children, Glasgow, Royal Melbourne Hospital, The Hospital for Sick Children, Great Ormond Street, London, UK, The University of Melbourne, The University of Queensland, University of Antwerp, Belgium, University of Bologna, Italy, University of Calgary, Canada, University of California, San Francisco, University of Otago, Wellington, New Zealand, University of Washington, Seattle, Walter and Eliza Hall Institute of Medical Research, Melbourne.

MAJOR AWARDS The seminal contributions to epilepsy research of Professor Ingrid Scheffer continue to be recognised with several major awards bestowed in 2014:

ҩҩ 2014 Prime Minister’s Prize for Science Most prestigious science prize in Australia ҩҩ 2014 Officer of the Order of Australia (AO) Awarded for distinguished service to medicine as a clinician, academic and mentor, and for her research identifying new epilepsy syndromes and genes ҩҩ 2014 Australian Academy of Science Fellowship (FAA) Elected as a Fellow for paradigm-shifting research into the genetic causes of epilepsy and defining new epilepsy syndromes. ҩҩ 2014 Founding Fellow and Vice-President of the Australian Academy of Health and Medical Sciences (FAHMS) ҩҩ 2014 Bethlehem Griffiths Research Foundation Medal In recognition of outstanding leadership and international contribution to medical research

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

ADVANCED MRI DEVELOPMENT GROUP Leader: Alan Connelly

IMAGING

Research highlights for 2014

Leaders: Professor Alan Connelly and Professor Graeme Jackson

A QUICK SNAPSHOT

The Florey Imaging Division encompasses the following research groups: Advanced Magnetic Resonance Imaging (MRI) Development, Epilepsy Imaging, and Small Animal MRI. These groups perform neuroscience related MRI research across a wide range of MRI methods, including diffusion MRI, perfusion MRI, functional MRI, and high resolution structural MRI. Much of this work involves the application of up to date MRI acquisition and analysis methods to disease related neuroscience issues, while the work of the Advanced MRI Development Group is at the forefront of developing novel methods to facilitate neuroscience investigations that were previously not possible.

RESEARCH HIGHLIGHT

AN IDEA LIKELY TO CHANGE LIVES BY 2035

The Advanced MRI Development team is a world leader in diffusion MRI innovation, and the methodological advances made at the Florey are being applied increasingly worldwide to further our understanding of the healthy brain and of how network connectivity is affected in disease. Such advances in technique will also have a major influence on human connectome investigations.

Understanding how structural connections relate to brain function is the subject of a major international program of research (the human ‘connectome’ project). The Florey’s methods development achievements will contribute significantly to this effort to move towards a more complete understanding of how the brain works, which has the potential to revolutionise human neuroscience.

Following a significant upgrade in 2012 to the 4.7 T animal scanner, thanks to support from the Victorian Biomedical Imaging Capability and the National Imaging Facility, research in 2014 has continued to progress over a wide range of applications and technical developments that were not previously possible, thus enabling new scientific collaborations to be established.

There are significant cross-relations between the Epilepsy and Imaging Divisions, which will be described in detail in the Epilepsy Division section of the annual report.

SENIOR STAFF

Major breakthroughs were achieved in 2014 in establishing improved methods to visualise fibre tracts within the brain, including advances that enable diffusion MRI data from multi-shell and multi-tissue to be acquired and processed. The latter is part of an international collaboration and has allowed significantly improved white matter fibre tracking (particularly in cortical regions – see example images). Application of our novel analysis methods to mouse models (see example images) is enabling in particular the study of genetic based epilepsies in conjunction with colleagues in neurophysiology at the Florey.

Also, such methods have been used in another international collaboration to study cerebello-thalamo-cortical pathways in the human brain (see example images), enabling an improved understanding of the connectivity network between functionally important areas of the brain.

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ҩҩ MRtrix: software package to enable white matter fibre tracking to be done in the brain using our constrained spherical deconvolution algorithm. (>7600 downloads) ҩҩ Numerical Fibre Generator: software package to generate realistic arrangements of bundles of fibres, with a complexity similar to that of white matter. Designed to be used as a test-bed for the development and evaluation of tractography methods. (>1700 downloads) Patent

A method for generating super-resolution images of fibrous tissue (such as white matter), based on tractography output. International patent application no: PCT/AU2010/000257.

ANIMAL MRI Leaders: Leigh Johnston (University of Melbourne; Hon Florey) and Alan Connelly (Florey) Research highlights for 2014

The Animal MRI lab continued research in a wide range of areas that included cortical development in the fetal brain, studies of potential treatment and MRI biomarkers for stroke, epilepsy, concussion and traumatic brain injury, structural assessment of human cardiac tissue, novel contrast agent testing, ultra-high resolution imaging of mouse anatomy for atlas construction, and technical developments in continuous wave magnetic resonance methods.

“

We achieved major advances during 2014 in developing world-leading methods to visualise fibre tracts within the brain, and introduced novel approaches to identify abnormalities in the densities of white matter fibre connections in the brain in disease states including epilepsy and Alzheimer’s disease.

”

Advantages of multi-shell diffusion weighted MRI acquisition for visualising white matter fibre tracts within the brain. The images show sagittal visualisation of a fibre tractogram obtained from white matter fibre orientation distributions estimated with single-shell single-tissue constrained spherical deconvolution (SSST-CSD) (left column) and multishell multi-tissue CSD (MSMT-CSD) (right column). The lower image in each case shows an expanded image of the region indicated by the yellow box in each of the upper images. MSMT-CSD is shown to directly benefit fibre tracking. The increased precision and reduced number of spurious peaks in the fibre orientation distributions result in less noisy tractograms near the WM–CSF and WM–GM interfaces, with better defined fine structures. [This work represents a collaboration involving the Florey and the Universities of Antwerp and Leuven, Belgium]

ADVANCED MRI DEVELOPMENT • Professor Alan Connelly • A/Professor Fernando Calamante • Dr David Raffelt • Dr Xiaoyun Liang • Dr Robert Smith • Dr Chun-Hung Yeh • Dr Thijs Dhollander • EPILEPSY IMAGING See Epilepsy Division section for details of Prof Graeme Jackson’s research group ANIMAL MRI • A/Professor Leigh Johnston (Honorary Florey) • Professor Roger Ordidge (Honorary Florey) • David Wright • Dr Hong Wang •

The development of novel network analysis methods have allowed us to use cerebral blood flow (CBF) not only to identify functional brain networks but also to identify quantitatively the CBF associated with important highly connected ‘hubs’ in order to better characterise functional networks within the brain (see example images).

Given that network abnormalities are increasingly believed to be associated with a number of important disease states, the latter information opens up potentially new areas of neuroscientific enquiry.

Software

The Advanced MRI Development group has created and made publicly available a number of software packages that have enabled research groups worldwide to be able to implement and use the technical advances that have been developed at the Florey.

These software packages have been extensively downloaded and are widely used throughout the research community.

Mouse brain thalamo-cortical connectivity visualized using targeted fibre tracking compared to virus mediated fluorescent protein expression. (A) Inverted fluorescent image of a coronal section taken from brain injected at the ventral posteromedial thalamic nucleus (VPM) with virally encoded fluorescent tag (injection needle track marked with a double-headed arrow). The whisker “barrels” indicated by the arrows are located in Layer IV cortex and are delineated by the axon terminations of thalamo-cortical projection neurons. The dotted black line, shown in panel A, indicates the orientation plane that allows visualization of the whisker barrels in Layer IV cortex as shown in panels C & D. (B) Coronal slice view of a ‘visitation count’ map (20μm isotropic resolution) shows extended tracking after seeding the VPM and targeting the cortex. One million streamlines were generated, which formed clusters of streamlines in the cortex. The ‘visitation count’ map created in this manner is overlaid (in hot colours) on a whole brain track density imaging (TDI) map for anatomical reference. The “barrel” regions (white arrows) have low signal intensity in the TDI map. (C) A tangential slice view of the posterior medial barrel subfield (PMBSF) pictured using the whole brain short-track TDI. (D) Image in (C) overlaid with ‘visitation count’ map from panel B (shown in hot colours). In this plane the streamlines are localized to the barrel septum. EC; external capsule; Hp; hippocampus; p, posterior; a, anterior; d, dorsal; v, ventral. Scale bars 200μm.

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

Contralateral cerebello-thalamo-cortical pathways: Images show a 3 dimensional view of the average cerebello-thalamocortical pathway across 15 subjects in MNI space. Cerebral (a), cerebellar (b) and deep grey matter (c) atlases are overlaid to assist visualization of cerebellar connections. (a) Distribution of left (red) and right (blue) tracts in the cerebral cortex: the reconstructed tracts reach the prefrontal (yellow), frontal (fuchsia) and temporal (violet) cortices with greater density of streamlines. (b) Streamlines distribution in the cerebellar cortex: the lateral Crus I–II (fuchsia) and the lateral lobules VIIb/ VIII (green) are showing the greatest density of tracts. (c) Streamlines distribution of deep grey matter nuclei: the thalami (violet), the caudate (light blue) and the putamen (fuchsia) show the greatest proportion of the overall tract grey matter belonging to specific cortical regions of interest. [This work represents a collaboration involving the Florey, University of Pavia (Italy) and UCL Institute of Neurology, London]

ADVANCED MRI DEVELOPMENT GROUP EDITORIAL POSITIONS ALAN CONNELLY

ҩҩ Member Editorial Board of Epilepsia MAJOR NATIONAL AND INTERNATIONAL CONFERENCES 2014 INVITED PRESENTATIONS

ҩҩ Alan Connelly - Recent advances in diffusion MRI analysis methods.

Annual Meeting of the Australian and New Zealand Society of Neuroradiology, Adelaide, 2014. ҩҩ Alan Connelly - Clinical and neuroscience applications of new approaches to diffusion MRI analysis. Annual Meeting of the Australian and New Zealand Society of Neuroradiology, Adelaide, 2014. ҩҩ Alan Connelly - Diffusion MRI at ultra-high field strength. Ultra High Field MRI Symposium, Centre for Advanced Imaging, University of Queensland, Brisbane 2014. ҩҩ Alan Connelly - Recent advances in diffusion MRI analysis methods.

Siemens ANZ MR R&D User Group Meeting, Brisbane, 2014. ҩҩ Fernando Calamante - Perfusion: Finding Flow. Case-based Session “Thinking Outside the Black Box: A Self-Help Guide to NeuroImaging Analysis”. The International Society for Magnetic Resonance in Medicine (ISMRM) Annual Meeting, Milan, Italy, 2014.

COLLABORATIONS In addition to a range of collaborations within the Florey, the Advanced MRI Development group has both national and international collaborations with a wide range of institutions, including: ҩҩ Universities of Adelaide, Queensland, Sydney, and Melbourne ҩҩ Murdoch Childrens Research Institute ҩҩ Royal Women’s Hospital Melbourne ҩҩ CSIRO, Brisbane

ҩҩ University College London ҩҩ Kings College London ҩҩ Stanford University, USA ҩҩ Karolinska Institute, Stockholm, Sweden ҩҩ Leiden University, Germany ҩҩ George Mason University, Washington DC ҩҩ Neuroscience Research Institute, Incheon, S Korea ҩҩ Max Planck Institute, Leipzig, Germany ҩҩ University of Antwerp, Belgium ҩҩ KU Leuven, Belgium

Pictured : Dr Jennifer Walz.

Introducing

ANIMAL MRI MAJOR NATIONAL AND INTERNATIONAL CONFERENCES 2014 INVITED PRESENTATIONS

ҩҩ David Wright - An MRI Study of Repeated Concussion, 13th Kushiro Neuroscience Workshop, Japan, 2014. ҩҩ Leigh Johnston - Compressed Sensing for Mouse Imaging, Sick Kids Hospital, Toronto, 2014.

COLLABORATIONS

ҩҩ CSIRO

ҩҩ Monash ARMI

ҩҩ Monash Institute of Medical Research ҩҩ Royal Women’s Hospital ҩҩ University of Melbourne

ҩҩ Neurological Institute of Radiological Science, Japan ҩҩ University of Freiburg, Germany ҩҩ University of Toronto, Canada

D

r Jennifer Walz has been with the Florey for a few months having completed her PhD in New York at Columbia University, specialising in biomedical engineering.

She brings a unique perspective of epilepsy to Graeme Jackson’s team of researchers. “I have deep insight from a patient’s perspective and as an engineer but until now, I haven’t had access to the clinical research side of the disease,” Jen says.

“The work I do involves simultaneous EEG and functional magnetic resonance imaging, which is a challenging and relatively new technique that most researchers still struggle to use.

There are experienced groups doing it in Montreal, UCL in London and in Seattle but when I heard about Graeme Jackson and the team in Melbourne, it was an easy decision to come. They have been successfully using these methods to study epilepsy for about 15 years.”

“I want to uncover the complex changes in brain networks that enable seizures to start, as well as those networks that prevent seizures from happening. If we could understand how these brain networks behave in individual patients, we could better cater treatments for each of them.”

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SCHIZOPHRENIA The relentless quest to find answers.

A

ssociate Professors Suresh Sundram and Elizabeth Scarr are researching one of the toughest mental illnesses to treat: schizophrenia. They hope to develop blood tests to identify those with the condition who are at risk of suicide, potentially reducing the terrible death toll within in this group.

As a young doctoral student, Elizabeth Scarr had the unusual opportunity to talk with people who suffered the disorders she was studying.

Elizabeth, then at the University of Saskatchewan in Canada, heard first-hand accounts of the huge impact schizophrenia, bipolar disorder and depression had on the lives of the people she met through the course. It was an eye-opener for the young neuropsychopharmacologist.

THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

“The brain bank is a huge resource – unparalleled in Australia – and the Florey also has access to technology platforms difficult to find elsewhere,” Suresh says.

Their investigations into a drug called clozapine are causing excitement.

Clozapine, first synthesised in 1959, is an anti-psychotic drug used to treat the 30 to 40 per cent of people with schizophrenia who don’t respond to other anti-psychotic medication. It also markedly reduces the rate of suicide among this group.

“I think that as a lab scientist you do get locked into your ivory tower, focussing on your little molecule of interest and you don’t have the opportunity to put it into context,” she says.

But clozapine, while highly effective, has potentially fatal side effects, including agranulocytosis, which severely reduces white blood cells, so is used only as a last resort.

It is perhaps little wonder then that Elizabeth later teamed up with psychiatrist Suresh Sundram, who heads the Northern Psychiatry Research Centre and who is also a scientific researcher.

The drug works by blocking receptors in the brain for several neurotransmitters including acetylcholine. Acetylcholine is thought to play a significant role in cognition – in learning, memory, understanding and in interpreting the outside world – factors that are profoundly changed in people with schizophrenia, Elizabeth explains.

The pair, who have collaborated on projects since the late ‘90s, are now working closely together at the Florey in a synergy they say gives them much greater capacity.

ACCORDING TO SURESH, 50 PER CENT OF PEOPLE WITH SCHIZOPHRENIA WILL ATTEMPT TO COMMIT SUICIDE AND 12 PER CENT WILL SUCCEED. THAT’S FIFTEEN TIMES THE GENERAL RATE OF SUICIDE IN THE POPULATION. “It’s rare that a basic scientist (one who doesn’t do clinical research) and a clinician can work together as closely as we do,” says Suresh.

They are combining clinical information with findings made through test-tube research and by investigating postmortem brain tissue from the Victorian Brain Bank Network at the Florey.

could be used in other medications – without the harmful side effects. Such medication would improve the overall symptoms of schizophrenia, enhancing the individual’s quality of life, says Elizabeth.

The researchers are also using clozapine as a tool to try to discover what’s wrong with the brains of people with schizophrenia.

“The bottom line with psychiatric disorders is there’s no objective test that says ‘this means you have this or that disorder’,” says Suresh. “There’s no abnormality in blood tests or lesions in the brain that can point to a disorder,” he says.

“What that means is that we’re all essentially floating around in the dark trying to identify the pathology.”

“But now we’re shining a little flashlight!” says Elizabeth.

Using post-mortem brain tissue, they are trying to discover markers in the blood that identify people with schizophrenia who are at risk of suicide.

The pair has investigated the neurostransmitter, and a receptor responsible for attracting it into cells, since 2000.

“If we can actually identify this abnormality when people first become sick with this disease, we can treat them better and potentially prevent them from killing themselves, which would be a sensational step forward.”

“What’s exciting is that there are drugs being developed now as a result of our work that target that particular muscarinic receptor – they’re probably going to be tested in humans in the next two or three years,” says Elizabeth.

“We’re certainly hot on the lead of something we think is potentially important.”

These drugs have the potential to improve cognitive impairment, helping with memory, attention and planning, among other things.

Suresh and Elizabeth are currently exploring several new strands of research.

They are trying to tease out the properties that make clozapine so effective and investigate how these

Associate Professor Suresh Sundram

Blood tests might also identify the patients who are not going to respond to standard medications.

“If these people could be introduced to clozapine early in their illness then a lot

of the complications we see – the homelessness, the loss of jobs and relationships, crime, the drug use – all those problems could be ameliorated,” says Suresh.

The tests may later be useful for patients living with bipolar disorder or depression.

Suresh says research, and the constant concerns about funding that go with it, can be a struggle and that scientific outcomes are always uncertain.

“But the findings we’re taking forward have very strong grounding,” he says.

“For me, I look at the lives of these people and I’m going to keep on trying.”

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

OXIDATION BIOLOGY UNIT Leaders: Ashley Bush and Professor Robert Cherny

MENTAL HEALTH Leader: Professor Colin Masters

A QUICK SNAPSHOT

RESEARCH HIGHLIGHT

The Mental Health division encompasses research into the causes of neurodegeneration (Alzheimer’s disease, Parkinson’s disease and other related conditions) and the psychoses (including schizophrenia and mood disorders).

Research also extends into discovering biomarkers using longitudinal cohorts of volunteers who are prepared to be followed up over many years. This creates an environment rich in opportunities for drug discovery and development.

Why is one antipsychotic drug, clozapine, effective in people for whom other antipsychotic drugs are not?

Our novel finding that clozapine activated the epidermal growth factor (EGF) system in the brain has led us to investigate if this system is dysregulated in people with psychotic disorders. From this we hope to gain insight into the pathology of psychotic disorders and develop more effective ways of treating them.

PEOPLE LIKELY TO CHANGE LIVES BY 2035

“

What’s exciting is that there are drugs being developed now as a result of our work that target that particular muscarinic receptor – they’re probably going to be tested in humans in the next two or three years. These drugs have the potential to improve cognitive impairment, helping with memory, attention and planning.

” SENIOR STAFF

• Professor Kevin Barnham • Professor Ashley Bush • Professor Robert Cherny • Professor Brian Dean • Professor Colin Masters • Professor Catriona McLean • Associate Professor Suresh Sundram •

This group has a particular interest in uncovering the pathways that lead to a variety of neurodegenerative diseases, especially those pathways in which metal ions (such as zinc, copper and iron) interact with key target proteins. Studies of these pathways have led to new insights for drug therapies for Alzheimer’s disease and Huntington disease. In association with Prana Biotechnology, further drug developments for Parkinson’s disease are in preclinical development. The Oxidation Biology Unit also contains several laboratories including the Molecular Gerontology Laboratory (Dr Gawain McColl), the Synaptic Neurobiology Laboratory (Dr Paul Adlard), the Parkinson’s Laboratory (A/Prof David Finkelstein) and the Prana Biotechnology Research Laboratory (Prof Robert Cherny).

NEUROPATHOLOGY GROUP

Understanding the molecular basis of Alzheimer’s disease is the main focus of this laboratory. We aim to identify the specific conformer of the Aβ amyloid peptide which accumulates in Alzheimer’s disease brain. In both familial early onset Alzheimer’s disease (in which Aβ is over-produced) and in late onset sporadic Alzheimer’s disease (in which Aβ is poorly cleared from the brain), the same underlying process causes the synapses in the brain to degenerate. Based on this knowledge, we are able to seek biomarkers in the CSF and blood and to discover suitable lead compounds which can target the Aβ oligomer itself.

Leader: Catriona McLean

An essential component of research into both neurodegenerative disorders and psychotic illness is the provision of brain tissue from donors who have suffered from these afflictions. Thus Brain Banking is fundamental to our research programs.

Dr Udina Ratnayake was awarded a coveted Victoria Fellowship, taking her to the US to study schizophrenia at Massachusetts Institute of Technology. She is now using a revolutionary technique called CLARITY allowing simultaneous imaging of molecular markers and network structure in the intact brain.

Clinical research unit (DIAN and A4)

Translation of our research findings into clinical practice will become more important over the next five years, as we move from a series of failed or equivocal phase 3 drug trials sponsored by the pharmaceutical industry. There is now general agreement that these drug trials need to be based at the earliest possible stage of Alzheimer’s disease, hence our participation in the Dominantly Inherited Alzheimer Network (DIAN) and the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s disease (the A4 study).

These two pre-clinical trials are designed to administer drugs in the preclinical phases of both familial and sporadic Alzheimer’s disease. They are being coordinated by Dr Maree Mastwyk and Ms Lesley Vidaurre and are currently recruiting.

The NHMRC program in neurodegenerative disease

Also involves collaborators at the University of Melbourne: Prof Andrew Hill (Biochemistry and Molecular Biology), Prof Roberto Cappai (Pathology), Prof Steven Collins (Pathology) and Prof Anthony White (Pathology).

Leader: Colin Masters

THE AUSTRALIAN BRAIN BANK NETWORK

Professor Ashley Bush won the prestigious 2014 Victoria Prize for Science and Innovation in recognition of his outstanding contribution to translational neuroscience.

He is the most cited neuroscientist in Australia and is credited with discovering the importance of metals in degenerative disease, particularly Alzheimer’s. He is actively working to develop improved disease-modifying drugs, as well as being a practising psychiatrist.

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MEDICINAL CHEMISTRY GROUP Leader: Kevin Barnham

The Barnham Laboratory has expertise in Medicinal Chemistry (in association with Prana Biotechnology) and in biomarker discovery.

More recently, it has focussed on the pathways leading to Parkinson’s disease, especially around the oxidative modifications of tau.

The Australian Imaging, Biomarker and Lifestyle (AIBL) Study, the Dementia Collaborative Research Centres (DCRC) and the Cooperative Research Centre for Mental Health (CRCMH)

AIBL, DCRC and the CRCMH are intimately involved in our research programs, relying on patient cohorts for biomarker and imaging discovery in both neurodegenerative and psychotic illness.

These consortia involve other groups including Austin Health, Edith Cowan University, National Aging Research Institute, CSIRO, University of Melbourne, University of Western Australia, Mercy Health, Hall and Prior, Cogstate, and Pfizer.

AIBL and the CRCMH have the capacity to generate large data sets, and these are coordinated by Dr Noel Faux working with colleagues at CSIRO. Coordination of biomarkers in the Melbourne node is run

by Dr Alan Rembach, the imaging program is directed by Prof C Rowe at Austin Health, and the cognitive stream is coordinated by Prof Paul Maruff at Cogstate.

MOLECULAR PSYCHIATRY GROUP Leader: Brian Dean

Our group seeks to identify the changes in gene expression that contribute to the onset of schizophrenia, bipolar disorder, major depressive disorder and suicide. Our approach is based on the understanding that clinically definable psychiatric disorders occur in people with a genetic predisposition who have encountered as yet unknown environmental factors. This interaction between genes and environment is then known to affect gene expression by a variety of epigenetic mechanisms. As psychiatric disorders primarily affect the human CNS we have a strong focus on studying gene expression in the CNS of people with psychiatric disorders and those who have died by suicide. On identifying changes in gene expression we then use an array of animal and cellular models to better understand the mechanisms that have brought about such a change in expression in the human CNS. Unlike some neurodegenerative disorders, some drugs have been developed that can be used to treat the symptoms in some people with psychiatric disorders, albeit with varying success. Therefore our group also seeks to understand the mechanisms of action of such drugs, which in the main remain obscure.

The major goal of the group, through the study of the pathophysiology of psychiatric disorders and suicide, as well as the mechanisms of action of psychotropic drugs, is to generate information that may point to new potential drug targets that will either improve outcomes in currently treatment responsive treatment and / or lead to the development of drugs that will be effective in currently treatment resistant people.

Importantly, our group has formed a seamless collaboration with the psychiatric neuropathology laboratory headed by Associate Professor Elizabeth Scarr and with the laboratory of Professor Ian Everall, both at the University of Melborune, to form the Parkville Psychoses group. This grouping ensures we have a coordinated approach to understanding how changes in gene expression in human can cause psychiatric disorders.

MOLECULAR PSYCHOPHARMACOLOGY AND NORTHERN PSYCHIATRY RESEARCH CENTRE Leader: Suresh Sundram

The Molecular Psychopharmacology laboratory is dedicated to understanding the molecular pathology of psychotic disorders such as schizophrenia, bipolar disorder and major depression. It aims to develop better and more effective markers and interventions for these illnesses. We do this by investigating how psychotropic

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medications and drugs interact with receptors and intracellular signalling mechanisms in nerve cells (neurons).

The understanding gained from this work can then be tested in clinical populations through the Northern Psychiatry Research Centre (NPRC) leading to the development of new treatments and markers. Moreover, the NPRC can collect clinical material and biological samples that can be examined in the laboratory to better understand these disorders.

CLINICAL RESEARCH GROUP Leader: Dr Alan Rembach (until November 20, 2014) and Dr Christopher Fowler

The Clinical Research Group (CRG) collects research data and stores biospecimens from human participants involved in neurodegeneration and healthy ageing studies.

The multi-disciplinary team includes biomarker researchers, neuropsychologists, research nurses, neuro imaging specialists and bioinfomaticians.

The group is currently involved in:

ҩҩ Australian Imaging, Biomarkers and Lifestyle (AIBL) Flagship Study of Ageing; ҩҩ AIBL Active (exercise intervention trial) ҩҩ the CRC for Mental Health

ҩҩ the Dementia Collaborative Research Centre (DCRC) - Early Risk Diagnosis and Prevention.

ҩҩ the Dominantly Inherited Alzheimer’s Network (DIAN) study; ҩҩ the Rates of Change in Cognition (ROCS) study; ҩҩ the Older Australian Twin Study (OATS);

ҩҩ the Woman’s Healthy Aging Project (WHAP); ҩҩ the A4 study.

Translation of our research findings into clinical practice will become more important over the next five years, as we move from a series of failed or equivocal phase III drug trials sponsored by the pharmaceutical industry.

There is now general agreement that these drug trials need to be based at the earliest possible stage of Alzheimer’s disease, hence our participation in the Dominantly Inherited Alzheimer Network (DIAN) and the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s disease (the A4 study). These two pre-clinical trials are designed to administer drugs in the preclinical phases of both familial and sporadic Alzheimer’s disease.

THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

NORTHERN PSYCHIATRY RESEARCH CENTRE

CLINICAL DISCOVERY UNIT

PERSONNEL AND COLLABORATIONS

ҩҩ Head: Associate Professor Suresh Sundram MBBS, MMed, FRANZCP, PhD ҩҩ Senior research physician: Dr Russell D’Souza MPM, MD ҩҩ Research coordinator: Fiona Bole RN ҩҩ Research nurse: Sumathy Sathiyamoorthy RN (Div II) ҩҩ Research physicians: Dr Rohit Lodhi MD, MRCPsych, FRANZCP and Dr Manish Sharma MD ҩҩ PhD student: Jody Stanley ҩҩ Postgraduate students: Daniel Bennett and Amy Dluzniak ҩҩ Advanced medical sciences (AMS) student: Zexi Allan COLLABORATIONS ҩҩ ҩҩ ҩҩ ҩҩ ҩҩ ҩҩ ҩҩ ҩҩ ҩҩ ҩҩ ҩҩ ҩҩ ҩҩ ҩҩ ҩҩ ҩҩ ҩҩ ҩҩ ҩҩ ҩҩ ҩҩ ҩҩ ҩҩ

Professor Michael Berk (The University of Melbourne) Dr Olivia Carter (The University of Melbourne) Dr Gursh Chana (The University of Melbourne) Dr Peter Crouch (The University of Melbourne) Professor Brian Dean (Mental Health Research Institute) Dr Seetal Dodd (The University of Melbourne) Professor Ian Everall (The University of Melbourne) Dr John Farhall (La Trobe University) Ms Marnie Graeco (Northern Hospital) Professor Brenda Happell (Central Queensland University) Ms Alison Harrington (Northern Area Mental Health Service) Dr Alexander Holmes (The University of Melbourne) Dr Ana Hutchinson (Northern Clinical Research Centre) Dr Nigel Jones (The University of Melbourne) A/Professor Gerard Kennedy (Victoria University) Dr Ken McAnally (Defense Science Technology Organization) Professor Ralph Martins (Edith Cowan University) Professor Terence O’Brien (The University of Melbourne) Dr Meaghan O’Donnell (The University of Melbourne) Dr Elizabeth Scarr (The University of Melbourne) Dr Elizabeth Thomas (Scripps Institute, USA) Professor Cyndi Shannon-Weickert (Neurosciences Australia) Dr Anthony White (The University of Melbourne)

Leader: Professor Michael Berk

A QUICK SNAPSHOT

RESEARCH HIGHLIGHTS

2014 was another productive year for the partnership between the Clinical Discovery Unit and the IMPACT Strategic Research Centre at Deakin University. The quality and quantity of our research output continues to grow with 145 (plus potentially more to be added) publications in 2014 including a number of high impact publications in the top journals in the field, including Molecular Psychiatry, Lancet Psychiatry, The American Journal of Psychiatry and The British Journal of Psychiatry.

The principal research focus of the unit is the discovery and implementation of novel therapies. The enduring partnership between the Florey and the IMPACT Strategic research centre continues actively. Following on our early projects showing the efficacy of N-acetyl cysteine in schizophrenia and bipolar disorder, we have recently published two studies showing the efficacy of N-acetyl cysteine in depression, as well as in smoking cessation.

A large number of follow-on studies of N-acetyl cysteine are planned and will be submitted to the current NHMRC funding round. Together with the CRC for Mental Health we continue to leverage the new understanding that bipolar disorder is associated with fundamental dysregulation in mitochondrial energy generation. We are completing a first-in-kind study of mitochondrial agents in the treatment of bipolar depression. In all of these studies, we aim to look at biomarker mediation and moderation to explore target engagement. This approach is concordant with the NIH mandated RDoC philosophy.

OUR FUNDING

The unit is supported by a number of funding bodies.

These include a NHMRC senior principal research fellow, three NHMRC project grants, NHMRC Targeted Call for Research grant, NHMRC CRE, CRC grant, one NIH R34 grant, two Stanley Medical Research Institute grants, a Simons Autism Foundation grant, two Rotary Health Grants and a National Natural Science Foundation of China grant.

The SRC continues to develop strong collaborative links with health service providers including: Barwon Health; research centres within Deakin including PRADA, Centre for Molecular and Medical Research, Centre for Mental Health and Wellbeing, Centre for Science, Engineering and Built Environment and Deakin Population Health; and multiple international partners in countries including the US, Brazil, Denmark, Portugal, Canada, Thailand, Spain and China. We would like to thank Deakin University and Barwon Health for their continuing support.

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

PSYCHOTROPIC DRUG ADVISORY SERVICE

VICTORIAN BRAIN BANK NETWORK Leader: Professor Catriona McLean

Leader: Associate Professor Suresh Sundram

A LITTLE ABOUT US

T

he Psychotropic Drug Advisory Service (PDAS) is an independent source for information on medicines used to treat mental illnesses and other drugs that affect the way we think, feel and behave. Service users include public mental health services, individuals, medical practitioners, health care professionals, mental health care support organisations and their staff, carers and consumers. Though predominantly telephone based, the service is also accessed via email and facsimile. The service responds to approximately 2000 enquiries each year. Associate Professor Suresh Sundram heads the unit and provides clinical support to pharmacist Christine Culhane who manages the service. We would like to take the opportunity to thank Professor Nicholas Keks for his long involvement as head of the unit and as an ongoing clinical support. Funding is provided by the Department of Human Services Victoria, Mental Health Division and is auspiced to the Mental Health Research Institute.

HIGHLIGHTS

PRESENTATIONS

Each year many people, young and old, are diagnosed with a mental illness. For some, psychosocial interventions adequately control their symptoms. Others will require biological treatments which include medications. Many do not fully understand the implications of the treatments or their role in managing their disorder despite the provision of this information by their prescriber or other healthcare professionals. Others wonder about what to expect from their medication: their benefits, side effects and the possibility of interactions with other medications they may be taking. This service provides a forum for discussion of prescribed medication that is timely and tailored to the needs of the caller. People have the opportunity to talk about their medication concerns in a confidential setting and receive current information.

Presentations to both professional and consumer groups are also part of the work undertaken by the service.

This is also an important service for carers of people with a mental illness who are concerned about the effects of these drugs on the person with the illness. The service can answer the questions of carers regarding the potential benefits of medications, adverse effects, safety and tolerability and possible interactions with other medications. Enquiries from the general public are nearly half of those recorded by the service.

A range of health care professionals also utilise this service: psychiatrists, other medical practitioners, health care professionals including nurses, pharmacists, psychologists and dieticians, as well as researchers. Electronic databases allow many professionals to research some of their own queries making their calls to PDAS when the clinical situation is complex or to gain extra insights when there are new medications or other complications involved. The provision of this information to service providers allows them to best manage the changing needs of their clientele.

This service also provides vital information for practitioners and consumers who reside or practice in rural or remote communities as they may not have the immediate resources to provide this extra information.

Presentations have been requested by and provided to a number of professional and lay audiences. Christine has ongoing involvement with The Delmont Hospital Psychopharmacology Master classes with Professor Nicholas Keks and Dr Judy Hope. These forums are held twice each year to update the knowledge of practicing psychiatrists and trainees. Tutorials and online discussions for undergraduate and post graduate pharmacists have also been provided.

Christine has also been to a number of carer and consumer support organisations to provide information on medications in a patient sensitive forum.

PROFESSIONAL DEVELOPMENT

The Psychotropic Drug Advisory Services provides a much needed source of specialised information to the broader mental health community in Victoria. Its value is measured by consistency of enquiry numbers and timeliness of responses.

In order to provide the best available information, professional development activities are undertaken including the requirements for continued registration as a pharmacist as well as attending psychiatry and pharmacy specific congresses and symposia.

HIGHLIGHTS

The Victorian Brain Bank Network collects, processes and stores post-mortem human brains and related samples from individuals who have had neurological diseases (e.g.

Alzheimer’s disease, motor neurone disease and Parkinson’s disease), psychiatric disorders (e.g. bipolar mood disorder, depression and schizophrenia) as well as normal ‘control’ cases. We facilitate research into the study of brain diseases by providing tissue to researchers who aim to unlock our understanding of how brain diseases occur. This will lead to improvements in diagnosis, early diagnostic tests, therapeutic interventions and ways to prevent brain disease.

We provide a vital and unique neuropathological diagnostic service that confirms a ante-mortem clinical diagnosis, increases clinicians’ awareness and understanding of atypical presentations of certain brain diseases, confirms a diagnosis for donor families, in whom neurological disease may have hereditary or familial association and may be at risk of developing the disease, generates pathological description of brain diseases and advances knowledge of some brain pathologies, thus providing a powerful tool for education and research and importantly, this service is relied on for the validation of research studies.

ACKNOWLEDGMENT

We would like to acknowledge the generosity shown by the donor and donor families in donating tissue to the brain bank. It is an act of great foresight and kindness to give at a time of loss, so that others may be helped in the future.

The clinicians and researchers who benefit from these donations are very grateful to the donors and their families who support them in these decisions.

BRAIN AND BRAIN/ SPINAL CORD DONATIONS The brain bank has a total of 1,050 cases available for research, with 59 new donations received in 2014. The new donations included cases diagnosed with Alzheimer’s disease, Frontotemporal dementia, Huntington’s disease, Lewy body disease, motor neurone disease, multiple sclerosis, Parkinson’s disease, schizophrenia, and control ‘normal’ cases.

TISSUES PROVIDED TO RESEARCHERS During 2014, we provided tissue to 47 Australian and international new or continuing research projects, with the main research focus being Alzheimer’s disease, motor neurone disease, schizophrenia and bipolar disorder. This equates to 3,199 diseased and ‘control’ samples being provided to researchers.

Research groups at the Florey are among the recipients of this tissue as well as research groups at Monash University, The University of Melbourne, La Trobe University, University of Wollongong NSW, Lund Univeristy Sweden, Chungbuk National University Korea and Kyungpook National University Korea.

During 2014 research using tissue from the brain bank resulted in 50 Australian and International publications and presentations.

NEW FUNDING OBTAINED Parkinson’s Victoria $7,500 (2014) In memoriam donations $1,033

We would like to acknowledge the support of the following funeral directors, Bethel, Jensen, Allison Monkhouse, Le Pine, Nelson Brothers, Tobin Brothers and WD Rose & Joseph Allison who provide metropolitan transfers for tissue retrieval at no cost to the brain bank.

SENIOR STAFF

HEAD Professor Catriona A McLean BSc, MBBS, FRCPA, MD, FFSc (RCPA) DIRECTOR Professor Brian Dean HND ApplBiol, MSc, PhD, Fl Biol

CONSULTANTS Professor Colin Masters BMedSc (Hons), MBBS, MD, HonDLitt WAust, FRCPath, FRACPA, FAA, FTSE Associate Professor Suresh Sundram MBBS, MMed, FRANZCP, PhD

COORDINATOR Ms Fairlie Hinton RESEARCH ASSISTANT Mr Geoff Pavey BSc (Hons) CONSULTANT HISTOLOGIST Dr Ian Birchall BAppSc, MSc, PhD

COLLABORATIONS

• Laboratory Manager and Mortuary Technicians, The Alfred • Pathologists and Mortuary Technicians at the Victorian Institute of Forensic Medicine • Ballarat Health Services, Bendigo Health, Royal Hobart Hospital and Launceston General Hospital • Transplant and Family Liaison Coordinators at the Donor Tissue Bank of Victoria •

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

OLIGODENDROCYTE BIOLOGY AND NEURONAL-GLIAL INTERACTIONS GROUP

MULTIPLE SCLEROSIS

Leader: Toby Merson

Leader: Professor Trevor Kilpatrick

The Merson laboratory investigates the life cycle of myelinating glial cells in the nervous system, in particular how they are generated during development, how they are regenerated after injury and their role in supporting the function of axons.

Research highlights for 2014

A QUICK SNAPSHOT

Multiple Sclerosis is the commonest neurodegenerative disease affecting young adults in our community. It is a complex disease that involves disrupted interactions between the immune and nervous system, resulting in the demyelination and loss of nerve cells. Our division focuses on novel ways to manipulate immune activation and to protect the nervous system to limit this damage as well as to develop new ways to repair damage.

RESEARCH HIGHLIGHT

RESEARCH OVERVIEW

A major highlight of our work in 2014 was the discovery

by Dr Toby Merson and his team that different types of nervous system precursor cells remyelinate the brain in different ways in response to a demyelinative insult.

This result indicates that it is now critically important to interrogate the functional consequences of these differences and, therefore how the differences influence the extent of recovery and to determine how the differences can be exploited for therapeutic benefit.

Multiple sclerosis has a variable course, with outcomes ranging from negligible to severe disability. Both the cause of the disease and the determinants of disease severity remain uncertain. The MS division, with strong collaborative interaction extending into the University of Melbourne and the Royal Melbourne Hospital, is adopting a multifaceted approach to researching the disease. Our approach focuses on understanding the genetic determinants and molecular drivers of MS. Our laboratory work has provided novel and important insights into how to promote nervous system repair, in particular remyelination; this understanding has been assisted via our research that has focussed on how myelinating cells and their precursors behave during both development and in the healthy adult, as well as in disease.

Our work has also provided important insights into how the immune cells in the brain interact with the myelinating cells during disease, thereby identifying approaches that have therapeutic potential.

AN IDEA LIKELY TO CHANGE LIVES BY 2035

We aim to identify and use novel treatments to prevent patients from developing progressive multiple sclerosis.

“

Our work has identified novel ways to reduce the burden of MS by either protecting the nervous system from damage or by promoting its repair.

” SENIOR STAFF

• Prof Trevor Kilpatrick • Dr Toby Merson • Dr Ben Emery • Dr Judith Field • Dr Michele Binder • Dr Andrew Fox • KEY COLLABORATORS FROM THE UNIVERSITY OF MELBOURNE:

• Dr Holly Cate • Dr Simon Murray • Dr Junhua Xiao • Dr Scott Kolbe • A/Prof Helmut Butzkueven • Dr Tomas Kalincik • A/Prof Owen White •

We continue to focus on how our preclinical work can be translated into the clinical environment for it to directly benefit people with MS. With this in mind, we continue to collaborate actively with colleagues throughout Australia to interrogate the genetics, epidemiology and pathogenesis of MS, in this way clarifying that our laboratory results are directly pertinent to the human disease.

Research in the Merson laboratory has revealed the major contribution made by neural precursor cells (NPCs) during oligodendrocyte regeneration following demyelination of CNS white matter. PhD student Lulu Xing has demonstrated that neural precursor cells (NPCs) that are normally involved in the production of neurons in the adult brain are recruited in large numbers into demyelinated white matter.

Published recently in the Journal of Neuroscience, we revealed that NPCs produce large numbers of oligodendrocytes that remyelinate broad territories of demyelinated white matter. In anterior regions of the brain the contribution made by NPCs exceeds that by oligodendrocyte progenitor cells (OPCs), cells previously attributed as the principal cell type responsible for myelin regeneration. We also made the important discovery that the quality of myelin made by oligodendrocytes depends upon the progenitor source. Remarkably, NPC-derived myelin is thicker than that produced by white matter OPCs and more closely reflects healthy myelin. These findings suggest that the cellular and molecular processes leading to regeneration of myelin from NPCs could result in better restoration of function to demyelinated axons than can be achieved by OPCs. Research conducted by PhD student Philipp Röth has further clarified the mechanisms underlying the generation and organisation of oligodendrocytes in white matter. Developmental analyses have revealed that postnatal myelination is preceded by the emergence of linear arrays of oligodendroglia whose cell bodies align with the axis of nerve fibre tracts. We have shown that complex cellular dynamics underlie linear array formation and that these mechanisms are largely reinstated during the process of remyelination. The work has stimulated us to rethink how myelination and neuronal activity could be coordinately regulated. The topographical organisation of oligodendrocytes into the glial networks that we have described, potentially explain how signals emanating from axons and acting upon single oligodendroglia could become amplified to facilitate broad-scale regional changes in myelination.

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Awards and research grants

PhD student Lulu Xing was awarded a Life Technologies/Florey Student Travel Prize and Melbourne Abroad Travelling Scholarship to attend the Cold Spring Harbor Laboratories Meeting on Glial Cells in Health and Disease. Lulu’s abstract was selected for oral presentation at the meeting. PhD student Philipp Röth was awarded a travel grant from the French Multiple Sclerosis Research Foundation (ARSEP) to undertake a two-month research project in the laboratory of Prof.

Catherine Lubetzki at L’Institut du Cerveau et de la Moelle Épinière, Hôpital de la Salpêtrière, Paris. This cemented an emerging collaboration between the laboratories of Dr Merson and Prof. Lubetzki.

During his stay Philipp learned techniques to enable long-term slice culture and real-time imaging of myelination in vitro. Applying this technique in Melbourne will allow him to pursue exciting new approaches to examine oligodendrocyte development in real time.

Dr Merson was the recipient of the following research grants in 2014: ҩҩ NHMRC project grant: Prevention of axonal pathology in early Multiple Sclerosis (APP1066199). TD Merson, TJ Kilpatrick; $655,558; 2014-16. ҩҩ NHMRC project grant: Functional Neurogenesis in the Injured Neocortex of the Nonhuman Primate (APP1057698). Bourne JA, Merson TD, Young KM; $935,558; 2014-16. ҩҩ CASS Foundation project grant: A new approach to prevent loss of neuronal function in Multiple Sclerosis. Merson TD; $48,000; 2014.

MYELIN DEVELOPMENT AND ITS APPLICATION TO DEMYELINATING DISEASE GROUP Leader: Ben Emery

The Emery laboratory focuses on understanding the key events that regulate the expression of myelin genes. In particular, the laboratory is focusing on a gene known as Myelin Regulatory Factor (Myrf) that Ben Emery and his collaborators have previously discovered to be vital for the generation of myelin during development.

Research highlights for 2014

We recently published the finding that Myrf is a novel example of a membrane-associated transcription factor, requiring a cleavage event to free it from the membrane and enable it to function as a transcription factor. Using ChIP-Seq techniques we were able to map the binding

During 2014 we have also developed a collaborative interaction with the Monash Institute of Pharmaceutical Sciences in order to scope the feasibility of developing therapeutic approaches targeting the activity of key molecular drivers of demyelinating disease that we have identified. Our collaborative work focusing on patients at the Royal Melbourne and Box Hill hospitals has also allowed us to develop new paradigms by which to assess the severity of the disease, which includes approaches focusing on imaging, eye movements and novel biomarkers in blood. These developments are important preambles to approaches that will ultimately focus on assessing the efficacy of new treatment paradigms involving either neuroprotection or remyelination.

Many oligodendrocytes that regenerate following experimental demyelination are born in the neural stem cell niche of the adult brain. Green cells depicted in the image derive from neural precursor cells (NPCs) born in the subventricular zone (SVZ) of the adult mouse brain. After demyelination newborn oligodendroglia generated from the NPC lineage are visualised as white oligodendrocyte progenitor cells (magenta+green) and yellow oligodendrocytes (red+green).

Visualisation of linear glial cell arrays within the white matter of a juvenile mouse brain. Contrary to the commonly held view, these linear arrays are comprised of various glial cell types. Oligodendrocytes, identified by their green Sox10 expressing nuclei, are most abundant. But astrocytes are also present within these liner arrays, visualised here by expression of the glial fibrillary acidic protein (GFAP, red).

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of the activated transcription factor to the genome, thus identifying the genes that it targets to promote myelination.

These findings were published in the prestigious journal Plos Biology, back-to-back with the complementary findings of another group.

Another 2014 highlight was a collaboration with Prof Bill Richardson’s laboratory at University College London, who have used our mice as a tool to demonstrate that ongoing myelination in the adult brain is required for types of motor learning (published in Science). Our current research is focussing on trying to understand how to stimulate both the expression and activity of Myrf to promote myelin repair in human diseases.

influences cells that are critical regulators of antigen presentation and, in consequence that it is an important regulator of autoimmune inflammatory demyelination. A second receptor in this family has been shown to directly influence the capacity of oligodendrocytes to myelinate neurones. We have shown that the expression of one of the key ligands of these receptors is supressed in a subset of patients with multiple sclerosis and that it could serve as a severity marker of the disease. We are currently also exploring strategies that involve modulation of TAM receptor activity to determine whether this might be a viable strategy to limit disease severity.

Leader: Judith Field

Leader: Trevor Kilpatrick, Michele Binder and Judith Field

We continue to study an important set of three receptors (the TAM family) that is expressed on both immune cells and oligodendrocytes in the brain and which influence both the susceptibility to and the severity of demyelinating disease. We are currently exploring how these receptors and their ligands influence cellular behaviour in order to both limit the extent of demyelination and enhance the capacity for remyelination.

Research highlights for 2014

We recently published the finding that Myrf is a novel example of a membrane-associated transcription factor, requiring a cleavage event to free it from the membrane and enable it to function as a transcription factor. Using ChIP-Seq techniques we were able to map the binding of the activated transcription factor to the genome, thus identifying the genes that it targets to promote myelination. These findings were published in the prestigious journal Plos Biology. Our prior research in this area identified that animals deficient in one of the TAM ligands (Gas6) exhibit worse disease when demyelination within the nervous system is induced.

Work currently being undertaken by PhD students, Gerry Ma and Rainer Akkermann is exploring how this occurs; in particular, whether TAMs exert their beneficial effects by influencing immune cell activation in the periphery or within the central nervous system, and which of the three receptors is predominantly responsible for exerting each of these effects. We have found that one of these receptors

OLIGODENDROCYTE BIOLOGY AND NEURONAL-GLIAL INTERACTIONS GROUP

Dr Judith Field and colleagues continue to focus on key genes that have recently been implicated in the susceptibility to multiple sclerosis. Particular areas of interest include understanding how these genes function, whether perturbations in particular genes might define subsets of people with MS and whether these or other genes are also important determinants of disease severity. In 2014 the work has also extended, in collaboration with Dr Andrew Fox, to establishment of ways to identify the signatures of gene methylation that are expressed by particular subsets of immune cells isolated from whole blood which are key determinants of molecular expression and to determine how these signatures are influenced

by MS. Research highlights for 2014

Research into the genetic contribution to the development of MS within the Multiple Sclerosis Division continues in collaboration with the ANZgene Consortium. Our work also continues to refine the genetic risk association within the TAM receptor gene MERTK, and also the role that the TAM genes play in demyelinating disease.

Importantly, the genetic changes in MERTK that lead to increased risk of developing MS have also been shown to influence the level of the MERTK gene in key immune cells in the blood.

This work has allowed us to identify gene expression and protein expression changes of potential functional significance, including the CD40 costimulatory molecule, which is expressed on both lymphocytes and monocytes as well as their progeny and which is likely to be key to the pathogenesis of MS.

ҩҩ Editorial board of Frontiers in Neuroanatomy, International Journal of Stem cell Research & Therapy; Journal of Stem Cell Research & Regenerative Medicine.

PRESENTER

ҩҩ Merson TD. “The role of remyelination in progressive MS”. 7th Congress of the Pan-Asian Committee for Treatment and Research in Multiple Sclerosis (PACTRIMS). Nov 6-8, 2014; Taipei, Taiwan.

(Invited platform presentation) ҩҩ Merson TD. “Stem Cells in Multiple Sclerosis and Neurological Disease”. MS Research Australia/NSW Stem Cell Network joint workshop, May 28, 2014; Sydney, NSW. (Invited oral presentation) ҩҩ Xing YL, Röth PT, Stratton JAS, Ellis SL, Chuang BHA, Ng SW, Kilpatrick TJ and Merson TD. “Myelin regeneration by precursor cells in the adult central nervous system” ComBio Meeting, 28th Sept – 2nd Oct 2014; Canberra, Australia. (Invited symposium presentation) ҩҩ Xing YL, Röth PT, Stratton JAS, Chuang BHA, Ng SW, Kilpatrick TJ, Merson TD. “Adult neural precursor cells from the subventricular zone contribute significantly to oligodendrocyte regeneration and remyelination”. 34th Annual Meeting of the Australian Neuroscience Society, 28th-31st January 2014; Adelaide, Australia.

(Invited symposium presentation) ҩҩ Merson TD, Chuang BHA, Kilpatrick TJ, Röth PT. “Cellular dynamics underlying the generation of linear arrays of oligodendrocytes in CNS white matter”. 44th Annual Meeting of the Society for Neuroscience, 15th-19th November 2014; Washington, DC, USA. (Poster presentation) ҩҩ Xing YL, Röth PT, Stratton JAS, Ellis SL, Chuang BHA, Ng SW, Kilpatrick TJ, Merson TD. “Neural precursor cells outcompete oligodendrocyte progenitor cells to remyelinate broad regions of the rostral corpus callosum” Glia in Health & Disease - Cold Spring Harbor Laboratory, July 17-21, 2014; New York, USA. (Selected for oral presentation) ҩҩ Röth PT, Stratton JAS, Xing YL, Chuang BHA, Kilpatrick TJ, Merson TD. “The cellular mechanisms underlying the generation of oligodendrocyte linear arrays in white matter”. 9th FENS Forum of Neuroscience, July 5-9, 2014; Milan, Italy. (Poster presentation).

COLLABORATIONS

Promotion of myelination in cell culture. Dorsal root ganglion neurons were isolated from one day-old Sprague-Dawley rats and cultured for 14-21 days. Oligodendrocyte precursor cells were then isolated from 5 day-old C57Bl/6 mice and grown on top of the neurons for 14 days to allow these cells to differentiate into mature oligodendrocytes and produce myelin sheaths that wrap the axons of the neurons.

The cells were fixed and subsequently stained for Myelin Basic Protein (red) and Neurofilament (green) to highlight the myelin sheaths and axons, respectively.

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NEUROIMMUNOLOGY GROUP EDITORIAL POSITIONS

EDITORIAL POSITIONS

MAJOR NATIONAL AND INTERNATIONAL CONFERENCES 2014 MS GENETICS GROUP

NEUROIMMUNOLOGY GROUP

THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

ҩҩ A/Prof. James Bourne (Australian Regenerative Medicine Institute, Monash University) ҩҩ Dr Kaylene Young (Menzies Research Institute for Medical Research, University of Tasmania) ҩҩ Prof James Wiley and Dr. Ben Gu (Florey Institute of Neuroscience and Mental Health) ҩҩ Prof Linda Richards (Queensland Brain Institute, University of Queensland) ҩҩ Prof Bill Richardson (University College London, UK) ҩҩ Prof Catherine Lubetzki (L’Institut du Cerveau et de la Moelle Épinière, Hôpital de la Salpêtrière, Paris.

ҩҩ Therapeutic Advances in Neurological Disorders (International Journal) (2008-) ҩҩ Experimental Neurology (International Journal) (2011-) MAJOR NATIONAL AND INTERNATIONAL CONFERENCES 2014 TREVOR KILPATRICK

ҩҩ Invited plenary speaker at ANS 2014 – Lawrie Austin Lecture, Adelaide, February 2014 ҩҩ Invited speaker at the 11th World Congress of the Society for Brain Mapping and Therapeutics 2014, Sydney, March 2014. ҩҩ Invited speaker at the endMS Research and Training Network, Alberta, Canada, April 2014 ҩҩ Invited speaker at Department of Clinical Neurosciences, University of Calgary, Canada, April 2014. ҩҩ Invited speaker at 20th Stem Cell Network Workshop, ‘Stem Cells in Multiple Sclerosis and Neurological Disease’. Sydney, May 2014. ҩҩ Invited keynote speaker at The University of Queensland, Advanced Imaging in MS Meeting, Brisbane June 2014. ҩҩ Invited speaker at the Neuropsychiatric Diseases Symposium 2014, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, August 2014. ҩҩ Invited speaker at John Curtin School of Medical Research Seminar Series, ANU, October 2014. ҩҩ Invited Chair of ‘MS Genetics’ session at PACTRIMS Taiwan, November 2014.

COLLABORATIONS

ҩҩ Greg Lemke, The Salk Institute for Biological Studies. ҩҩ Jonathan Baell, Monash Institute of Pharmaceutical Sciences.

MS GENETICS GROUP COLLABORATIONS

ҩҩ Assoc Prof Helmut Butzkueven, Department of Medicine, University of Melbourne ҩҩ Assoc Prof David Booth, University of Sydney ҩҩ Prof Jim Wiley, Florey Institute of Neuroscience and Mental Health ҩҩ ANZgene Consortium ҩҩ The International Multiple Sclerosis Genetics Consortium ҩҩ Phil Hodgkin, The Walter and Eliza Hall Institute of Medical Research.

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

“

I’m driven by a lifelong curiosity to understand how the nervous system works. Designing experiments to uncover the brain’s hidden mechanisms is a gratifyingly creative process.

Then there’s the thrill of seeing your hypothesis finally come to light. Sometimes months of work culminate in the blazing reality of seeing something down the microscope for the first time. This always brings a sense of excitement and anticipation. Sometimes this stirs delight, sometimes surprise and, at other times, angst.

Sharing this process of discovery with a team of likeminded students and colleagues is wonderfully motivating. I consider it a great privilege to be able to make this my career.

” Dr Tobias Merson Lab Head, Multiple Sclerosis Division.

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

HIGHLIGHTS FOR 2014

NEURODEGENERATION Leader: Professor Phil Beart

A QUICK SNAPSHOT

Scientists in the Neurodegeneration division interrogate how neurones live, die and can be rescued to improve brain function in degenerative conditions such as Parkinson’s and Motor Neuron Diseases. There is no effective treatment for Motor Neurone Disease (MND) and the incidence of Parkinson’s disease (PD) is rising alarmingly in our aging community. Gene abnormalities, energy deprivation, toxic rubbish accumulation and inflammation all contribute to a toxic environment for brain cells. Our teams study these events in animal models and cultured cells, with a view to translating knowledge into new therapies for human patients.

RESEARCH HIGHLIGHT

The brain contains much more than neurones and injury is followed by an inflammatory response that involves a population of glial cells, astrocytes, which proliferating locally and becoming reactive. This process is defensive and subsequently the astrocytic response supports repair and reconstruction of circuitry. Persistence of astrocytes in the “defensive” mode, often called glial scarring, limiting functional recovery. Scientists in our team have exciting signposts on how astrocytes can be persuaded to adopt a healthy phenotype supportive of the regenerative phase. Mature astrocytes maintained on 3 dimensional, engineered bioscaffolds display a healthy phenotype characterized by elevated trophic and anti-oxidant mechanisms, and display a stellated in vivo morphology. This technology and its application has potential uses in many brain pathologies. Ongoing work applies neuro-bioengineering to various cell types as a strategy to prevent damage spread in stroke, Parkinson’s disease and traumatic brain injury.

SENIOR STAFF

AN IDEA LIKELY TO CHANGE LIVES BY 2035

• Professor Philip Beart• Professor Malcolm Horne • Associate Professor Clare Parish • Dr Lachlan Thompson • Dr Tim Aumann • Dr Wah Chin Boon • Dr Brad Turner •

Plasticity of adult neurones continues to attract attention as Australian society ages. Florey scientists have evidence that the number of brain cells increase or decrease following drug administration and environmental stimulation in adult mice. New work with post-mortem human brains of people who died in mid-summer (long days) or mid-winter (short days) shows there were appreciably more dopamine neurones in summer than winter in the human midbrain.

The adult human brain is far more adaptable than previously thought, and given that dopamine is a “feel good” chemical, this might explain why our mood is elevated during summer. Environmental stimulation offers a unique way of keeping our brain healthy.

“

Our research has identified the putative “infectious particle” in MND, and we have imaged for the first time microscopic particles released by motor neurones, called exosomes, which may be responsible for intercellular spread of misfolded, toxic proteins in MND. Importantly, blocking these particles with antibodies halts the spread of misfolded proteins between cells, raising hope that this approach could potentially halt MND in its tracks.

”

Lachlan Thompson and Clare Parish continue to advance their impressive work on stem cell-based therapies for brain repair and recently have been investigated the capacity of neurones generated from human stem cells to survive and integrate after transplantation into the stroke-damaged brain. Not only do these neurones survive, but they are capable of an extensive degree of growth, including the re-formation of long-distance pathways related to motor circuitry.

Furthermore, the stem cell grafts also protect the host brain against the progressive degeneration that can result from an acute injury such as stroke. Thus the therapeutic strategy of stem cell grafting may have a neuro-protective benefit in addition to regenerative value by replacing pathways lost to injury.

Brain plasticity remains a topic of great interest and Tim Aumann and his team have continued their work on the plasticity of neurones and its relevance to the human brain. They recently analysed adult human brains of people who died in mid-summer (long days) or mid-winter (short days) and found four times more dopamine neurones in summer than winter in the human midbrain. Clearly the adult human brain is more adaptable than previously thought, and our environment can alter the amount of dopamine in our brains.

These findings support their hypothesis that the number of neurones exhibiting a particular neurochemistry is changing constantly depending upon our environment. Environmental enrichment works in many animal models of human neuropathology, so this new insight supports efforts to understand how neuronal chemistry can be manipulated to benefit function in various disorders, including Parkinson’s disease.

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removal mechanisms. If the load becomes too extreme or if the autophagic mechanisms become compromised, the process can become a form of programmed cell death. Most research into the controlling mechanisms has been performed in non-mammalian cells, so our work in primary neurones is groundbreaking. Damaged mitochondria also enter the autophagic cascade through a process termed mitophagy. We have found that disturbed energy generation causes mitochondria to lose their membrane potential with a concomitant drop in ATP production and entry into mitophagy. Since disturbed energetics underpins various forms of neurodegeneration, we believe that this cascade contributes to many degenerative conditions. We are currently investigating autophagy in other brain injury models.

Over many years our team has studied the neurobiology of astrocytes and made impressive advances in defining “good” or “bad” responses which relate to the state of inflammation in brain patholgies. By culturing mature astrocyes in 3D on bioscaffolds, we found a healthy astrocytic phenotype displaying reduced GFAP, and increased G-actin, glutamate transport, brain-derived trophic factor (BDNF) and anti-oxidant activity. These “signposts” guide current studies where a novel bioscaffold presenting sugar moieties has shown promise in minimising inflammation in studies performed in cultured astrocytes and in vivo in a model of traumatic brain injury. The ultimate goal is a safe, bio-injectable scaffold to prevent untoward glial scarring and to promote regeneration.

Sex hormones such as oestrogens and androgens also exert local effects by modulating neuronal function and Wah Chin Boon has shown the key enzyme, aromatase, is discretely localized in limbic brain regions involved in overt behaviours. Malcolm Horne continues his translational success with the Parkinson’s Kinetigraph system for measuring the motor symptoms, and disorders of sleep and impulse control in Parkinson’s disease. This development is now in routine clinical use in some 40 major Parkinson’s centres in Europe, Asia and Australia.

Dysfunctional energetics happens in most brain pathologies, and Brad Turner’s laboratory has unique insights that energetic stress occurs early in motor neurones of genetic mouse models of motor neurone disease (MND). An important energy-sensing kinase called AMPK is abnormal. Importantly, blocking an enzyme that controls AMPK activation called PP2A can restore AMPK function in cells.

This evidence suggests that therapeutic targeting of PP2A and AMPK could help correct defective energy metabolism in MND. Intracellular debris, be it damaged molecules, organelles or toxic aggregates, accumulates in all neurones during stress. Autophagy, a key mechanism for debris removal, is a key focus in the laboratory of Philip Beart. The focus is not only on its fundamental mechanistic aspects, but also on its therapeutic potential. Philip Beart, Brad Turner and Malcolm Horne, in a wide-ranging collaboration with interstate and international colleagues, are currently harnessing autophagy to combat motor neurone pathology in mouse models to evaluate its therapeutic potential in MND. This wide-ranging study has also revealed activation of various components of the brain’s inflammatory response in both astrocytes and microglia.

MOLECULAR NEUROPHARMACOLOGY GROUP Leader: Phil Beart

Pathological mechanisms affecting neurons and astrocytes, which have an interdependent relationship essential to brain health, are the focus of our laboratory. Diverse experimental approaches provide insights into how new strategies may be targeted to rescue threatened neurones and to establish a supportive environment near an injury zone.

Ageing or injured neurones accumulate damaged molecules and organelles which affect their function. This process is termed autophagy (“self-eating”) and represents one of the cellular rubbish

Three dimensional rendered image showing primary mouse astrocytes (GFAP in red, Hoechst in blue) at 22 days in vitro maintained on a poly-ε-caprolactone scaffold (white). Imaged using a Leica SP8 Confocal (scale bar = 10µm)(image credit Linda Lau).

NEURODEGENERATION GROUP Leader: Tim Aumann

In 2014 we furthered our research into plasticity of adult midbrain dopamine neurones. We had earlier shown that the number of these cells increases or decreases following drug administration and environmental stimulation in adult mice. This year we compiled the first evidence that this might occur also in the adult human brain. To test this we obtained human brains from the Edinburgh Brain Bank in Scotland of people who died in mid-summer (long days) or midwinter (short days). Research from our collaborators overseas had shown that adult rats exposed to long days have fewer hypothalamic dopamine neurones than those exposed to short days, and we thought this might extend to midbrain in humans (although the other way around because rats are nocturnal and humans diurnal).

Indeed we did find there were four times more dopamine neurones in summer than winter in the human midbrain. This indicates that the adult human brain is far more adaptable than previously thought, and that our environment can alter the amount of dopamine in our

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brains. Given that dopamine is a ‘feel good’ chemical, this might explain why our mood is elevated during summer. More importantly, our research findings indicate that environmental stimulation might be helpful in treating a number of diseases and disorders of the brain linked with midbrain dopamine imbalances, such as Parkinson’s disease, schizophrenia, attention deficit and hyperactivity disorder (ADHD) and drug addiction.

as neuritic outgrowth and connectivity in the developing brain. Our goal is to adapt key concepts in this area to the development of stem cell-based therapies for brain repair; a central focus is the generation of midbrain dopamine neurones from pluripotent stem cells for use in transplantation-based procedures for Parkinson’s disease. We are also working on similar approaches for other neurological conditions including MND and Huntington’s disease. In the stroke-damaged brain we have found these neurones are capable of an extensive degree of growth, including the re-formation of long-distance pathways related to motor circuitry. In addition to transplantationbased strategies, we are also exploring other novel avenues for brain repair including the use of viral vectors to deliver trophic factors that can protect neurones from injury or even promote ‘self-repair’ from the brain’s own stem cells.

THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

The Parish laboratory has also developed a successful programme in neural engineering. The team is developing and testing bioengineered scaffolds with recent success focusing on GDNF tethered to a bioscaffold, which holds significant potential to enhance brain repair.

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MOLECULAR NEUROPHARMACOLOGY GROUP MAJOR COLLABORATIONS NATIONAL:

ҩҩ Dr David Nisbet, Research School of Engineering, Australian National University. Bioengineering. ҩҩ Dr Hakan Mudyerman, Department of Biochemistry, Flinders University. Astrogliosis in MND. ҩҩ Dr Steve Cheung, School of Life and Environmental Sciences, Deakin University. Programmed cell death. ҩҩ Prof Phillip Nagley, Department of Biochemistry and Molecular Biology, Monash University. Programmed cell death. ҩҩ Prof Rod Devenish, Department of Biochemistry and Molecular Biology, Monash University. Autophagy.

INTERNATIONAL:

ҩҩ Prof Ulf Nilsson, Department of Chemistry, University of Lund.

Inhibitors of inflammation.

MAJOR NATIONAL AND INTERNATIONAL CONFERENCES 2014 PHILIP BEART - INVITED PRESENTATIONS

There are more dopamine neurones in the human midbrain in summer than in winter. Shown are sections through the human midbrain (at two different locations; rostral and caudal) that have been processed to colour dopamine neurones black (using two different markers of dopamine neurones; tyrosine hydroxylase (TH) and dopamine transporter (DAT). The 1st and 3rd rows are low-power images in summer and winter, respectively, and the 2nd and 4th rows are higher-power images of the areas outlined in rows 1 and 3, respectively. Note the many more ‘black’ dopamine neurones in summer compared with winter. A8 = dopaminergic group A8; cp = cerebral peduncle; DBC = decussation of the brachium conjunctivum; M = medial dopaminergic group; Mv = medioventral dopaminergic group; RN = red nucleus; SNc = substantia nigra pars compacta.

STEROID NEUROPATHOLOGY GROUP Leader: Wah Chin Boon

Sex hormones such as oestrogens and androgens (e.g. testosterone) affect human behaviour. Oestrogens are produced in the brain from testosterone and these locally synthesised oestrogens may modulate neuronal functions and provide neuroprotection. The conversion of oestrogens from androgens is catalysed by the enzyme aromatase, but its localisation in the brain is poorly understood. We overcame this problem by using a transgenic mouse model with an enhanced green fluorescence protein (EGFP) tagged to the aromatase to examine its functional disposition.

Our lab has identified EGFP-aromatase expression in the neurones of many brain regions under normal physiological conditions, and these brain regions have been previously reported to be involved in behaviour. Male adult mice have more aromatase-expressing neurones. Furthermore, we noticed that oestrogen receptors are found in neurones expressing aromatase or in close proximity to aromatase-positive neurons, supporting the idea that locally produced oestrogens modulate neuronal functions.

Figure 1: Cartoon illustrating the various sources of stem cells and their potential application in Parkinson’s disease. Stem cells, differentiated into dopaminergic progenitors, can be used for transplantation, in vitro modelling of the disease, screening compound libraries in the identification of new drug targets and development. Alternatively, is the potential to stimulation of quiescent stem cell populations in the adult brain to promote self-repair.

MOTOR NEURONE DISEASE GROUP Leader: Brad Turner

Legend - The gold colour is an immunohistochemical labelling of a neural graft generated from human embryonic stem cells after transplantation in a rat brain. A significant feature of these grafts is that the contain neurones that have the capacity to re-form very long distance pathways in the brain that are normally associated with motor function.

STEM CELLS AND NEURAL DEVELOPMENT GROUP Leader: Clare Parish

The Parish laboratory has a broad interest in repairing the injured brain and places a strong emphasis on understanding neural development, with the idea that repairing the injured brain will require recapitulation of these early events. Major research themes running within the laboratory, include: understanding the neural development (notably wnt signalling); directed differentiation of pluripotent stem cells; molecular mechanisms underlying axonal targeting and synaptogenesis and improving cell-replacement therapy for neural injuries. While historically the major focus of the group has been on understanding dopamine development and developing cell replacement therapies for Parkinson’s, more recently the team has expanded its interests to apply similar approaches to Huntington’s disease and stroke. Much of this work is done in close collaboration with the laboratory of Dr Lachlan Thompson, based at the Florey Institute.

The Turner lab seeks to unravel the molecular pathogenesis of MND, also called amyotrophic lateral sclerosis (ALS). His team employs a combination of biochemistry, cell and molecular biology to study motor neurone pathogenesis in cell culture and mouse models seeking to identify and understand the primary mechanisms underlying motor neurone stress and injury in MND, while translating discoveries into candidate biomarkers and effective therapeutic targets. Our group is particularly interested in the molecular determinants of protein misfolding, mistrafficking and accumulation within neurones and harnessing endogenous cellular protective mechanisms to combat protein misfolding. A further area of investigation is the therapeutic action of survival motor neurone (SMN) protein for MND. Here we found that its restoration slows disease onset and improves motor neurone survival in a mouse model of MND. This approach is being extended to SMN gene therapy in other mouse models of MND, while developing new therapy approaches for efficient and sustained SMN gene delivery.

LINDA LAU

ҩҩ ISN Special Conference, Dynamic Change of Nanostructure in the Brain in Health and Disease - Cutting Edge of the Technical Innovation, Tokyo, Japan.

STEROID NEUROPATHOLOGY GROUP EDITORIAL POSITIONS

ҩҩ Editorial Board of Progress in Neuro-Psychopharmacology & Biological Psychiatry - awarded excellence in review ҩҩ Editorial Board of Frontiers in Molecular and Structural Endocrinology ҩҩ Editor of Pharmacology, Research & Perspectives (PR&P) Journal reappointed for 2 more years.

NEUROGENESIS AND NEURAL TRANSPLANTATION GROUP SPEAKING INVITATIONS 2014

ҩҩ 24th Annual meeting for the Network of European CNS Transplantation and Repair. ҩҩ Murdoch Children’s Research Institute. ҩҩ Monash Medical Centre.

STEM CELLS AND NEURAL DEVELOPMENT GROUP

MAJOR NATIONAL AND INTERNATIONAL CONFERENCES 2014 ҩҩ Network of European CNS Transplantation & Restoration meeting, Galway, United Kingdom. ҩҩ Karolinska Institute, Stockholm, Sweden. ҩҩ International Parkinson’s disease day, Melbourne Brain Centre. ҩҩ Monash Institute Medical Research-Prince Henry’s Institute. ҩҩ Walter and Eliza Hall Institute.

NEUROGENESIS AND NEURAL TRANSPLANTATION GROUP

MOTOR NEURONE DISEASE GROUP

Leader: Lachlan Thompson

Regenerative therapies for brain and spinal cord repair are a key focus of our efforts. We share the view that success in this area will be closely aligned with a deeper understanding of the complex processes that underlie brain development. Our particular interests involve the molecular mechanisms that trigger neurogenesis as well

ҩҩ 12th Meeting of the Asian-Pacific Society for Neurochemistry, Kaohsiung, Taiwan. ҩҩ 16th International Neuroscience Winter Conference, Solden, Austria. ҩҩ Joint Biochemical Society / British Neuroscience Association Meeting, Astrocytes in Health and Neurodegenerative Disease, London, United Kingdom. ҩҩ Proteostasis and Disease Symposium 2014, Wollongong.

EDITORIAL POSITIONS

Activated astrocytes (green) surrounding motor neurones (red) in lumbar spinal cord of the mutant TDP-43 mouse model of MND at an early presymptomatic age (image credit Nirma Perera).

ҩҩ 25th International Symposium on ALS/MND, Brussels, Belgium. ҩҩ 2nd Proteostasis and Disease Symposium, Wollongong. ҩҩ MND Australia Research Meeting, Melbourne.

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

Drug Targets in Sight Daniel Scott

I DRUG TARGETS IN SIGHT Diseases including Alzheimer’s, Parkinson’s disease, and epilepsy in the firing line.

n March 2011, Daniel Scott was working on what he describes as a risky line of research - new technologies in receptor engineering.

If successful, his plan was to solve a big problem in modern drug discovery – the instability of membrane proteins – and to enable the design of vital new medications.

“In general, diseases are caused when the natural signalling networks such as hormones or neurotransmitters become corrupted. Drugs are then prescribed to act on receptors and restore the signalling balance,” Daniel explains.

Pictured: Dr Daniel Scott, head of membrane protein engineering in the Neuropeptides division.

“The challenge is to discover drugs that can modulate specific receptors associated with this aberrant signalling in disease without disrupting normal signals and causing side effects.”

One way to do this is to analyse the molecular structure of the target receptors and design drugs that can “fit” into the target. But most receptors are very unstable and “fall apart” during the experiments needed to perform “structure-based drug design”.

Daniel, who was researching in a renowned protein-engineering laboratory at the University of Zurich, Switzerland, had already spent three-and-a-half years trying to solve this problem and had started to worry about whether his ideas would work.

The project was using a molecular biology technique called “directed evolution” to select receptor genes that exhibited enhanced stability, cycling them through evolutionary rounds until the receptors were very stable.

His supervisor liked the idea for the new technology but had doubts. Daniel’s wife Melissa was expecting their first child.

“I was starting to stress out because I’d taken a big risk to go to Switzerland and was doing this crazy work. I thought that as a family we had to start thinking about stability,” he says.

But then the breakthrough came. Daniel’s son Hamish was born and the research results were validated soon after. “At last I could relax and enjoy Hamish,” he says.

Daniel returned to the Florey in late 2011 with his innovative technology, CHESS, or Cellular High-throughput Encapsulation Solubilisation and Screening, which allows researchers to engineer very stable receptors for drug discovery. CHESS had been patented, and publication of Daniel’s work in 2012 received international recognition.

The Florey is only one of two places in the world using CHESS. Daniel has used the technology to stabilise several G protein-coupled receptors (GPCR) that are key drug targets for central nervous system disorders.

Some of these GPCRs are currently untargeted by drugs.

His work has attracted two prestigious awards – the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists (ASCEPT) Denis Wade Johnson & Johnson New Investigator Award, and the BPS/ASCEPT Outstanding Young Investigator Prize.

Daniel’s next challenge is to work with others at the Florey to mass-produce these engineered receptors, for which he needs new equipment.

“We hope that by opening new avenues to GPCR drug discovery, our technology will ultimately lead to new drugs to help people living with diseases such as Alzheimer’s disease, Parkinson’s disease, epilepsy and schizophrenia.”

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

Leader: Ross Bathgate

between brain relaxin-3 and serotonin networks and demonstrated that relaxin-3 may play a role in stress-associated changes in anxiety by interactions with specific brain serotonin systems.

The Neuropeptide receptor laboratory studies G protein-coupled receptors (GPCRs) which represent the most important class of biomolecules for pharmaceutical development, being targeted by ~30 per cent of current drugs. Our studies on the structure and function of novel neuropeptide GPCRs will enable the development of new drugs to specifically target neurological and other diseases.

These findings improve our understanding of state-dependent, motivated behaviours and affective function in general, as arousal/ motivation and reward circuits are often aberrant in anxiety disorders and depression, and further highlight the therapeutic potential of targeting the RXFP3 system in appetitive, affective and addictive conditions.

NEUROPEPTIDE RECEPTOR GROUP

NEUROPEPTIDES Leader: Professor Ross Bathgate

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Research highlights for 2014

A QUICK SNAPSHOT

The Neuropeptides Division primarily conducts multi-disciplinary studies on the relaxin family of peptides/hormones and their receptors. The division focuses on determining the role of these peptides and the receptors they target in a wide range of physiological and disease states. These studies are coupled with fundamental drug discovery research on both these and other peptides and their G protein-coupled receptors. The aim of this research is to develop new biological knowledge and fundamental understanding about how to best therapeutically target these peptide systems with the long term view to develop drugs which target the peptide receptors to treat vascular, fibrotic, metabolic and psychiatric diseases.

An example of the success of this approach is the completion of a Phase III trial using the hormone relaxin for the treatment of acute heart failure by the Swiss Pharmaceutical Company Novartis. A Phase IIIb trial is ongoing and the relaxin drug, serelaxin, has been approved in Russia to treat patients with acute heart failure. Hence fundamental research on the mechanism of action of a hormone, in the case of relaxin pioneered at the Florey by the former Neuropeptides Division Head, Prof Geoffrey Tregear, can ultimately lead to its use to treat disease in patients.

Studies by the group continue to demonstrate the unique mechanism by which the hormone relaxin binds to and activates its receptor, RXFP1. Two recent publications (one in the prestigious Journal of Biological Chemistry) have furthered our understanding of the mechanism of interaction between relaxin and RXFP1 to enable new drug design. Relaxin was recently demonstrated to be an effective treatment for acute heart failure in Phase III clinical trials and will soon be used clinically to treat this disease.

However, the patients must be treated by continuous intravenous infusion of relaxin which is not an ideal method to deliver the drug.

Studies by our group, which are concentrating on determining the precise mode of interaction of relaxin with RXFP1, will lead to the development of smaller drugs that can be taken orally for the treatment of heart failure and other diseases.

PEPTIDE NEUROBIOLOGY GROUP Leader: Andrew Gundlach

RESEARCH HIGHLIGHT

AN IDEA LIKELY TO CHANGE LIVES BY 2035

We received four NHMRC project grants for our researchers in a very competitive funding environment, and two key publications in the prestigious journal, the Proceedings of the National Academy of Sciences USA (see details below).

Powerful insights into how the brain controls behaviour are being obtained by ‘systems neuroscience’ analysis, using sophisticated optogenetic and pharmacogenetic manipulation of neural circuits and advanced complementary methods to record their impact. Combined with a greater knowledge of brain peptide and hormone neuromodulatory systems, these studies will allow the improved design of drugs that target ‘receptor states’ or ‘receptor combinations’ present in specific brain regions/circuits under pathological conditions

Together with collaborators at Cambridge University and the pharmaceutical company Takeda Cambridge, we identified insulin-like peptide 5 (INSL5) as a product of colonic endocrine L-cells, and demonstrated that INSL5 levels were elevated in calorie-restricted mice and reduced after feeding. Consistent with this profile, INSL5 administration stimulated food intake in mice, making it only the second identified gut hormone after ghrelin that enhances appetite.

Modulating the INSL5 axis presents a new strategy for the treatment of metabolic disease and obesity.

Neuropeptides modulate cells in the brain by interacting with neuropeptide receptors. Detailed understanding of these molecular interactions is crucial for the design of neuropeptide and small molecule drugs to treat various diseases. Neuropeptide receptors however, are complicated membrane proteins that are unstable and thus difficult to study in the biochemistry laboratory.

Using state-of-the-art technology, with our collaborators at the University of Zurich we engineered highly stabilised neuropeptide receptors, leading to several X-ray crystal structures (or molecular snapshots) of a neuropeptide interacting with its receptor. .

SENIOR STAFF

• Professor Ross Bathgate • Associate Professor Andrew Gundlach • Dr Mohammed Akhter Hossain • Dr Daniel Scott • Professor John Wade •

Dementia and psychiatric illnesses remain major clinical, scientific, societal and economic problems. A better understanding of how the brain controls physiology and behaviour and how this becomes dysfunctional due to ageing and disease pathology is urgently required. Basic research studies are therefore needed to identify new structural and molecular neural targets that may form the basis of novel therapeutic approaches in the future. In this regard, our laboratory conducts ‘systems neuroscience’ research and a primary interest is to understand the role of neuropeptide signalling in the control of complex behaviours including arousal, stress, mood motivation and reward, and associated memory processes, under normal and pathophysiological conditions. We conduct experimental studies in animal models of normal physiology and psychiatric disorders, using a range of biomolecular tools including receptorselective peptides, ‘viral-vector delivered’ designer receptors, and a range of transgenic mouse strains.

Research highlights for 2014

Since its discovery at the Florey in 2002, we have been studying the neurobiology of the peptide transmitter, relaxin-3. We and others have demonstrated that relaxin-3 and its neural receptor RXFP3 appear to play a role in anxiety, cognition, motivation, and other modalities in rodents that are commonly aberrant in human sufferers of affective disorders. In 2014, we made further key discoveries about this neuropeptide-receptor system.

Importantly, we demonstrated that in mice central RXFP3 blockade reduced motivational behaviours such as the consumption of palatable food (Smith CM et al., 2014), and in ongoing studies with the Florey Addiction Neuroscience lab, we demonstrated that modulation of activity in relaxin-3 receptor-rich brain areas alters stress-induced relapse in alcohol-preferring rats. In collaborative studies with our colleagues in Krakow, Poland, we observed strong modulation of relaxin-3 neurone activity in brain slices by arousal peptides including the orexins. We also observed that life-long relaxin-3 and RXFP3 gene deletion or ‘knockout’ mice display a hypersensitivity to stress-induced insomnia and highly fragmented circadian activity, which is indicative of a lack of sustained motivation and possible sleep/wake disturbances. Furthermore, in studies with scientists at La Trobe University, we investigated the interactions

Examining the function of the rat nucleus incertus using pharmacogenetic methods. (A) Viral vector-mediated expression of an ‘excitatory’ hM3Dq DREADD fused to an mCherry fluorophore (inset), in neurones of the rat nucleus incertus (red fluorescence). (B) Recordings of rat behaviour are made in an automated locomotor cell, with and without hM3Dq-induced nucleus incertus activation by administration of the designer drug, clozapine-N-oxide (CNO). (C) Examples of the ambulatory paths of an hM3Dq (hM3Dq-CNO) and control rat (mChr-CNO) during a 3 hour session in a locomotor cell reflect the increased distance travelled and persistent movement during nucleus incertus activation.

In a major initiative involving several staff and student members, we have modulated the activity of nucleus incertus neurones in adult rats using viral-vector delivered ‘designer’ receptors (DREADDs) and observed strong effects on brain activity (EEG), physiology (stressinduced cardiovascular responses) and behaviour (locomotor activity, spatial memory).

This research has been assisted by the development of advanced software for the automated analysis of EEG and EMG activities.

Planned studies will help us model similar changes that occur in stress- and trauma-induced clinical anxiety and mood disorders.

Ongoing studies will also better define the projections of nucleus incertus neurones into key brain areas and their effects on brain activity and behaviour.

These and related studies will continue in 2015 with ongoing support from NHMRC (Australia), Brain & Behavior Research Foundation (USA), Bethlehem Griffiths Research Foundation, Alzheimer’s Australia Dementia Research Foundation and The University of Melbourne.

Other research highlights include:

ҩҩ Dr Sherie Ma, a senior research officer, undertook a four-month Commonwealth Endeavour Fellowship at the Department of Neurobiology, University of California, Berkeley, USA, where she trained in the use of optogenetics to dissect neural pathways and their effects on behaviour.

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ҩҩ Mouna Haidar, a PhD student, was awarded a postgraduate scholarship from Alzheimer’s Australia Dementia Research Foundation for 2014-2016.

ҩҩ Cary Zhang, a PhD student, was awarded a Rebecca Hotchkiss International Scholar Exchange Hotchkiss Brain InstituteMelbourne Trainee Exchange Fellowship to undertake scientific research in the laboratory of Professor Jaideep Bains at the Hotchkiss Brain Institute in Calgary, Canada.

ҩҩ Giancarlo Allocca, a PhD student, conducted valuable testing of newly developed software for the automated analysis of brain sleep/wake activity in experimental animals in several international laboratories, as part of a commercialization program, with support from the Florey Institute Geoffrey Tregear Travel Award and The University of Melbourne.

ҩҩ Dr Craig Smith, a research officer, and students in the laboratory, together with colleagues from Quebec Canada, used a newly established transgenic mouse strain to explore the distribution of relaxin-3 receptors (RXFP3) in brain and to identify the neurochemical content of these target neurones in key neural circuits (Figure below). These data improve our understanding of the anatomy of relaxin-3 / RXFP3 systems and facilitate the design and interpretation of functional studies.

Our interest and experience lies in the design and development of insulin and insulin-like peptide-based drugs.

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MEMBRANE PROTEIN ENGINEERING GROUP Leader: Daniel Scott

Research highlights for 2014

ҩҩ INSL5 was until recently an identified gut hormone of unknown function. In a major breakthrough, we identified INSL5 as a novel orexigenic gut hormone which promotes appetite during conditions of energy deprivation (Grosse J et al., PNAS (USA) 2014). ҩҩ Central to the successful clinical use of new and improved insulin analogues is the availability of efficient methods to prepare them. We have developed a novel procedure, in which one of the three disulfide connections in insulin is formed in aqueous media by irradiation with light, resulting in significantly improved overall yield (Karas J et al., Chemistry 2014).

ҩҩ We developed a single chain peptide, B7-33, as an agonist for RXFP1 and examined the efficacy of B7-33 in a pathophysiological model of myocardial infarction (MI)induced heart failure (Fig. 1). The systemic administration of both B7-33 and H2 relaxin, after 8-weeks of MI-induced injury and over a 4-week treatment period, significantly reduced the build-up of MI-induced collagen density (Fig. 1A, B) and improved left ventricular function by reducing left ventricular end-diastolic pressure (LVEDP, Fig. 1C). This confirmed that B7-33 could act as a potential replacement of H2 relaxin for the treatment of patients with heart failure.

A provisional patent application was filed in April 2014 based on this new intellectual property. ҩҩ Awarded a Melbourne Research Grant Support Scheme (MRGSS) Grant from the Faculty of Medicine, Dentistry and Health Sciences.

B7-33 reduced fibrosis and improved health function in rat model of myocardial infarction induced heart failure Mapping the distribution and function of relaxin-3 receptor, RXFP3, in brain, using transgenic mice. A hemi-coronal section through the hippocampus of a mouse in which putative RXFP3-positive neurones and their projections contain a green fluorescent protein and different populations of neurones are identified by multi-label immunohistochemistry for parvalbumin (blue), somatostatin (red) and calretinin (white). These studies indicate the presence of RXFP3 in a specific population of neurones in the dentate hilar region than can be further studied using viral-based methods.

Protein instability poses a major barrier to the characterisation and deployment of many proteins into industrial and biotechnological applications. Membrane proteins are a class of proteins that are particularly unstable, yet are highly important as they are the main targets for most prescription drugs. Membrane proteins are located on the surface of all types of cells and are involved in processes such as sensing neurotransmitters, driving neural impulses and responding to drug treatment. The instability of membrane proteins, however, makes them difficult to study. We use novel technology (CHESS) to engineer stabilised membrane proteins, particularly neuropeptide-binding G protein-coupled receptors (GPCRs), to aid in elucidating the atomic level mechanisms that govern their function and to facilitate novel drug discovery.

A particular focus of the laboratory is engineering members of the relaxin receptor family to enable greater understanding of how these receptors work at the molecular level and in turn enable the design of drugs targeting these important receptors. We also use this technology to engineer highly stable versions of other protein classes, such as fluorescent proteins and enzymes, for biotechnological and industrial applications.

PEPTIDE AND PROTEIN CHEMISTRY GROUP

Research highlights for 2014

Leader: Prof John Wade

Specific research highlights include:

We employ modern chemical peptide synthesis methods together with structure-based drug design and development to produce novel peptidomimetics with improved receptor selectivity, potency and pharmacokinetics. Our primary research focus is on complex insulin-like peptides including the peptide hormone, relaxin, and the neuropeptide, relaxin-3.

ҩҩ A critical proof-of-principle study was published in the prestigious journal, PNAS (USA), describing several X-ray crystal structures of GPCRs engineered with CHESS (Egloff P et al., PNAS (USA), 2014).

ҩҩ We successfully demonstrated that CHESS could be applied to non-membrane protein classes, by using CHESS to engineer ultra-stable fluorescent proteins. These proteins are useful tools for next generation imaging methods (Yong KJ & Scott DJ, Biotech Bioeng, 2014).

ҩҩ Kelvin Yong, a PhD Candidate, achieved a “special mention” in the poster prize section of the Australasian Society of Clinical and Experimental Pharmacology and Toxicology (ASCEPT) annual scientific meeting, 2014. ҩҩ Nicholas Smith, an Honours student, won the undergraduate poster prize at the Australasian Society of Clinical and Experimental Pharmacology and Toxicology (ASCEPT) annual scientific meeting, 2014. ҩҩ Awarded three NHMRC project grants for applications submitted in 2014 totaling $1.8 M.

ҩҩ Dr David Hawkes, a research officer, and other lab members, raised funds for the development of new viral vectors for our research as part of the Florey’s first Crowd Funding project. As part of the “Name the Virus” project, David made several media appearances, including on ABC television and radio, and one of the new viral vectors will be named after TV presenter and journalist, Virginia Trioli.

Ultrastable fluorescent proteins engineered with CHESS will be useful tools for next generation imaging techniques.

Research highlights for 2014

Relaxin is principally an ovarian hormone that has a number of physiological roles, one of which is to regulate the level of collagen throughout the body. Relaxin-3 is a neuropeptide expressed in the brain which has an important role in regulating mood and stress systems. Because of their similar chemical structures, relaxin-3 can cross react with the receptor for relaxin, which is also present in high levels in the brain; and this can complicate our attempts to better understand the biological role of relaxin-3.

However, in addition to our ability to chemically produce relaxin and relaxin-3, we have prepared a series of progressively truncated relaxin and relaxin-3 analogues and identified the minimum size that endows near-full biological activity at the distinct receptors.

Unexpectedly, we discovered that relaxin’s activity could be maintained within a single small peptide chain, which promises considerable savings in both cost and effort of production and biological insights.

The peptide has been patented and is the subject of significant interest from major pharma to determine if it fully replicates all the known beneficial actions of native relaxin. A similar minimization strategy has been applied to relaxin-3 and, together with a chemical conformation-constraining approach, a single chain peptide has been identified that mimics the agonist actions of the native neuropeptide. This peptide is now under further investigation within the Neuropeptides Division to better determine the clinical potential of relaxin-3 receptor-related drugs for treating psychiatric disorders such as anxiety and depression.

INSULIN PEPTIDES GROUP Leader: Mohammed Akhter Hossain

Insulin is one of the most clinically important peptide drugs on the market. It still represents the only treatment for diabetes (particularly for type 1). There are seven other insulin-like peptides (also called the relaxin family of peptides: H1, H2 and H3 relaxins, INSL3, 4, 5 and 6) which have similar structures to insulin (2 chains, 3 disulfide bonds), but have a diverse range of physiological functions. H2 relaxin is the most studied peptide in our laboratory and has recently passed phase III clinical trials for the treatment of acute heart failure.

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Figure 1 - Effect of H2 relaxin and B7-33 treatment on cardiac fibrosis and function. Representatives photo micrographs of picrosirius red stained left ventricles of the heart from vehicle (Saline), H2 relaxin (H2) and B7-33 treated rats (A), H2 and B7-33 was found significantly reduce the percentage of collagen in the interstitial area compared with saline-treated rats (B).

Animals treated with H2 and B7-33 also showed a reduced left ventricular end-diastolic pressure (LVEDP) compared to saline-treated animals (C) suggesting improved heart function 12 weeks following myocardial infarction **p<0.01 vs saline group: * p<0.05 vs saline group.

X-ray crystal structures of stabilised versions of neurotensin receptor 1 (NTS1), from Egloff P et al., PNAS (USA), 2014.

We have also continued our studies on antimicrobial peptides (AMPs), a novel class of antibiotic that displays clinical promise in bypassing the vexing problem of resistance development by bacteria. In particular, we have examined a novel insect-derived AMP called A3-APO and shown that a dimer of this compound is a powerful antibiotic against Gram-negative bacteria as well as an immunostimulant which does not induce resistance. Studies are underway to determine if its efficacy can be further increased in combination therapy with conventional antibiotics.

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

NEUROPEPTIDE RECEPTOR GROUP EDITORIAL POSITIONS

ҩҩ Ross Bathgate ҩҩ Associate Editor of Frontiers in Molecular and Structural Endocrinology ҩҩ Editorial Board Member of Journal of Pharmacological Sciences ҩҩ Associate Editor of Molecular and Cellular Endocrinology ҩҩ Member – IUPHAR subcommittee on relaxin receptors COLLABORATIONS

ҩҩ Department of Biochemistry and Molecular Biology, University of Melbourne ҩҩ School of Biomedical Sciences, University of Queensland ҩҩ Monash Institute of Pharmacological Sciences, Monash University ҩҩ Baker Heart Research Institute, Melbourne ҩҩ Department of Pharmacology, University of Melbourne ҩҩ Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, Florida International University, USA ҩҩ Corthera (owned by Novartis), San Mateo, USA ҩҩ Chinese National Compound Library, Shanghai, China ҩҩ Department of Pharmacology, University of Pittsburgh, USA

ҩҩ School of Psychological Science, La Trobe University ҩҩ Department of Physiology, University of Melbourne ҩҩ Department of Medicine, University Jaume I, Castellón, Spain ҩҩ Department of Neurophysiology and Chronobiology, Jagiellonian University, Poland ҩҩ Department of Neurobiology, Weizmann Institute of Science, Israel ҩҩ Department of Psychology, University of Otago, New Zealand ҩҩ Department of Neurobiology, University of California, Berkeley, USA ҩҩ Institute François Magendie, University of Bordeaux, France ҩҩ Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil ҩҩ Department of Psychiatry and Neurosciences, Laval University, Quebec, Canada

INSULIN PEPTIDES GROUP EDITORIAL POSITIONS

ҩҩ Mohammed Akhter Hossain ҩҩ Review Editor of Frontiers in Chemical Endocrinology ҩҩ Editorial Board Member of Modern Chemistry

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ҩҩ Monash University, Australia ҩҩ University of Queensland, Australia ҩҩ CSIRO, Australia ҩҩ IBM Research Collaboratory in Life Sciences & IBM Australia Research Laboratory

PEPTIDE AND PROTEIN CHEMISTRY GROUP EDITORIAL POSITIONS

ҩҩ John Wade ҩҩ Editor-in-Chief, Frontiers in Chemical Biology ҩҩ Editor-in-Chief, International Journal of Peptide Research & Therapeutics ҩҩ Editor-in-Chief, Biochemical Compounds ҩҩ Editor, Journal of Peptide Science ҩҩ Editor, Protein & Peptide Letters ҩҩ Editor, Amino Acids ҩҩ Editorial Board Member, Chemical Biology & Drug Design ҩҩ Editorial Board Member, BioMed Research International ҩҩ Editorial Board Member, International Journal of Peptides ҩҩ Editorial Board Member, Frontiers in Endocrinology - Molecular and Structural Endocrinology

MAJOR NATIONAL AND INTERNATIONAL CONFERENCES 2014 PEPTIDE NEUROBIOLOGY GROUP EDITORIAL POSITIONS

ҩҩ Andrew Gundlach ҩҩ Editorial Board Member, Journal of Chemical Neuroanatomy ҩҩ Editorial Board Member, Neuropeptides ҩҩ Editorial Board Member, Frontiers in Molecular Neuroscience ҩҩ Editorial Board Member, Frontiers in Neuroanatomy ҩҩ Editorial Board Member, NeuroSignals ҩҩ Editorial Board Member, Scientific Reports ҩҩ Chair, IUPHAR Database Committee on Galanin Receptors ҩҩ Guest Editor, Neurochemical Research MAJOR NATIONAL AND INTERNATIONAL CONFERENCES 2014

ҩҩ Australasian Neuroscience Society Annual Scientific Meeting, Adelaide, Australia ҩҩ European Molecular and Cellular Cognition Society Meeting, Milan, Italy ҩҩ Mediterranean Neuroscience Society, FENS Satellite Meeting, Milan, Italy ҩҩ FENS Congress of Neuroscience, Milan, Italy ҩҩ Associated Professional Sleep Societies, Sleep 2014, Minneapolis, USA ҩҩ Endocrine Society of Australia Annual Scientific Meeting, Neuroendocrinology Symposium, Melbourne, Australia ҩҩ Congress of European Sleep Research Society, Tallinn, Estonia ҩҩ Cardiovascular and Respiratory Control Meeting, Melbourne, Australia ҩҩ Society for Neuroscience Annual Scientific Meeting, Washington, DC, USA COLLABORATIONS

ҩҩ Florey Behavioural Neuroscience and Neurophysiology Divisions ҩҩ School of Biomedical Sciences, University of Queensland ҩҩ Monash Institute of Pharmaceutical Sciences, Monash University

ҩҩ 3rd International Conference on Medicinal Chemistry and Computer Aided Drug Design, December 8-10, 2014, San Francisco, USA [Mohammed Akhter Hossain, Invited Speaker] COLLABORATIONS

ҩҩ School of Chemistry, University of Melbourne ҩҩ Department of Biochemistry and Molecular Biology, University of Melbourne ҩҩ Department of Pharmacology, University of Melbourne ҩҩ School of Biomedical Sciences, University of Queensland ҩҩ Department of Pharmacology, Monash University ҩҩ Department of Chemistry, Monash University ҩҩ Monash Institute of Pharmacological Sciences, Monash University ҩҩ School of Medicine, Flinders University ҩҩ Department of Chemistry, Osaka University, Japan ҩҩ Takeda Cambridge Ltd., United Kingdom MEMBRANE PROTEIN ENGINEERING GROUP MAJOR NATIONAL AND INTERNATIONAL CONFERENCES 2014

ҩҩ Keystone Meeting on GPCRs, 2014, Snowbird (International), Utah, USA ҩҩ GPCR Forum, Monash Institute of Pharmaceutical Sciences [Daniel Scott, Invited speaker] ҩҩ Endocrine Society of Australia ASM Neuroendocrinology Symposium, 2014 [Daniel Scott, Invited speaker] ҩҩ Pharmacology 2014, London, UK [Daniel Scott attended as the 2013 British Pharmacological Society/ASCEPT Outstanding Young Investigator Prize winner] COLLABORATIONS

ҩҩ The University of Melbourne, Australia ҩҩ University of Zurich, Switzerland ҩҩ Monash Institute of Pharmaceutical Sciences

MAJOR NATIONAL AND INTERNATIONAL CONFERENCES 2014

ҩҩ 13th International Chinese Peptide Symposium, Datong, China, July 2014 (John Wade, plenary speaker) ҩҩ 50th Anniversary Symposium of the MRC Laboratory of Molecular Biology, Cambridge, UK, 2014 ҩҩ 33rd European Peptide Symposium, Sofia, Bulgaria, September 2014 ҩҩ 4th MipTec Symposium, Basel, Switzerland, September 2014 (John Wade, plenary speaker) COLLABORATIONS

ҩҩ Bio21 Institute, University of Melbourne ҩҩ School of Chemistry, University of Melbourne ҩҩ Department of Pharmacology, University of Melbourne ҩҩ Department of Pharmacology, Monash University ҩҩ Department of Biology, Temple University, USA ҩҩ Institute of Bioanalytical Chemistry, Leipzig University, Germany ҩҩ Faculty of Medicine, Semmelweis University, Budapest, Hungary ҩҩ Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany ҩҩ Sanofi-Aventis, Frankfurt, Germany ҩҩ Cooperative Research Center of Life Sciences, Kobe Gakuin University, Japan ҩҩ Novartis Institutes for Biomedical Research, Basel, Switzerland ҩҩ Institute of Protein Research, Tongji University, Shanghai, China

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SLIPPING FROM STROKE INTO DEMENTIA Fitness could be a key to recovery and ongoing health after stroke

D

r Amy Brodtmann is a stroke and cognitive neurologist and is co-head of the Florey’s Behavioural Neuroscience division.

Amy Brodtmann is on a quest. She wants to solve a conundrum in neuroscience.

The puzzle: why does it seem that one in three stroke victims will go on to develop dementia?

The scientific literature on the topic has been described as “scant” and “confusing” and that is enough to take Amy out of the consulting room and into the research space at the Florey’s campus next to Austin Health.

Typically people who experience a stroke have problems with speech, memory and thinking, but most are fortunate to recover many of these skills following drug treatment and rehabilitation. But Amy is searching for an answer – does stroke cause ongoing neurodegeneration?

She and her team are immersed in a world-first longitudinal study, the early findings of which have been remarkable.

Since 2011, Florey researchers have approached 135 people who had just had a stroke and who were admitted to the Austin. They are members of the CANVAS study, (Cognition And Neocortical Volume After Stroke),

Dr Michele Veldsman, a post-doctoral research fellow working in the stroke division.

undergoing three-years of cognitive testing and a series of brain scans.

“We’ve been looking at how their brain volumes change over time and we have given them cognitive tests for memory, reason, judgement, how they visually process information and how well they pay attention,” Amy explains.

Amy is working closely with Dr Michele Veldsman, a post-doctoral research fellow who joined the Florey in late 2013 from Cambridge University, and who has a strong neuro imaging background. She had heard about Amy’s work at Cambridge and was interested in its clinical direction.

Michele looks at the connections in the brain using 3D imaging of blood flow.

The study is still underway but Amy and her team have already had some significant results.

“We’ve found that certain parts of the brain are very sensitive to deterioration following stroke, including the hippocampus and the thalamus, which are structures deep in the brain important for many cognitive processes,” she says.

“The changes occur in many, but not all, the patients so our next step is to ask ‘why those people and why not others?’”

Michele says: “Ultimately, we want to use the network changes we see in the brain to predict if someone will go on to develop dementia.”

The research also shows the baseline brain volumes of the stroke survivors in

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the first scan are smaller than expected, causing Amy to wonder if long term high blood pressure and hypertension have caused earlier shrinking of the brain.

Another striking finding has been that there is an improvement in the brain connectivity of participants who are physically active: exercise helps “preserve” their brain networks.

“We know that in certain dementia syndromes, some brain networks are affected. We’ve looked at some of those networks and found that if you’re more active during the day, you preserve them,” says Amy. “And that’s very exciting!”

Amy has presented the findings internationally and is publishing her results.

She is also incorporating her findings into advice she gives patients following a stroke.

“I gave a talk to Alzheimer’s Australia yesterday and they’re working it into their advice for this group of patients as well.

“I advise people to get as fit as they can be. If they can’t run then they should walk.

If they can’t walk they should ride a bike. If they can’t do that they should swim – just keep moving!”

She also urges patients to have checks to ensure their blood pressure, cholesterol levels and diabetes blood sugar levels are “perfect”, and to “get lean”.

Kel Glare AO, former Victorian Police Commissioner, says he is taking part in CANVAS to do his bit towards helping future stroke victims.

Kel had a stroke in August 2011 but recovered with only some loss of vision.

It’s a real pain when he’s playing golf and going for a putt, he quips, but he is otherwise “lucky”.

He is a keen supporter of the Florey, where he’s a Governor, and an advocate of the new Medical Research Future Fund.

“In my background, you can’t solve crime by building more prisons, and in medicine you can’t solve medical problems by building more hospitals – it takes medical research.

“The Florey’s great but needs more funding from government,” he says.

Amy, whose future research into stroke and neurodegeneration depends on securing further funding, says that while curiosity compels her to investigate, she is also driven by concern for better outcomes for the people she treats in hospital.

“What I want to eventually be able to do when I’m on a ward with a stroke patient who’s just been admitted, is not only give them information about what’s going to happen in the next few weeks as they recover, but also information on what they can do in the days, months and years after that to make sure they have good brain health.”

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

STROKE PRECLINICAL SCIENCE Leader: David Howells

STROKE Leaders: Professor Julie Bernhardt and Associate Professor David Howells

The 17 member preclinical stroke laboratories comprise Australia’s leading translational stroke research team with expertise in therapeutic assessment in animal models of stroke, the use of human stem cell derived neurons and glia to explore stroke biology and identify novel drugs and the use of systematic review and meta-analysis to understand why translation to the clinic is so difficult and to provide evidence based selection of agents for clinical trial.

Research highlights for 2014

A QUICK SNAPSHOT

15 million strokes and six million stroke deaths occur each year leaving 55 million survivors suffering the consequences of stroke. The Stroke Division of the Florey Institute of Neuroscience and Mental Health comprises a team of 80 basic and clinical scientists whose aim is to understand the pathophysiology of stroke, optimise existing therapies and develop new treatments and techniques to both prevent and reduce the impact of stroke.

The division has five research teams: Stroke Preclinical Science, the AVERT Early Intervention Research Program, the Neurorehabilitation and Recovery group, Public Health and Epidemiology including the Stroke Telemedicine program and the Australian Stroke Clinical Registry, and Clinical Trials.

RESEARCH HIGHLIGHT

AN IDEA LIKELY TO CHANGE LIVES BY 2035

The Florey Public Health and Epidemiology group is responsible for the integrity of the Australian Stroke Clinical Registry (AuSCR). This important national infrastructure provides the ability for hospitals around Australia to enter standardised data about their patients and compare their clinical care to a national standard. Currently, 51 hospitals are approved to use AuSCR. The registry is about to provide information on how many patients are receiving clotbusting thrombolysis medication within the first 4.5 hours of stroke and receiving access to stroke units. Both these treatment offer patients the best opportunity for a good outcome after stroke, however not all hospitals provide these treatments consistently for a variety of reasons.

Through use of AuSCR, for the first time in Australia, we are able to understand that factors that influence access to these treatments and also how this impacts on longer term outcomes within 180 days of stroke.

Our Stroke Telemedicine program is improving equity of access to the best available care for Victorians, whether they live in the city or country. It is the most comprehensive program of its kind that has been developed for acute stroke care in Australia. By 2035, we’d hope to see the program used across Australia.

SENIOR STAFF

• Associate Professor David Howells • Professor Julie Bernhardt • Associate Professor Dominique Cadilhac • Professor Christopher Bladin • Professor Geoff Donnan • Professor Leeanne Carey •

“

Recruitment to the AVERT trial, an international, 56 multicentre, randomised controlled trial of very early rehabilitation, completed in October 2014. Participants were recruited from five countries. This single blind, Phase III trial, tests whether starting out-of-bed mobility training within 24 hours of stroke is superior to current care. The results are eagerly awaited by the international stroke community and the first results of the trial will be reported at the European Stroke Organisation Conference in Glasgow, April 2015.

”

In both Stroke and SCI our analyses show that stem cell transplants improve outcome. However, in both circumstances facets of the disease modelling account for more of detected effect size than stem cell biology. This led us to concentrate on using stem cells as a source of human neurons for drug testing rather than implantation and the demonstration that hypothermia protects human neurons against ischemia via an oxidative and glucose dependent mechanism. This has led to a new collaboration to expand the use of human stem cell derived neurons and glia to explore stoke biology (Dr Cooper-White, UQ; Dr Dottori, UoM; Dr Wilson, CSIRO).

Evidence from meta analysis of the impact of hypothermia and hypertension on outcome in animal models of stroke contributed to the design of experiments which confirm that hypothermia is effective in animal models of stroke and that pethidine, used to supress shivering in human clinical trials of hypothermia, does not interfere in provision of this benefit.

Cumulative evidence from our analyses of the stroke literature and experimentation in co-morbid animals have contributed to the launch of the Multi-PART consortium (Multicentre Preclinical Animal Research Team; www.multi-part.org), an international in vivo collaboration designed to develop the capacity to undertake international multicentre animal studies to improve the validity, and generalizability of current preclinical research to improve the prospects of success for translation of efficacy to human clinical trials. The internal validity of experiments designed to examine candidates prioritized for in vivo testing will be assured by centralized statistical planning, randomization, outcome adjudication, and quality control to reduce the risk of bias. Initial “proof of concept” experiments designed to confirm in vivo activity will be followed by robust exploration of the limits to efficacy (time to treatment, age and sex of animals, efficacy in hypertensive or diabetic animals, efficacy in different models of stroke). The consortium is now established and funded by the EU. A/Prof Howells chair the project management committee of this EU funded multinational, multidisciplinary consortium and provided guidance for the NINDS call for US researchers to join the initiative (http://tinyurl.com/p6mvjfm).

AVERT EARLY INTERVENTION RESEARCH PROGRAM Leader: Professor Julie Bernhardt

We believe that the best way to advance science is by collaboration between individuals from a wide range of backgrounds who work together to tackle complex problems. Finding more effective ways to help stroke patients to recover is a key goal the world over. Our group of six post-doctoral researchers, seven research staff and students are working to develop, test and implement new ways of treating people with stroke. Starting active rehabilitation very early after stroke is a relatively new concept with enormous potential to reduce death and chronic disability. While there is some evidence that exercise and purposeful, task specific activity aids recovery after stroke, currently there are no specific recommendations about post stroke exercise. Pilot work by our group suggests that commencing activity within 24 hours of stroke may lead to faster recovery of

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function, less disability and better long term quality of life at a lower cost than current care. To test these hypotheses, we are conducting the first randomised controlled trial of very early rehabilitation (AVERT - A Very Early Rehabilitation Trial). Over 2000 patients with stroke have been recruited to this international, multicentre, Phase III efficacy and cost effectiveness clinical trial. The findings of this study have the potential to change clinical practice around the world.

Our group also aims to identify key mechanisms by which exercise may improve the physical, cognitive, mood and fatigue outcomes of people affected by stroke.

Research highlights for 2014

Completing recruitment to the AVERT trial, was a highlight for 2014.

We witnessed a magnificent effort by hundreds of investigators from five countries (Australia, New Zealand, Malaysia, Singapore, and the UK; Northern Ireland, Wales, England, Scotland) who have been involved in this study over the course of its eight years. The most important time point for review of patient outcomes is at three months post stroke, so we expect to have all of our data in and ready to present for the first time in April 2015. The results are eagerly awaited by the international stroke community. We follow all patients over the first year of their life after stroke, so final results will not be known until 2016. Further information about the trial can be found at the ANZCRT trials register: http://www.anzctr.org.au or on the Florey website.

Another highlight for 2014 was the development of our new acute exercise laboratory at the Austin Campus. This lab will support our acute exercise testing and training of people affected by stroke, with much of the equipment making bedside assessment and testing a possibility. We are now uniquely positioned to interrogate and develop treatments to help the profound deconditioning that occurs quickly after stroke.

Optimising health environments forum

We held our second optimising health environments forum in 2014, which brings together clinicians, architects, researchers and consumers of health care. The purpose of the forum is to build strong linkages across the different sectors to improve the science that underpins decisions about the environments in which health care is delivered. Julie has the view that hospitals are expensive to build and the built environment (as well as the care services within) influences patient outcomes, so, if we can improve the evidence base for decision making about the health care environment itself, everyone benefits. This is an emerging area of interest in Australia and the Florey is taking a role in advancing the science of design and building strong collaborative partnerships. Julie’s vision is to design the best rehabilitation building and service model in the world, and then one day see that design become a reality.

Key research projects and staff

Toby Cumming: The energy cost of walking in the first week after stroke: Stroke can have a major impact on walking ability, fitness and muscle strength, and these impairments may make being physically active more demanding. We are measuring the energy used by patients during steady-paced walking in the first week after stroke, and comparing this to energy used by healthy controls. Data from an unobtrusive electronic activity monitor are compared to ‘gold standard’ measurement of energy expenditure, which involves wearing a mask to measure oxygen intake. Understanding how hard patients can work early after stroke will inform treatment and rehabilitation programs.

Julie Bernhardt: Dose escalation study for stroke survivors with impaired mobility: In partnership with Royal Talbot Rehabilitation Centre, Austin Health, we conducted a dose escalation study of exercise in stroke survivors with significant difficulty with walking.

In clinical practice and clinical trials the selection of treatment dose (amount, frequency, intensity) is rarely based on solid data.

We aimed to challenge this approach and develop a new way of identifying the best dose of training to get the best results.

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Computer games as a tool for rehabilitation: In collaboration with Melbourne Health and gaming company Current Circus, we have conducted a pilot study with 40 stroke affected individuals in rehabilitation to explore whether computer games (using the Kinect system) can be a useful tool for training in this population. We found that the training was fun, well tolerated and engaging.

Evaluating the effect of ward redesign on patient behaviour: In collaboration with Royal Talbot hospital, we conducted a study of the activity patterns of patients in rehabilitation in an old rehabilitation ward, and then repeated the study following a redevelopment of the Mellor Ward. This study piloted a method for exploring how the environment in which care is delivered affects patients behaviour and we found some interesting differences between old and new ward environments.

Karen Borschmann: Understanding changes in bone, glucose and muscle after stroke and their relationship to physical activity. Having a stroke often leads to physical inactivity, and the combination of these two things can have a range of negative physiological effects.

In this study we track changes in bone density, glucose metabolism and lean muscle mass which occur over six months after stroke, and investigate the effect of physical activity on these physiological outcomes, with a sub-study to two years. The final six-month assessment of participants has recently been undertaken, results will be presented internationally in 2015.

Coralie English: Sitting time and physical activity in people with stroke: Sitting for long periods each day is an independent risk factor for cardiovascular disease and recurrent stroke. New advances in wearable activity monitors provide us with the tools to be able to accurately and precisely measure sitting time, physical activity and energy expenditure of people with stroke living in the community.

We completed an observational study of sitting time and physical activity in stroke survivors and healthy controls, and a pilot RCT testing a novel intervention to reduce sitting time in stroke survivors.

Julie Luker: Exploring the implementation of early stroke rehabilitation in acute settings. The barriers and enablers of providing early rehabilitation in acute settings are poorly understood. This qualitative study explores the experiences of 41 allied health and nursing staff at 17 acute stroke units where the AVERT early mobilisation protocol was implemented.

Patients’ experiences of physical rehabilitation after stroke. This systematic review synthesises the best available evidence from 31 studies on the perspectives and preferences of stroke survivors undertaking physical rehabilitation as inpatients. The review’s findings inform patient centred care and future research.

Liam Johnson: This is my first year with AVERT and we spent 2014 establishing the exercise laboratory and started to establish methods for measuring cardiovascular fitness in people early after stroke. Planning for an observational study of fitness after stroke was a key focus on 2014.

Dr Liam Johnson, a postdoctoral research fellow, putting a stroke patient through his paces.

NEUROREHABILITATION AND RECOVERY Lead: Professor Leeanne Carey

The potential to drive adaptive neural plastic changes through rehabilitation is enormous and likely to lead to major changes in rehabilitation practice and better outcomes for stroke survivors.

However, we do not have effective means of identifying individuals who may benefit from therapy nor how to select the most optimal therapy for an individual. The Neurorehabilitation and Recovery research program focuses on stroke recovery: in particular how the brain adapts and how we can harness that potential in rehabilitation.

The research involves development of novel rehabilitation approaches and personalised stroke rehabilitation informed by neuroscience. MRI is used to investigate how changes in the brain can help target rehabilitation most optimally to individual stroke survivors. Our research also examines factors, such as depression and cognition, that impact on stroke recovery. An important focus is to translate these discoveries into clinical practice and better outcomes for stroke survivors.

Research highlights for 2014

In 2014 the Neurorehabilitation and Recovery group achieved major steps forward in advancing its program of research focused on harnessing real world drivers of neuroplasticity. The major objective of our group is to translate knowledge from neuroscience into evidence-based clinical practice protocols and better outcomes for stroke survivors. This goal represents a paradigm shift for stroke rehabilitation and better outcomes for the one in six people who experience a stroke. Our research is focussed on: Targeting rehabilitation to the individual based on accessible brain networks; Neurobiology of recovery and impact of depression on outcome; and Implementation of evidence-based practice, as outlined below.

In 2014, we achieved 100% recruitment to the START longitudinal stroke cohort study and continued to lead the advanced imaging and clinical arm of the study. We received final ethics approval and initiated the first site for our new study SENSe Implement. Our aim here is to develop a template and clinical practice guidelines for implementation of evidence-based rehabilitation in clinical practice settings. Our national and international standing in translational neuroscience and stroke rehabilitation, and scope for accelerated influence in the field, has been affirmed by our success in 2014 as lead site and Principal Investigator of an international James S. McDonnell Collaborative Award to Translate Neuroscience to Rehabilitation and Everyday Life (2015-2017; $528,000 USD; a consortium of 70 researchers worldwide) and lead of the clinical discovery and neuroimaging stream on the NHMRC Centre for Research Excellence in Stroke Rehabilitation and Brain Recovery (20152019; $2,500,000).

Targeting rehabilitation to the individual based on viable brain networks

Few rehabilitation interventions are based on robust principles of neuroscience. With a rare combination of expertise in clinical rehabilitation and neuroscience our program of research is designed to build stroke rehabilitation evidence: from clinical discovery to implementation. Our group has demonstrated changes in the brain associated with rehabilitation and how therapy may be used to drive neuroplastic changes. However, as yet, we do not have effective means of identifying individuals who may benefit from therapy nor how to select the most optimal therapy for an individual. In our current study we examine for the first time, how different training conditions (task-specific vs transfer-enhanced) and different lesion sites (cortical vs subcortical) impact on reorganization of brain networks involved in recovery of touch sensation. This project Effective sensory rehabilitation after stroke: Targeting viable brain networks is funded by an NHMRC Project grant (2012-2015; CIA Carey). In 2014 we expanded our recruitment sites and increased our recruitment to the study. We continue to collaborate with expert neurologists in Germany and Newcastle (Aus) and with the Advanced MRI Development team at the Florey. We are also involved

THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

in the program of research into neuroimaging outcomes of motor recovery after stroke conducted in Newcastle at the Hunter Medical Research Institute. Our findings will guide therapists in choosing the best therapy for the right individual, based on knowledge of brain networks that have capacity to adapt. Translation: We developed a video animation to depict the translation of neuroscience to an effective rehabilitation intervention: i.e. Connect: Neurogenesis to Neurorehabilitation. The video is available at: http://youtu.be/ G9V3I30pn68 and has been sought after by therapists and stroke survivors alike. Our systematic approach to development of the SENSe neuroscience-base intervention now provides a template for future development of interventions and is the topic of keynote presentations (see below). Expected outcomes from this program of research include: (i) First-ever knowledge of how brain networks alter under different sensory training conditions; and (ii) Evidencebased guidelines to better target sensory rehabilitation to individuals, informed by knowledge of brain networks with capacity to adapt.

The clinical value is on identifying strengths of an individual, i.e. neurobiological potential, to use in therapy, and best use of limited resources. Targeting therapy according to viable brain networks is a paradigm shift for stroke rehabilitation.

Neurobiology of recovery and impact of depression on outcome after stroke

One barrier to successful rehabilitation and a major factor impacting recovery and quality of life is post-stroke depression. Despite evidence that depression and stroke are epidemiologically linked, our recent meta-analyses indicate few reliable associates. Our group are using a multimodal approach to investigate the neurobiological associates of recovery and post-stroke depression in a longitudinal stroke cohort. This cohort study is influential in its measurement of a profile of outcomes from mechanisms to participation, and includes blood-based biomarkers, changes in brain structure and function, mood, cognition, lifestyle, and activity participation over 12 months. The cohort, known as START: STroke imAging pRevention and Treatment, is funded by a CSIRO preventative health flagship ($3,000,000; 2010-2015). START PrePARE (Prediction and Prevention to Achieve optimal Recovery Endpoints), the longitudinal cohort arm with advanced imaging and clinical outcomes is led through the Neurorehabilitation and Recovery group. 100% of the sample was recruited as of 2014 and the final data will be collected in April 2015. The imaging and biomarker work is supported by teams from CSIRO (Biomedical Imaging and Molecular Biomarkers), the Florey Advanced MRI Development group, and the La Trobe Institute for Molecular Science. Findings are contributing new insights to stroke rehabilitation that is founded in neuroscience.

Expected outcomes include: (i) Novel insight into the neurobiology of post-stroke depression and functional outcome; (ii) Identification of imaging and molecular associates of post-stroke depression to help identify people ‘at risk’ of depression early, inform personalised approach to rehabilitation, and guide more targeted interventions; (iii) Identification of individual patient characteristics that impact on outcome during the 12-month period; (iv) Quantification of the impact of stroke-associated depression on participation in household, social, and leisure activities.

Implementation of evidence-based practice in clinical practice settings

The main objective of this research theme is to develop a template and clinical practice guidelines for implementation of evidence-based rehabilitation in clinical practice settings. This will be achieved in the first instance through implementation of the SENSe intervention.

This therapy has been described as ‘life changing’ from stroke survivors. The SENSe Implement study will address one important knowledge-practice gap in stroke rehabilitation: treatment of sensory loss after stroke. Our national survey of current evidencebased assessment and treatment of sensory impairment after stroke, accepted for publication in 2014, highlighted this important evidence-practice gap. This gap now needs to be systematically and urgently addressed. We have produced specialised therapeutic tools, manuals and training videos to teach therapists to effectively

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use SENSe therapy with their clients. These tool are now available for use in clinical practice settings nationally and internationally.

We will now implement this effective neuroscience-based sensory intervention in clinical practice settings using recommended ‘knowledge-to-action’ methods. The SENSe Implement project will be funded in-kind from hospitals and a dedicated SENSe fund.

Three experienced therapists who will be involved in the study have enrolled in a PhD and Masters research program. All have now received competitive scholarships to support their work in this field.

The team also includes a rehabilitation physician/director, senior therapist and 5-10 therapists at each site. Professor Marion Walker and Dr Louise Connell will support implementation in the UK. Expected outcomes include: (i) Improved outcomes for stroke patients receiving evidence-based SENSe rehabilitation; (ii) A community of ‘up-skilled’ champion therapists; (iii) New evidence of the success of knowledge-transfer methodologies in stroke rehabilitation; and (iv) Dissemination of the implementation template, with application to interventions for other functions.

Application of SENSe in children

The SENSe intervention is also being applied to children with cerebral palsy using randomised controlled methodology. A research group (n=8) comprising a paediatrician, therapists and PhD students are conducting this research in Perth in collaboration with us.

PUBLIC HEALTH AND EPIDEMIOLOGY Leader: Associate Professor Dominique Cadilhac

Our group conducts various projects related to improving the clinical management and outcomes of stroke. Research on the quality of stroke care in public hospitals continues to be a major objective, as well as designing and evaluating systems to improve the delivery of evidence-based care and achieve better health outcomes after stroke.

Research highlights for 2014

In 2014, our team continued to lead the expansion of the Australian Stroke Clinical Registry and the Victorian Stroke Telemedicine Program. In addition, there was terrific progress with the Stroke123 NHMRC partnership project whereby AuSCR data were linked to the National Death Index and the acute hospital quality improvement intervention, facilitated by the Stroke Foundation, was delivered across 20 hospitals in Queensland. These are our major flagship projects. We also continued to provide research support for the National Stroke Foundation ‘Know your numbers program’ with approximately 190,900 registrants data from 1,519 health check stations (93 per cent were from pharmacy locations) processed for analysis. The ‘Know your numbers’ program promotes the importance of regular blood pressure checks and the awareness of other stroke risk factors in the community. People who are identified as potentially being at high risk of stroke or cardiovascular disease are referred to their doctor for advice on how to lower their risk and stay healthy. The research program associated with this initiative is being conducted in collaboration with Monash University, where Associate Professor Dominique Cadilhac is also based. Assoc Prof Cadilhac was also successful in obtaining an NHMRC grant ($475K) to undertake a comprehensive cost-effectiveness analysis of the Victorian Stroke Telemedicine program with Monash and Deakin Universities. In 2014, our team also co-hosted the second national workshop with the Stroke Foundation on stroke data, quality and telemedicine which was attended by over 100 delegates.

Stroke Telemedicine (leaders Professor Chris Bladin and Associate Professor Dominique Cadilhac)

The Victorian Stroke Telemedicine initiative is a ground breaking program of work that has the potential to transform the way clinicians collaborate across organisational boundaries to deliver the best care possible to stroke patients irrespective of their location.

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The objective of the program is to improve the care of acute stroke patients across Victoria through the use of cutting edge technology.

We aim to do this by implementing a seamless videoconference service to 16 regional hospitals providing 24 hour access to a stroke neurologist roster. Professor Chris Bladin and Assoc Prof Cadilhac, who co-lead this work, have secured over $8.96 million in funding for this program with an additional $475K for a more complete costeffectiveness analysis with project funding from the NHMRC. The Victorian Stroke Telemedicine Program includes three projects.

The initial project was the VST – Bendigo, a successful single site telemedicine project undertaken at Bendigo Health which concluded in 2013. The VST - Loddon Mallee project was commenced in 2013 and is funded by the Victorian Government under the Broadband Enabled Innovation Program (BEIP) grant. This project was the basis for expanding support using the Bendigo model to include Echuca Regional Health, Swan Hill District Health and Mildura Base Hospital in 2014. This work has been project managed by Michelle Vu who joined our team in 2014. At the conclusion of the twoyear BEIP funding, Loddon Mallee health services will continue to receive support under the VicStroke Project. The VicStroke Project is funded by the Australian Government Health and Hospital Fund and will continue to support the VST Loddon Mallee project whilst increasing the scope to include a further 12 hospitals across the other regions of Victoria. This will enable state wide coverage of the teleneurology service and which is funded until 2018. These projects form the largest acute stroke telemedicine program in Australia. Our project partners include Victorian Stroke Clinical Network (Victorian Department of Health), Monash University, Telstra, Polycom, Ambulance Victoria, National Stroke Foundation and the Loddon Mallee Rural Health Alliance. Boehringer Ingleheim has also provided an educational grant to support adaptations to the AuSCR web-tool and education.

In the Victorian Stroke Telemedicine program there are three key research themes: i) clinical ii) implementation science, and iii) health economics. The data collection has been developed to use the infrastructure available through the Australian Stroke Clinical Registry (AuSCR) (Assoc Prof Cadilhac and The Florey are national data custodians) which has been expanded to include stroke telemedicine variables. In this way, ongoing benefits of the program can be captured to measure sustainability impacts beyond 2018.

Australian Stroke Clinical Registry and Stroke123 NHMRC partnership project (leader Associate Professor Dominique Cadilhac)

Our team leads expansion of the Australian Stroke Clinical Registry (AuSCR), mainly across Queensland and Victoria where these respective State governments have invested in its use for monitoring and improving stroke care. The data from AuSCR are also being used as part of a NHMRC Partnership grant whereby a non-randomised, multi-centre, historical, controlled cohort substudy in Queensland that involves quality improvement interventions is being undertaken. Through this work, Assoc Prof Cadilhac is also leading efforts to advance cross-jurisdictional data linkage in Australia and, as such, has established a highly imminent working party that includes members of the Australian Institute of Health and Welfare, the Population Health Research Network and lead researchers from various states who have undertaken data linkage projects, as well as representatives of various State Health Departments. In 2014, she convened a national workshop to progress collectively these efforts to achieve cross-jurisdictional data linkage).

In 2014, there were 51 hospitals with ethical approval to collect data in AuSCR which is an increase from 47 in 2013 (AuSCR 2013 annual report available at www.auscr.com.au). At the end of 2014, there were over 23,000 registered patients of which 5435 were added in 2014. Overall, 2.7 per cent have opted out information from the registry. The Florey AuSCR team, in particular registry manager Brenda Grabsch, data managers Francis Kung and Kate Paice, Queensland coordinator Enna Salama and Victorian Coordinator Kasey Wallace have been the driving force behind the expansion of

AuSCR in 2014. At the end of 2014, the team were informed that the Victorian Department of Health, through the Victorian Stroke Clinical Network, had committed about $785,000 to support greater establishment of AuSCR within Victorian hospitals. The Victorian government has provided, to date, the largest commitment we have received from government to support this initiative.

CLINICAL TRIALS Leader: Professor Geoffrey Donnan

The Clinical Trials Platform crosses an array of clinical trial initiatives in stroke. The platform services of Neuroscience Trials Australia (NTA), housed within the Florey, are utilised. These include project management, regulatory and monitoring issues, statistical and data storage.

Research highlights for 2014

The main focus of clinical trial activity continues to be around the extended time window for neurological deficits (EXTEND) series of trials. This is in partnership with Professor Stephen Davis at the Melbourne Brain Centre@RMH and his colleagues.

This family of trials is designed to extend the time window for the most commonly used stroke intervention, thrombolysis (clot dissolving). We are testing the hypotheses that the time window may be extended out to nine hours from 4.5 hours and that clot removal with the SOLITAIRE device may improve outcomes. This trial has now been completed and the results will be presented at the International Stroke Congress in the US in February 2015.

A further study in which the hypothesis that administration of tranexamic acid (a clot promoting agent) may improve outcomes in patients with intracerebral haemorrhagic by minimising further bleeding into the brain. Analysis has been completed on an earlier trial (ARCH trial - prevention of second stroke events in patients with stroke caused by clots coming from the main artery from the heart. Although the trial was stopped early because of the inability of the European arm to continue, the combination of the antiplatelet agents aspirin and clopidogrel were found to be safe and as effective as the anticoagulant warfarin. Given the simplicity of use of the combination antiplatelet agents, these would be the obvious ones to use in clinical practice. The results were published in the journal Stroke.

Clinical trial activity is built upon national and international collaboration. Of the numerous trials conducted at the Florey, the majority are conducted by collaborating with numerous academic colleagues throughout Australia and commonly with those in other countries. Particular collaborations occur with Professors Stephen Davis at the Royal Melbourne Hospital, Christopher Levi and Mark Parson at Newcastle, Greg Albers at Standford University USA, Pierre Amarenco Paris France, and Werner Hacke Heidelberg Germany.

Commercial projects conducted through Neuroscience Trials Australia (NTA)

Clinical trial activity in stroke also includes very important partnerships and collaborations with pharmaceutical and biotechnology companies (both local and global). The trials range from Phase II to III and include drug as well as devices. One of the products assessed aims to assist in dissolving clots that are associated with stroke. Another trial is assessing the use of aspirin compared to another agent in the prevention of TIAs.

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STROKE PRECLINICAL SCIENCE

AVERT EARLY INTERVENTION RESEARCH PROGRAM

COLLABORATIONS

KEY COLLABORATIONS

ҩҩ International cooperation in preclinical stroke research: Correcting the problems of bias, lack of statistical power and lack of generalizability in preclinical research requires larger, more rigorously controlled and replicated experiments. Our approach to achieve this is establishment of the Multi-PART (mentioned above). This platform has the potential to transform preclinical animal research across the life sciences, similar to the tremendous improvements in clinical research that occurred through the introduction of multicenter clinical trials. This program is now being geared up for the conduct of the first multi-center pre-clinical studies. ҩҩ NHMRC Program (Donnan, Davis, Hankey, Parsons & Howells).

Our NHMRC program (AppID’s 251525, 454417, 1013612) established a unique vertically integrated program with basic and clinical science elements to select neuroprotectants for clinical trial.

We then expanded our basic science so that we had the capacity to identify novel targets for therapy and study the role of long term plasticity and are now exploring the use of stem cell derived human neurons as a drug screening tool and the use of blood biomarkers to select stroke patients for treatment. ҩҩ Stroke on a chip: Since our understanding of human stroke pathophysiology is incomplete, we may not have targeted the right cells or the right molecular processes within these cells in our attempts to develop drugs for stroke. A new collaboration with colleagues from University of Queensland (Prof Justin CooperWhite, A/Prof Ernst Wolvetang), University of Melbourne (Dr Mirella Dottori) and CSIRO (Dr William Wilson, Dr Dadong Wang) will use human neurons, astroglia and oligodendroglia derived from embryonic stem cells grown on and microbioreactor arrays, to better define the human ischemic cascade. The multifactorial capacity of the MBAs will allow rapid and reproducible examination of complex interactions between the cells and of the effects of ischemia and of the pharmacological injuries, previously used to identify the key steps in the rodent ischemic cascade, on the biology of these cells.

This data will allow us to build the first quantitative and statistically robust map of the human ischemic cascade. The nodes of the map most easily disrupted by ischemia and related insults and those that allow for the greatest degree of normalization when treated will be identified as therapeutic targets for future drug testing. ҩҩ Eng Lo, Harvard, USA, Novel lipoxygenase inhibitors to reduce oxidative injury after stroke (US Patent 2012/0053220 A1); ҩҩ Dave Lambeth, Emory University, USA, Novel NOX inhibitors to treat stroke. ҩҩ William Wilson & Lance Macaulay, CSIRO, Biomarkers to generate a stroke clock (Patent PCT/AU2012/000071).

EDITORIAL POSITIONS

ҩҩ Evidence based preclinical medicine (Editor in chief) ҩҩ International Journal of Stroke (Associate Editor) ҩҩ Virtual Medical Centre (Editorial board member) ҩҩ Journal of Experimental Stroke Translational Medicine (Editorial board member) ҩҩ Translational Stroke Research (Editorial board member).

STAFF

ҩҩ Dr Katherine Jackman ҩҩ Dr Ana Antonic ҩҩ Dr Sarah McCann ҩҩ Dr Sarah Rewell ҩҩ Dr Taryn Wills ҩҩ Dr Marie Dagonnier

ҩҩ Charlotte Krenus ҩҩ Alice Liu ҩҩ Heidi Ho ҩҩ Katie Ardipradja ҩҩ Kate Sidon

Gothenburg University, Sweden; St Olav’s University Hospital, Norway; Glasgow University, UK; Edinburgh University, UK; Hunter Medical Research Institute, NSW; Austin Health, Vic; Melbourne Health, Victoria; Linköping University, Sweden.

EDITORIAL POSITIONS

ҩҩ Stroke ҩҩ International Journal of Stroke, Section editor Rehabilitation ҩҩ Topics in Stroke Rehabilitation ҩҩ International Journal of Therapy and Rehabilitation ҩҩ Journal for Neurologic Physical Therapy ҩҩ American Heart Association writing group “Physical Activity and Exercise Recommendations for Stroke Survivors.” (2014) ҩҩ Editorial board member, BMC Neurology MAJOR NATIONAL AND INTERNATIONAL CONFERENCES

ҩҩ World Stroke Conference, Invited speaker. Istanbul. ҩҩ Physiotherapy New Zealand Conference, Linking the Chain, Auckland. Keynote Speaker. ҩҩ World Federation for Neurorehabilitation, Invited speaker & Plenary chair – Advancing Clinical Trials in Neurorehabilitation. Istanbul. ҩҩ Singapore Rehabilitation Conference. Invited speaker. Singapore. ҩҩ International Stroke Conference, San Diego. ҩҩ NTRI Forum. (National Trauma Research Institute) Using Evidence Briefs and Structured Stakeholder Dialogues to address challenges in trauma care, Melbourne. ҩҩ University of Melbourne, Melbourne. Evidence based medicine – views from a researcher, clinician and guideline developer. ҩҩ Stroke Society of Australasia Scientific Meeting, Hamilton Island. ҩҩ The Florey Institute of Neuroscience and Mental Health, Stroke Division. Annual Scientific Meeting. Nelson Bay. ҩҩ Occupational Therapy Conference, Adelaide. ҩҩ Australasian Nursing & Allied Health Stroke Conference, Sydney. ҩҩ Australasian Faculty of Rehabilitation Medicine (AFRM) 2014 ASM, Adelaide. ҩҩ International Cognitive Neuroscience Conference, Brisbane. ҩҩ Australian Faculty of Rehabilitation Medicine Conference (invited speaker).

KEY STAFF

ҩҩ Fiona Ellery ҩҩ Dr Janice Collier ҩҩ Jan Chamberlain ҩҩ Tara Purvis ҩҩ Dr Toby Cumming ҩҩ Dr Coralie English

ҩҩ Dr Julie Luker ҩҩ Dr Liam Johnson ҩҩ Karen Borschmann ҩҩ Sharon Kramer ҩҩ Anne Hokstad ҩҩ Nat Fini

NEUROREHABILITATION AND RECOVERY COLLABORATIONS INTERNATIONAL

ҩҩ Washington Uni. St. Louis. USA ҩҩ Heinrich Heine University, Germany ҩҩ University of Haifa, Israel

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ҩҩ University of Nottingham, UK ҩҩ Department of Psychological and Brain Sciences, Indiana Uni, USA ҩҩ Department of OT Education, Kansas Medical Centre, USA ҩҩ A/Prof Thomas Linden. Neurologist/psychiatrist, Gothenburg, Sweden. ҩҩ Dept. of Occupational Science and Occupational Therapy and Graduate Dept. of Rehabilitation Science, University of Toronto, Canada ҩҩ Dept. of Clinical and Biological Neurosciences, University. Hospital, Grenoble, France ҩҩ McDonnell consortia: Advancing the Science of Rehabilitation. 70 scientists from North America, Israel/Europe and Australasia. ҩҩ Implementation Science consortia (UK, Canada, Aus). ҩҩ International Post Stroke Upper Extremity Working Group. ҩҩ National Institute of Health (NIH) Toolbox: Assessment of Neurological and Behavioural Function group.

NATIONAL

ҩҩ CSIRO preventative Health Flagship. START program of research. ҩҩ Hunter Medical Research Institute, Newcastle, Centre for Brain and Mental Health Research ҩҩ University of Newcastle, NSW ҩҩ Advanced MRI Development, Florey Institute ҩҩ La Trobe University: School of Allied Health; Research Focus Area, Sport Exercise and Rehabilitation; and Living with Disability research group (LiDS). ҩҩ La Trobe Institute of Molecular Sciences (LIMS) ҩҩ School of Paediatric and Child Health, University of Western Australia ҩҩ Australian National University, Canberra ҩҩ Allied and Public Health, Australian Catholic University, Melbourne. ҩҩ Neurology, Austin Health EDITORIAL POSITIONS

ҩҩ Neurorehabilitation and Neural Repair ҩҩ Occupational Therapy International ҩҩ Australian Occupational Therapy Journal ҩҩ Brain Impairment.

trends and gender differences in stroke between United States, Australia and Singapore: An In-depth cross-country comparison.

McDonnell International Scholars Academy 5th International Symposium.

St Louis. MO. ҩҩ Stroke rehabilitation and services in late stages of recovery and return to the community: Comparisons from three corners of the globe.

McDonnell International Scholars Academy 5th International Symposium.

St Louis. MO. ҩҩ Same intervention-Different reorganization: Impact of lesion location on training touch after stroke. 2014 Organisation of Human Brain Mapping. Hamburg, Germany. ҩҩ Brain Regions Activated during Tactile Stimulation in Healthy Individuals: An ALE meta-analysis. 2014 Organisation of Human Brain Mapping. Hamburg, Germany. ҩҩ Functional and structural connectivity in the brain associated with depression after stroke. 8th World Congress for NeuroRehabilitation.

Istanbul, Turkey. ҩҩ SENSe: Individual patient characteristics that predict favorable outcomes for sensory rehabilitation after stroke. 8th World Congress for NeuroRehabilitation. Istanbul, Turkey. ҩҩ The Path through Life project. ICNE 2014. International Conference of Neurology and Epidemiology. ҩҩ Automated detection of brain regions associated with post-stroke depression: A hypothesis. ISMRM 2014. Milan, Italy. ҩҩ Automated lesion detection from multimodal brain MRI using Markov random fields and random forest. ISMRM 2014. Milan, Italy. ҩҩ Fish oil diet associated with acute reperfusion related haemorrhage, and with reduced stroke-related sickness behaviours and motor impairment. Modulating the Brain: Facts, Fiction, Future Conference.

Belgian Brain Council. ҩҩ Sensory discrimination training in children with hemiplegic cerebral palsy: 2 case studies. 8th World Congress for NeuroRehabilitation.

Istanbul, Turkey. ҩҩ Advancing the Science of Rehabilitation: Translating Neuroscience and Rehabilitation into Everyday Life. 16th World Federation of Occupational Therapy Congress. Yokohama, Japan. ҩҩ Understanding occupational/activity participation after stroke. 16th World Federation of Occupational Therapy Congress. Yokohama, Japan. ҩҩ Extending the Time for Thombolysis in Emergency Neurological Deficits - The Extend Trial. International Stroke Conference 2014. San Diego, CA.

MAJOR NATIONAL AND INTERNATIONAL CONFERENCES 2014 INTERNATIONAL – KEYNOTE AND INVITED

ҩҩ Cross-Cultural Issues in Stroke: Policy, Population and Clinical Comparisons. Global Ageing Research Network Meeting. McDonnell International Scholars Academy 5th International Symposium. The Role of Research Universities in Addressing Global Challenges. St Louis. MO. ҩҩ Neuroscience makes Sense for Occupational Therapy. Washington University at St Louis. St Louis. 8th October 2014. ҩҩ Post-Stroke Rehabilitation; Translating Neuroscience to neurorehabilitation. 11th International Conference on Low Vision.

Advancing Research, Upgrading Practice, Improving Participation.

Melbourne. ҩҩ A learning based model of recovery and rehabilitation post-stroke in the Symposium: Rehabilitation of Neurological Vision Impairment.

11th International Conference on Low Vision. Advancing Research, Upgrading Practice, Improving Participation. Melbourne. ҩҩ Imaging associates of post-stroke depression and functional outcome: A longitudinal cohort study. 12th International Conference on Cognitive Neuroscience. Symposia. Brisbane. ҩҩ The Stroke Profile and Recovery Journey: Across Countries and Over time. McDonnell International Scholars Academy 5th International Symposium. St Louis. MO. ҩҩ Health indicators, incidence, prevalence and mortality rates, temporal

PUBLIC HEALTH AND EPIDEMIOLOGY COLLABORATIONS Stroke and Ageing Research, School of Clinical Sciences at Monash Health, Monash University; The George Institute for Global Health; Stroke Society of Australasia, La Trobe University; Hunter Stroke Service, NSW Australia; New South Wales Health, Australia; National Stroke Foundation, Australia; Australian Catholic University, Australia; Centre for Translational Excellence in Neuroscience, Melbourne Health; Queensland Statewide Stroke Clinical Network; Victorian Stroke Clinical Network; Victoria; Victorian Department of Health, Edith Cowan University, Western Australia; University of Western Australia; South Australian Statewide Stroke Clinical Network; NSW Statewide Stroke Clinical Network; Queensland Health; Michigan State University, USA; Ottawa Hospital Research Institute, Canada;; Telehealth Connect, Australia; NBNCo, Australia; Loddon Mallee Rural Health Alliance, Australia; Loddon Mallee Rural Health Alliance; Bendigo Health, Echuca Hospital, Swan Hill Hospital, Wangaratta Hospital, Albury and Wodonga Hospitals, Victoria Australia; Ambulance Victoria; Telstra, Australia; Polycom, Australia; School of Population Health, University of Melbourne; University of South Australia; Menzies Institute, University of Tasmania; University of Newcastle, NSW; Hunter Medical Research Institute, NSW;

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Nursing Research Institute, NSW; Population Health Research Network, Eastern Health, Monash University; Health Outcomes Institute, Arizona US; University of Tennessee Health Science Center, Memphis US; School of Health, University of Central Lancashire, Preston, UK EDITORIAL POSITIONS

ҩҩ Cadilhac: International Journal of Stroke, Clinical Audit, Dove Medical Press and World Journal of Hypertension ҩҩ Dewey: Stroke journal and International Journal of Stroke ҩҩ Bladin: Current Neurology and Neuroscience Reports and British Journal of Sports Medicine STAFF

ҩҩ Dr Adele Gibbs ҩҩ Alison Dias ҩҩ Brenda Grabsch ҩҩ Prof Christopher Bladin ҩҩ Enna Salama ҩҩ Francis Kung ҩҩ Gary Eaton ҩҩ Prof Helen Dewey (honorary) ҩҩ Karen Moss ҩҩ Kasey Wallis

ҩҩ Kate Paice ҩҩ Dr Katie Bagot ҩҩ Linda Francis ҩҩ Michelle Vu ҩҩ Monique Kilkenny (honorary) ҩҩ Nancy Capitanio ҩҩ Sally Berger ҩҩ Tara Purvis (honorary)

MAJOR NATIONAL AND INTERNATIONAL CONFERENCES CADILHAC

ҩҩ Reviewing the options for performance benchmarks for acute stroke care in Australia NHMRC Research Translation faculty conference, Melbourne, November 2014 ҩҩ Update on the Victorian Stroke Telemedicine (VST) Project. Smart Strokes, Sydney. August 2014 ҩҩ Stroke data collection in the Australian Stroke Clinical Registry – Progress with a purpose, Smart Strokes, Sydney August 2014 ҩҩ Introduction to Research Principles, Smart Strokes, Sydney August 2014 (Invited) ҩҩ Variances in hospital mortality: Experiences from the Australian Stroke Clinical Registry (AuSCR). Stroke Society of Australasia, Hamilton Island. August 2014 ҩҩ NSW Stroke Services Clinical Network, panel discussion with Agency for Clinical Innovation on stroke data May 2014 (Invited) ҩҩ The economic implications of practice gaps in stroke care: an Australian case study. European Stroke Conference, Nice, France, May 2014 ҩҩ Co-convenor National Stroke Data, Quality and Telemedicine workshop, Florey, Melbourne March 2014 BLADIN

ҩҩ Co-convenor National Stroke Data, Quality and Telemedicine workshop, Florey, Melbourne March 2014 DEWEY

ҩҩ Generalisability of imaging selection for intra-arterial therapy in ischaemic stroke – up to 30% of tPA eligible patients are potentially eligible. European Stroke Conference, Nice, France May 2014. ҩҩ Early mobilisation after thrombolysis (rt-PA) in acute stroke: are rtPA treated patients enrolled in a trial of early mobilisation (AVERT) different from those that are not? International Stroke Conference, San Diego, USA, February 2014.

VU

ҩҩ Experience with scaling up the Victorian Stroke Telemedicine Programme, Successes and Failures in Telehealth (SFT-14), Adelaide November 2014

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GRABSCH

ҩҩ Australian Stroke Clinical Registry: progress and future plans.

Registry Special Interest Group, Melbourne, September, 2014.

KILKENNY

ҩҩ Quality of life and readmission after stroke: the Australian Stroke Clinical Registry experience, Stroke Society of Australasia, Hamilton Island, July 2014 ҩҩ Influence of area-level socioeconomic status and risk factors for stroke: impact of the New South Wales (NSW) Know your numbers program, Stroke Society of Australasia, Hamilton Island, July 2014

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on their body fat levels. These findings show that fat can be metabolised in dehydrated animals to produce water. We suspect that this process is controlled by osmoreceptors in the brain.

AUTONOMIC NEUROSCIENCE GROUP

SYSTEMS NEUROPHYSIOLOGY Leader: Professor Robin McAllen & Professor Richard Macdonell

A QUICK SNAPSHOT

In Systems Neurophysiology we seek to learn how the nervous system controls various bodily functions and how that control is altered in disease. Our disease focus includes not only neurological disorders such as epilepsy and multiple sclerosis, but also how the nervous system impacts on non-neurological diseases such as heart failure and inflammatory diseases. A clear understanding of basic mechanisms is crucial in developing better therapies and reducing the impacts of illness.

OUR FOCUS

AN IDEA LIKELY TO CHANGE LIVES BY 2035

Professor Robin McAllen heads the Systems Neurophysiology group at Parkville, which researches brain function in health and disease. A particular focus is on how the brain controls basic bodily functions such as blood pressure, body temperature, body fluids and breathing.

We have shown that a key area for upper airway control can be identified by a single gene-marker. This maker will allow us to investigate critical cell populations in animals, but importantly also in the human brain. These finding will significantly help us understand and treat neurodegenerative upper airway disorders.

“

We’ve made a very exciting finding about a primitive part of the brain called the nucleus of the solitary tract or NTS. We have found that adult neurogenesis occurs in the NTS and, importantly, that this process plays a critical role in the regulation of blood pressure. Using a synthetic analogue of the building blocks of DNA, our group found that adult neurogenesis in the solitary tract is increased in both genetically and experimentally induced hypertensive models.

The main challenge now is to understand how increased neurogenesis within the NTS contributes to hypertension. We believe this research will help us better understand the neurogenic origins of high blood pressure and reveal a new target for treating hypertensive patients.

” SENIOR STAFF

• Professor Robin McAllen • Emeritus Professor Derek Denton • Professor Richard Macdonell • Associate Professor Mathias Dutschmann • Dr David Farmer • Dr Davide Martelli • Associate Professor Clive May • Professor Michael McKinley • Dr Glenn Pennington • Dr Rohit Ramchandra • Dr Davor Stanić • Dr Song Yao • Dr Stuart McDougall • Dr Tara Bautista • Dr Lindsay Booth • Dr Tony Shafton • Dr Yugeesh Lankadeva • Dr Junko Kosaka •

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Leader: Robin McAllen

We investigate the central nervous pathways that regulate basic bodily functions such as blood pressure and body temperature, as well as their transmission to bodily targets via autonomic nerves.

RESPIRATORY NEUROBIOLOGY LAB Leader: Mathias Dutschmann

Research highlights for 2014

It has long been known that, to control body temperature and maintain it within a narrow range, the brain uses temperature signals from the skin and from deep body structures as well as from the brain itself. Tony Shafton, Michael McKinley and Robin McAllen are tracking down the brain’s intrinsic temperature sensors but in order to do this, we need to eliminate temperature signals arriving at the brain from the rest of the body. Others have shown that skin temperature signals relay in brainstem nuclei called the parabrachial nuclei: eliminating those structures prevents the influence of skin temperature on thermoregulatory responses such as increasing or decreasing blood flow to the skin. We hypothesised that temperature signals from deep body structures, such as the stomach and abdominal organs, are transmitted by to the brain by pathways closely similar to those that transmit skin temperature signals. In anaesthetised rats, we first showed that the nerves to blood vessels in the tail (its major organ of heat exchange) responded to temperature changes in the abdomen, and did so independently of brain or skin temperatures.

Next, we made lesions of the parabrachial nuclei, and confirmed that they blocked any influence of skin temperature on the thermoregulatory response of the rat’s tail nerves. Finally, we showed that these same lesions also blocked the effects of temperature changes in the abdomen. But the influence of brain temperature was preserved. Now we can remove the influence of temperature signals from the rest of the body and investigate the actions and neural pathways of the brain temperature sensors acting alone.

The research focus of the team hasn’t changed over the last 12 months and most of the time has been used to investigate the neural control of immune function. During 2014, we published a study (Martelli D., Yao S.T., McKinley M.J., McAllen R.M. Reflex control of inflammation by sympathetic nerves, not the vagus. J. Physiol., 592, 2014:1677-1686.

This was recommended in Faculty of 1000 and as the editor’s choice of the published issue), where we described a neural reflex, termed the inflammatory reflex, that controls inflammation. This study contradicts the current dogma, that considers the vagus nerve as the main player of the inflammatory reflex, and shows how inflammation is controlled by the splanchnic sympathetic nerves. We also performed a thorough investigation on the target organ of the inflammatory reflex. Our results (still unpublished), once again, contradict the common view that it’s the spleen the principal organ where nerves physiologically interact with white cells to inhibit inflammation. We now have data that demonstrate how this interaction is generalised to all the organs innervated by the greater splanchnic nerves (spleen, adrenal glands, liver, stomach and intestine).

We study the basic neural mechanisms underlying breathing, how these patterns of nerve activity adjust to accommodate other behaviours such as swallowing, and how they are modified during development and in neurodegenerative disease.

Research highlights for 2014

Our main research focus is how the central nervous system controls upper airway muscles to modulate respiratory airflow during normal breathing (eupnoea). We also want to understand how the same brain circuitry adapts during important oro-pharyngeal behaviours, such as swallowing and breathing. The upper airway control circuits are prone to neurodegeneration including symptoms such as breath and vocal disorders, and also dysphagia (swallowing disorders). We are showing that a key area for upper airway control can be identified by a single gene-marker (foxp2). This maker will allow us to investigate critical cell populations in animals, but importantly also in the human brain.

These finding will significantly facilitate our translational research program which aims to understand and treat neurodegenerative upper airway disorders.

NEUROCARDIOVASCULAR GROUP Leader: Clive May

The Neuro-cardiovascular group is investigating the effects of the sympathetic nervous system in diseases including heart failure and septic shock.

Research highlights for 2014

Effects of electrical stimulation of the renal nerve

Heart Failure

Heart failure is a complex syndrome resulting from structural changes in the heart that reduce cardiac output and thus perfusion of tissues. It is a major public health problem in all Western countries where, in addition to the human cost in terms of morbidity and mortality, it is estimated to cost more than five per cent of health budgets. Disturbingly, the incidence of new cases of heart failure is increasing due to the ageing of the population and the conversion of acute cardiac problems into chronic disorders. A novel technique that has been used for the treatment of hypertension, denervation of the renal nerves, has been proposed as a treatment for heart failure. It is however unclear how effectively this technique denervates the renal nerves and whether the nerves subsequently regrow.

Professor Michael McKinley has been on mean arterial pressure (MAP), heart rate (HR), investigating the relationship between fat renal vascular conductance (RVC) and renal blood flow (RBF). The left panel shows that the and hydration. When fat is broken down by Studies conducted by Dr Lindsea Booth responses in the control situation (black) were metabolism, it generates water as well as demonstrated that renal denervation with abolished acutely after renal denervation (green). energy. We wondered whether the body uses a clinically used radiofrequency catheter The right panel shows that the response at 5.5 this process to generate water when it is needed effectively denervated both the renal (red) and 11 months (blue) after denervation were to offset dehydration. We tested this idea in afferent and efferent renal nerves. This was similar to the control responses (black). rats. Using an MRI instrument designed for the demonstrated by a loss of renal sympathetic purpose, we measured their total body fat and nerve activity, lack of responses to electrical total body water before and after 24 hours of water deprivation. After this, stimulation of the renal nerve and absence of anatomical markers for their total body water fell by eight per cent and their body fat by 16 per afferent and efferent nerves in the kidney. We then demonstrated that cent. The fat levels returned to normal within 48 hours of restoring access at five months after denervation the level of renal nerve activity, the to water. Although dehydrated rats ate less food, reducing the food intake responses to electrical stimulation and level of anatomical markers of normally hydrated rats by the same amount had only a very small effect were close to normal, and had fully returned to normal by 11 months

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after denervation. These findings demonstrate that radiofrequency catheter-based renal denervation is effective, but raise questions regarding the mechanism by which renal denervation causes a prolonged fall in blood pressure in hypertensive patients.

NEUROVASCULAR BIOLOGY LAB Lead: Song Yao Research highlights for 2014

Septic shock

Sepsis is the major cause of death in intensive care units with a high mortality rate of 30-70 per cent. Sepsis causes more deaths than prostate cancer, breast cancer and AIDS combined and the annual number of cases of sepsis is increasing. Despite the high costs in terms of morbidity, mortality and health budgets, few advances have been made in understanding of the pathophysiological mechanisms of sepsis, and consequently new therapeutic strategies have not been developed.

One of the hallmarks of sepsis is a large fall in blood pressure that can lead to multi-organ failure and death. A primary treatment is to give vasopressor drugs to increase blood pressure, but in sepsis the responsiveness to the drugs is reduced, leading to severe hypotension.

One theory to explain this desensitisation is that the large increase in sympathetic nerve activity, that helps maintain blood pressure in sepsis, also has a detrimental action to reduce responsiveness of blood vessels. Dr Yugeesh Lankadeva and Dr Junko Kosaka have therefore investigated the effect of treatment with a drug, clonidine, that acts in the brain to inhibit sympathetic nerve activity. Although clonidine might be expected to cause a greater degree of hypotension, it in fact reduced the decrease in blood pressure during sepsis. An explanation for this is our finding that in sepsis treatment with clonidine fully restored the responsiveness of blood vessels to drugs that increase blood pressure. Clonidine might therefore be a useful treatment for septic patients who are resistant to vasopressor drugs and it is now important to confirm these experimental findings in a clinical trial in septic patients.

THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

Our group has made a very exciting finding in a primitive part of the brain call the nucleus of the solitary tract (NTS). This region of the brain stem is essential for regulating blood pressure. For many decades it was assumed that the adult brain does not acquire more brain cells (or neurones) in adulthood.

This was shown to be an incorrect assumption in the 1960’s when an American group at MIT showed that the birth of new brain cells, termed ‘adult neurogenesis’ occurs in only two parts of the adult brain - one responsible for memory and the other responsible for smell.

AUTONOMIC NEUROSCIENCE GROUP

NEUROVASCULAR BIOLOGY LAB

EDITORIAL POSITIONS AND AWARDS

MAJOR INTERNATIONAL CONFERENCES

MCALLEN

YAO

ҩҩ American Journal of Physiology (Regulatory, Comparative and Integrative Physiology). ҩҩ Temperature. ҩҩ Faculty of 1000. ҩҩ International Presentation. ҩҩ Physiology and Pharmacology of Temperature Regulation, Kruger National Park, South Africa, September 2014. ҩҩ Best 2014 research article published in the journal Temperature.

MARTELLI

Newly born brain cells (shown in red) have been discovered in the nucleus of the solitary tract or NTS. This region of the brain is essential for controlling blood pressure. We are currently trying to identify the function of these nascent cells and to understand how they contribute to high blood pressure.

We have recently demonstrated that adult neurogenesis also occurs in the NTS and, importantly, that this process plays a critical role in the regulation of blood pressure. Using a synthetic analogue of the building blocks of DNA our group found that adult neurogenesis in the solitary tract is increased in both genetically and experimentally induced hypertensive models. The main challenge now is to understand how increased neurogenesis within the NTS contributes to hypertension. We believe this research will help us better understand the neurogenic origins of high blood pressure and reveal a new target for treating hypertensive patients.

ҩҩ 2014: Editorial Board of the Journal of Immune Research. ҩҩ 2014: “Post-doctoral/Early Career Investigator Award” from the American Physiological Society (Neural Control/Autonomic Regulation section). Presented at EB2014 in San Diego, California, USA. ҩҩ 2015: Awarded with a IBRO Research Fellowship.

MCKINLEY

ҩҩ American Journal of Physiology.

(Regulatory, Comparative and Integrative Physiology) ҩҩ Faculty of 1000.

RESPIRATORY NEUROBIOLOGY LAB INTERNATIONAL CONFERENCES & EDITORIAL POSITIONS DUTSCHMANN

ҩҩ Oxford breathing meeting, Sydney 2014. ҩҩ Session speaker, session chair. ҩҩ Tara Bautista, session speaker. ҩҩ Editor in chief: Respiratory Physiology & Neurobiology (Elsevier).

CLINICAL BRAIN FUNCTION IN HEALTH AND DISEASE GROUP An infected neuron in the amygdala forced to express a light sensitive ion channel and fluorescent protein. Light activates the neuron.

A neuron in the brain stem is inhibited as light evokes neurotransmitter release in amygdala axons.

VISCEROSENSORY LAB Lead: Stuart McDougall Research highlights for 2014

One of the lab’s investigative aims is to understand how the brain coordinates internal organ function with behaviour, during stress and in diseases like depression or hypertension. We take a reductionist approach to study components of the neuronal network involved in these ‘automatic’ functions. With funding from the University of Melbourne Early Career Researcher Grants Scheme, my lab has utilised optogentic technology to pick these circuits apart over the last year. We are the first to demonstrate at the synaptic level how hypothalamic and amygdala neurones alter viscerosensory signals as they first enter the brain. With these fundamental findings the lab can establish how these networks are altered in autonomic related disease states. This work was presented at the meeting Central Cardiovascular and Respiratory Control at the Baker Institute during 2014 and I have been invited to present this work at the a combined meeting of the world’s major Autonomic Societies in 2015.

Lead: Richard Macdonell

NEUROCARDIOVASCULAR GROUP

Our lab studies how diseases such as epilepsy and multiple sclerosis change the excitability of neurones. A second focus is on the physiology of neurorehabilitation and neural repair.

COLLABORATIONS

Research highlights for 2014

ҩҩ Rush University Medical School, Chicago, USA.

We are currently conducting a placebo controlled study investigating whether the drug (4-aminopyridine) can be used to improve upper limb and hand function in patients with multiple sclerosis. The drug has previously been shown to improve walking speed and quality of life in patients suffering from MS. We use clinical measures of hand function which may respond to using the drug, such as strength and dexterity and tactile discrimination.

We are also conducting neurophysiological measures of conduction in central nervous system pathways using the techniques of transcranial magnetic stimulation and somatosensory evoked potentials. The drug is thought to produce benefits by blocking potassium channels in demyelinated axons thus permitting conduction to be through areas damaged by MS. We are on track to have results of this study available in early 2016.

ҩҩ Baker IDI, Melbourne. ҩҩ University of Lyon, France. ҩҩ University of Iowa, USA.

EDITORIAL POSITIONS MAY

ҩҩ American Journal of Physiology, Regulatory, Integrative and Comparative Physiology. ҩҩ Clinical and Experimental Pharmacology and Physiology. ҩҩ Frontiers in Integrative Physiology. ҩҩ Frontiers in Autonomic Neuroscience. ҩҩ Faculty of 1000.

MAJOR NATIONAL AND INTERNATIONAL CONFERENCES 2014 ҩҩ World Congress of Cardiology, Melbourne. ҩҩ PanAmerican Congress of Physiology, Iguassu Falls, Brazil. ҩҩ High Blood Pressure Research Council of Australia, Adelaide.

ҩҩ Pan-American Congress of Physiological Societies, Brazil 2014.

COLLABORATIONS

ҩҩ University of Sao Paulo, Sao Paulo Brazil. ҩҩ Roslin Institute, University of Edinburgh, Scotland. ҩҩ University of Bristol, United Kingdom.

CLINICAL BRAIN FUNCTION IN HEALTH AND DISEASE GROUP COLLABORATIONS MACDONELL

ҩҩ University of Queensland. ҩҩ Monash University. ҩҩ Biogen Idec (Australia).

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“

I am passionate about improving the lives of people with Parkinson ’s disease. It’s my life’s work. The thirst for scientific knowledge is important to me but knowing that the field can be directly applied to people, is immensely rewarding. My work gives me a real sense of achievement.

Finding a cure is no small task and it will take a coordinated effort. I would like to see all of the Parkinson’s groups, scientists and clinicians unite and to convince politicians to make this a national health priority. Together, we will win this battle.

”

Associate Professor David Finkelstein: Head, Parkinson’s disease laboratory

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ҩҩ Mr Andrew Abercrombie ҩҩ Mr Charles Allen AO

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FLOREY GOVERNORS

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NOMINATION

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

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OUR DONORS

OUR DONORS

We appreciate the generosity of our donors and would like to especially thank those who have given $100 or more during 2014

We appreciate the generosity of our donors and would like to especially thank those who have given $100 or more during 2014

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PUBLICATIONS CHAPTER BRAIN DEVELOPMENT AND REGENERATION

15.

Mo, C. Renoir, T., Hannan, A.J. (2014) Novel ethological endophenotypes in a transgenic mouse model of Huntington’s disease. Behavioral Brain Research 276:17-27 (Epub 2014 Apr 18; invited article for Special Issue on ‘Neuropsychiatric spectra’).

Hammond, V.E., Gunnersen, J.M., Goh, C.P., Low, L.H., Hyakumura, T., Tang, M.M., Britto, J.M., Putz, U., Howitt, J.A., and Tan, S-S (2014) Ndfip1 is required for the development of pyramidal neurone dendrites and spines in the neocortex.Cereb. Cortex 24:3289-3300

16.

Du X, Leang L, Mustafa T, Renoir T, Pang TYC, Hannan AJ (2014) The influence of the HPG axis on stress response and depressive-like behaviour in a transgenic mouse model of Huntington’s disease. Exp. Neurol.

263:63-71 [Epub 20 Sep. 2014].

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Goh, C.P., Putz, U., Howitt, J., Low, L.H., Gunnersen, J., Bye, N., Morganti-Kossmann, C. and Tan, S-S. (2014) Nuclear trafficking of Pten after brain injury leads to neurone survival not death Exp. Neurol 252:37-46

17.

Spanagel R, Vengeliene V, Jandeleit B, Fischer WF, Grindstaff K, Zhang X, Gallop M, Krstew EV, Lawrence AJ & Kiefer F (2014) Acamprosate produces its anti-relapse effects via calcium. Neuropsychopharmacology, 39, 783-791.

4.

Nivison-Smith, L., Chua, J., Tan, S-S, and Kalloniatis, M. (2014) Amino acid signatures in the developing mouse retina. Int J. Dev. Neurosci. 33C:62-80

18.

Duncan JR, Gibbs SJ & Lawrence AJ (2014) Chronic intermittent toluene inhalation in adolescent rats alters behavioural responses to amphetamine and MK801. Eur. Neuropsychopharmacol., 24, 480-486

5.

Howitt, J., Gybers, A., Ayton, S., Carew-Jones, F., Putz, U., Finkelstein, D., Halliday, G., and Tan, S-S. (2014). Increased Ndfip1 in the substantia nigra of Parkinsonian brains is associated with elevated iron levels. Plos One 9(1):e87119.

19.

6.

Altin, J.A., Daley, S.R., Howitt, J., Rickards, H.J., Batkin, A.K., Horikawa, K., Prasad, S.J., Nelms, K.A., Kumar, S., Wu, L.C., Tan, S-S., Cook, M.C., and Goodnow, C.C. (2014) Ndfip1 mediates peripheral tolerance to self and exogenous antigen by inducing cell cycle exit in responding CD4+ T cells. Proc Natl Acad Sci (USA) 111:2067-2074

Dick AL, Axelsson, M, Lawrence AJ* & Duncan JR* (2014) Specific impairments in instrumental learning following chronic intermittent toluene inhalation in adolescent rats. Psychopharmacology, 231, 1531-1542. * denotes co-corresponding authors.

20.

Wang YT, Qin WJ, Liu Q, Li YL, Liang H, Chen F, Lawrence AJ, Zhang XL, Liang JH (2014) Chaperone heat shock protein 70 in nucleus accumbens core: a novel biological target of behavioural sensitization to morphine in rats.

Int. J. Neuropsychopharmacol., 17, 469-484.

21.

Bird MK, Lohmann P, West B, Brown RM, Kirchhoff J, Raymond CR & Lawrence AJ (2014) The mGlu5 receptor regulates extinction of cocaine-driven behaviors. Drug Alc. Depend., 137, 83-89.

22.

Handford CE, Tan S, Lawrence AJ & Kim JH (2014) The effect of the mGlu5 negative allosteric modulator MTEP and NMDA receptor partial agonist D-cycloserine on Pavlovian conditioned fear. Int. J. Neuropsychopharmacol., 17, 1521-1532.

23.

Dick AL, Lawrence AJ* & Duncan JR* (2014) Chronic intermittent toluene inhalation initiated during adolescence in rats does not alter voluntary consumption of ethanol in adulthood. Alcohol, 48, 561-569. * denotes cocorresponding authors.

24.

Ryan PJ, Krstew EV, Sarwar M, Gundlach AL & Lawrence AJ (2014) Relaxin-3 mRNA levels in nucleus incertus correlate with alcohol and sucrose intake in rats. Drug Alc. Depend., 140, 8-16.

25.

Ash BL, Quach T, Williams SJ, Lawrence AJ & Djouma E (2014) Galanin-3 receptor antagonism by SNAP 37889 reduces motivation to self-administer alcohol and attenuates cue-induced reinstatement of alcohol-seeking in iP rats. J. Pharmacol. Sci., 125, 211-216.

26.

Li YL, Liu Q, Gong Q, Li JX, Wei SP, Wang YT, Liang H, Zhang M, Jing L, Yong Z, Lawrence AJ & Liang JH (2014) Brucine suppresses ethanol intake and preference in alcohol-preferring Fawn-Hooded rats. Acta Pharmacol Sin., 35, 853-861.

1.

Britto, J.M., Tait, K.J., Lee, E.P., Gamble, R.S. Hattori, M. and Tan, S-S (2014) Exogenous reelin modifies the migratory behavior of neurones depending upon cortical location. Cereb. Cortex 24:2835-2847

2.

PAGES 40–42

7.

CHAPTER BEHAVIOURAL NEUROSCIENCE PAGES 46–51

1.

Li, Y., Low, L.H., Putz, U., Goh, C.P., Tan, S-S, and Howitt, J. (2014) Rab5 and Ndfip1 are involved in Pten ubiquitination and nuclear trafficking. Traffic 15:749-761 (cover feature)

Murphy, B.P., Pang, T.Y., Hannan, A.J., Proffitt, T-M., McConchie, M., Kerr, M., Markulev, C., O’Donnell, C., McGorry, P.D., Berger, G.E. (2014) Vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF) in quetiapine treated first-episode psychosis. Schizophrenia Research and Treatment 2014: 719395 [Epub 2014 Feb 5].

2.

Hannan, A.J. (2014) Environmental enrichment and brain repair: Harnessing the therapeutic effects of cognitive stimulation and physical activity to enhance experience-dependent plasticity. Neuropathology and Applied Neurobiology 40: 13-25 (invited article for Annual Review Issue).

3.

Loy, C.T. and Hannan, A.J. (2014) Neurotoxicity in Huntington Disease. In: Handbook of Neurotoxicity, Springer (invited book chapter).

4.

Evans-Galea, M.V., Lockhart, P.J., Galea, C.A., Hannan, A.J., Delatycki. M.B. (2014). Beyond loss of frataxin: the complex molecular pathology of Friedreich ataxia. Discovery Medicine 17:25-35.

5.

Mo, C., Pang, T.Y., Ransome, M., Renoir, T., Hannan, A.J. (2014) High stress hormone levels accelerates the onset of memory decline in male Huntington’s disease mice. Neurobiology of Disease 69:248-262 [Epub 2014 May 10].

27.

6.

Lim, N.K.H., Pang, T.Y., McLean, C.A., Liddell, J.R., Hilton, J.B., Li, Q.-X., White, A.R., Hannan, A.J., Crouch, P.J. (2014) Localised changes to glycogen synthase kinase-3 and collapsin response mediator protein-2 in the Huntington’s disease affected brain. Human Molecular Genetics 23: 4051-4063 23: 4051-4063 [Epub 2014 Mar 14].

Chen NA, Jupp B, Sztainberg Y, Lebow M, Brown RM, Kim JH, Chen A & Lawrence AJ (2014) Knockdown of CRF1 receptors in the ventral tegmental area attenuates cue- and acute food deprivation stress-induced cocaineseeking in mice. J. Neurosci., 34, 11560 –11570 (featured in “This week in the journal”).

28.

Darwinkel A, Stanic D, Booth LC, May CN, Lawrence AJ & Yao ST (2014) Distribution of orexin-1 receptor-green fluorescent protein- (OX1-GFP) expressing neurons in the mouse brain stem and pons: co-localisation with tyrosine hydroxylase and neuronal nitric oxide synthase. Neuroscience, 278, 253–264 (front cover illustration).

29.

Ganella DE, Thangaraju P, Lawrence AJ & Kim JH (2014) Fear extinction in 17 day old rats is dependent on metabotropic glutamate receptor 5 signaling. Behav. Brain Res. 2014 Dec 10. pii: S0166-4328(14)00795-5.

30.

Perry C, Zbukvic I, Kim JH & Lawrence AJ (2014) The role of cues and contexts on drug-seeking behaviour. Br. J. Pharmacol., 171, 4636-4672.

31.

Kim JH & Lawrence AJ (2014) Drugs currently in Phase II clinical trials for cocaine addiction. Expert Opin.

Investig. Drugs., 23, 1105-1122.

32.

Giles EK, Lawrence AJ & Duncan JR (2014) Exploring the modulation of hypoxia-inducible factor (HIF)-1α by volatile anesthetics as a possible mechanism underlying volatile anesthetic-induced CNS injury. Neurochem. Res., 39, 1640-1647.

33.

Lawrence AJ & Cryan JF (2014) Found in translation? Commentary on a BJP themed issue about animal models in neuropsychiatry research. Br. J. Pharmacol., 171, 4521-4523.

34.

Veldsman M, Cumming T, Brodtmann A. Beyond BOLD: Optimizing functional imaging in stroke populations.

Hum Brain Mapp. 2014 Dec 2. doi: 10.1002/hbm.22711. [Epub ahead of print].

35.

Li Q, Lichter, R, Raffelt, A, Werden E, Pardoe H, Cumming T, Brodtmann, A Cortical thickness estimation in longitudinal stroke studies: a comparison of 3 measurement methods NeuroImage:Clinical 2014 Available online 23 August 2014.

36.

Brodtmann A. Vascular risk, depression, and stroke: Post hoc ergo propter hoc … or not. Neurology. 2014 Nov 4;83(19):1688-9. doi: 10.1212/WNL.0000000000000968. [Epub 2014 Oct 1].

37.

Cumming TB, Brodtmann A, Darby D, Bernhardt J. The importance of cognition to quality of life after stroke.

J Psychosom Res. 2014 Nov;77(5):374-9. doi: 10.1016/j.jpsychores.2014.08.009. [Epub 2014 Aug 29].

38.

Brodtmann A, Werden E, Pardoe H, Li Q, Jackson G, Donnan G, Cowie T, Bradshaw J, Darby D, Cumming Charting cognitive and volumetric trajectories after stroke: protocol for the Cognition And Neocortical Volume After Stroke (CANVAS) study. T. Int J Stroke. 2014 Aug;9(6):824-8.

7.

Hill, R.A., Klug, M., Von Soly, S.K., Binder, M.D., Hannan, A.J., van den Buuse, M. (2014) Sex-specific disruptions in spatial memory and anhedonia in a ‘two hit’ rat model correspond with alterations in hippocampal brainderived neurotrophic factor expression and signalling. Hippocampus 2014;24(10):1197-211.

8.

McOmish, C.E., Burrows, E.L. and Hannan, A.J. (2014) Identifying novel interventional strategies for psychiatric disorders: Integrating genomics, ‘enviromics’ and gene-environment interactions in valid preclinical models.

British Journal of Pharmacology 171: 4719-4728 (invited review for Special Issue on ‘Animal models of psychiatric disorders’).

9.

Tomas D, Prijanto A, Burrows EL, Hannan AJ, Horne MK, Aumann TD (2014) Environmental modulations of the number of midbrain dopamine neurons in adult mice. J. Vis. Exp. (accepted July 2014).

10.

Mo, C., Renoir, T., Hannan, A.J. (2014) Ethological endophenotypes are altered by elevated stress hormone levels in both Huntington’s disease and wildtype mice. Behavioural Brain Research 274: 118-127.

11.

12.

13.

14.

Mo, C., Renoir, T., Hannan, A.J. (2014) Effects of chronic stress on the onset and progression of Huntington’s disease in transgenic mice. Neurobiology of Disease 71: 81-94.

Hill, R.A, Ratnayake, U., Kiss von Soly, S., Klug, M., Binder, M.D., Hannan, A.J., Van Den Buuse, M (2014) Longterm effects of combined neonatal and adolescent stress on brain-derived neurotrophic factor and dopamine receptor expression in the rat forebrain. Biochim. Biophys. Acta 1842: 2126-2135.

Mazarakis NK, Mo C, Renoir T, van Dellen A, Deacon R, Blakemore C, Hannan AJ (2014) ‘Super-enrichment’ reveals dose-dependent therapeutic effects of environmental stimulation in a transgenic mouse model of Huntington’s disease. J. Huntington’s Dis. 3:299-309.

Renoir T, Argyropoulos A, Chevarin C, Lanfumey L, Hannan AJ (2014) Sexually dimorphic dopaminergic dysfunction in a transgenic mouse model of Huntington’s disease. Pharmacol. Biochem. Behav. 127C:15-20 [Epub 12 Oct. 2014].

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

Borschmann K, Pang MY, Iuliano S, Churilov L, Brodtmann A, Ekinci EI, Bernhardt J. Changes to volumetric bone mineral density and bone strength after stroke: A prospective study. Int J Stroke. 2013 Dec 23. doi: 10.1111/ij

40. Louey AG, Cromer JA, Schembri AJ, Darby DG, Maruff P, Makdissi M, Mccrory P. Detecting cognitive impairment after concussion: sensitivity of change from baseline and normative data methods using the CogSport/Axon cognitive test battery. Arch Clin Neuropsychol. 2014 Aug;29(5):432-41. doi: 10.1093/arclin/acu020. [Epub 2014 May 9].

41.

Lim YY, Maruff P, Pietrzak RH, Ellis KA, Darby D, Ames D, Harrington K, Martins RN, Masters CL, Szoeke C, Savage G, Villemagne VL, Rowe CC; AIBL Research Group. Aβ and cognitive change: Examining the preclinical and prodromal stages of Alzheimer’s disease. Alzheimers Dement. 2014 Nov;10(6):743-751.e1. doi: 10.1016/j. jalz.2013.11.005. [Epub 2014 Feb 28].

42.

Zhou L, Salvado O, Dore V, Bourgeat P, Raniga P, Macaulay SL, Ames D, Masters CL, Ellis KA, Villemagne VL, Rowe CC, Fripp J; AIBL Research Group. MR-less surface-based amyloid assessment based on 11C PiB PET. PLoS One. 2014 Jan 10;9(1):e84777. doi: 10.1371/journal.pone.0084777. eCollection 2014.

43.

Ellis KA, Szoeke C, Bush AI, Darby D, Graham PL, Lautenschlager NT, Macaulay SL, Martins RN, Maruff P, Masters CL, McBride SJ, Pike KE, Rainey-Smith SR, Rembach A, Robertson J, Rowe CC, Savage G, Villemagne VL, Woodward M, Wilson W, Zhang P, Ames D; AIBL Research Group. Rates of diagnostic transition and cognitive change at 18-month follow-up among 1,112 participants in the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing (AIBL). Int Psychogeriatr. 2014 Apr;26(4):543-54. doi: 10.1017/S1041610213001956.

[Epub 2013 Nov 20].

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60.

Kim JH, & Lawrence AJ (2014). Drugs currently in phase II trials for cocaine addiction. Expert Opinion On Investigational Drugs. 23: 1105-1122.

61.

Ganella DE & Kim JH (2014). Developmental rodent models of fear and anxiety: From neurobiology to pharmacology. British Journal of Pharmacology. 171: 4556-4574.

62.

Perry C, Zbukvic I, Kim JH, & Lawrence AJ (2014). The role of cues and contexts on drug-seeking behaviour.

British Journal of Pharmacology. 171: 4636-4672.

63.

Chen N, Jupp B, Sztainberg Y, Brown RM, Kim JH, Chen A, Lawrence AJ (2014). Knockdown of CRF1 receptors in the ventral tegmental area attenuates cue- and acute food deprivation stress-induced cocaine-seeking in mice.

Journal of Neuroscience. 34: 11560-11570. (This week in the journal article)

64.

Handford CE, Tan S, Lawrence AJ, & Kim JH (2014). The effects of mGlu5 negative allosteric modulator MTEP and NMDA receptor partial agonist D-cycloserine on Pavlovian conditioned fear. International Journal of Neuropsychopharmacology, 17: 1521-1532.

CHAPTER EPILEPSY

AUSTIN CAMPUS –

PAGES 54–59

1.

44. Moore EM, Mander AG, Ames D, Kotowicz MA, Carne RP, Brodaty H, Woodward M, Boundy K, Ellis KA, Bush AI, Faux NG, Martins R, Szoeke C, Rowe C, Watters DA; AIBL Investigators. Increased risk of cognitive impairment in patients with diabetes is associated with metformin. Diabetes Care. 2013 Oct;36(10):2981-7. doi: 10.2337/dc130229. [Epub 2013 Sep 5]. Erratum in: Diabetes Care. 2013 Nov;36(11):3850.

Ahmed OH, Lee H, Schneiders AG, McCrory P, Sullivan SJ. Concussion and Comedy: No Laughing Matter?

Pm&R 2014;6:1071-1072.

2.

Archer JS, Warren AEL, Jackson GD, Abbott DF. Conceptualizing lennox-gastaut syndrome as a secondary network epilepsy. Frontiers in neurology 2014;5:225-225.

45.

3.

Archer JS, Warren AEL, Stagnitti MR, Masterton RAJ, Abbott DF, Jackson GD. Lennox-Gastaut syndrome and phenotype: Secondary network epilepsies. Epilepsia 2014;55:1245-1254.

4.

Bagnall RD, Crompton DE, Cutmore C, Regan BM, Berkovic SF, Scheffer IE, Semsarian C. Genetic analysis of PHOX2B in sudden unexpected death in epilepsy cases. Neurology 2014;83:1018-1021.

5.

Berkovic SF, Jackson GD. ‘Idiopathic’ no more! Abnormal interaction of large-scale brain networks in generalized epilepsy. Brain 2014;137:2400-2402.

6.

Bhaganagarapu K, Jacksonw GD, Abbott DF. De-noising with a SOCK can improve the performance of eventrelated ICA. Frontiers in Neuroscience 2014;8.

7.

Brodtmann A, Werden E, Pardoe H, Li Q, Jackson G, Donnan G, Cowie T, Bradshaw J, Darby D, Cumming T. Charting cognitive and volumetric trajectories after stroke: protocol for the Cognition And Neocortical Volume After Stroke (CANVAS) study. International Journal of Stroke 2014;9:824-828.

8.

Carney PW, Jackson GD. Insights into the mechanisms of absence seizure generation provided by EEG with functional MRI. Frontiers in neurology 2014;5:162-162.

9.

Carvill GL, Weckhuysen S, McMahon JM, Hartmann C, Moller RS, Hjalgrim H, Cook J, Geraghty E, O’Roak BJ, Petrou S, Clarke A, Gill D, Sadleir LG, Muhle H, von Spiczak S, Nikanorova M, Hodgson BL, Gazina EV, Suls A, Shendure J, Dibbens LM, De Jonghe P, Helbig I, Berkovic SF, Scheffer IE, Mefford HC. GABRA1 and STXBP1: Novel genetic causes of Dravet syndrome. Neurology 2014;82:1245-1253.

10.

Coe BP, Witherspoon K, Rosenfeld JA, van Bon BWM, Vulto-van Silfhout AT, Bosco P, Friend KL, Baker C, Buono S, Vissers LELM, Schuurs-Hoeijmakers JH, Hoischen A, Pfundt R, Krumm N, Carvill GL, Li D, Amaral D, Brown N, Lockhart PJ, Scheffer IE, Alberti A, Shaw M, Pettinato R, Tervo R, de Leeuw N, Reijnders MRF, Torchia BS, Peeters H, O’Roak BJ, Fichera M, Hehir-Kwa JY, Shendure J, Mefford HC, Haan E, Gecz J, de Vries BBA, Romano C, Eichler EE. Refining analyses of copy number variation identifies specific genes associated with developmental delay. Nature Genetics 2014;46:1063-1071.

11.

Culvenor AG, Lai CCH, Gabbe BJ, Makdissi M, Collins NJ, Vicenzino B, Morris HG, Crossley KM. Patellofemoral osteoarthritis is prevalent and associated with worse symptoms and function after hamstring tendon autograft ACL reconstruction. British Journal of Sports Medicine 2014;48:435-U122.

12.

Darby D, Moriarity J, Pietrzak R, Kutcher J, McAward K, McCrory P. Prediction of winning amateur boxers using pretournament reaction times. Journal of Sports Medicine and Physical Fitness 2014;54:340-346.

13.

Derry CP, Scheffer IE. Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE) (July 2009, November 2010, April 2012, January 2014). In: Gilman S, editor-in-chief. MedLink Neurology. San Diego: Medlink Corporation. Available at www.medlink.com.

14.

Euro E-RESC, Epilepsy Phenome/Genome P, Epi KC. De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. American journal of human genetics 2014;95:360-370.

46.

47.

Harrington KD, Lim YY, Ellis KA, Copolov C, Darby D, Weinborn M, Ames D, Martins RN, Savage G, Szoeke C, Rowe C, Villemagne VL, Masters CL, Maruff P. The association of Aβ amyloid and composite cognitive measures in healthy older adults and MCI. Int Psychogeriatr. 2013 Oct;25(10):1667-77. doi: 10.1017/S1041610213001087.

[Epub 2013 Jul 18].

Lim YY, Villemagne VL, Laws SM, Ames D, Pietrzak RH, Ellis KA, Harrington KD, Bourgeat P, Salvado O, Darby D, Snyder PJ, Bush AI, Martins RN, Masters CL, Rowe CC, Nathan PJ, Maruff P; Australian Imaging, Biomarkers and Lifestyle (AIBL) Research Group. BDNF Val66Met, Aβ amyloid, and cognitive decline in preclinical Alzheimer’s disease. Neurobiol Aging. 2013 Nov;34(11):2457-64. doi: 10.1016/j.neurobiolaging.2013.05.006.

[Epub 2013 Jun 12].

Sahathevan R, Mohd Ali K, Ellery F, Mohamad NF, Hamdan N, Mohd Ibrahim N, Churilov L, Cumming TB. A Bahasa Malaysia version of the Montreal Cognitive Assessment: validation in stroke. Int Psychogeriatr. 2014 May;26(5):781-6. doi: 10.1017/S1041610213002615. [Epub 2014 Jan 28].

48.

Kramer SF, Cumming T, Churilov L, Bernhardt J. Measuring activity levels at an acute stroke ward: comparing observations to a device. Biomed Res Int. 2013;2013:460482. doi: 10.1155/2013/460482. [Epub 2013 Oct 27].

49.

Bernhardt J, Cumming T. The elephant in the single room debate: keeping patients active. BMJ. 2013 Oct 22;347:f6333. doi: 10.1136/bmj.f6333.

50.

Vogel AP, Folker J, Poole ML. Treatment for speech disorder in Friedreich ataxia and other hereditary ataxia syndromes. Cochrane Database Syst Rev. 2014 Oct 28;10:CD008953. doi: 10.1002/14651858.CD008953.pub2.

51.

Poole ML, Wee JS, Folker JE, Corben LA, Delatycki MB, Vogel AP. Nasality in Friedreich ataxia. Clin Linguist Phon.

2014 Sep 10:1-13. [Epub ahead of print]

52.

Ryan NP, Catroppa C, Cooper JM, Beare R, Ditchfield M, Coleman L, Silk T, Crossley L, Rogers K, Beauchamp MH, Yeates KO, Anderson VA. Relationships between acute imaging biomarkers and theory of mind impairment in post-acute pediatric traumatic brain injury: A prospective analysis using susceptibility weighted imaging (SWI).

Neuropsychologia. 2014 Nov 6;66C:32-38. doi: 10.1016/j.neuropsychologia.2014.10.040. [Epub ahead of print]

53.

Catroppa C, Crossley L, Hearps SJ, Yeates KO, Beauchamp M, Rogers K, Anderson V. Social and Behavioral Outcomes: Pre-Injury to Six Months following Childhood Traumatic Brain Injury. J Neurotrauma. 2014 Apr 28.

[Epub ahead of print]

54.

J.R. Duncan, S. Gibbs, A. Lawrence (2014) Chronic intermittent toluene inhalation in rats alters behavioural responses to amphetamine and MK801, European Neuropsychopharmacology, 24(3).:480-6 (IF 4.046)

55.

A. Dick, M. Axelsson, A. J. Lawrence, J. R. Duncan (2014) Specific impairments in reinforcement learning following chronic intermittent toluene inhalation in adolescent rats, Psychopharmacology 231:1531-42 (IF 4.06)

56.

A. Dick, A. J. Lawrence, J. R. Duncan (2014) Chronic intermittent toluene inhalation initiated during adolescence in rats does not alter voluntary consumption of ethanol in adulthood, Alcohol 48(6):561-9 (IF: 2.53)

57.

J. R. Duncan, M. Garland, R. Stark, M. Myers, W. Fifer, M. Yang, H. Kinney, Prenatal Nicotine Exposure Selectively Affects Nicotinic Receptor Expression in Primary and Associative Visual Cortices of the Fetal Baboon, Brain Pathology, accepted May 29th, 2014, Jun 5. doi: 10.1111/bpa.12165. [Epub ahead of print]

58.

E. Giles, A. Lawrence, J. Duncan (2014) Exploring the modulation of hypoxia-inducible factor (HIF)-1α by volatile anesthetics as a possible mechanism underlying volatile anesthetic-induced CNS injury, Neurochem Res, 39(9):1640-7 (IF 2.55)

15.

Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, Engel J, Jr., Forsgren L, French JA, Glynn M, Hesdorffer DC, Lee BI, Mathern GW, Moshe SL, Perucca E, Scheffer IE, Tomson T, Watanabe M, Wiebe S. ILAE Official Report: A practical clinical definition of epilepsy. Epilepsia 2014;55:475-482.

59.

E. Black, S. MacLean, J. R. Duncan (2014), Inhalants-what you need to know, Facts sheet for the National Drug and Alcohol Research Centre, Australia.

16.

Flanagan D, Badawy RAB, Jackson GD. EEG-fMRI in focal epilepsy: Local activation and regional networks.

Clinical Neurophysiology 2014;125:21-31

116

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

17.

Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, Engel J, Jr., Forsgren L, French JA, Glynn M, Hesdorffer DC, Lee BI, Mathern GW, Moshe SL, Perucca E, Scheffer IE, Tomson T, Watanabe M, Wiebe S. ILAE Official Report: A practical clinical definition of epilepsy. Epilepsia 2014;55:475-482.

39.

18.

Flanagan D, Badawy RAB, Jackson GD. EEG-fMRI in focal epilepsy: Local activation and regional networks.

Clinical Neurophysiology 2014;125:21-31.

19.

Franklyn-Miller A, Bilzon J, Wilson C, McCrory P. Can RSScan footscan() D3D software predict injury in a military population following plantar pressure assessment? A prospective cohort study. Foot (Edinburgh, Scotland) 2014;24:6-10.

40. Puskarjov M, Seja P, Heron SE, Williams TC, Ahmad F, Iona X, Oliver KL, Grinton BE, Vutskits L, Scheffer IE, Petrou S, Blaesse P, Dibbens LM, Berkovic SF, Kaila K. A variant of KCC2 from patients with febrile seizures impairs neuronal Cl- extrusion and dendritic spine formation. Embo Reports 2014;15:723-729.

20.

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Pietersen ANJ, Cheong SK, Solomon SG, Tailby C, Martin PR. Temporal response properties of koniocellular (blue-on and blue-off) cells in marmoset lateral geniculate nucleus. Journal of Neurophysiology 2014;112:14211438.

41.

Gardner A, Iverson GL, McCrory P. Chronic traumatic encephalopathy in sport: a systematic review. British Journal of Sports Medicine 2014;48:84-U88.

Reid CA, Leaw B, Richards KL, Richardson R, Wimmer V, Yu C, Hill-Yardin EL, Lerche H, Scheffer IE, Berkovic SF, Petrou S. Reduced dendritic arborization and hyperexcitability of pyramidal neurons in a Scn1b-based model of Dravet syndrome. Brain 2014;137:1701-1715.

42.

21.

Guandalini M, Butler A, Mandelstam S. Spectrum of imaging appearances in Australian children with central nervous system hemophagocytic lymphohistiocytosis. Journal of Clinical Neuroscience 2014;21:305-310.

Reid CA, Mullen S, Kim TH, Petrou S. Epilepsy, energy deficiency and new therapeutic approaches including diet. Pharmacology & Therapeutics 2014;144:192-201.

43.

22.

Hildebrand MS, Damiano JA, Mullen SA, Bellows ST, Oliver KL, Dahl H-HM, Scheffer IE, Berkovic SF. Glucose metabolism transporters and epilepsy: Only GLUT1 has an established role. Epilepsia 2014;55:E18-E21.

23.

Hildebrand MS, Damiano JA, Mullen SA, Bellows ST, Scheffer IE, Berkovic SF. Does variation in NIPA2 contribute to genetic generalized epilepsy? Human Genetics 2014;133:673-674.

Reinthaler EM, Lal D, Lebon S, Hildebrand MS, Dahl H-HM, Regan BM, Feucht M, Steinboeck H, Neophytou B, Ronen GM, Roche L, Gruber-Sedlmayr U, Geldner J, Haberlandt E, Hoffmann P, Herms S, Gieger C, Waldenberger M, Franke A, Wittig M, Schoch S, Becker AJ, Hahn A, Maennik K, Toliat MR, Winterer G, Lerche H, Nuernberg P, Mefford H, Scheffer IE, Berkovic SF, Beckmann JS, Sander T, Jacquemont S, Reymond A, Zimprich F, Neubauer BA, Consortium PE, Consortium E, Euro EC. 16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy. Human Molecular Genetics 2014;23:6069-6080.

24.

Hinman RS, McCrory P, Pirotta M, Relf I, Forbes A, Crossley KM, Williamson E, Kyriakides M, Novy K, Metcalf BR, Harris A, Reddy P, Conaghan PG, Bennell KL. Acupuncture for Chronic Knee Pain A Randomized Clinical Trial. Jama-Journal of the American Medical Association 2014;312:1313-1322.

25.

Int League Epilepsy Consortium C, Grp KS. Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies. Lancet Neurology 2014;13:893-903.

26.

Jamuar SS, Lam A-TN, Kircher M, D’Gama AM, Wang J, Barry BJ, Zhang X, Hill RS, Partlow JN, Rozzo A, Servattalab S, Mehta BK, Topcu M, Amrom D, Andermann E, Dan B, Parrini E, Guerrini R, Scheffer IE, Berkovic SF, Leventer RJ, Shen Y, Wu BL, Barkovich AJ, Sahin M, Chang BS, Bamshad M, Nickerson DA, Shendure J, Poduri A, Yu TW, Walsh CA. Somatic Mutations in Cerebral Cortical Malformations. New England Journal of Medicine 2014;371:733-743.

27.

Kim YO, Bellows S, McMahon JM, Iona X, Damiano J, Dibbens L, Kelley K, Gill D, Cross JH, Berkovic SF, Scheffer IE. Atypical multifocal Dravet syndrome lacks generalized seizures and may show later cognitive decline. Developmental Medicine and Child Neurology 2014;56:85-90.

28.

Lee H, Sullivan SJ, Schneiders AG, Ahmed OH, Balasundaram AP, Williams D, Meeuwisse WH, McCrory P. Smartphone and tablet apps for concussion road warriors (team clinicians): a systematic review for practical users. Br J Sports Med. 2014 Mar 25. doi: 10.1136/bjsports-2013-092930.

29.

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44. Scheffer IE. Epilepsy Genetics Revolutionizes Clinical Practice. Neuropediatrics 2014;45:70-74.

45.

Scheffer IE, Dravet C. Transition to adult life in the monogenic epilepsies. Epilepsia 2014;55:12-15.

46. Scheffer IE, Heron SE, Regan BM, Mandelstam S, Crompton DE, Hodgson BL, Licchetta L, Provini F, Bisulli F, Vadlamudi L, Gecz J, Connelly A, Tinuper P, Ricos MG, Berkovic SF, Dibbens LM. Mutations in Mammalian Target of Rapamycin Regulator DEPDC5 Cause Focal Epilepsy with Brain Malformations. Annals of Neurology 2014;75:782-787.

47.

Scheffer IE, Mefford HC. EPILEPSY Beyond the single nucleotide variant in epilepsy genetics. Nature Reviews Neurology 2014;10:490-491.

48. Speed D, Hoggart C, Petrovski S, Tachmazidou I, Coffey A, Jorgensen A, Eleftherohorinou H, De Iorio M, Todaro M, De T, Smith D, Smith PE, Jackson M, Cooper P, Kellett M, Howell S, Newton M, Yerra R, Tan M, French C, Reuber M, Sills GE, Chadwick D, Pirmohamed M, Bentley D, Scheffer I, Berkovic S, Balding D, Palotie A, Marson A, O’Brien TJ, Johnson MR. A genome-wide association study and biological pathway analysis of epilepsy prognosis in a prospective cohort of newly treated epilepsy. Human Molecular Genetics 2014;23:247-258.

49.

Tailby C, Weintrob DL, Saling MM, Fitzgerald C, Jackson GD. Reading difficulty is associated with failure to lateralize temporooccipital function. Epilepsia 2014;55:746-753.

50.

Leventer RJ, Jansen FE, Mandelstam SA, Ho A, Mohamed I, Sarnat HB, Kato M, Fukasawa T, Saitsu H, Matsumoto N, Itoh M, Kalnins RM, Chow CW, Harvey AS, Jackson GD, Crino PB, Berkovic SF, Scheffer IE. Is focal cortical dysplasia sporadic? Family evidence for genetic susceptibility. Epilepsia 2014;55:E22-E26.

White PE, Newton JD, Makdissi M, Sullivan SJ, Davis G, McCrory P, Donaldson A, Ewing MT, Finch CF. Knowledge about sports-related concussion: is the message getting through to coaches and trainers? British Journal of Sports Medicine 2014;48:119-U127.

51.

Louey AG, Cromer JA, Schembri AJ, Darby DG, Maruff P, Makdissi M, McCrory P. Detecting Cognitive Impairment After Concussion: Sensitivity of Change From Baseline and Normative Data Methods Using the CogSport/Axon Cognitive Test Battery. Archives of Clinical Neuropsychology 2014;29:432-441.

Williams D, Sullivan SJ, Schneiders AG, Ahmed OH, Lee H, Balasundaram AP, McCrory PR. Big hits on the small screen: an evaluation of concussion-related videos on YouTube. British Journal of Sports Medicine 2014;48:107-111.

52.

Williams J, Crowe LM, Dooley J, Collie A, Davis G, McCrory P, Clausen HM, Maddocks D, Anderson VA. Developmental trajectory of information processing skills in children: computer-based assessment. Applied Neuropsychology: Child 2014; published online http://dx.doi.org/10.1080/21622965.2014.939271

53.

Zelko FA, Pardoe HR, Blackstone SR, Jackson GD, Berg AT. Regional brain volumes and cognition in childhood epilepsy: Does size really matter? Epilepsy Research 2014;108:692-700.

31.

Makdissi M. Sports-related concussion Reply. Australian Family Physician 2014;43:9-10.

32.

Makdissi M, Davis G, McCrory P. Updated guidelines for the management of sports-related concussion in general practice. Australian Family Physician 2014;43:94-99.

33.

Martin HC, Kim GE, Pagnamenta AT, Murakami Y, Carvill GL, Meyer E, Copley RR, Rimmer A, Barcia G, Fleming MR, Kronengold J, Brown MR, Hudspith KA, Broxholme J, Kanapin A, Cazier J-B, Kinoshita T, Nabbout R, Bentley D, McVean G, Heavin S, Zaiwalla Z, McShane T, Mefford HC, Shears D, Stewart H, Kurian MA, Scheffer IE, Blair E, Donnelly P, Kaczmarek LK, Taylor JC, Consortium WGS. Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis. Human Molecular Genetics 2014;23:3200-3211.

34.

Milligan CJ, Li M, Gazina EV, Heron SE, Nair U, Trager C, Reid CA, Venkat A, Younkin DP, Dlugos DJ, Petrovski S, Goldstein DB, Dibbens LM, Scheffer IE, Berkovic SF, Petrou S. KCNT1 Gain of Function in 2 Epilepsy Phenotypes is Reversed by Quinidine. Annals of Neurology 2014;75:581-590.

35.

Newton JD, White PE, Ewing MT, Makdissi M, Davis GA, Donaldson A, Sullivan SJ, Seward H, Finch CF. Intention to use sport concussion guidelines among community-level coaches and sports trainers. Journal of Science and Medicine in Sport 2014;17:469-473.

36.

Oliver KL, Lukic V, Thorne NP, Berkovic SF, Scheffer IE, Bahlo M. Harnessing Gene Expression Networks to Prioritize Candidate Epileptic Encephalopathy Genes. Plos One 2014;9.

37.

Orhan G, Bock M, Schepers D, Ilina EI, Reichel SN, Loeffler H, Jezutkovic N, Weckhuysen S, Mandelstam S, Suls A, Danker T, Guenther E, Scheffer IE, De Jonghe P, Lerche H, Maljevic S. Dominant-negative effects of KCNQ2 mutations are associated with epileptic encephalopathy. Annals of Neurology 2014;75:382-394.

38.

Patricios JS, Makdissi M. The sports concussion picture: fewer ‘pixels’, more HD. British Journal of Sports Medicine 2014;48:71-72.

PARKVILLE CAMPUS – 54.

Jens Witsch, Daniel Golkowski, Thomas T. G. Hahn, Steven Petrou and Hartwig Spors. Cortical Alterations in a Model for Absence Epilepsy and Febrile Seizures: In Vivo Findings in Mice Carrying a Human GABA(A)R Gamma2 Subunit Mutation Neurobiology of Disease. accepted)

55.

Melody Li; Dana Jazayeri; Ben Corry; Melodi McSweeney; Erin L Heinzen; David B Goldstein; Steven Petrou. A functional correlate of severity in alternating hemiplegia of childhood. Neurobiology of Disease, Accepted

56.

Mefford, Heather; Allen, Andrew; Berkovic, Samuel; Coe, Bradley; Cook, Joseph; Cossette, Patrick; Delanty, Norman; Dlugos, Dennis; Eichler, E.; Epistein, Michael; Glauser, Tracy; Goldstein, David; Heinzen, E; Johnson, Michael; Krumm, Nik; Kuzniecky, Ruben; Lowenstein, Daniel; Marson, Anthony; Nelson, Ben; Esmaeeli Nieh, Sahar; O’Brien, Terence; Ottman, Ruth; Petrou, Steven; Petrovski, Slave; Poduri, Annapurna; Raja, Archana; Ruzzo, Elizabeth; Scheffer, Ingrid; Sherr, Elliott; Abou-Khalil, Bassel; Allredge, Brian; Andermann, Eva; Andermann, Frederick; Amron, Dina; Bautista, Jocelyn; Boro, Alex; Cascino, Gregory; Consalvo, Damian; Crumrine, Patricia; Devinsky, Orrin; Fiol, Miguel; Fountain, Nathan; French, Jacqueline; Friedman, Daniel; Geller, Eric; Glynn, Simon; Haut, Sheryl; Hayward, Jean; Helmers, Sandra; Joshi, Sucheta; Kanner, Andres; Kirsch, Heidi; Knowlton, Robert; Kossoff, Eric; Kuperman, Rachel; McGuire, Shannon; Motika, Paul; Novotny, Edward; Paolicchi, Julian; Parent, Jack; Park, Kristen; Shellhaas, Renee; Shih, Jerry; Singh, Rani; Sirven, Joseph; Smith, Michael; Sullivan, Joseph; Thio, Liu Lin; Venkat, Anu; Vining, Eileen; Von Allmen, Gretchen; Weisenberg, Judith; Widdess-Walsh, Peter; Winawer, Melodie. CNV analysis from exome data in 349 patients with epileptic encephalopathy”. Annals of Neurology, Accepted.

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

57.

Harty RC, Wimmer VC, Richards KL, Phillips AM, Miyazaki A, Nukina N, Petrou S. Sodium channel β1 subunit localizes to axon initial segments of excitatory and inhibitory neurons and shows regional heterogeneity in mouse brain. J Comp Neurol. Accepted 14 Nov 2014

58.

Gazina EV, Leaw BTW, Richards KL, Wimmer VC, Kim TH, Aumann TD, Featherby TJ, Churilov L, Hammond VE, Reid CA, Petrou S. Neonatal NaV 1.2 reduces neuronal excitability and affects seizure susceptibility and behavior. Human Mol Genetics (accepted).

59.

Epilepsy Phenome/Genome Project; Epi4K Consortium; EuroEPINOMICS-RES Consortium; Epilepsy Phenome/Genome Project; Epi4K Consortium. De Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies. EuroEPINOMICS-RES Consortium. Am J Hum Genet. 2014 Oct 2;95(4):360-70. doi: 10.1016/j.ajhg.2014.08.013. [Epub 2014 Sep 25].

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1.

S. Groeschel, J-D.Tournier, G.B.Northam, T.Baldeweg, J.Wyatt, B.Vollmer, A.Connelly. Identification and interpretation of microstructural abnormalities in motor pathways in adolescents born preterm. NeuroImage, 87, 209-219 (2014).

2.

L.Willats, D.Raffelt, R.E.Smith, J-D.Tournier, A.Connelly, F.Calamante. Quantification of track-weighted imaging (TWI): characterisation of within-subject reproducibility and between-subject variability. NeuroImage, 87, 18-31 (2014).

3.

X.Liang, A. Connelly, F.Calamante. Graph analysis of resting-state ASL perfusion MRI data: nonlinear correlations among CBF and network metrics. NeuroImage, 87, 265-275 (2014).

4.

J.L.Y.Cheong, A.C.Burnett, K.J.Lee, G.Roberts, D.K.Thompson, S.J.Wood, A.Connelly, P.J.Anderson, L.W.Doyle.

Association between postnatal dexamethasone for treatment of bronchopulmonary dysplasia and brain volume at adolescence in infants born very preterm. J Pediatrics, 164, 737-743 (2014).

5.

I.E.Scheffer, S.E.Heron, B.M.Regan, S.Mandelstam , D.E.Crompton, B.L.Hodgson, L.Licchetta, F.Bisulli, L.Vadlamudi, A.Connelly, P.Tinuper, M.G.Ricos, S.F.Berkovic, L.M.Dibbens. Mutations in mammalian target rapamycin regulator DEPDC5 cause focal epilepsy with brain malformations. Ann Neurol, 75, 782-787 (2014).

6.

C.E Kelly, J.L.Y.Cheong, C.Molloy, P.J Anderson, K.J.Lee, A.C.Burnett, A.Connelly, L.W. Doyle, D.K.Thompson. Neural correlates of impaired vision in adolescents born extremely preterm and/or extremely low birthweight. PLoS ONE, 9, e93188 (2014).

7.

J.Mitra, P.Bourgeat, J.Fripp, S.Ghose, S.Rose, O.Salvado, A.Connelly, B.Campbell, S.Palmer, G.Sharma, S. Christensen, L.Carey. Lesion segmentation from multimodal MRI using random forest following ischemic stroke. NeuroImage, 98, 324-335 (2014).

8.

K.L.Richards, F.Calamante, J-D.Tournier, N.D.Kurniawan, F. Sadeghian, A.R.Retchford, G.D.Jones, C.A.Reid, D.C.Reutens, R.J.Ordidge, A.Connelly*, S.Petrou*. Mapping somatosensory connectivity in adult mice using diffusion MRI tractography and super-resolution track density imaging. NeuroImage, 102, 381-392 (2014).* equal contribution.

64. Milligan CJ, Li MYS, Petrou S. KCNT1 gain-of-function mutations linked to human epilepsy are modulated by quinidine. Molecular & Cellular Epilepsy (Accepted)

9.

X.Liang, A. Connelly, J-D. Tournier, F.Calamante. A variable flip angle-based method for reducing blurring in 3D GRASE ASL. Physics in Medicine and Biology, 18, 5559-5574 (2014).

65.

Wimmer VC, Li MYS, Berkovic SF and Petrou S. Cortical microarchitecture changes in genetic epilepsy.

Neurology, Accepted

10.

B.Jeurissen, J-D.Tournier, T.Dhollander, A.Connelly, J.Sijbers. Multi-tissue constrained spherical deconvolution for improved analysis of multi-shell diffusion MRI data. Neuroimage, 103, 411-426 (2014).

66.

Holien JK, Gazina EV, Elliott RW, Jarrott B, Cameron CE, Williams SJ, Parker MW and Petrou S. Computational analysis of amiloride analogue inhibitors of coxsackievirus B3 RNA polymerase . Journal of Proteomics & Bioinformatics Accepted

11.

Palesi F, Tournier J-D, Calamante F, Muhlert N, Castellazzi G, Chard D, D’Angelo E, Wheeler-Kingshott CAM. Contralateral cerebello-thalamo-cortical pathways with prominent involvement of associative areas in humans in vivo. Brain Struct. Funct. (in press, accepted 21 July 2014).

67.

Mendis D, Petrou S, Halgamuge S. Neuromechatronics with In-Vitro Microelectrode Arrays. In Mechatronics Ed Clarence De Silva. 2014

12.

Chappell MA, Mehndiratta A, Calamante F. Correcting for large vessel contamination in DSC perfusion MRI by extension to a physiological model of the vasculature. Magn. Reson. Med. (in press, accepted 7 July 2014).

68.

Richards K, Calamante F, Tournier JD, Kurniawan ND, Sadeghian F, Retchford AR, Jones GD, Reid CA, Reutens DC, Ordidge R, Connelly A and Petrou S. Mapping somatosensory connectivity in adult mice using diffusion MRI tractography and super-resolution track density imaging. Neuroimage 2014 (accepted)

13.

Mehndiratta A, Calamante F, MacIntosh BJ, Crane DE, Payne SJ, Chappell MA. Modeling the Residue Function in DSC-MRI simulations: Analytical Approximation to in vivo data. Magn. Reson. Med. 72:1486–1491 (2014).

14.

69.

Oliva MK, McGarr TC, Beyer BJ, Gazina EV, Kaplan DI; Cordeiro L, Thomas EA, Dib-Hajj SD, Waxman SG, Frankel WN, Petrou S. Physiological and genetic analysis of multiple sodium channel variants in a model of genetic absence epilepsy. Neurobiology of Disease 2014, Accepted.

Mehndiratta A, Calamante F, MacIntosh BJ, Crane DE, Payne SJ, Chappell MA. Modelling and Correction of Bolus Dispersion Effects in DSC-MRI. Magn. Reson. Med. 72: 1762-74 (2014). [Editor’s pick for December 2014 issue]

15.

Kurniawan ND, Richards K, Yang Z, She D, Ullmann JFP, Moldrich RX, Liu S, Urriola Yaksic J, Leanage G, Kharatishvili I, Wimmer V, Calamante F, Galloway GJ, Petrou S, Reutens DC. Visualization of Mouse Barrel Cortex using Ex-vivo Track Density Imaging. NeuroImage 87: 465–475 (2014).

16.

Jahng G-H, Li K-L, Ostergaard L, Calamante F. Perfusion Magnetic Resonance Imaging: A Comprehensive Update on Principles and Techniques. Korean J. Radiol. 15: 554-577 (2014).

17.

Cho ZH, Kang CK, Son YD, Choi SH, Lee YB, Paek SH, Park CW, Chi JG, Calamante F, Law M, Kim YB, Pictorial Review of In Vivo Human Brain: From Anatomy to Molecular Imaging. World Neurosurgery 82: 72–95 (2014).

18.

P. Crack, M. Zhang, M.C. Morganti-Kossmann, A.J. Morris, J.M. Wojciak, J.K. Fleming, I. Karve, D. Wright, M. Sashindranath, Y. Goldshmit, A. Conquest, M. Daglas, L.A. Johnston, R.L. Medcalf, R.A. Sabbadini, A. Pebay, Antilysophosphatidic acid antibodies improve traumatic brain injury outcomes, Journal of Neuroinflammation, 11:37, pp.1-11, 2014.

19.

N. Bye, O. E. Hutt, T.M. Hinton, D.P. Acharya, L.J. Waddington, B.A. Moffat, D.K. Wright, H.X. Wang, X. Mulet, B.W. Muir, Nitroxide-loaded hexosomes provide MRI contrast in vivo. Langmuir, 30, pp. 8898−8906, 2014.

20.

R. Shishegar, J.M. Britto and L.A. Johnston, A method for assessing nonlinear growth in the fetal cortex, Proc. IEEE EMBC, pp.1525-1528, 2014.

21.

K.J. Layton, B. Tahayori, I.M.Y. Mareels, P.M. Farrell, L.A. Johnston, Rabi resonance in spin systems: theory and experiment, Journal of Magnetic Resonance, 242:136-142, 2014.

22.

S.R. Shultz, X.L. Tan, D.K. Wright, S.J. Liu, A.D. Cook, N.C. Jones, B.D. Semple, L. Johnston, J.A. Hamilton, T.J. O’Brien, Granulocyte-macrophage colony-stimulating factor (GM-CSF) is neuroprotective in experimental traumatic brain injury, Journal of Neurotrauma, vol. 31(10), pp.976-83, 2014.

60. Mendis DC, Halgamuge SK, Morrisroe E, Petrou S. Changes in Propagation Delays for Quantifying Pharmacological Effects on Cortical Cultures. Conference paper accepted. Knowledge Discovery in Biological Systems at ICIAfS (International Conference on Information and Automation for Sustainability) 61.

Reid CA, Mullen S, Kim TH, Petrou S. Epilepsy, energy deficiency and new therapeutic approaches including diet. Pharmacol Ther. 2014 Nov;144(2):192-201.

62.

Oxcarbazepine and its active metabolite, (S)-licarbazepine, exacerbate seizures in a mouse model of genetic generalised epilepsy. Kim TH, Reid CA, Petrou S. Epilepsia. accepted.

63.

Muona M, Berkovic SF, Dibbens LM, Oliver KL, Maljevic S, Bayly MA, Joensuu T, Canafoglia L, Franceschetti S, Michelucci R, Markkinen S, Heron SE, Hildebrand M, Andermann E, Andermann F, Gambardella A, Tinuper P, Licchetta L, Scheffer IE, Criscuolo C, Filla A, Ferlazzo E, Ahmad J, Ahmad A, Baykan B, Said E, Topcu M, Riguzzi P, King MD, Ozkara C, Andrade DM, Engelsen BA, Crespel A, Lindenau M, Lohmann E, Saletti V, Massano J, Privitera M, Espay AJ, Kauffmann B, Duchowny M, Møller RS, Straussberg R, Afawi Z, Ben- Zeev B, Samocha KE, Daly MJ, Petrou S, Lerche H, Palotie A, Lehesjoki AE. A recurrent de novo mutation in KCNC1 is a major cause of progressive myoclonus epilepsy. Nature Genetics (Accepted).

70.

Puskarjov M, Seja P, Heron SE, Williams TC, Ahmad F, Iona X, Oliver KL, Grinton BE, Vutskits L, Scheffer EI, Petrou S, Blaesse P, Dibbens LM, Berkovic SF, Kaila K. A variant of KCC2 from patients with febrile seizures impairs neuronal Cl- extrusion and dendritic spine formation. EMBO Reports 2014 Accepted

71.

Milligan CJ, Li MYS, Gazina EV, Heron SE, Nair U, Trager C, Reid CA, Venkat A, Younkin DP, Dlugos DJ, Petrovski S, Goldstein DB, Dibbens LM, Scheffer IE, Berkovic SF, Petrou S. KCNT1 Gain of Function in Two Epilepsy Phenotypes Is Reversed by Quinidine. Annals of Neurology 2014 Accepted

72.

Reid CA, Leaw B, Richards KL, Richardson R, Wimmer VC, Yu C, Hill-Yardin EL, Lerche H, Scheffer IE, Berkovic SF, Petrou S. Reduced dendritic arborisation and hyperexcitability of pyramidal neurons in a Scn1b-based model of Dravet syndrome. Brain 2014 Accepted

73.

Hatch RJ, Reid CA and Petrou S. Enhanced in vitro CA1 network activity in a sodium channel SCN1B(C121W) subunit model of genetic epilepsy. Epilepsia 2014 Accepted.

74.

Carvill GL, Weckhuysen S, McMahon JM, Hartmann C, Møller RS, Hjalgrim H, Cook J, Geraghty E, O’Roak BJ, Petrou S, Clarke A, Gill D, Sadleir LG, Muhle H, von Spiczak S, Nikanorova M, Hodgson BL, Gazina EV, Suls A, Shendure J, Dibbens LM, De Jonghe P, Helbig I, Berkovic SF, Scheffer IE, Mefford HC.GABRA1 and STXBP1: Novel genetic causes of Dravet syndrome. Neurology. 2014 Mar 12. [Epub ahead of print]

75.

TH Kim, S Petrou, CA Reid. Low glycaemic index diet reduces seizure susceptibility in a syndrome-specific mouse model of generalized epilepsy. Epilepsy Research 2014 Jan;108(1):139-43

76.

Gu BJ, Sun C, Fuller S, Skarratt KK, Petrou S, Wiley JS. A quantitative method for measuring innate phagocytosis by human monocytes using real-time flow cytometry. Cytometry A. 2014 85(4):313-21

PAGES 60–62

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121

20.

Moore E, Ames D, Mander A, Carne R, Brodaty H, Woodward M, Boundy K, Ellis K, Bush A, Faux N, Martins R, Masters C, Rowe C, Szoeke C, Watters D, and the AIBL investigators. Among vitamin B12 deficient older people, high folate levels are associated with worse cognitive function: combined data from three cohorts. J Alz Dis. 2014; 39: 661-668.

Lim YY, Villemagne VL, Laws SM, Ames D, Pietrzak RH, Ellis KA, Harrington K, Bourgeat P, Salvado O, Bush AI, Martins RN, Masters CL, Rowe CC, Maruff P for the AIBL Research Group. Effect of BDNF Val66Met on memory decline and hippocampal atrophy in prodromal Alzheimer’s disease: A preliminary study. PLoS One 2014; 9: e86498. Doi: 10.1371/journal.pone.0086498.

21.

Brown BM, Bourgeat P, Peiffer JJ, Burnham S, Laws SM, Rainey-Smith SR, Bartrés-Faz D, Villemagne VL, Taddei K, Rembach A, Bush A, Ellis KA, Macaulay SL, Rowe CC, Ames D, Masters CL, Maruff P, Martins RN for the AIBL Research Group. Influence of BDNF Val66Met on the relationship between physical activity and brain volume.

Neurol 2014; 83: 1345-1352.

3.

Villemagne VL and Masters CL. Alzheimer disease. The landscape of ageing – insights from AD imaging markers.

Nat Reviews Neurol. 2014; 10: 678-679.

22.

4.

Buckley RF, Saling MM, Irish M, Ames D, Rowe CC, Lautenschlager NT, Maruff P, Macaulay SL, Martins RN, Masters CL, Rainey-Smith S, Rembach A, Savage G, Szoeke C, Ellis KA. Personal memory function in mild cognitive impairment and subjective memory complaints: results from the Australian Imaging, Biomarkers, and Lifestyle (AIBL) study of ageing. J Alz Dis. 2014; 40: 551-561.

Thomas JB, Brier MR, Bateman RJ, Snyder AZ, Benzinger TL, Xiong C, Raichle M, Holtzman DM, Sperling RA, Mayeux R, Ghetti B, Ringman JM, Salloway S, McDade E, Rossor MN, Ourselin S, Schofield PR, Masters CL, Martins RN, Weiner MW, Thompson PM, Fox NC, Koeppe RA, Jack CR, Mathis CA, Oliver A, Blazey TM, Moulder K, Buckles V, Hornbeck R, Chhatwal J, Schultz AP, Goate AM, Fagan AM, Cairns NJ, Marcus DS, Morris JC and Ances BM. Functional connectivity in autosomal dominant and late-onset Alzheimer disease. JAMA Neurol.

2014; 71: 1111-1122.

23.

5.

Lim YY, Maruff P, Pietrzak RH, Ames D, Ellis KA, Harrington K, Lautenschlager NT, Szoeke C, Martins RN, Masters CL, Villemagne VL, Rowe CC for the AIBL Research Group. Effect of amyloid on memory and non-memory decline from preclinical to clinical Alzheimer’s disease. Brain. 2014; 137: 221-231.

Rembach A, Faux NG, Watt AD, Pertile KK, Rumble RL, Trounson BO, Fowler CJ, Roberts BR, Perez KA, Li Q-X, Laws SM, Taddei K, Rainey-Smith S, Robertson JS, Vandijck M, Vanderstichele H, Barnham KJ, Ellis KA, Szoeke C, Macaulay L, Rowe CC, Villemagne VL, Ames D, Martins RN, Bush AI, Masters CL, the AIBL research group.

Changes in plasma amyloid beta in a longitudinal study of aging and Alzheimer’s disease. Alz Dement 2014; 10: 53-61.

6.

Caine JM, Churches Q, Waddington L, Nigro J, Breheney K, Masters CL, Nuttall SD, Streltsov VA. Design of nonaggregating variants of Aβ peptide. Biochem Biophys Res Comm. 2014; 453: 449-454.

24.

7.

Klug GM, Boyd A, Sarros S, Stehmann C, Simpson M, McLean C, Masters CL, Collins SJ. Creutzfeldt-Jakob Disease surveillance in Australia, update to December 2013. Commun Dis Intell. 2014; 38: E348-E355.

Hare DJ, Lei P, Ayton S, Roberts BR, Grimm R, George JL, Bishop DP, Beavis AD, Donovan SJ, McColl G, Volitakis I, Masters CL, Adlard PA, Cherny RA, Bush AI, Finkelstein DI and Doble PA. An iron-dopamine index predicts risk of parkinsonian neurodegeneration in the substantia nigra pars compacta. Chemical Science. 2014; 5: 2160-2169.

25.

8.

Burnham SC, Faux NG, Wilson W, Laws SM, Ames D, Bedo J, Bush AI, Doecke JD, Ellis KA, Head R, Jones G, Kiiveri H, Martins RN, Rembach A, Rowe CC, Salvado O, Macaulay SL, Masters CL, Villemagne VL, Alzheimer’s Disease Neuroimaging Initiative and Australian Imaging Biomarker and Lifestyle Research Group. A blood-based predictor for neocortical Aβ burden in Alzheimer’s disease: results from the AIBL study. Molec Psych. 2014; 19: 519-526.

Villemagne VL, Fodero-Tavoletti M, Yates P, Masters CL and Rowe CC. Aβ imaging in aging, Alzheimer’s disease and other neurodegenerative conditions. In: PET and SPECT in Neurology. Edited by RAJO Dierckx, A Otte, EFJ de Vries, A van Waarde, and KL Leenders. Springer Verlag (Berlin-Heidelberg-New York). 2014, Chap 10: pp 213-254.

26.

Zwan MD, Okamura N, Fodero-Tavoletti MT, Furumoto S, Masters CL, Rowe CC, Villemagne VL. Voyage au bout de la nuit: Aβ and tau imaging in dementias. QJ Nucl Med Mol Imaging. 2014; 58: 398-412.

1.

Verdile G, Laws SM, Henley D, Ames D, Bush AI, Ellis KA, Faux NG, Gupta VB, Li Q-X, Masters CL, Pike KE, Rowe CC, Szoeke C, Taddei K, Villemagne VL, and Martins RN and for the AIBL Research Group. Associations between gonadotropins, testosterone, and β amyloid in men at risk of Alzheimer’s Disease. Molec Psych 2014; 19: 69-75.

2.

9.

Masters CL. Shaken, not sonicated? N Eng J Med. 2014; 371: 571-572.

27.

10.

Faux NG, Rembach A, Wiley J, Ellis KA, Ames D, Fowler CJ, Martins RN, Pertile KK, Rumble RL, Trounson B, Masters CL, The AIBL Research Group, Bush AI. An anemia of Alzheimer’s disease. Molec Psych. 2014; 19: 12271234.

Yates PA, Villemagne VL, Ellis KA, Desmond PM, Masters CL, Rowe CC. Cerebral microbleeds: a review of clinical, genetic and neuroimaging associations. Frontiers in Neurology. 2014; 4: 205.

28.

Johnson P, Vandewater L, Wilson W, Maruff P, Savage G, Graham P, Macaulay SL , Ellis KA, Szoeke C, Martins RN, Rowe CC, Masters CL, Ames D, Zhang P. Genetic algorithm with logistic regression for prediction of progression of Alzheimer’s disease. BMC Bioinformatics. 2014; 15 (Suppl 16): S11.

29.

Coleman BM, Harrison CF, Guo B, Masters CL, Barnham KJ, Lawson VA, Hill AF. Pathogenic mutations within the hydrophobic domain of the prion protein lead to the formation of a protease sensitive prion species with increased lethality. J Virol. 2014; 88: 2690-2703.

30.

Rembach A, Watt AD, Wilson WJ, Rainey-Smith S, Ellis KA, Rowe CC, Villemagne VL, Macaulay SL, Bush AI, Martins RN, Ames D, Masters CL, Doecke JD and the AIBL research group. An increased neutrophil-lymphocyte ratio in Alzheimer’s disease is a function of age and is weakly correlated with neocortical amyloid accumulation. J Neuroimmunology. 2014; 273: 65-71.

31.

Zhou L, Salvado O, Dore V, Bourgeat P, Raniga P, Macaulay SL, Ames D, Masters CL, Ellis KA, Villemagne VL, Rowe CC, Fripp J, AIBL Research Group. MR-less surface-based amyloid assessment based on 11C PiB PET. PLOS One. 2014; 9: e84777.

32.

Hare DJ, George JL, Bray L, Volitakis I, Vais A, Ryan TM, Cherny RA, Bush AI, Masters CL, Adlard PA, Doble PA and Finkelstein DI. The effect of paraformaldehyde fixation and sucrose cryoprotection on metal concentration in murine neurological tissue. J Anal At Spectrom. 2014; 29: 565-570.

33.

Yates PA, Desmond PM, Phal PM, Steward C, Szoeke C, Salvado O, Ellis KA, Martins RN, Masters CL, Ames D, Villemagne VL, Rowe CC for the AIBL Research Group. Incidence of cerebral microbleeds in preclinical Alzheimer disease. Neurology. 2014; 82: 1266-1273.

34.

Villemagne VL, Furumoto S, Fodero-Tavoletti MT, Mulligan RS, Hodges J, Harada R, Yates P, Piguet O, Pejoska S, Doré V, Yanai K, Masters CL, Kudo Y, Rowe CC, Okamura N. In vivo evaluation of a novel tau imaging tracer for Alzheimer’s disease. Eur J Nucl Med Molec Imag. 2014; 41: 816-826.

35.

Ryman DC, Acosta-Baena N, Aisen PS, Bird T, Danek A, Fox N, Goate A, Frommelt P, Ghetti B, Langbaum JBS, Lopera F, Martins R, Masters CL, Mayeux RP, McDade E, Moreno S, Reiman EM, Ringman JM, Salloway S, Schofield PR, Sperling R, Tariot PN, Xiong C, Morris JC, Bateman RJ and the Dominantly Inherited Alzheimer Network. Symptom onset in autosomal dominant Alzheimer disease. A systematic review and meta-analysis.

Neurology. 2014; 83: 253-260.

36.

Ellis KA, Szoeke C, Bush AI, Darby D, Graham PL, Lautenschlager NT, Macaulay SL, Martins RN, Maruff P, Masters CL, McBride SJ, Pike KE, Rainey-Smith SR, Rembach A, Robertson J, Rowe CC, Savage G, Villemagne VL, Woodward M, Wilson W, Zhang P, Ames D and the AIBL research group. Rates of diagnostic transition and cognitive change at 18-month follow-up among 1,112 participants in the Australian Imaging, Biomarkers and Lifestyle flagship study of ageing (AIBL). Int Psychogeriatrics. 2014; 26: 543-554.

37.

Fodero-Tavoletti MT, Furumoto S, Taylor L, McLean CA, Mulligan RS, Birchall I, Harada R, Masters CL, Yanai K, Kudo Y, Rowe CC, Okamura N and Villemagne VL. Assessing THK523 selectivity for tau deposits in Alzheimer’s disease and non-Alzheimer’s disease tauopathies. Alzheimer Res & Therapy. 2014; 6:11.

11.

Fagan AM, Xiong C, Jasielec MS, Bateman RJ, Goate AM, Benzinger TLS, Ghetti B, Martins RN, Masters CL, Mayeux R, Ringman JM, Rossor MN, Salloway S, Schofield PR, Sperling RA, Marcus D, Cairns NJ, Buckles VD, Ladenson JH, Morris JC, Holtzman DM. Longitudinal change in CSF biomarkers in autosomal-dominant Alzheimer’s disease. Science Translat Med. 2014; 6: 226ra30doi10.112b/scitranslmed.3007901.

12.

Pham CLL, Kirby N, Wood K, Ryan T, Roberts B, Sokolova A, Barnham KJ, Masters CL, Knott RB, Cappai R, Curtain CC and Rekas A. Guanidine hydrochloride denaturation of dopamine induced α-synuclein oligomers: A smallangle X-ray scattering study. Proteins: Structure, Function and Bioinformatics 2014; 82: 10-21.

13.

Villemagne VL, Dorè V, Yates P, Brown B, Mulligan R, Bourgeat P, Veljanoski R, Rainey-Smith SR, Ong K, Rembach A, Williams R, Burnham SC, Laws SM, Salvado O, Taddei K, Macaulay SL, Martins RN, Ames D, Masters CL, Rowe CC. En attendant centiloid. Advances in Research. 2014; 2: 723-729.

14.

Roberts BR, Lim NKH, McAllum EJ, Donnelly PS, Hare DJ, Doble PA, Turner BJ, Price KA, Lim SC, Paterson BM, Hickey JL, Rhoads TW, Williams JR, Kanninen KM, Hung LW, Liddell JR, Grubman A, Monty J-F, Llanos RM, Kramer DR, Mercer JFB, Bush AI, Masters CL, Duce JA, Li Q-X, Beckman JS, Barnham KJ, White AR, Crouch PJ. Oral treatment with CuII(atsm) increases mutant SOD1 in vivo but protects motor neurons and improves the phenotype of a transgenic mouse model of amyotrophic lateral sclerosis. J Neurosci. 2014; 34: 8021-8031.

15.

16.

17.

Adlard PA, Li Q-X, McLean C, Masters CL, Bush AI, Fodero-Tavoletti M, Villemagne V and Barnham KJ. β-amyloid in biological samples: not all Aβ detection methods are created equal. Front Aging Neurosci. 6:203. Doi: 10.3389/ fnagi.2014.00203.

Lim YY, Maruff P, Pietrzak RH, Ellis KA, Darby D, Ames D, Harrington K, Martins RN, Masters CL, Szoeke C, Savage G, Villemagne VL, Rowe CC for the AIBL Research Group. Aβ and cognitive change: Examining the preclinical and prodromal stages of Alzheimer’s disease. Alzheimers Dement. 2014; 10: 743-751.

Buckley RF, Saling MM, Irish M, Ames D, Rowe CC, Villemagne VL, Lautenschlager NT, Maruff P, Macaulay SL, Martins RN, Szoeke C, Masters CL, Rainey-Smith SR, Rembach A, Savage G, Ellis KA and the Australian Imaging Biomarkers and Lifestyle Study of Ageing (AIBL) Research Group. Autobiographical narratives relate to Alzheimer’s disease biomarkers in older adults. Int Psychogeriatrics. 2014; 26: 1737-1746.

18.

Johanssen VA, Johanssen T, Masters CL, Hill AF, Barnham KJ, Collins SJ. C-terminal peptides modelling constitutive PrPC processing demonstrate ameliorated toxicity predisposition consequent to α-cleavage. Biochem J. 2014; 459: 103-115.

19.

Rembach A, Hare DJ, Doecke JD, Burnham SC, Volitakis I, Fowler CJ, Cherny RA, McLean C, Grimm R, Martins R, Ames D, Masters CL, Bush AI, Roberts BR. Decreased serum zinc is an effect of ageing and not Alzheimer’s disease. Metallomics: integrated biometal science. 2014; 6: 1216-1219.

122

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38.

Pietrzak RH, Scott JC, Neumeister A, Lim YY, Ames D, Ellis KA, Harrington K, Lautenschlager NT, Szoeke C, Martins RN, Masters CL, Villemagne VL, Rowe CC, Maruff P for the Australian Imaging, Biomarkers and Lifestyle (AIBL) Research Group. Anxiety symptoms, cerebral amyloid burden and memory decline in healthy older adults without dementia: 3-year prospective cohort study. Brit J Psychiat. 2014; 204: 400-401.

39.

Rembach A, Watt AD, Wilson WJ, Villemagne VL, Burnham SC, Ellis KA, Maruff P, Ames D, Rowe CC, Macaulay SL, Bush AI, Martins RN, Masters CL, Doecke JD and the AIBL Research Group. Plasma amyloid-β levels are significantly associated with a transition towards Alzheimer’s disease as measured by cognitive decline and change in neocortical amyloid burden. J Alz Disease. 2014; 40: 95-104.

THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

59.

Hung YH, Faux NG, Killilea DW, Yanjamin N, Firnkes S, Volitakis I, Ganio G, Walterfang M, Hastings C, Porter FD, Ory DS, Bush AI. Altered transition metal homeostasis in Niemann-Pick disease, Type C1. Metallomics 2014; 6(3), 542-553.

42.

Squitti R, Simonelli I, Ventriglia M, Siotto M, Pasqualetti P, Rembach A, Doecke J, Bush AI. Meta-analysis of serum non-ceruloplasmin copper in Alzheimer’s disease. J Alzheimers Dis 2014; 38(4), 809-22. [DOI: 10.3233/JAD-131247].

43.

Bruno Dubois, Howard H Feldman, Claudia Jacova, Harald Hampel, José Luis Molinuevo, Kaj Blennow, Steven T DeKosky, Serge Gauthier, Dennis Selkoe, Randall Bateman, Stefano Cappa, Sebastian Crutch, Sebastiaan Engelborghs, Giovanni B Frisoni, Nick C Fox, Douglas Galasko, Marie-Odile Habert, Gregory A Jicha, Agneta Nordberg, Florence Pasquier, Gil Rabinovici, Philippe Robert, Christopher Rowe, Stephen Salloway, Marie Sarazin, Stéphane Epelbaum, Leonardo C de Souza, Bruno Vellas, Pieter J Visser, Lon Schneider, Yaakov Stern, Philip Scheltens, Jeffrey L Cummings. Advancing research diagnostic criteria for Alzheimer’s disease: the IWG2 criteria. Lancet Neurol 2014; 13: 614–629.

60. Elias A, Woodward M, Rowe CC. Management Impact of FDG PET in a Tertiary Memory Disorders Clinic. J Alzheimer’s Disease, 2014; 42:885-892.

40. Okamura N, Furumoto S, Fodero-Tavoletti M, Mulligan R, Harada R, Yates P, Pejoska S, Kudo Y, Masters C, Yanai K, Rowe C, Villemagne V. Noninvasive assessment of Alzheimer’s disease neurofibrillary pathology using 18F-THK5105 PET. Brain. 2014; 137: 1762-1771.

41.

123

Ayton S, Zhang M, Roberts BR, Lam LQ, Lind M, McLean C, Bush AI, Frugier T, Crack PJ, Duce JA. Ceruloplasmin and beta amyloid precursor protein confer neuroprotection in traumatic brain injury and lower neuronal iron. Free Radical Biology & Medicine 2014; 69, 331-337.

61.

Woodward M, Rowe CC, Jones GA, Villemagne VL, Varos T. Differentiating the frontal presentation of Alzheimer’s disease with FDG-PET. J Alzheimer’s Disease. Accepted 21 August 2014.

62.

Klunk WE, Robert A Koeppe; Julie C Price; Tammie Benzinger; Michael D Devous Sr.; William Jagust; Keith Johnson; Chester A Mathis; Davneet Minhas; Michael J Pontecorvo; Christopher C Rowe; Daniel Skovronsky; Mark Mintun. The Centiloid Project: Standardizing Quantitative Amyloid Plaque Estimation by PET. Alzheimer’s & Dementia. On-line October 2014. (Impact factor 17)

63.

Villemagne VL, Kim SY, Rowe CC, Iwatsubo T. Imago Mundi, Imago AD, Imago ADNI. Alzheimer’s Research and Therapy, 2014; 6:62-72.

64. Kerbler GM, Fripp J, Rowe CC, Villemagne VL, Salvado O, Rose S, Coulson EJ; Alzheimer’s Disease Neuroimaging Initiative. Basal forebrain atrophy correlates with amyloid β burden in Alzheimer’s disease.

Neuroimage Clin. 7:105-13, 2014.

44. Ayton S, Lei P, Adlard PA, Volitakis I, Cherny RA, Bush AI*, Finkelstein DI*. Iron accumulation confers neurotoxicity to a vulnerable population of nigral neurons: implications for Parkinson’s disease. Molecular Neurodegeneration 2014; 9: 27 [doi: 10.1186/1750-1326-9-27].*co-senior authors

65.

Ly JV, Singhal S, Rowe CC, Kempster P, Bower S, Thanh G. Convexity Subarachnoid Hemorrhage with PiB Positive Pet Scans: Clinical Features and Prognosis. J Neuroimaging 2014, DOI: 10.1111/jon.12188

66.

Hocking DC, Kennedy GA, Sundram S. Mental disorders in asylum seekers: the role of the refugee determination process and employment. J Nerv Ment Dis. 2015; 203(1):28-32. doi: 10.1097/NMD.0000000000000230.

67.

Loi S, Sundram S. To flee, or not to flee, that is the question for older asylum seekers. Int Psychogeriatr. 2014 Jun 13:1-4. [Epub ahead of print].

68.

Pereira A, Zhang B, Malcolm P, Sugiharto-Winarno A, Sundram S. Quetiapine and aripiprazole signal differently to ERK, p90RSK and c-Fos in mouse frontal cortex and striatum: role of the EGF receptor. BMC Neurosci. 2014 Feb 20;15:30. doi: 10.1186/1471-2202-15-30.

69.

48. Ciccotosto GD, James SA, Altissimo M, Paterson D, Vogt S, Lai B, de Jonge MD, Howard DL, Bush AI, Cappai R. Quantitation and localization of intracellular redox active metals by X-ray fluorescence microscopy in cortical neurons derived from APP and APLP2 knockout tissue. Metallomics 2014; 6, 1894–1904.

Dean B, Tawadros N, Suk Seo MS, Jeon WJ, Everall I, Scarr E, Gibbons A (2014) Lower cortical serotonin 2A receptors in major depressive disorder, suicide and in rats after administration of imipramine. International Journal of Neuropsychopharmacology 17: 895-906.

70.

Seo MS, Scarr E, Lai C-Y, Dean B (2014) Potential molecular and cellular mechanism of psychotropic drugs.

Clinical Psychopharmacology and Neuroscience 12: 94-110.

49.

71.

Seo MS, Scarr E, Brian Dean (2014) An investigation of the factors that regulate muscarinic receptor expression in schizophrenia. Schizophrenia Research 158: 247-254.

72.

Gozes I, Merenlender-Wagner A, Malishkevich A, Shemer A, Udawela M, Gibbons A, Scarr E, Dean B, Levine J, Agam G, Gozes I (2015) Autophagy plays a key role in the pathophysiology of schizophrenia. Molecular Psychiatry 20:126-132.

1.

Xing YL, Röth PT, Stratton JA, Chuang BHA, Danne J, Ellis SL, Ng SW, Kilpatrick TJ, Merson TD. Adult neural precursor cells from the subventricular zone contribute significantly to oligodendrocyte regeneration and remyelination. J Neurosci. 2014;34(42), 14128–14146.

2.

Merson TD, Bourne JA. Endogenous neurogenesis following ischemic brain injury: insights for therapeutic strategies. Int J Biochem Cell Biol. (2014) pii: S1357-2725(14)00254-4.

45.

Lu Z, Marks E, Chen J, Moline J, Barrows L, Raisbeck M, Volitakis I, Cherny RA, Chopra V, Bush AI, Hersch S, Fox JH. Altered selenium status in Huntington’s disease: neuroprotection by selenite in the N171-82Q mouse model. Neurobiology of Disease 2014; 71, 34-42.

46. Lei P, Ayton S, Moon S, Zhang Q, Volitakis I, Finkelstein DI*, Bush AI*. Motor and cognitive deficits in aged tau knockout mice in two background strains. Molecular Neurodegeneration 2014; 9: 29. [doi:10.1186/1750-13269-29]. *co-senior authors 47.

Wong BXW, Ayton S, Lam LQ, Lei P, Adlard PA, Bush AI*, Duce JA*. A comparison of ceruloplasmin to biological polyanions in promoting the oxidation of Fe2+ under physiologically relevant conditions. Biochimica et Biophysica Acta – General Subjects 2014; 1840(12), 3299-3310. [doi: 10.1016/j.bbagen.2014.08.006] *cosenior authors

Castro PA, Ramirez A, Sepulveda FJ, Peters C, Fierro H, Waldron J, Luza S, Fuentealba J, Munoz JF, De Ferrari JV, Bush AI, Aguayo LG, Opazo CM. Copper-uptake is critical for the down regulation of synapsin and dynamin induced by neocuproine: modulation of synaptic activity in hippocampal neurons. Frontiers in Aging Neuroscience 2014 Dec 3; 6, 319. [doi: 10.3389/fnagi.2014.00319]

50.

Wong BX, Tsatsanis A, Lim LQ, Adlard PA, Bush AI*, Duce JA*. β-amyloid precursor protein does not possess ferroxidase activity but does stabilize the cell surface ferrous iron exporter ferroportin. PLoS ONE 2014; 9(12), e114174. [doi:10.1371/journal.pone.0114174] *co-senior authors

51.

Berk M, Dean OM, Cotton SM, Jeavons S, Tanious M, Kolmann K, Hewitt K, Moss K, Allwang C, Schapkaitz I, Robbins J, Cobb H, Ng F, Dodd S, Bush AI, Malhi GS. The efficacy of adjunctive N-acetylcysteine in major depressive disorder: A double-blind, randomized, placebo-controlled trial. Journal of Clinical Psychiatry 2014; 75(6), 628-636.

CHAPTER MULTIPLE SCLEROSIS PAGES 72–75

52.

Takeda A, Nakamura M, Fujii H, Uematsu C, Minamino T, Adlard PA, Bush AI, Tamano H. Amyloid β-mediated Zn2+ influx into dentate granule cells transiently induces a short-term cognitive deficit. PLoS One 2014; 9(12):e115923. [doi:10.1371/journal.pone.0115923]

53.

Adlard PA, Parncutt J, Lal V, James S, Hare D, Doble P, Finkelstein DI, Bush AI. Metal chaperones prevent zinc-mediated cognitive decline. Neurobiology of Disease 2014 (online Dec 27, 2014). DOI: 10.1016/j. nbd.2014.12.012

3.

Jonas A, Thiem S, Kuhlmann T, Wagener R, Aszodi A, Nowell C, Hagemeier K, Laverick L, Perreau V, Jokubaitis V, Emery B, Kilpatrick T, Butzkueven H, Gresle M. Axonally derived matrilin-2 induces proinflammatory responses that exacerbate autoimmune neuroinflammation. J Clin Invest. 2014;124(11):5042-56.

54.

Barnard ND, Bush AI, Ceccarelli A, Cooper J, de Jager CA, Erickson KI, Fraser G, Kesler S, Levin SM, Lucey B, Morris MC, Squitti R. Dietary and Lifestyle Guidelines for the Prevention of Alzheimer’s Disease. Neurobiology of Aging 2014; 35S2, S74-S78.

4.

55.

Wong BXW, Hung YH, Bush AI*, Duce JA*. Metals and cholesterol: two sides of the same coin in Alzheimer’s disease pathology. Frontiers in Aging Neuroscience 2014; 6, 91 [doi: 10.3389/fnagi.2014.00091].*co-senior authors

Gresle MM, Schulz K, Jonas A, Perreau VM, Cipriani T, Baxter AG, Miranda-Hernandez S, Field J, Jokubaitis VG, Cherny R, Volitakis I, David S, Kilpatrick TJ, Butzkueven H. Ceruloplasmin gene-deficient mice with experimental autoimmune encephalomyelitis show attenuated early disease evolution. J Neurosci Res. 2014;92(6):732-42

5.

Kolbe SC, Kilpatrick TJ, Mitchell PJ, White O, Egan GF, Fielding J. Inhibitory saccadic dysfunction is associated with cerebellar injury in multiple sclerosis. Hum Brain Mapp. 2014;35(5):2310-9.

56.

Opazo CM, Greenough MA, Bush AI. Copper: From neurotransmission to neuroproteostasis. Frontiers in Aging Neuroscience 2014; 6, 143 [doi: 10.3389/fnagi.2014.00143].

6.

McKenzie IA, Ohayon D, Li H, de Faria JP, Emery B, Tohyama K, Richardson WD. Motor skill learning requires active central myelination. Science. 2014;346(6207):318-22.

57.

Barnham KJ, Bush AI. Biological Metals and Metal-targeting Compounds in Major Neurodegenerative Diseases. Chemical Society Reviews 2014; 43, 6727-6749.

7.

58.

Adlard P, Tran B, Finkelstein D, Desmond P, Johnston L, Bush AI, Egan G. A review of β-amyloid neuroimaging in Alzheimer’s disease. Frontiers in Neuroscience 2014; 8, 327. [doi: 10.3389/fnins.2014.00327].

Shahijanian F, Parnell GP, McKay FC, Gatt PN, Shojoei M, O’Connor KS, Schibeci SD, Brilot F, Liddle C, Batten M; ANZgene Multiple Sclerosis Genetics Consortium, Stewart GJ, Booth DR. The CYP27B1 variant associated with an increased risk of autoimmune disease is underexpressed in tolerizing dendritic cells. Hum Mol Genet.

2014;23(6):1425-34.

124

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Davidson S.M., Lopaschuk G.D., Spedding M., Beart P.M. Mitochondrial pharmacology: energy, injury and beyond.

British Journal of Pharmacology 171, 1795–1797 (2014).

Grad LI, Yerbury JJ, Turner BJ, Guest WC, Pokrishevsky E, O’Neill MA, Yanai A, Silverman JM, Zeineddine R, Corcoran L, Kumita JR, Luheshi LM, Yousefi M, Coleman BM, Hill AF, Plotkin SS, Mackenzie IR, Cashman NR (2014) Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosomedependent and -independent mechanisms. Proc Natl Acad Sci USA 111: 3620-3625.

23.

Lau C.L., Kovacevic M., Tingleff T.S., Forsythe J.S., Cate H.S., Merlo D., Cederfur C., Maclean F.L., Parish C.L., Horne M.K., Nisbet D.R., Beart P.M. 3D Electrospun scaffolds promote a cytotrophic phenotype of cultured primary astrocytes. Journal of Neurochemistry 130, 215-226 (2014).

Turner BJ, Alfazema N, Sheean RK, Sleigh JN, Davies KE, Horne MK, Talbot K (2014) Overexpression of survival motor neuron improves neuromuscular function and motor neuron surival in mutant SOD1 mice. Neurobiol Aging 35: 906-915.

24.

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Perera ND, Sheean RK, Scott JW, Kemp BE, Horne MK, Turner BJ (2014) Mutant TDP-43 deregulates AMPK activation by PP2A in ALS models. PLoS One 9: e95549.

25.

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Davidson S.M., Lopaschuk G.D., Spedding M., Beart P.M. (Eds) “Mitochondrial Pharmacology: Energy, Injury and Beyond”. British Journal of Pharmacology 171, pp. 1795–2249 (2014). “Mitochondrial Pharmacology: Energy, Injury and Beyond”.

Polling S, Mok YF, Ramdzan YM, Turner BJ, Yerbury JJ, Hill AF, Hatters DM (2014) Misfolded polyglutamine, polyalanine and superoxide dismutase 1 aggregate via distinct pathways in the cell. J Biol Chem 289: 6669-6680.

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Roberts BR, Lim NK, McAllum EJ, Donnelly PS, Hare DJ, Doble PA, Turner BJ, Price KA, Lim SC, Paterson BM, Hickey JL, Rhoads TW, Williams JR, Kanninen KM, Hung LW, Liddel JR, Grubman A, Monty JF, Llanos RM, Kramer DR, Mercer JF, Bush AI, Masters CL, Duce JA, Li QX, Beckman JS, Barhnham KJ, White AR, Crouch PJ (2014) Oral treatment with Cu(atsm) increases mutant SOD1 in vivo but protects motor neurons and improves the phenotype of a transgenic mouse model of ALS. J Neurosci 34: 8021-8031.

7.

Gazina Ev, Leaw Bt, Richards Kl, Wimmer Vc, Kim Th, Aumann Td, Featherby Tj, Churilov L, Hammond Ve, Reid Ca, Petrou S. Neonatal Nav1.2 reduces neuronal excitability and affects seizure susceptibility and behaviour. Hum Mol Genet. 2014 pii: ddu562.

27.

Fernando CV, Kele J, Bye CR, Niclis JC, Alsanie W, Blakely BD, Stenman J, Turner BJ, Parish CL (2014) Diverse roles for Wnt7a in ventral midbrain neurogenesis and dopaminergic axon morphogenesis. Stem Cells Dev 23: 1991-2003.

8.

Stanić D., Dubois S., Chua H.K., Tonge B., Rinehart N., Horne M.K., Boon W.C. Characterization of aromatase expression in the adult male and female mouse brain. I. Coexistence with oestrogen receptors α and β, and androgen receptors. PLoS One. 2014 9: e90451.

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9.

Bell Jr, Bernasochi Gb, Varma U, Boon Wc, Ellem SJ, Risbridger GP, Delbridge LM. Aromatase transgenic upregulation modulates basal cardiac performance and the response to ischemic stress in male mice. Am J Physiol Heart Circ Physiol. 2014 306: H1265-74.

29.

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30.

Kotschet K, Johnson W, Mcgregor S, Kettlewell J, Kyoong A, O’Driscoll DM, Turton Ar, Griffiths RI, Horne MK. Daytime sleep in Parkinson’s disease measured by episodes of immobility. Parkinsonism Relat Disord. 2014 20: 578-83.

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33.

Lau C.L., Kovacevic M., Tingleff T.S., Forsythe J.S., Cate H.S., Merlo D., Cederfur C., Maclean F.L., Parish C.L., Horne M.K., Nisbet D.R., Beart P.M. 3D Electrospun scaffolds promote a cytotrophic phenotype of cultured primary astrocytes. J Neurochem. 2014 130: 215-26.

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Bird M., Needham K., Frazier A.E., Van Rooijen J., Leung J., Hough S., Denham M., Thornton M.E., Parish C.L., Nayagam B., Pera M., Thornburn D.R, Thompson L.H., Dottori M. Functional characterization of Friedreich Ataxia iPS-derived neuronal progenitors and their integration in the adult brain. PLoS One 2014 7,: e101718

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Sahin G., Thompson L.H., Lavisse S., Ozgur M., Carta M., Rbah L., Dolle F., Hantraye P., Kirik D. Differential dopamine receptor occupancy underlies L-DOPA-induced dyskinesia in a rat model of Parkinson’s disease. PLoS One 2014, 9: e90759.

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Turner B.J., Alfazema N., Sheean R.K., Sleigh J.N., Davies K.E., Horne M.K., Talbot K. Overexpression of survival motor neuron improves neuromuscular function and motor neuron survival in mutant SOD1 mice. Neurobiol Aging. 2014 35: 906-15.

14.

Rodriguez AL, Wang TY, Bruggeman KF, Horgan C, Li R, Williams RJ, Parish CL, Nisbet DR. In vivo assessment of grafted cortical neural progenitor cells and host response to functionalized self-assembling peptide hydrogels and implications for tissue repair. Journal of Materials Chemistry. B, 2014,2, 7771-7778..

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Atkin J.D., Farg M.A., Soo K.Y., Walker A.K., Halloran M., Turner B.J., Nagley P., Horne M.K. Mutant SOD1 inhibits ER-Golgi transport in amyotrophic lateral sclerosis. J Neurochem. 2014 129: 190-204.

15.

Bird M, Needham K, Frazier A, Van Rooijen J, Leung J, Hough S, Denham M, Thornton Me, Parish Cl, Pera M, Thorburn D, Thompson Lh, Dottori M. Functional characterization of Friedreich Ataxia iPS-derived neuronal progenitors and their integration in the adult brain. PLoS One (2014) 9: e101718.

1.

Binder, C., Chuang, E., Habla, C., Bleckmann, A., Schulz, M., Bathgate, R., Einspanier A. Relaxins enhance growth of spontaneous murine breast cancers as well as metastatic colonization of the brain. Clin Expl Metastasis 31, 57-65, 2014.

2.

Wang TY, Bruggeman KA, Sheean RK, Turner BJ, Nisbet DR, Parish CL. Characterisation of the stability and biofunctionality of tethered proteins on bioengineered scaffolds J Biol Chem (2014) 289: 15044-15051.

Chow, B.S., Kocan, M., Bosnyak, S., Sarwar, M., Wigg, B., Jones, E.S., Widdop, R.E., Summers, R.J., Bathgate, R.A., Hewitson, T.D., Samuel, C.S. Relaxin requires the angiotensin II type 2 receptor to abrogate renal interstitial fibrosis. Kidney Int 86, 75-85, 2014.

3.

C.L. Lau, M. Kovacevic, T. Tingleff, J.S. Forsythe, H.S. Cate, D. Merlo, C. Cederfur, F.L. Maclean, C.L. Parish, M.K. Horne, D.R. Nisbet, P.M. Beart. 3D Electrospun scaffolds promote a cytotrophic phenotype of cultured primary astrocytes J Neurochem. (2014) 130: 215-226.

Diepenhorst, N.A., Petrie, E.J., Chen, C.Z., Wang, A., Hossain, M.A., Bathgate, R.A., Gooley, P.R. Investigation of interactions at the extracellular loops of the relaxin family peptide receptor 1 (RXFP1). J Biol Chem 289, 3493852, 2014.

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Egloff, P., Hillenbrand, M., Klenk, C., Batyuk, A., Heine, P., Balada, S., Schlinkmann, K. M., Scott, D.J., Schutz, M., Pluckthun, A. Structure of signaling-competent neurotensin receptor 1 obtained by directed evolution in Escherichia coli. Proc Natl Acad Sci USA 111, 655-662, 2014.

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Grosse, J., Heffron, H., Coll, A.P., Burling, K., Hossain, M.A., Habib, A.M., Rogers, G.J., Richards, P., Larder, R., Rimmington, D., Parton, L., Binda, M., Colledge, W., Doran, J., Toyoda, Y., Wade, J.D., Aparicio, S., Carlton, M., Coll, A.P., Reimann, F., O’Rahilly, S., Gribble, F.M. Insulin-like peptide 5 is an orexigenic gastro-intestinal hormone. Proc Natl Acad Sci USA 111, 11133-11138, 2014.

6.

Hossain M.A., Wade, J.D. Synthetic relaxins. Curr Opin Chem Biol, 22, 47-55, 2014.

7.

Hojo, K., Shinozaki, N., Hidaka, K., Tsuda, Y., Fukumori, Y., Ichikawa, H., Wade, J.D. Aqueous microwave-assisted solid phase peptide synthesis using Fmoc- strategy. III. Racemization studies and water-based synthesis of histidine-containing peptides. Amino Acids 46, 2347-2354, 2014.

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Fernando CV, Kele J, Bye CR, Blakely BD, Niclis J, Alsanie W, Stenman J, Turner BJ, Parish CL. Wnt7a regulates ventral midbrain neurogenesis and dopaminergic axon morphogenesis in development and embryonic stem cells.

Stem Cells and Dev (2014) 23: 1991-2003.

Kim HA, Jiang L, Madsen H, Parish CL, Massalas J, Smardencas A, O’leary C, Gantois I, O’tuathaigh C, Waddington JL, Ehrlich ME, Lawrence AJ, Drago J. Loss of striatal D1 dopamine receptor neurons gives a Huntington disease Westphal variant-like model. Neurobiology of Disease (2014); 62: 323-337.

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Parish CL, Thompson LH. Modulating Wnt signaling to improve cell replacement therapy for Parkinson’s disease.

J Mol Cell Biol. (2014) 6: 54-63.

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Grad LI, Yerbury JJ, Turner BJ, Guest WC, Pokrishevsky E, O’Neill MA, Yanai A, Silverman JM, Zeineddine R, Corcoran L, Kumita JR, Luheshi LM, Yousefi M, Coleman BM, Hill AF, Plotkin SS, Mackenzie IR, Cashman NR (2014) Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosomedependent and -independent mechanisms. Proc Natl Acad Sci USA 111: 3620-3625.

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Jamasbi, E., Batinovic, S., Sharples, R., Sani, M-A., Robins-Browne, R.M., Wade, J.D., Separovic, F., Hossain, M.A. Melittin peptides exhibit different activity on different cells and model membranes. Amino Acids 46, 2759-2766, 2014.

9.

Kocan, M., Sarwar, M., Hossain, M.A., Wade, J.D., Summers, R.J. Signalling profiles of H3 relaxin, H2 relaxin and the novel antagonist R3(BΔ23-27)R/I5 acting at the relaxin family peptide receptor 3 (RXFP3). Br J Pharmacol 171, 2827-2841, 2014.

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Kong, R.C., Bathgate, R.A., Bruell, S., Wade, J.D., Gooley, P.R., Petrie, E.J. Mapping key regions of the RXFP2 lowdensity lipoprotein class-A module that are involved in signal activation. Biochemistry 53, 4537-4548, 2014.

11.

Karas, J.A., Scanlon, D.B., Forbes, B.E., Vetter, I., Lewis, R.J., Gardiner, J., Separovic, F., Wade, J.D., Hossain, M.A. 2-Nitroveratryl as a photocleavable thiol protecting group for directed disulfide bond formation in the chemical synthesis of insulin. Chemistry 20, 9549-9552, 2014.

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Li W., Tailhades, J., O’Brien-Simpson, N., Separovic, F., Otvos, L., Hossain, M.A., Wade, J.D. Proline-rich antimicrobial peptides. Amino Acids 46, 2287-2294, 2014.

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Otvos, L., Knappe, D., Hoffmann, R., Kovalszky, I., Olah, J., Hewitson, T., Wade, J.D., Surmacz, E., Lovas, S. Development of a second generation peptide agonist and a first generation antagonist of the adiponectin receptor. Front Chem 2, 93, 2014.

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Otvos, L., Flick-Smith, H., Ostorhazi, E., Dawson, R.M. and Wade, J.D. The designer proline-rich antibacterial peptide A3-APO prevents Bacillus anthracis mortality by deactivating bacterial toxins. Prot Pept Lett 21, 374-381, 2014.

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Otvos, Jr, L., Vetter, S.W., Koladia, M., Knappe, D., Schmidt, R., Ostorhazi, E., Kovalszky, I., Bionda, N., Cudic, P., Surmacz, E., Wade, J.D., Hoffmann, R. The designer leptin antagonist peptide allo-aca compensates for short serum half-life with very tight binding to the receptor. Amino Acids 46, 873-882, 2014.

16.

Otvos, L., Wade. J.D. Current challenges in peptide-based drug discovery. Front Chem 2, 62, 2014.

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Cadilhac DA and Anderson CS. Pathways to enhancing the quality of stroke care through national data monitoring systems for hospitals [Letter], MJA 2014 Apr 21;200(7):393

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Cadilhac D, Moloczij N, Denisenko S, Dewey H, Disler P, Winzar B, Mosely I, Donnan G, Bladin C. Establishment of an effective acute stroke telemedicine program for Australia: protocol for the Victorian Stroke Telemedicine project. Int J Stroke 2014 Feb;9(2):252-8, DOI: 10.1111/ijs.12137

13.

Cadilhac D.A, Vos T, Thrift A.G. Estimating the annual number of strokes and the issue of imperfect data: an example from Australia. Int J Stroke 2014 Jan;9(1):19-22. DOI: 10.1111/ijs.12246

14.

Campbell BCV, Mitchell PJ, Yan B, Parsons MW, Christensen S, Churilov L, Dowling RJ, Dewey H, Brooks M, Miteff F, Levi CR, Krause M, Harrington TJ, Faulder KC, Steinfort BS, Kleinig T, Scroop R, Chryssidis S, Barber PA, Hope A, Moriarty M, McGuinness B, Wong AA, Coulthard A, Wijeratne T, Lee A, Jannes J, Leyden J, Phan TG, Chong W, Holt M, Chandra RV, Bladin C, Badve M, Rice H, de Villiers L, Ma H, Desmond PM, Davis SM, Donnan GA.A multicenter, randomized, controlled study to investigate EXtending the time for Thrombolysis in Emergency Neurological Deficits with Intra-Arterial therapy (EXTEND-IA). International Journal of Stroke 2014; 9:126-132.

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Campbell BC, Davis SM, Donnan GA. Uric acid for stroke: glimmer of hope or false dawn? Lancet Neurol. 2014 May;13(5):440-1.

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Campbell BC, Mitchell PJ, Yan B, Parsons MW, Christensen S, Churilov L, et al. A multicenter, randomized, controlled study to investigate EXtending the time for Thrombolysis in Emergency Neurological Deficits with Intra-Arterial therapy (EXTEND-IA). Int J Stroke. 2014 Jan;9(1):126-32.

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Carey, L.M. (2014) Core Concepts in Sensory Impairment and Recovery Following Stroke. In Wolf, T. Stroke: Interventions to Support Occupational Performance. AOTA Press. Pp. 95-118. (ISBN: 1569003645)

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Carey, L.M. (2014). Loss of somatic sensation. In Selzer, N., Clarke, S., Cohen, L., Kwakkel, G., Miller. R. Textbook of Neural Repair and Rehabilitation (2nd ed). Cambridge University Press. (ISBN: 9781107011687)

Ryan, P.J., Krstew, E.V., Sarwar, M., Gundlach, A.L., Lawrence, A.J. Relaxin-3 mRNA levels in nucleus incertus correlate with alcohol and sucrose intake in rats. Drug Alcohol Depend 140, 8-16, 2014.

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Carey, L., Cusick, A., Hoffman, T., Elliot, C., Froude, E., O’Reilly, N. (2014). Occupational Therapy Australia Research Foundation: Building a Research Foundation for all occupational therapists. Connections 11 (1): 12-13.

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Smith, C.M., Chua, B.E., Zhang, C., Walker, A.W., Haidar, M., Hawkes, D., Hossain, M.A., Shabanpoor, F., Wade, J.D., Rosengren, K.J., Gundlach, A.L. Central injection of relaxin-3 receptor antagonist peptides reduces motivated food seeking and consumption in mice. Behav Brain Res 268, 117-126, 2014.

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Churilov L, Arnup S, Johns H, Leung T, Roberts S, Campbell BC, et al. An improved method for simple, assumption-free ordinal analysis of the modified Rankin Scale using generalized odds ratios. Int J Stroke. 2014 Sep 4.

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Smith, C.M., Walker, A.W., Hosken, I.T., Chua, B.E., Zhang, C., Haidar, M., Gundlach, A.L. Relaxin-3/RXFP3 networks: an emerging target for the treatment of depression and other neuropsychiatric diseases? Front Pharmacol 5, 46, 2014.

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Clarey J, Lasserson, D, Levi C, Parsons M, Dewey H, Barber PA, Quain D, McElduff P, Sales M, Magin P. Absolute cardiovascular risk and GP decision-making in TIA and minor stroke. Family Practice 2014 (accepted 4 August 2014).

20.

Scott, D.J., Kummer, L., Egloff, P., Bathgate, R.A., Pluckthun, A. Improving the apo-state detergent stability of NTS1 with CHESS for pharmacological and structural studies. Biochim Biophys Acta 1838, 2817-2824, 2014.

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Craig L, Wu O, Bernhardt J. Langhorne P, Approaches to economic evaluations of stroke rehabilitation: a systematic review. International Journal of Stroke. 9:88-100

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Unsworth N.B., Dawson, R.M., Wade, J.D., Liu, C-Q. Synergistic effect of antimicrobial peptides on the in vitro growth of Coxiella burnetti. Prot Pept Lett 21, 115-123, 2014.

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Cumming T, Brodtmann A, Darby D, Bernhardt J. The importance of cognition to quality of life after stroke.

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Drury, P, Levi C, D’Este C, McElduff P, McInnes E, Hardy J, Dale S, Cheung N W, Grimshaw J, Quinn C, Ward J, Evans M, Cadilhac D, Griffiths R, Middleton S. Quality in Acute Stroke Care (QASC): Process evaluation of an intervention to improve the management of fever, hyperglycemia and swallowing dysfunction following acute stroke. Int J Stroke 2014;9(6):766-76 DOI: 10.1111/ijs.12202

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Andrew NE, Kilkenny M, Naylor R, Purvis T, Lalor E, Moloczij N, Cadilhac DA. Understanding long-term unmet needs in Australian survivors of stroke. Int J Stroke, available online 15 Jul 2014 DOI: 10.1111/ijs.12325

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Andrew NE, Hankey GJ, Cadilhac DA. Evidence-to-practice gaps in post-stroke management: a focus on care in a stroke unit and anticoagulation to prevent death, disability and recurrent stroke. Future Neurology 2014; 9(4):449-459 DOI: 10.2217/fnl.14.30

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Andrew N, Kilkenny M, Harris D, Price C, Cadilhac D. Outcomes for people with atrial fibrillation in an Australian national audit of stroke care. Int J Stroke 2014 Apr;9(3):270-7 DOI: 10.1111/ijs.12087

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Askim T, Salveson O, Bernhardt J. Indredavik B. Physical activity early after stroke and its association to functional outcome 3 months later. Journal of Stroke and Cerebrovascular Diseases. 23:5:e305-e312

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Bath PM, Brainin M, Brown C, Campbell B, Davis SM, Donnan GA, et al. Testing devices for the prevention and treatment of stroke and its complications. Int J Stroke. 2014 Aug;9(6):683-95.

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Billinger S, Arena, R, Bernhardt J, Eng J, Franklin B, Johnson C, MacKay-Lyons M, Macko R, Mead G, Röth E, Shaughnessy M, Tang A. Physical Activity and Exercise Recommendations for Stroke Survivors: A Statement for Healthcare Professionals from the American Heart Association/American Stroke Association. Stroke. http:// stroke.ahajournals.org/content/early/2014/05/20/STR.0000000000000022

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Cadilhac DA, Vu M, Bladin C. Experience with scaling up the Victorian Stroke Telemedicine programme, Journal of Telemedicine and Telecare 2014, Vol. 20(7) 413–418.

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Grimmer K, JM, Milanese S, King E, Beaton K, Thorpe O, Lizarondo L, Luker J, Machotka Z, Kumar S. Efficient clinical evaluation of guideline quality: development and testing of a new tool. BMC Medical Research Methodology 2014; 14(1):63.

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Hersh D, Godecke E, Armstrong E, Ciccone N, Bernhardt J. “Ward talk”: Nurses’ interaction with people with and without aphasia in the very early period poststroke. Aphasiology. http://dx.doi.org/10.1080/02687038.2014.93 3520

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Hubbard, I., Carey, LM., Budd, T. W. Levi, C, McElduff, P., Hudson, S., Bateman, G., Parsons, MW. (2014) A randomized controlled trial of early upper limb training on stroke recovery and brain activation. Neurorehabilitation and Neural Repair. (Published online before print; DOI: 10.1177/1545968314562647)

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Li Q, Pardoe H, Lichter R, Werden E, Raffelt A, Cumming T, Brodtmann A (in press). Cortical thickness estimation in longitudinal stroke studies: A comparison of 3 measurement methods. Neuroimage: Clinical. doi:10.1016/j. nicl.2014.08.017.

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Lynch L, Luker J, Cadilhac DA, Hillier S. Rehabilitation assessments for patients with stroke in Australian hospitals do not always reflect the patients’ rehabilitation requirements, Archives of Physical Medicine and Rehabilitation, accepted 12 December 2014

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Zhang W, Cadilhac DA, Churilov L, Donnan GA, O’Callaghan C, Dewey HM. Does abnormal circadian blood pressure pattern really matter in patients with transient ischemic attack or minor stroke? Stroke. 2014; 45(3): 865-7.

78.

Zhang WW, Speare S, Churilov L, Thuy M, Donnan G, Bernhardt J. Stroke rehabilitation in China: a systematic review and meta-analysis. Int J Stroke. 2014; 9(4): 494-502.

79.

Antonic, A., Dottori, M., Leung, J., Sidon, K., Batchelor, P.E., Wilson, W., Macleod, M.R., and Howells, D.W. (2014).

Hypothermia protects human neurons. Int J Stroke 9, 544-552.

80.

Ardipradja, K., Yeoh, S.D., Alt, K., O’Keefe, G., Rigopoulos, A., Howells, D.W., Scott, A.M., Peter, K., Ackerman, U., and Hagemeyer, C.E. (2014). Detection of activated platelets in a mouse model of carotid artery thrombosis with 18 F-labeled single-chain antibodies. Nuclear medicine and biology 41, 229-237.

56.

O’Halloran P, Blackstock F, Shields N, Holland A, Iles R, Kingsley M, Bernhardt J, Lannin N, Morris M, Taylor N. Motivational interviewing to increase physical activity in people with chronic health conditions: a systematic review and meta-analysis. Clinical Rehabilitation Vol. 28(12) 1159–1171

57.

Palmer, S.M., Crewther, S.G., Carey, L.M. and the START project team. (2015) A meta-analysis of changes in brain activation and connectivity in clinical depression. Frontiers in Human Neuroscience, 8, 1045 (DOI: 10.3389/ fnhum.2014.01045)

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81.

Chalmers, I., Bracken, M.B., Djulbegovic, B., Garattini, S., Grant, J., Gulmezoglu, A.M., Howells, D.W., Ioannidis, J.P., and Oliver, S. (2014). How to increase value and reduce waste when research priorities are set. Lancet 383, 156-165.

13.

Bautista TG, Dutschmann M. Ponto-medullary nuclei involved in the generation of sequential pharyngeal swallowing and concomitant protective laryngeal adduction in situ. J Physiol. 2014 Jun 15;592(Pt 12):2605-23. doi: 10.1113/jphysiol.2014.272468.

82.

Dagonnier, M., Howells, D.W., Donnan, G.A., and Dewey, H.M. (2014). Recruitment to trials of late thrombolysis: Lessons from the EXTEND study. J Clin Neurosci 21, 1215-1219.

14.

83.

Egan, K.J., Janssen, H., Sena, E.S., Longley, L., Speare, S., Howells, D.W., Spratt, N.J., Macleod, M.R., Mead, G.E., and Bernhardt, J. (2014). Exercise reduces infarct volume and facilitates neurobehavioral recovery: results from a systematic review and meta-analysis of exercise in experimental models of focal ischemia. Neurorehabil Neural Repair 28, 800-812.

Bautista TG, Dutschmann M. Inhibition of the pontine Kölliker-Fuse nucleus abolishes eupneic inspiratory hypoglossal motor discharge in rat. Neuroscience. 2014 May 16;267:22-9. doi: 10.1016/j. neuroscience.2014.02.027.

15.

Dutschmann M, Bautista TG, Mörschel M, Dick TE. Learning to breathe: habituation of Hering-Breuer inflation reflex emerges with postnatal brainstem maturation. Respir Physiol Neurobiol. 2014 May 1;195:44-9. doi: 10.1016/j.resp.2014.02.009.

84.

Howells, D.W., Sena, E.S., and Macleod, M.R. (2014). Bringing rigour to translational medicine. Nature reviews.

Neurology 10, 37-43.

16.

Langenberg C, Gobe G, Hood S, May CN, Bellomo R. Renal Histopathology during Experimental Septic Acute Kidney Injury and Recovery. Critical Care Medicine 42: e58-67; 2014.

85.

Howells, D.W. (2014). Stroke, Animal Models. In Encyclopedia of the Neurological Sciences, Volume Accepted 13th July, 2nd Edition, M.J. Aminoff and R.B. Daroff, eds. (San Diego: Academic Press).

17.

Lu Ke Calzavacca P, Bailey M, Wei-qin Li, Bellomo R, May CN. Acid-base changes after fluid bolus: sodium chloride vs. sodium octanoate. Intensive Care Medicine Experimental 1: 4; 2014.

86.

McCann, S.K., Irvine, C., Mead, G.E., Sena, E.S., Currie, G.L., Egan, K.E., Macleod, M.R., and Howells, D.W. (2014).

Efficacy of antidepressants in animal models of ischemic stroke: a systematic review and meta-analysis. Stroke 45, 3055-3063.

18.

Lu Ke, Calzavacca P, Bailey M, Wei-qin Li, Bellomo R May CN. Systemic and renal haemodynamic effects of fluid bolus therapy: sodium chloride versus sodium octanoate-balanced solution. Critical Care and Resuscitation. 16:29-33; 2014.

87.

O’Collins, V.E., Markus, R., and Howells, D.W. (2014). Neurotoxicity and Stroke. In Handbook of Neurotoxicity, Volume 2, R.A. Kostrzewa, ed. (New York: Springer), pp. 1483-1509.

19.

88.

Pascoe, M.C., Howells, D.W., Crewther, D.P., Constantinou, N., Carey, L.M., Rewell, S.S., Turchini, G.M., Kaur, G., and Crewther, S.G. (2014). Fish oil diet associated with acute reperfusion related hemorrhage, and with reduced stroke-related sickness behaviors and motor impairment. Frontiers in neurology 5, 14.

Calzavacca P, Bailey M, Velkoska E, Burrell LM, Ramchandra R, Bellomo R, May CN. Effects of Renal Denervation on Regional Hemodynamics and Kidney Function in Experimental Hyperdynamic Sepsis. Critical Care Medicine 42: e401-9; 2014.

20.

Sena, E.S., Currie, G.L., McCann, S.K., Macleod, M.R., and Howells, D.W. (2014). Systematic reviews and metaanalysis of preclinical studies: why perform them and how to appraise them critically. J Cereb Blood Flow Metab 34, 737-742.

Frithiof R, Xing T, McKinley MJ, May CN, and Ramchandra R. Intracarotid hypertonic sodium chloride differentially modulates sympathetic nerve activity to the heart and kidney. American Journal of Physiology 15: R567-75; 2014.

21.

Calzavacca P, May CN, Bellomo R. Glomerular hemodynamics, the sympathetic system and sepsis-induced acute kidney injury. Nephrology Dialysis Transplantation 29: 2178-2184; 2014.

22.

Booth LC, Ramchandra R, Calzavacca P, May CN. Role of Prostaglandins in Determining the Increased Cardiac Sympathetic Nerve Activity in Ovine Sepsis. American Journal of Physiology 307: R75-81; 2014.

23.

Ramchandra R, Hood SG, May CN. Central nitric oxide decreases cardiac sympathetic drive and improves baroreflex control of heart rate in ovine heart failure. American Journal of Physiology 307: R271-80; 2014.

24.

Xing DT, May CN, Booth LC, Ramchandra R. Tonic arterial chemoreceptor activity contributes to cardiac sympathetic activation in mild ovine heart failure. Experimental Physiology 99(8):1031-41; 2014.

25.

Martelli D, Silvani A, McAllen RM, May CN, Ramchandra R. The low frequency power of heart rate variability is neither a measure of cardiac sympathetic tone nor of baroreflex sensitivity. American Journal of Physiology 307: H1005-12; 2014.

26.

Darwinkel A, Stanić D, Booth LC, May CN, Lawrence AJ, Yao ST. Distribution of orexin-1 receptor-green fluorescent protein- (OX1-GFP) expressing neurons in the mouse brain stem and pons: co-localisation with tyrosine hydroxylase and neuronal nitric oxide synthase. Neuroscience 278: 253-64; 2014.

89.

CHAPTER SYSTEMS NEUROPHYSIOLOGY

THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

90.

Vesterinen, H.M., Sena, E.S., Egan, K.J., Hirst, T.C., Churolov, L., Currie, G.L., Antonic, A., Howells, D.W., and Macleod, M.R. (2014). Meta-analysis of data from animal studies: A practical guide. J Neurosci Methods 221, 92-102.

91.

Watzlawick, R., Sena, E.S., Dirnagl, U., Brommer, B., Kopp, M.A., Macleod, M.R., Howells, D.W., and Schwab, J.M. (2014). Effect and Reporting Bias of RhoA/ROCK-Blockade Intervention on Locomotor Recovery After Spinal Cord Injury: A Systematic Review and Meta-analysis. JAMA Neurol 71, 91-99.

1.

Martelli D, McKinley MJ, McAllen RM. (2014) The cholinergic anti-inflammatory pathway: A critical review. Auton Neurosci. 182:65-9.

2.

Martelli D, Yao ST, McKinley MJ, McAllen RM. (2014) Reflex control of inflammation by sympathetic nerves, not the vagus. J Physiol. 592(Pt 7):1677-86.

3.

Martelli D, Silvani A, McAllen RM, May CN, Ramchandra R. (2014) The low frequency power of heart rate variability is neither a measure of cardiac sympathetic tone nor of baroreflex sensitivity. Am J Physiol Heart Circ Physiol. 2014 Oct 1;307(7):H1005-12.

27.

Calzavacca P, Lankadeva Y, Bailey SR, Bailey M, Bellomo R, May CN. Effects of Selective β1-Adrenoceptor Blockade on Cardiovascular and Renal Function and Circulating Cytokines in Ovine Hyperdynamic Sepsis.

Critical Care 18: 610; 2014.

4.

Martelli D, Yao ST, Mancera J McKinley MJ, McAllen RM. (2014) Reflex control of inflammation by the splanchnic anti-inflammatory pathway is sustained and independent of anesthesia. Am J Physiol Regul Integr Comp Physiol. 2014 Nov 1;307(9):R1085-91.

28.

Schneider GA, Calzavacca P, Schelleman A, Huynh T, Bailey M, May CN, Bellomo R. Contrast-enhanced ultrasound evaluation of renal microcirculation in sheep. Intensive Care Medicine Experimental 2: 33; 2014.

29.

5.

Martelli D, Yao ST, McKinley MJ, McAllen RM. (2014) Neural control of inflammation by the greter splanchnic nerves. Temperature 1 (1) 14-15.

Calzavacca P, Ishikawa K, Bailey M, May CN, Bellomo R. Systemic and Renal Hemodynamic Effects of Intraarterial Radiocontrast. Intensive Care Medicine Experimental 2: 32; 2014.

30.

6.

Shafton AD, McKinley MJ, Kitchener P, McAllen RM. (2014) Reflex control of rat tail sympathetic nerve activity by abdominal temperature. Temperature 1 (1) 37-41.

Ruchaya PJ, Antunes VR, Paton JF, Murphy D, Yao ST. The cardiovascular actions of fractalkine/CX3CL1 in the hypothalamic paraventricular nucleus are attenuated in rats with heart failure. Exp Physiol. 2014 Jan;99(1):11122.

7.

Farrell MJ, Trevaks D, McAllen RM. (2014) Preoptic activation and connectivity during thermal sweating in humans. Temperature 1 (2) 135-141.

31.

Darwinkel A, Stanić D, Booth LC, May CN, Lawrence AJ, Yao ST. Distribution of orexin-1 receptor-green fluorescent protein- (OX1-GFP) expressing neurons in the mouse brain stem and pons: Co-localization with tyrosine hydroxylase and neuronalitric oxide synthase. Neuroscience. 2014 Oct 10;278:253-64.

8.

Dutschmann M. ‘Big Chief’ - for Respiratory Physiology & Neurobiology. Respir Physiol Neurobiol. 2015 Jan 30. pii: S1569-9048(15)00028-2. doi: 10.1016/j.resp.2015.01.015.

32.

9.

Dutschmann M, Jones SE, Subramanian HH, Stanic D, Bautista TG. The physiological significance of postinspiration in respiratory control. Prog Brain Res. 2014;212:113-30. doi: 10.1016/B978-0-444-634887.00007-0.

Martelli D, Yao ST, Mancera J, McKinley MJ, McAllen RM. Reflex control ofinflammation by the splanchnic anti-inflammatory pathway is sustained andindependent of anesthesia. Am J Physiol Regul Integr Comp Physiol. 2014 Nov1;307(9):R1085-91.

33.

Dick TE, Dutschmann M, Feldman JL, Fong AY, Hülsmann S, Morris KM, Ramirez JM, Smith JC; the respiratory neurobiology consortium. Facts and challenges in Respiratory Neurobiology. Respir Physiol Neurobiol. 2015 Jan 30. pii: S1569-9048(15)00027-0. doi: 10.1016/j.resp.2015.01.014.

Qiu J, Kleineidam A, Gouraud S, Yao ST, Greenwood M, Hoe SZ, Hindmarch C, Murphy D. The use of proteinDNA, chromatin immunoprecipitation, and transcriptome arrays to describe transcriptional circuits in the dehydrated male rat hypothalamus. Endocrinology. 2014 Nov;155(11):4380-90.

34.

Martelli D, Yao ST, McKinley MJ, McAllen RM. Reflex control of inflammation by sympathetic nerves, not the vagus. J Physiol. 2014 Apr 1;592(Pt 7):1677-86.

11.

Bautista TG, Fong AY, Dutschmann M. Spontaneous swallowing occurs during autoresuscitation in the in situ brainstem preparation of rat. Respir Physiol Neurobiol. 2014 Oct 1;202:35-43. doi: 10.1016/j.resp.2014.07.015.

35.

12.

Farmer DG, Bautista TG, Jones SE, Stanic D, Dutschmann M. The midbrain periaqueductal grey has no role in the generation of the respiratory motor pattern, but provides command function for the modulation of respiratory activity. Respir Physiol Neurobiol. 2014 Dec 1;204:14-20. doi: 10.1016/j.resp.2014.07.011.

Booth LC, Nishi EE, Yao ST, Ramchandra R, Lambert GW, Schlaich MP, May CN. Reinnervation of renal afferent and efferent nerves at 5.5 and 11 months after catheter-based radiofrequency renal denervation in sheep.

Hypertension. 2015 Feb;65(2):393-400.

36.

Booth LC, Nishi EE, Yao ST, Ramchandra R, Lambert GW, Schlaich MP, May CN. Reinnervation following catheter-based radio-frequency renal denervation. Exp Physiol. 2015 Jan 8.

PAGES 100–103

10.

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

37.

Brunton PJ, Donadio MV, Yao ST, Greenwood M, Seckl JR, Murphy D, Russell JA. 5α-reduced neurosteroids sexdependently reverse central prenatal programming of neuroendocrine stress responses in rats. J Neurosci. 2015 Jan 14;35(2):666-77.

38.

McAllen R.M., Cook A.D., Khiew H.W., Martelli D., Hamilton J.A. The interface between cholinergic pathways and the immune system and its relevance to arthritis. Arthritis Res. Ther. 2015 (accepted).

39.

Martelli D., Silvani A., McAllen R.M., May C.N., Ramchandra R. Reply to “Letter to the editor: Does low-frequency power of heart rate variability correlate with cardiac sympathetic tone in normal sheep?”. Am. J. Physiol. Heart Circ. Physiol. 308(2), 2015:H148-9.

40. Cerri M., Del Vecchio F., Mastrotto M., Luppi M., Martelli D., Perez E., Tupone D., Zamboni G., Amici R. Enhanced Slow-Wave EEG Activity and Thermoregulatory Impairment following the Inhibition of the Lateral Hypothalamus in the Rat. Plos One, 9(11), 2014: e112849.

41.

Martelli D., Yao S.T., Mancera J., McKinley M.J., McAllen R.M. Reflex control of inflammation by the splanchnic anti-inflammatory pathway is sustained and independent of anaesthesia. Am. J. Physiol. Regul. Int. Comp. Physiol.

307(9), 2014: R1085-91.

42.

Martelli D., Silvani A., McAllen R.M., May C.N., Ramchandra R. The low frequency power of heart rate variability is neither a measure of cardiac sympathetic tone nor of baroreflex sensitivity. Am. J. Physiol. Heart Circ. Physiol.

307(7), 2014:H1005-12.

43.

Martelli D., Yao S.T., McKinley M.J., McAllen R.M. Neural control of inflammation by the greater splanchnic nerves. Temperature. 2014 Epub: https://www.landesbioscience.com/article/29135/full_text/#load/info/all.

44. Martelli D., Yao S.T., McKinley M.J., McAllen R.M. Reflex control of inflammation by sympathetic nerves, not the vagus. J. Physiol., 592, 2014:1677-1686.

45.

Martelli D., Luppi M., Cerri M., Tupone D., Perez E., Zamboni G., Amici R. The Direct Cooling of the PreopticHypothalamic Area Elicits the Release of Thyroid Stimulating Hormone during Wakefulness but Not during REM Sleep. Plos One, 9(2), 2014: e87793.

46.

Martelli D., McKinley M.J., McAllen R.M. The cholinergic anti-inflammatory pathway: a critical review. Auton.

Neurosci., 182, 2014:65-69.

47.

Chambers B, Chambers J, Churilov L, Cameron H, Macdonell R. Internal jugular and vertebral vein volume flow in patients with clinically isolated syndrome or mild multiple sclerosis and healthy controls: results from a prospective sonographer-blinded study. Phlebology. 2014 Sep;29(8):528-35.

48.

Confavreux C, O’Connor P, Comi G, Freedman MS, Miller AE, Olsson TP, Wolinsky JS, Bagulho T, Delhay JL, Dukovic D, Truffinet P, Kappos L; TOWER Trial Group. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13:247-56

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Miller AE, Macdonell R, Comi G, Freedman MS, Kappos L, Mäurer M, Olsson TP, Wolinsky JS, Bozzi S, DivePouletty C, O’Connor PW. Teriflunomide reduces relapses with sequelae and relapses leading to hospitalizations: results from the TOWER study. J Neurol. 2014;261:1781-8.

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Broadley SA, Barnett MH, Boggild M, Brew BJ, Butzkueven H, Heard R, Hodgkinson S, Kermode AG, LechnerScott J, Macdonell RA, Marriott M, Mason DF, Parratt J, Reddel SW, Shaw CP, Slee M, Spies J, Taylor BV, Carroll WM, Kilpatrick TJ, King J, McCombe PA, Pollard JD, Willoughby E. Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: An Australian and New Zealand perspective. Part 1 Historical and established therapies. J Clin Neurosci. 2014;21:1835-46

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Broadley SA, Barnett MH, Boggild M, Brew BJ, Butzkueven H, Heard R, Hodgkinson S, Kermode AG, LechnerScott J, Macdonell RA, Marriott M, Mason DF, Parratt J, Reddel SW, Shaw CP, Slee M, Spies J, Taylor BV, Carroll WM, Kilpatrick TJ, King J, McCombe PA, Pollard JD, Willoughby E. Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: An Australian and New Zealand perspective Part 2 New and emerging therapies and their efficacy. J Clin Neurosci. 2014;21: 1847-56

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Broadley SA, Barnett MH, Boggild M, Brew BJ, Butzkueven H, Heard R, Hodgkinson S, Kermode AG, LechnerScott J, Macdonell RA, Marriott M, Mason DF, Parratt J, Reddel SW, Shaw CP, Slee M, Spies J, Taylor BV, Carroll WM, Kilpatrick TJ, King J, McCombe PA, Pollard JD, Willoughby E. Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: An Australian and New Zealand perspective. Part 3 Treatment practicalities and recommendations. J Clin Neurosci. 2014;21: 1857-65

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Mehndiratta MM, Mehndiratta P, Tsai CP, Kaji R, Gulati NS, Wasay M, Macdonell R.Evolution, current status, and way forward for the Asian Oceanian Association of Neurology. Neurology. 2014;83:1853-5.

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“

One in four Australians are diagnosed with an anxiety disorder during their lifetime. This peaks during adolescence and the outcome following therapy is often extremely poor during this age compared to adults. I am trying to understand the neurobiology underlying this impairment while testing novel therapeutics.

The impact of treating anxiety early in life will be tremendous because it will forestall the persistence of anxiety into adulthood and the development of secondary disorders such as depression. My goal is to translate our preclinical findings from the lab bench to the clinic.

” Dr Despina Ganell

134

DIRECTOR’S OFFICE Director

ҩҩ Professor Geoffrey Donnan AO

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ҩҩ Colleen Buchhorn

DIVISION OF BEHAVIOURAL NEUROSCIENCE Addiction Neuroscience Laboratory

ҩҩ Robyn Brown ҩҩ Jhodie Duncan ҩҩ Despina Ganella ҩҩ Morgan James ҩҩ Bianca Jupp ҩҩ Elena Krstew ҩҩ Andrew Lawrence ҩҩ Liubov Lee-Kardashyan ҩҩ Nathan Marchant ҩҩ Christina Perry ҩҩ Phillip Ryan ҩҩ Craig Smith PhD Students

ҩҩ Rose Chesworth ҩҩ Nicola Chen ҩҩ Alec Dick ҩҩ Sophia Luikinga ҩҩ Karlene Scheller ҩҩ Sarah Sulaiman Ch’ng ҩҩ Leigh Walker ҩҩ Isabel Zbukvic Students

ҩҩ Katherine Beringer ҩҩ Katherine Drummond ҩҩ Emma Giles ҩҩ Rosa Heller ҩҩ Jan Koeleman ҩҩ Ashleigh Qama ҩҩ Felicia Reed ҩҩ Jirawoot Srisontiyakul ҩҩ Shawn Tan Developmental Pschobiology

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

OUR PEOPLE

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ҩҩ Sujeevan Sinnatamby ҩҩ Vaidy Swaminathan Student

ҩҩ Alejandro Ezquerro Nassar DIVISION OF MENTAL HEALTH NEURODEGENERATION

ҩҩ Simon Drew ҩҩ Carolin Tumpach PhD Student

ҩҩ Mariusz Mital Bio21 Laboratory

ҩҩ Kevin Barnham ҩҩ Jacky Chan ҩҩ Adam Gunn ҩҩ Lin Wai Hung ҩҩ Laura Jacobson-Hoyer ҩҩ Xuelei (Shelly) Li ҩҩ Xiang Liu ҩҩ Keyla Perez ҩҩ Andrew Watt ҩҩ Laura Vella Neuropathology Laboratory

ҩҩ Adel Barakat ҩҩ Michelle Fodero-Tavoletti ҩҩ George Ganio ҩҩ Vijaya Kenche ҩҩ Scott Laffoon ҩҩ Monica Lind ҩҩ Blaine Roberts ҩҩ Anne Roberts ҩҩ Tim Ryan ҩҩ David Stapleton PhD Students

ҩҩ Xin Yi Choo ҩҩ Amber Lothian ҩҩ Aaron Wagen Students

ҩҩ Nijlah Enayatzada ҩҩ Jade Rae Oxidation Biology Laboratory

ҩҩ Scott Ayton ҩҩ AbdelBelaidi ҩҩ Jessica Billings ҩҩ Lisa Bray ҩҩ Ashley Bush ҩҩ Feng Chen ҩҩ Mun-Joo Chuei ҩҩ Krista Dent

135

ҩҩ JamesDuce ҩҩ Bruce Etherton ҩҩ Noel Faux ҩҩ David Finkelstein ҩҩ Simote Foliaki ҩҩ Katherine Ganio ҩҩ Kristen Grant ҩҩ Mark Greenough ҩҩ Kali Perronnes (nee Hubbert) ҩҩ Dominic Hare ҩҩ Ya Hui Hung ҩҩ Nicole Jenkins ҩҩ Sharon La Fontaine ҩҩ Linh Lam ҩҩ Peng Lei ҩҩ Timothy Lovell ҩҩ Toni Lynch ҩҩ Sandra Luza ҩҩ Celeste Mawal ҩҩ Gawain McColl ҩҩ Suzie McNicol ҩҩ Steve Moon ҩҩ Lydia Nugroho ҩҩ Carlos Opazo Martinez ҩҩ Stuart Portbury ҩҩ Ashley Portbury ҩҩ Amelia Sedjahtera ҩҩ Charlotte Sgamelloni (nee Jordan) ҩҩ Adam Southon ҩҩ Brian Stevens ҩҩ Fransisca Sumardy ҩҩ Ambili Thoppuvalappil Appukuttan ҩҩ Irene Volitakis ҩҩ Bruce Wong PhD Students

ҩҩ Yifat Biran ҩҩ Patricia Chege Mugure ҩҩ Katherine Ganio ҩҩ Stephanie Guiney ҩҩ Adam Gunn ҩҩ Sara Hancock ҩҩ LinhLam ҩҩ Tim Lovell ҩҩ Nakisa Malakooti ҩҩ Stuart Portbury ҩҩ Alejandra Ramirez Munoz ҩҩ He (Olivia) Xu ҩҩ Luz Fernanda YevenesUgarte Students

ҩҩ RebeccaWorthing

136

Synaptic Biology

ҩҩ Paul Adlard ҩҩ Robert Cherny ҩҩ Krutika Wikhe DIVISION OF MULTIPLE SCLEROSIS

ҩҩ Michele Binder ҩҩ BernardChuang ҩҩ Ben Emery ҩҩ Judith Field ҩҩ Andrew Fox ҩҩ Laura Johnson ҩҩ Trevor Kilpatrick ҩҩ Daniel Merlo ҩҩ Tobias Merson ҩҩ Maria Papaioannou PhD Students

ҩҩ Zhi-Ming (Gerry) Ma ҩҩ Philipp Roth ҩҩ Yao (Lulu) Xing

THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

OUR PEOPLE

OUR PEOPLE

03/05

04/05

ҩҩ Simon McKenzie-Nickson ҩҩ Nirma Perera ҩҩ Agustinus Prijanto Neurogenesis and Neural Transplantation Laboratory

ҩҩ Jennifer Holland ҩҩ Lachlan Thompson ҩҩ Mong Tien

PhD Students

ҩҩ Charlotte Ermine ҩҩ Brett Kagan ҩҩ Fahad Somaa ҩҩ Christopher Turner ҩҩ Jordan Wright

Stem Cells and Neurodevelopment Laboratory

ҩҩ Christopher Bye ҩҩ Jonathan Niclis ҩҩ Clare Parish ҩҩ Ting Yi Wang

ҩҩ Sarah Calvert

PhD Students

DIVISION OF NEURODEGENERATION

Students

Student

Adult Neurogenesis Laboratory

ҩҩ Timothy Aumann ҩҩ Anupa Dey ҩҩ Mai Raabus ҩҩ Doris Tomas PhD Student

ҩҩ Parisa Farzanehfar

Molecular Neuropharmacology Laboratory

ҩҩ Philip Beart ҩҩ Cecilia Cederfur ҩҩ Chew Lau ҩҩ Linda Mercer PhD Student

ҩҩ Walaa Alsanie ҩҩ Jessica Kauhausen

ҩҩ Layla El Bouazzaoui ҩҩ Carlos Gantner

Steroid Neurobiology Laboratory

ҩҩ Wah Chin Boon ҩҩ Hui Kheng Chua ҩҩ Shilpi Dixit ҩҩ Tomris Mustafa ҩҩ Mark Ransome

Student

ҩҩ Kristina Vacy

DIVISION OF NEUROPEPTIDES

ҩҩ Yea Seul Shin

Insulin Peptides Laboratory

Motor Neuron Disease Laboratory

Membrane Protein Engineering Laboratory

ҩҩ Rebecca Sheean ҩҩ Bradley Turner

Neurodegeneration Laboratory

ҩҩ Malcolm Horne ҩҩ Katya Kotschet PhD Students

ҩҩ Wendy Lang

ҩҩ Mohammed Akhter Hossain ҩҩ Natasha Lam ҩҩ Daniel Scott

PhD Student

ҩҩ Fabian Bumbak

Students

ҩҩ Riley Cridge ҩҩ Rebecca Tan

Neuropeptide Receptor Laboratory

ҩҩ Ross Bathgate ҩҩ Tania Ferraro ҩҩ Sharon Layfield PhD Students

ҩҩ Shoni Bruell ҩҩ Bryna Chow ҩҩ Bradley Hoare ҩҩ Samantha Lagaida ҩҩ Lilian Wong ҩҩ Kelvin Yong Students

ҩҩ Spoorthi Karanan ҩҩ Alastair Keen ҩҩ Nicholas Smith

Peptide and Protein Chemistry Laboratory

ҩҩ Mohammed Hossain ҩҩ Feng Lin ҩҩ Fazel Shabanpoor ҩҩ Julien Tailhades ҩҩ John Wade PhD Students

ҩҩ John Karas ҩҩ Wenyi Li ҩҩ Vino Nair ҩҩ Nitlin Patil

Peptide Neurobiology Laboratory

ҩҩ Sherie Aizen ҩҩ Andrew Gundlach ҩҩ David Hawkes PhD Students

ҩҩ Giancarlo Allocca ҩҩ Mouna Haidar ҩҩ Ihaia Hosken ҩҩ Hanna Kastman ҩҩ Emma Ong-Palsson ҩҩ Valeria Rytova ҩҩ Azadeh Sabetghadam Esfahani ҩҩ Andrew Walker ҩҩ Cary Zhang DIVISION OF STROKE Stroke - Clinical

ҩҩ Henry Ma ҩҩ Atte Meretoja PhD Student

ҩҩ Marie Dagonnier

Avert

ҩҩ Julie-Ann Bernhardt ҩҩ Leeanne Bennett ҩҩ Karen Borschmann ҩҩ Jan Chamberlain ҩҩ Janice Collier ҩҩ Toby Cumming ҩҩ Coralie English ҩҩ Liam Johnson ҩҩ Kylie King ҩҩ Sharon Kramer ҩҩ Cecilia Li ҩҩ Julie Luker ҩҩ Tara Purvis ҩҩ Audrey Raffelt ҩҩ Anne Rohrer PhD Students

ҩҩ Karen Borschmann ҩҩ Natalie Fini ҩҩ Anne Hokstad ҩҩ Sharon Kramer ҩҩ Michelle Shannon Basic Science

ҩҩ Ana Antonic-Baker ҩҩ Kathryn Ardipradja ҩҩ Sarah Bannister (nee Rewell) ҩҩ Heidi Ho ҩҩ David Howells ҩҩ Katherine Jackman ҩҩ Sarah McCann ҩҩ Tara Sidon Students

ҩҩ Kathryn Ardipradja ҩҩ Marie Dagonnier ҩҩ Charlotte Krenus ҩҩ Ye Liu ҩҩ Sarah Rewell Clinical Trials

ҩҩ Sandra Petrolo ҩҩ Lisa Walker Cognitive Neuroscience

ҩҩ Laura Bird ҩҩ Amy Brodtmann ҩҩ Qi Li ҩҩ Emile Werden ҩҩ Michelle Veldsman Neuro Rehabilitation

ҩҩ Caroline Bailey ҩҩ Leeanne Carey ҩҩ Peter Goodin ҩҩ Alex Kavanagh

ҩҩ Gemma Lamp ҩҩ Christine Marsh ҩҩ Mary Mastos ҩҩ Susan Palmer ҩҩ Tamara Tse ҩҩ Megan Turville PhD Students

ҩҩ Brendan Haslam ҩҩ Belinda McLean ҩҩ Susan Taylor ҩҩ Tamara Tse ҩҩ Megan Turville ҩҩ Barbara Wolfenden Student

ҩҩ Liana Cahill Public Health

ҩҩ Robyn Armstrong ҩҩ Katie Bagot ҩҩ Christopher Bladin ҩҩ Sally Berger ҩҩ Dominique Cadilhac ҩҩ Nancy Capitanio ҩҩ Alison Dias ҩҩ Gary Eaton ҩҩ Adele Gibbs ҩҩ Brenda Grabsch ҩҩ Monique Kilkenny ҩҩ Francis Kung ҩҩ Charlotte Krenus ҩҩ Natasha Moloczij ҩҩ Karen Moss ҩҩ Kate Paice ҩҩ Chris Price ҩҩ Enna Salama ҩҩ Emma Tod ҩҩ Michelle Vu ҩҩ Lisa Walker ҩҩ Kasey Wallis DIVISION OF SYSTEMS NEUROPHYSIOLOGY Neurocardiovascular Laboratory

ҩҩ Lindsea Booth ҩҩ Amber Darwinkel ҩҩ Anthony Dornom ҩҩ Sally Hood ҩҩ Junko Kosaka ҩҩ Yugeesh Lankadeva ҩҩ Clive May ҩҩ Colleen Thomas ҩҩ Song Yao

Students

ҩҩ Amber Darwinkel ҩҩ Erika Nishi ҩҩ Megan Lawson Jakob ҩҩ Anthony Setiadi Systems Neurophysiology Laboratories

ҩҩ Tara Bautista ҩҩ Derek Denton ҩҩ Mathias Dutschmann ҩҩ David Farmer ҩҩ Melinda Goga ҩҩ Haoyao Guo ҩҩ Robin McAllen ҩҩ Stuart McDougall ҩҩ Michael McKinley ҩҩ Davide Martelli ҩҩ Glenn Pennington ҩҩ Davor Stanic ҩҩ Anthony Shafton ҩҩ David Trevaks ҩҩ Lesley Walker ҩҩ Frank Weissenborn PhD Students

ҩҩ Yonis Abukur ҩҩ Sarah Jones ҩҩ Natasha Pracejus ETHICS Animal Ethics

ҩҩ Helen Mansour Neuro Ethics

ҩҩ Neil Levy INTERNATIONAL JOURNAL OF STROKE

ҩҩ Carmen Lahiff-Jenkins BUSINESS DEVELOPMENT Business Development

ҩҩ Henry De Aizpurua ҩҩ Jackie Finn ҩҩ Karin Sitte-Meagher ҩҩ Michael Vovos Neuroscience Trials Australia

ҩҩ Julie Andrew ҩҩ Camila Battistuzzo ҩҩ Sophie Beasy ҩҩ Lisa Brauman ҩҩ Elise Cowley ҩҩ Su Cox

ҩҩ Silvia Done ҩҩ Fiona Ellery ҩҩ Mary Hayek ҩҩ Melanie Hurley ҩҩ Anne Jian ҩҩ Rachael McCoy ҩҩ Cleo Moore ҩҩ Kathy Skoff ҩҩ Robynnee Stevenson ҩҩ Sandra Petrolo ҩҩ Tina Soulis ҩҩ Anita Thompson Statistics

ҩҩ Leonid Churliov ҩҩ Liudmyla Olenko ҩҩ Mahsa Keshtkaran ҩҩ Li-Chun Quang PhD Student

ҩҩ Mahsa Keshtkaran Student

ҩҩ Hayden Johns

SCIENTIFIC SERVICES Core Services

ҩҩ Nathalie Braussaud ҩҩ Travis Featherby ҩҩ Jacqueline Mills ҩҩ Brett Purcell ҩҩ Angela Vais Core Animal Services

ҩҩ Cristian Bustos ҩҩ Shannon Currin ҩҩ Megan Davis ҩҩ Jacqueline House ҩҩ Helen Huckle ҩҩ Jose Lopez ҩҩ Alan McDonald ҩҩ Marco Orlowski ҩҩ Monica Ramos ҩҩ Craig Thomson ҩҩ Michelle Witte ҩҩ Jenny Vien Embryo Services

ҩҩ Fiona Christensen ҩҩ Taryn Knight ҩҩ Rian Mackenzie ҩҩ Vicki Hammond Laboratory Services

ҩҩ Melanie Chapple ҩҩ Anna Sellens ҩҩ Elsa Tsui

137

ҩҩ Annie Yang Mouse Facility

ҩҩ Krista Brown ҩҩ Leah Catalano ҩҩ Brittany Cuic ҩҩ Daniel Drieberg ҩҩ Jessica Hartley ҩҩ Ana-Kiwa Hudson ҩҩ Maddison Ible ҩҩ Roxanne Monaghan ҩҩ Mathew Salzone ҩҩ Kim Schafers Ryan ҩҩ Elissa Wells Quality Systems/Histology

ҩҩ Ian Birchall ҩҩ Mirjana Bogeski ҩҩ Rachel Kenny ҩҩ Dhanya Menon ҩҩ Tammie Money Rat Facility

ҩҩ Maria Bastias ҩҩ Johanna Henry ҩҩ Gregory Thomas ҩҩ Thomas Vale Spinal Research Lab

ҩҩ Stephen Davies ҩҩ Jeanette Davies ҩҩ Jennifer Frame PhD Students

ҩҩ Yeompyo Lee

SUPPORT SERVICES Administration

ҩҩ Rainer Akkermann ҩҩ Alistair Kittson ҩҩ Ihaia Hosken Building Management

ҩҩ Paul Deland ҩҩ Benny Gregersen ҩҩ Peter Ward Finance / Operations

ҩҩ Tina Bertelle ҩҩ Karen Dent ҩҩ Danielle Di Sarno ҩҩ Brian Fleming ҩҩ Ross Humphreys ҩҩ Connie Jacobs ҩҩ Carmel Jacobson ҩҩ Irina Kouchnareva

138

THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

139

OUR PEOPLE 05/05

Fundraising and Marketing

ҩҩ Ross Johnstone ҩҩ Anna Marcon ҩҩ Amanda Place ҩҩ Margit Simondson ҩҩ Jane Standish ҩҩ Astrid Sweres ҩҩ Hazel Westbury Human Resources

ҩҩ Rita Alampi ҩҩ Cara Cortese ҩҩ Rachel Mostacci ҩҩ Rodi Neri ҩҩ Melissa Perenc

Information Technology

ҩҩ Timothy Brewer ҩҩ Li Mei Brusey ҩҩ Ricardo Casama ҩҩ Gary Eaton ҩҩ Kenny Jao ҩҩ Tom Keeble ҩҩ Simon Miller ҩҩ Gena Shoykhet

Management

ҩҩ Gary Gray

Occupational Health and Safety

ҩҩ Damian Carroll ҩҩ Frances Tait

ҩҩ Steven Oliphant ҩҩ Mick Petrovski ҩҩ Kristina Vacy Reception Parkville

ҩҩ Clementine BendleThompson ҩҩ Margaret Black ҩҩ Vera Phipps

Dr Chris Tailby

STEM CELLS Stem Cells Research Centre

ҩҩ Martin Pera

Purchasing

ҩҩ Bradley Hoare ҩҩ Christine Johnston-Balls

Pictured : Dr David Vaughan, Dr Chris Tailby and Mangor Pedersen.

ҩҩ Anita Pejic ҩҩ Peter Plecher ҩҩ Bill Ristevski ҩҩ Hannah Soulaiman

“The human brain is fascinating, not only in the processes it supports when healthy, but also in the manner in which it ‘breaks down’ in the face of insult, and the way it attempts to ‘right itself’ when break down occurs. I want to understand how cognitive function is supported by brain networks, and how network disruption through epilepsy alters cognitive ability.”

140

THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

FINANCIAL STATEMENTS

FINANCIAL STATEMENTS

Consolidated Statement of Comprehensive Income (For the year ended 31 December 2014)

Consolidated Statement of Comprehensive Income (For the year ended 31 December 2014) 2014

141

2014

$’000

$’000

Revenues from ordinary activities

54,164

Salaries and employee benefits

(36,474)

Current Assets

Raw materials and consumables used

(3,793)

Conferences and collaborations

(1,562)

Building occupancy

(4,130)

Research support services

(2,779)

Cash and short-term deposits Trade and other receivables Available-for-sale financial assets Prepayments Inventory

27,312 4,369 5,858 122 73

General administration

(2,844)

Distribution of grant funds

(3,799)

Total Current Assets

37,734

Net operating deficit before depreciation, amortisation and impairment

(1,217)

Depreciation and amortisation

(6,375)

ASSETS

Non-Current Assets

Fair value adjustment of non-financial assets

2,133

Impairment of non-financial assets

(228)

Net operating deficit after depreciation, amortisation and impairment

(5,687)

Building project income

46

Expenses related to the building project

(859)

Net deficit for the year

(6,500)

Other comprehensive income: Net gain on revaluation of financial assets

61

Other comprehensive income for the year – surplus

61

Total comprehensive income for the year – deficit

(6,439)

Total comprehensive income attributable to members of the entity – deficit

(6,439)

Property, plant and equipment Investment property Other assets

9,982 5,546 60,875

Total Non-Current Assets

76,403

TOTAL ASSETS

114,137

LIABILITIES Current Liabilities Trade and other payables Provisions Income in advance

4,445 6,455 158

Total Current Liabilities

11,058

Non-Current Liabilities Provisions

661

Total Non-Current Liabilities

661

TOTAL LIABILITIES NET ASSETS

11,719 102,418

SOURCES OF REVENUE (Year Ended 31 December 2014)

SOURCES OF INCOME 2014

• • • • • •

$M

% OF TOTAL

Government bodies

34.7

64%

Commercial income

6.9

13%

Private donors

4.5

8%

Peer review funding

4.4

8%

Miscellaneous

2.1

4%

Investment income

1.6

3%

54.2

100%

TOTAL

FUNDS Retained surplus 40,739 Unrealised investment reserve 640 Merger / reorganisation reserve 61,039

TOTAL FUNDS 102,418 We acknowledge the Victorian Government’s strong support, particularly through funding from the Operational Infrastructure Support Grant. All funding received through the Department of State Development, Business and Innovation and other government agencies are expended on our research activities and services to support the science. We also thank the State and Federal governments, the Potter Foundation and the Myer Foundation for their huge support for the Melbourne Neuroscience Project including the building of our new facilities. We also gratefully acknowledge the support of the Victorian Department of Health through the provision of an ongoing mental health grant.

THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2014

Dedication

Dr Alan Rembach

On November 20, 2014, the Florey family was shocked by the loss of Alan, a much-admired scientist and colleague.

He was the friendliest and most enthusiastic of researchers – always ready to lend a hand or to share a joke. His care of his own staff was renowned. Alan’s research will stand the test of time, contributing to our knowledge of dementia and helping us find a way to understand this terrible disease. Alan was poised to make some major advances in the pursuit of a peripheral Aβ-related biomarker for Alzheimer’s disease. Working closely with Ben Gu and James Wiley, he was convinced that a solution to this quest was close at hand. It now remains to us, his colleagues, to continue this quest in his memory.

The Florey has established the Dr Alan Rembach Memorial Travel Scholarship. Each year, we will award a young, talented researcher with the opportunity to collaborate with colleagues overseas at a conference or in a laboratory.

Alan’s enormous contribution to science will live on.

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The Florey Institute of Neuroscience and Mental Health acknowledges the traditional owners of this land, the people of the Wurundjeri people and the Kulin Nations.

We pay our respects to their elders, past and present.

We would like to acknowledge that our three sites rest on this precious land.

Parkville campus

Howard Florey laboratories

Austin campus

30 Royal Parade Parkville, Victoria 3052 Australia

Royal Parade Parkville, Victoria 3052 Australia

Melbourne Brain Centre 245 Burgundy Street Heidelberg, Victoria 3084 Australia

T +61 3 9035 6789

T +61 3 9035 7000

F +61 3 9035 3107

F +61 3 9035 7301

FLOREY.EDU.AU ABN: 92 124 762 027