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ANNUAL REPORT 2012

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our mission, vision and values

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our missioN To improve lives through brain research

our visioN To create significant knowledge about the brain

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

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

The Florey’s global collaborations

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US

Switzerland Austria Singapore Belgium Brazil

Japan

South Africa

Taiwan

South Korea

Canada Germany

United Kingdom Spain

Chile Malaysia Netherlands China

Holland

Czech Republic

Hong Kong

New Zealand Sweden

Denmark Finland

Hungary

France

Ireland

Norway

Italy

Philippines Poland

A selection of Florey scientists on editorial boards and societies around the world

Scotland

Wales

THE FLOREY'S GLOBAL REACH – COUNTRIES WITH WHICH OUR SCIENTISTS COLLABORATE

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

TABLE OF CONTENTS

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table of contents ;

Our mission, vision and values

1

Mental illness: the push to find some answers 70

The Florey’s global collaborations

3

Do illicit drugs cause psychosis?

72

Florey in a flash

6

Multiple Sclerosis

74

Chairman’s report

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Neurodegeneration 80

The Florey – the place to be

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Confronting dementia head-on

84

The Florey Financials at a glance

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Welcome Charlotte Ermine

86

Director’s report

12

Neuro-ethics with Neil Levy

89

The Karolinska Stroke Award

15

Neuropeptides 90

Chief Operating Officer’s report

17

Psychotropic Drug Advisory Service

96

Foundation Chairman’s report

18

Delivering stroke rehab through play

98

Neuroscience Trials Australia

20

Stroke 100

Board of Directors

22

The future of our science

111

Division Heads

28

Dr Yen Ying Lim

113

Equality in Science

33

Systems Neurophysiology

114

The Science

34

Victorian Brain Bank Network

118

Brain Development and Regeneration

36

Governors 120

Behavioural Neuroscience

38

Board Committees

121

The Clinical Discovery Unit

44

Foundation Council

121

Clinical Research Group

46

The Florey Faculty

122

Epilepsy 50

Faculty and senior positions

123

A voice like no other

Our donors

124

Imaging 60

Financial Statements

130

Mental Health

Our people

132

58

64

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

florey in a flash

FLOREY IN A FLASH

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591

Staff and students

113 Honoraries

105

PhD students in 2012

7

Future fellows

3

Members of the Faculty of 1000

 1373 Alumni

Discovery Early Career Researcher Awards

The average impact factor of the journals publishing the Florey’s science

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6.008

132

2772

Graduate students

58

The Florey's Faculty

504

Research staff and students

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Karolinska

27,613,567 audience reached Audited by Sentia Media for Media Monitors, March

3

2012 fellowships Countries represented by our staff and students

24

Year 12 school students visiting the Florey for our Mindfields outreach education program

2500 students from 24 schools invited 26 Florey scientists to visit and talk about life as a neuroscientist

Countries collaborating with our scientists

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appointed

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New NHMRC project grants in 2012: 14 at a success rate of

36%

462

papers, chapters, books edited and abstracts in 2012

Average citations per item

19.56 appointed

Average citations per item 2002–12

Media mentions

529

Cumulative citations over 10 years

Scientific papers published in 2012

UCLA Neuro

Early career fellows

⌂ 900

Scientific papers published over 10 years

361

54,216

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Riken Neurology

Inst Neurol London The Florey Montreal Neurol NINDS NIMH Salk Neuro

Citations cumulative 2002–12 UCLA Neuro Salk Neuro Inst Neurol London Riken Neurology Inst of Psychiatry Montreal Neurol The Florey NINDS NIMH Karolinska

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

CHAIRMAN'S REPORT

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CHAIRMAN'S report ;

Harold Mitchell AC, Chairman Since taking over as Chairman of the Florey’s Board in August 2012, my appreciation of the complexities of funding medical research has grown enormously. I am taking over at a time of growth and purpose for the Florey which is clearly facing the future with renewed strength. Back in August, the Florey Neuroscience Institutes merged with the Mental Health Research Institute. This represented the culmination of several years of planning and amalgamation with other institutes, namely the Brain Research Institute and the National Stroke Research Institute. The beauty of this type of planning will be seen in the science. Some 450 talented neuroscientists are now working side-by-side; administrative expenses have been reduced and more funds are available for scientific endeavour. Former Chairman, Charles Allen was at the helm during this time of reinvention, steering the $42 million turnover enterprise as it grew, attracted more funding and strengthened links with the University of Melbourne, Austin Health and the Royal Melbourne Hospital. He also oversaw the transition into extraordinary purposebuilt buildings he helped to realise. The Florey Board thanks Charles most sincerely for his wise leadership, calm management of the organisation and his philanthropic support for over five years, particularly during the recently challenging times of global financial instability. Charles and his wife Jocelyn – who has also been a wonderful friend of the Florey - took a well-earned trip to see the northern lights on an Icelandic cruise after retiring from the Board. What a wonderful way to change focus. I would also like to thank Board members who have retired after the amalgamation of the Florey Neuroscience Institutes with the Mental Health Research Institute. From the Florey board we farewell and thank Emeritus Professor Richard Larkins and Professor James McCluskey, Dr Thomas Schneider and Mr Robert Trenberth. From the Mental Health Research Institute we acknowledge the enormous contribution of former Chair Dr Sandra Hacker, Deputy Chair Mr Trevor Clark and Professor Ingrid Winship. Please take a moment to read about the members of the new Board on the following pages. Since August we have been working together closely and have found a fine rhythm. Committing to a Board position means an individual will serve many hours of unpaid time. The demands are similar to taking on the responsibilities of running a publicly listed company. A deep interest in public health is essential, as is an ability to make tough decisions, to share valued contacts and one’s knowledge of, and commitment to, a not-for-profit enterprise. I’m confident the Board is capable of great innovation. We are driven to support the neuroscientists who are working for the good of humankind. The not-for-profit sector is a very crowded space but medical research is wonderfully tangible. It’s hard to imagine a more worthwhile cause. Australia has long been home to some of the best scientific researchers and medical pioneers in the world. Our geographical location is an absolute bonus as Asia increasingly invests in scientific advancement as its middle class emerges. There are wonderful connections to be made. The success of our researchers – both as individuals and as part of our organisation – has meant less disease, better care and improved quality of life and longevity for Australians. Back in September 2011, Simon McKeon, a former Australian of the Year, was commissioned by the Federal Government to recommend a 10-year strategic health and medical research plan for the nation. Mr McKeon delivered his report to the Federal Health Minister, Tanya Plibersek on February 28, 2013. The Florey Board looks forward to the Commonwealth embracing Mr McKeon’s findings which were released in April and represent the ambitions and expertise of more than 170 research groups and 200 individuals, including many from the Florey. Our wonderful medical researchers deserve a secure environment as they anticipate their futures. The world of the Florey is set to have worldwide influence and benefit. It deals with many issues but at the top of the list are near breakthroughs in Alzheimer's, epilepsy and addictions. Solutions to these problems will transform mankind.

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Harold Mitchell AC

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

the Florey financials at a glance

The Florey – the place to be

Alzheimer’s hope through collaboration

The Florey is embedded in the Parkville precinct and in Heidelberg, alongside two major teaching hospitals. It is a key contributor within the medical research sector, vital to Victoria’s economy.

European pharmaceutical giant Servier has thrown its support behind a new drug being developed in Victoria that may halt the development of Alzheimer’s disease while also alleviating its symptoms.

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Victorian medical research •

employs 4000 staff and students (not including direct health care) and generates four per cent of the state’s wealth

per worker, is third behind mining and finance/ property as a wealth generator for Victoria

attracts 42 per cent of NHMRC funding

contributes more than $300m in clinical trial activity in Victoria each year, bringing novel medicines at low cost and creating economic activity

brought 38,000 national and international visitors to Victoria and created in excess of $200m in economic activity over two years

leverages more than $12 in direct research funding for every dollar provided by the state •

has a total of 42 life science companies listed on the Australian Stock Exchange, with a combined market capitalisation of A$21.4 billion. In 2012 these companies had 85 life science products on the market, with 39 phase II and 15 phase III clinical trial programs underway. (AAMRI)

Investment in Australian medical research by governments and donors will help us •

Reduce costs and improve health

Invent new diagnostics, treatments and technologies

Improve efficiency and cost-effectiveness of health care

holds 51 per cent of the 379 new and ongoing research fellowships funded by the NHMRC

Safeguard the community against health threats of tomorrow

companies, in the last financial year, generated $7.6 billion of revenue and $731 million in exported goods and services (Bio21)

Keep Australian ingenuity at home rather than buying it from overseas

Honour the 80 per cent of Australians who believe it is very important to increase funding for health and medical research. (AAMRI)

consistently receives more than a 40 per cent share of Commonwealth NHMRC funding and

did you know?

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Seven Nobel prizes in medicine have been awarded to Australians, three of them to Victorians

 Melbourne’s 13 major medical research institutes had a combined annual turnover of $433.8 million in 2012–13, an increase of 29 per cent compared with 2008–09. Income was sourced from competitive government grants, foundations/philanthropic grants, donations, bequests and industry.

$ Every $1 invested in health and medical research returns, on average, $2.17 in health benefits (ASMR)

❤ About 75 per cent of Australians have a long-term health condition? (AIHW)

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The French company is backing research by the Florey, Monash University and St Vincent’s Institute of Medical Research into developing drugs that target the protein Insulin-Regulated AminoPeptidase (IRAP). Drugs that block the IRAP protein show strong signs of actually halting the disease, in contrast to all current prescribed therapies. The only Food and Drug Administration approved drugs for the treatment of Alzheimer’s disease all treat the symptoms – the memory loss. There are no drugs on the market that can actually arrest the disease progression.

“Talent flows to where the resources are. "We are actively retaining and recruiting first class scientists from here and overseas. We’re also acutely aware of the competitive threat of China, Singapore and Taiwan so we’re investing in long-term career opportunities.” – Dr Henry De Aizpurua Key financials at a glance

The collaboration was the first to demonstrate that compounds that block IRAP, the IRAP inhibitors, had memory-enhancing properties. These compounds were recently discovered to have the ability to stop Alzheimer’s from progressing. Servier has announced it will provide funding for the researchers to develop their findings and determine exactly how IRAP inhibitors work to reduce amyloid plaque load in the brain.

Dr Henry De Aizpurua heads the Florey’s Business Development team

A number of clinical trials of Alzheimer’s treatments have fallen over, due to unforeseen outcomes.

enture capital finance V total into Florey spin-out companies 2002-2012: 7.9 million

atent families currently P either granted or being prosecuted around the world: 46

42.666 million – total $ annual income 2012

Biotech companies spun-off •

Neuroprotect Pty Ltd

Gervartec Pty Ltd

 lobal Kinetics G Corporation

With the funding from Servier, the team is hoping to reduce that by figuring out exactly how and why these treatments have the effects they do. The project is still in its early stages and new therapies based on IRAP are likely to be at least a few years away from fruition.

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

director's report

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DIRECTOR'S report ;

Geoffrey Donnan AO, Director The world of medical research is currently at the most exciting phase I have experienced during my 30 years as a neurologist. There has been an explosion in discovery in neuroscience over the last 20 years. This is just so important because a disease of the brain or mind will affect 75 per cent of Australians in their lifetime. Never has the Florey enjoyed research facilities as advanced as ours, a workforce so willing to emigrate to, or remain in Melbourne, and scientific progress so relentless. It would’ve seemed unimaginable when I began my career. Neuroscience is clearly the place to be – as genes are discovered for epilepsy, stroke therapies are having such a positive impact and imaging and drug therapies offer a new level of analysis and hope for those tackling dementia. Unparalleled advances have been made in cell biology and with these, new insights into cell function. Our time has come. It is with this ambitious overview in mind that we also need to face the obstacles confronting the work of our scientists. Science is a notoriously insecure career with most our researchers applying for funding every three years. An unsuccessful grant round can see a talented researcher leave for a career overseas. Most immediately, we need to see the contents of the Strategic Review of Health and Medical Research in Australia, embraced by the Commonwealth Government. I believe this document, created by Mr Simon McKeon and his expert panel, provides a clear blueprint for the next 10 years, ensuring medical research institutes are funded adequately and supported to compete internationally. It is well known that for every $1 invested in Australian health and medical research, $2.17 is returned, on average, in health benefits.

The McKeon Review provides a clear blueprint for the next 10 years, ensuring medical research institutes are funded adequately and supported to compete internationally. It is well known that for every $1 invested in Australian health and medical research, $2.17 is returned, on average, in health benefits.

As the population ages, governments know their health costs are set to increase by at least a third by 2050. Some 600 staff are toiling at the Florey, generating knowledge, diagnostics, treatments and ways to prevent age-related illness. But they need a wellresourced environment to keep them here. We have the magnificent buildings. We need the secure funding to ensure the science happens within. As Director, one of my most important tasks is to secure the future so our team can continue to create knowledge of significance.

CREATING NETWORKS The last year has seen the final stage of our amalgamation process with the Mental Health Research Institute joining the Florey. This initiative makes us a lean, efficient, scientific powerhouse. We welcome our colleagues who bring expertise in depression, bipolar disorder, schizophrenia, Parkinson’s and Alzheimer’s disease. Collaborative and translational research is progressing under our new structure. We continue to work with clinical colleagues at the Royal Melbourne Hospital and Austin Health, taking our research to the ward and the imaging suite. During the year we became a department of the University of Melbourne, a move that will attract significant funding opportunities and link us with new networks, further establishing our place in the evergrowing and influential Parkville precinct. Beyond Melbourne, we have established several memorandums of understanding with institutes in France and China and we are in discussions with colleagues in Israel and the UK as we build collaborative initiatives, emphasising the global nature of research. OUR SCIENCE AND PEOPLE Significant scientific advances have been celebrated during the year. In November the Lancet journal announced successful phase III clinical results for the use of a hormone that has been the subject of tireless research here for nearly four decades. Back in 1975, now retired colleague, Professor Geoff Tregear, began work at the Florey on the possible uses of the hormone, relaxin. After five clinical trials and collaboration with six different biotechnology companies, a synthetic version of relaxin is the key ingredient in a new class of pharmaceuticals that have been shown to improve symptoms and reduce deaths from acute heart failure. Geoff’s dedication demonstrates the importance of funding to allow long-term investigations to progress. And I suspect this particular application of relaxin is just the beginning. The next generation of Florey researchers, led by Professor Ross Bathgate, will continue investigating this fascinating case. While Geoff’s latest news occurred at the age of 75, another significant result came for a young researcher at the age of 26. PhD student Yen Ying Lim published in the journal Neurology with the finding that people with plaques in the brain associated with Alzheimer’s disease may have

Professor Geoffrey Donnan

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

a greater risk for cognitive impairment than those who have a gene tied to the dementia-causing illness. Yen’s work suggests that brain plaques may be a more important factor in determining Alzheimer’s risk than the gene. Yen will continue to investigate whether drugs designed to stop amyloid accumulation in the brain can actually prevent people from progressing to the severe stages of the disease. In mid-June, Yen is leaving for the US to start a postdoc with the Dominantly Inherited Alzheimer's Network Trials Unit at Brown University on Rhode Island. A career off to a flying start. Associate Professor Julie Bernhardt, the co-head in our Stroke Division won a Churchill Fellowship to study how enriched environments in hospitals improve the physical, emotional and cognitive outcomes of the thousands of people affected by stroke each year. Assoc Prof Bernhardt will visit hospitals in the US, UK and Europe. The Michael J Fox Foundation awarded just two Parkinson’s grants in Australia, both to Florey teams led by Assoc Prof David Finkelstein and Assoc Prof Robert Cherny and Assoc Prof Kevin Barnham. Andrea Gogos won an ARC Early Career Fellowship so she could continue her research into the role of sex hormones in schizophrenia. Finally, Dr Peng Lei and Professor Ashley Bush published in Nature Medicine on the role of Tau in Alzheimer’s and Parkinson’s disease. I am pleased to report a very successful grant round this year. Along with our newly merged colleagues, we attracted a record number of grants and this is testament to our rigorous grant preparation process, led by Dr Henry de Aizpurua. Particular congratulations must go to Professor Robin McAllen and the Systems Physiology Division, for his NHMRC success. Our researchers continue to be recognised with awards and prizes. Dr Emma Burrows won a Victoria Fellowship which will allow her to travel to Cambridge University to collaborate on new touchscreen technology with the long term aim of treating dementia, schizophrenia and autism spectrum disorders. Dr Ben Emery received a Young Tall Poppy award, recognising the significance of his research and passion to engage with the community in science. Ben is working in our multiple sclerosis division and is studying the machinations of oligodendrocytes in the brain and the communication between nerve cells and the oligodendrocytes that stimulate adjacent nerve fibres. Earlier in 2012, Ben was also awarded the Australian Neuroscience Society’s AW Campbell Award for early career excellence. Dr Jee Hyun Kim received two awards in 2012. The Australian Psychological Society conferred an Early

Career Research Award, recognising excellence in scientific achievement in psychology among psychologists at early stages of their research careers in Australia. Jee also won the American D. G. Marquis Behavioral Neuroscience Award for ‘best paper published’ in the journal, Behavioral Neuroscience. Jee and her colleagues showed that a different neural circuitry underlies fear regulation early in life, and that the lack of prefrontal cortical involvement may reflect a less flexible emotional regulation system in infant animals. Jee holds an Australian Research Council ‘Discovery Early Career Research’ Fellowship which is awarded to support and advance promising early career researchers and to enhance opportunities for diverse career pathways. The award is given to those working in high quality and supportive environments.

The Karolinska Stroke Award

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The Karolinska Stroke Award ;

In conclusion, I would like to share one last achievement involving many people – a project that demonstrates the wide spectrum of innovative research undertaken at the Florey. While some are toiling at the lab bench, others are rolling-out knowledge gleaned. It says much about the Florey’s ability to serve the health of Australians. A dedicated team from the Stroke Division has attracted significant funding from both state and federal governments, to the tune of $8 million, to roll-out a telemedicine program across Victoria, with a view to developing a research base for national implementation. Country patients suffering a suspected stroke now receive time-critical advice – via high-capacity broadband - between the country hospital’s emergency department and a Melbourne-based neurologist. Stroke requires fast diagnosis and Florey research has been pivotal in determining the importance of immediate intervention. There are powerful pharmaceuticals available to arrest the damage caused by stroke for patients carefully assessed as being suitable for intervention. This type of project requires collaborative innovation. The Florey team has brought together a wide range of consortium partners including the Department of Health, Victorian Stroke Clinical Network, Monash University, Polycom, Telstra, Loddon Mallee Rural Health Alliance, Ambulance Victoria, National Stroke Foundation, the Stroke Society of Australia, Bendigo Health, Mildura Base Hospital, Bendigo Health, Swan Hill District Hospital and Echuca Regional Health. The program is the brainchild of neurologist Professor Chris Bladin and Associate Professor Dominique Cadilhac. Congratulations to all of our staff and students for a great year’s work. Thank you to the Board for your energy and enthusiastic support of our great institute – and a deep thanks to our retiring Chairman, Charles Allen, for his diplomatic and astute leadership through a time of huge change.

Professor Geoffrey Donnan and Professor Stephen Davis

The Karolinska Institutet in Sweden has honoured two of our most experienced leaders, acknowledging careers devoted to stroke research and patient care. The Karolinska Stroke Award, presented once every two years, was presented to Professor Geoffrey Donnan and Professor Stephen Davis. Prof Davis is the newly appointed President of the World Stroke Organisation and, among his many roles, is the Director of Neurology for Melbourne Health. He is the co-principal investigator with Geoff of EXTEND, a stroke trial aimed at expanding the time window for thrombolysis using magnetic resonance imaging (MRI) in treatment. Stroke is the second biggest killer of Australians and the Florey is at the forefront of the search for better treatment, rehabilitation and prevention. The award recognises more than 30 years of work by both Prof Donnan and Prof Davis. The Karolinska Institute's stroke research is the most cited in the world. The Florey is the fourth most cited, recognising the quality of the research conducted in Melbourne. As well as receiving the Karolinska award, Prof Donnan was honoured during 2012 with an Order of Australia and a Leadership in Stroke award from the World Stroke Organisation in Brasilia, Brazil.

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

CHIEF OPERATING OFFICER'S REPORT

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chief operating officer'S report ;

Gary Gray, Chief Operating Officer

My research explores the intricacies of brain development. Our work helps explain the cause of certain brain diseases and provides knowledge that can lead to new therapies. Dr Joanne Britto

There were several major themes during the year; winding down the Melbourne Neuroscience Project governance structure, signing an Enhanced Collaborative Research Agreement (Agreement) with the University of Melbourne, and uplift of the Mental Health Research Institution (MHRI) into the Group as a subsidiary. In addition there were much wider developments which ultimately should have a significant impact upon the medical research sector.

envisaged almost 10 years ago by some who may no longer have a direct involvement in the group but lasting interest in its success.

For many years the Florey had assumed a lead role in project management governance over the Melbourne Neuroscience Project. The project was inclusive of two new world-class research facilities. Early this year, with occupancy of both facilities assumed, the Project Committee disbanded and residual responsibilities assigned to executive management representatives from both the Florey and University of Melbourne. These responsibilities included management of several parcels of work ranging in scale up to $2 million; the refit and creation of additional offices for senior scientific staff and procurement of scientific equipment.

Subsequent to the uplift I was formerly reappointed Chief Operating Officer of the group and numerous initiatives were triggered. They included appointment of key management staff and consolidation of management processes, policies and procedures across the group.

During the year the Florey signed an Agreement with the University of Melbourne. There are many key features to the Agreement inclusive of establishing the “Florey” Department within the University, to facilitate direct engagement of higher education students in research, dual appointment of the Florey Director as head of the “Florey” Department, and a mechanism which will ultimately allow a higher level of government funds to support the indirect costs of research. There were major challenges in negotiating the Agreement to satisfy collective and individual interests. Ultimately, the Florey was satisfied and entered an Agreement which does not threaten its independence, or capacity to manage and control its cash. PKF Advisor Services were engaged to conduct a financial Due Diligence associated with the uplift of the MHRI into the Florey. Following their report, and others including agreements around governance, the uplift was unanimously supported by the Governors and MHRI members. It became operational on the 1 August 2012. This marked the final phase of a corporate structure bringing together neuroscience and mental health

The uplift brought many new faces together at the Board level including Mr Harold Mitchell as its new Chair. We look forward to his leadership and take this opportunity to thank Mr Charles Allen, Prof Sandra Hacker and other directors who retired upon uplift of MHRI into the Florey.

The group has managed to reduce anticipated outlays in the vicinity of $1.5 million pa during 2013 associated with indirect cost of research through rationalisation of management and economies of scale. There have been many staff departures due to a combination of events including retirement, career advancement elsewhere and, regrettably, targeted redundancy. Amongst these there are those whose contribution to MHRI or the Florey in its former guise should be acknowledged and they are Ms Lisa Keam, Mr Nick Catton, Ms Christine Corbett, and Ms Jenni Elliot. A solid foundation for growth has been laid during 2013 and beyond. Yet there are perennial issues of concern around finance from one year to the next. The evidence is clear. For every $ in direct research funds received you require an additional 60 cents to fund indirect costs. There are very few (if any) independent medical research institutes capable of generating this level of funds to support indirect costs either through government, commercialisation or philanthropic means. Consequently, there is an ongoing drain upon reserves and capacity to take discretionary leaps of faith supporting science. There has been a process initiated this year to make collective representation to the State Government to increase its contribution towards indirect costs. There is also anticipation associated with the McKeon Report which could influence Federal Government policy around medical research for many years to come.

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

foundation chairman'S report ;

Stephen Spargo, Foundation Chairman The Florey Foundation exists to raise funds to support research at the Florey into illness affecting the brain. Philanthropic funding is essential to support young emerging scientists, recruit the best and brightest scientists, develop new discoveries and provide our researchers with the latest technologies to do their work. In 2012 the Foundation raised over $3.331 million from fundraising events, appeals, individual donations, grants, trusts and bequests. Once again we are indebted to our donors who have provided most generous support to improve the lives of people affected by illnesses such as stroke, Alzheimer’s and Parkinson’s disease, MS, epilepsy, depression and bipolar disorder. COMMUNITY SUPPORT As we look forward under our new name - the Florey Institute of Neuroscience and Mental Health - and with a much broader range of research, it is important to recognise the wonderful support we receive from voluntary groups in the community. For example, River’s Gift is an initiative of parents Alex and Karl Wardell, who formed a group to raise funds for SIDS research following the death of their much loved son, River. Since starting their group in early 2012 they have raised over $125,000. Another group of trusted community fundraisers is known as One in Five, recognising the incidence of mental illness in the community and commemorating a family member and friend who took his own life. The family and friends of Matt Wardlaw raise funds for mental health research and are continuing their support for a research project investigating a targeted and more effective drug treatment for depression and bipolar disorder. Since inception in 2004 they have raised a staggering $1.6 million. We also recognise the work of Charityworks for MS which was formed by Linda Marrocco in 2002 and is dedicated to raising funds to help find a cure for multiple sclerosis. Over the years, this hard working committee has organised five very successful gala events and is now approaching their goal of raising $1 million. We are indebted to these individuals and organisations for their extraordinary support.

WOMEN IN SCIENCE In 2011 Ms Naomi Milgrom AO made a substantial gift to launch an endowment fund of $5 million dollars to support the careers of female scientists. Her generosity has been supported by the Trust Company through a Fellowship from the Fred P Archer Charitable Trust. During 2012 we have developed a number of initiatives to support and encourage the career development of the Florey’s women. We look forward to the growth of this fund and subsequently greater numbers of women in the senior ranks of science. To support this development a mentoring program has been established, a professional development series of talks and discussion commenced and, through the introduction of more flexible working hours, the Florey has become a much more family friendly employer. In addition a case study to better understand how to address cultural change was undertaken to identify barriers to career progression. 2012 KENNETH MYER LECTURE In late October, Martyn Myer AO welcomed to the stage the original Thunderbolt Kid, internationally loved author and traveller, Bill Bryson. Inviting Bill to deliver the 2012 Kenneth Myer Lecture represented a change of direction for this annual event but was a stroke of genius by Martyn. More than 2,000 people poured into the Melbourne Town Hall. The crowd was not disappointed, as with great warmth and humour, Bill talked about his boyhood growing up in America, his later life in England and his love for remarkable and weird scientific facts. He easily held the attention of the capacity audience and we were delighted to be able to introduce the Florey to a whole new audience. COMMUNICATING WITH OUR SUPPORTERS The Public Affairs office was busy in 2012, spreading news of the Florey’s work through publications and the media. Our popular Brain Matters magazine is reaching a growing list of supporters who respond with enthusiasm to stories of scientific endeavour and personal stories involving patients and Florey staff.

FOUNDATION CHAIRMAN'S REPORT

The national media reported on a number of significant stories during the year. The Florey was involved in 529 stories in print, radio, TV and websites. While we promoted our work, staff were also contacted regularly by the media for comment, cementing our position as a respected voice in neuroscience. Professor Geoff Donnan was in the press regularly, commenting on political developments in Canberra surrounding science policy as well as for his research and awards, including his Order of Australia. Other media highlights included: •

Professor Geoff Tregear’s celebration of the commercial application for a synthetic form of the hormone relaxin – to address heart failure – after nearly four decades of work;

Bill Bryson’s visit and the numerous interviews he cheerfully and tirelessly attended;

A major publication reported on people with plaques in the brain associated with Alzheimer’s disease and their cognitive risk compared to those with a gene tied to the disease;

Several articles appeared in The Conversation, a valuable new opportunity for scientists to write to a general audience in their specialty areas;

Research into the role of stress in Huntington’s disease, the role of serotonin in SIDS and the launch of a new CT imaging faculty in Parkville.

The team conducted many tours and events within our superb new facilities. A highlight was Melbourne’s Open House weekend when significant pieces of architecture were opened to the public in a once a year special event. More than 1000 people visited our new home in Parkville.

INVESTMENTS Our ability to support our scientists in their work depends on the success of peer-reviewed grants, investments and the generosity of our philanthropic supporters and donors. In the face of continuing global financial instability, we are pleased to report our investment portfolio recorded a total return of 10.4 per cent in interest and dividends.

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BENEFACTORS Awards and prizes We are very proud of the Florey’s wonderful young scientists. They are our future leaders. To assist their career development a number of generous donors provide scholarships, awards and prizes. We are particularly grateful to: Andrew and Cathryn Darbyshire, the Browne Family, Alan and Elizabeth Finkel, the Goodsight Company, the Miller Family, Millipore, John Milne, the Harold Mitchell Foundation, Allan and Maria Myers, the family of the late Jared Franklin Purton and Life Technologies. Major donors The Ian Potter Foundation and the Myer Foundation and family have been with us from the beginning. Their funding helped to establish the original Howard Florey Institute and has continued through our now 50 years of existence. In 2012 we have also been fortunate to receive generous funding from; Charles Allen AO, The L.E.W. Carty Foundation, the Joan and Peter Clemenger Trust, J G Donaldson AO, Equity Trustees, Geoff and Helen Hanbury, Peiter Huveneers, John and Alison Kearney, the Scobie and Claire Mackinnon Trust, Mark A Nelson, Perpetual Trustees Australia, Reece Australia, the Harry Secomb Foundation, Trust Company and James S Wiley. The significance of the contribution of these individuals and organisations to the growth of the Florey and, most importantly, to the generation of new knowledge for treating and preventing brain illnesses has been immense. A full list of our generous donors is set out in this report. Our most grateful thanks is extended to each and every supporter. Their generosity is improving life through brain research. In closing, I would like to thank the Foundation team for their tremendous support and hard work throughout the year. The current economic climate presents a challenge for raising funds. The team has risen to this challenge and produced a very credible fundraising result and at the same time raised the profile of the Florey in the community while preparing for our new branding following amalgamation. I would like to thank Jenni Elliott who has so successfully led the team for the last four years and wish her well for her retirement in Florida. I also extend a welcome to Ross Johnstone who has replaced Jenni. Ross joins us from the Mental Health Research Institute which amalgamated with the Florey in August.

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

Neuroscience Trials Australia ;

Neuroscience Trials Australia is a 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. Access to: Clinical networks, KOLs and sites

Phase I

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 Neuroscience Trials Australia (NTA) 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. The team’s areas of expertise include stroke and stroke-related conditions, multiple sclerosis, epilepsy, Parkinson’s disease, spinal cord injuries, Huntington’s disease, neurosurgery, pain, neuromuscular disease, mental illness and migraine. They have 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. 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 outlined in the diagram above. 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, below, are examples of projects currently underway.

The role of Vitamin D in preventing MS We are currently managing one of the most important developments in the prevention of multiple sclerosis (MS) in a world first clinical trial set to take place in Australia and New Zealand. It will test whether Vitamin D can prevent MS in those at risk of developing the disease. It is a randomized, double blind, placebocontrolled, dose ranging trial of Vitamin D3 in Patients with a First Demyelinating Event (FDE). This study, called the PrevANZ trial, is sponsored by Multiple Sclerosis Research Australia (MSRA), and aims to assess the efficacy of oral Vitamin D in preventing the development of multiple sclerosis in participants at high risk of MS (those experiencing their very first episode of symptoms suggestive of MS, a first demyelinating event or FDE). There are currently no evidence-based interventions to prevent the development of MS in this group of people, therefore, if effective, oral Vitamin D

NEUROSCIENCE TRIALS AUSTRALIA

supplementation could provide a low cost MS therapy with virtually no side effects. A collaborative Australian/NZ research team, funded by MSRA, will undertake this study, led by Assoc Prof Helmut Butzkueven from MBC@RMH, and co-ordinated by NTA. The trial is being conducted at over 20 hospitals throughout Australia and New Zealand and aims to recruit 240 patients.

Once again, NTA is the program manager and is responsible for setting up the program studies and project management across 10 hospitals throughout Australia and New Zealand.

Oils ain’t oils – the TRIP-E study in epilpesy The TRIP-E study is the first of its kind. This project is assessing the safety and tolerability of an oil (triheptanoin) in patients with epilepsy. The patients involved in this project have a resistance to the drugs usually used to treat their condition. This study is led by Dr Karin Borges from the University of Queensland and funded by the Epilepsy Therapy Project in the US.

NTA is the program manager and is responsible for setting up the project, the data management systems, sourcing and labelling of the Viatmin D and project management.

Getting to the POINT of the matter Trans Ischemic Attacks (TIAs) are common, with an estimated 250,000350,000 occurring each year in the US alone, an incidence about 30-40 per cent that of stroke. The distinction between a minor stroke and TIA is unimportant in terms of prognosis. Both groups are at high short-term risk of new a stroke event.

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This trial is looking at whether patients are able to tolerate taking the oil and the project will have recruited up to 60 patients by the time it is completed.

General manager, Neuroscience Trials Australia, Dr Tina Soulis

The Platelet-Oriented Inhibition in New TIA and minor ischemic stroke trial, known as the POINT study, is a global project in which 4,150 subjects from 150 centres with high-risk TIA minor stroke will be assigned to treatment within 12 hours of symptom onset. Their treatment will be either a commonly used anti-clotting agent called clopidogrel or a placebo. All patients will also receive aspirin. The purpose of the study is to determine whether clopidogrel is effective in improving survival (without other events occurring) at 90 days when initiated within 12 hours of a TIA or minor ischemic stroke onset in patients receiving aspirin.

We have assisted the sponsor to develop the study from its initial concept following grant success, through to day to day management of the involved hospitals.

A Very Early Rehabilitation Trial (the AVERT trial) Not all of our projects involve assesssment of drugs. The AVERT trial is a phase III, multicentre, randomised controlled trial of very early rehabilitation after stroke and is known as the AVERT trial. The project is aiming to recruit 2104 subjects with three-quarters of recruitment now completed. AVERT will compare early rehabilitation to standard care in stroke patients. It is an investigator-initiated clinical trial, funded by an NHMRC grant intially in 2006 and again in 2011. Our group has been involved from the very start of this project with overall programme management from concept to execution.

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

BOARD OF DIRECTORS

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MR HAROLD MITCHELL AC

Chairman (Appointed 1 August 2012) Mr Harold Mitchell is the founder of Mitchell & Partners and 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.

BOARD OF DIRECTORS ;

Mr Mitchell holds a large number of community roles including Chairman of CARE Australia; Chairman of the Melbourne Symphony Orchestra; Chairman of the Melbourne Rebels Rugby Union Team; Chairman of TVS, University of Western Sydney’s television service for Greater Sydney; Chairman of Arts Exhibitions Australia; Vice President of Tennis Australia; Director New York

Philharmonic, and Director of Crown Ltd. He has also been 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.

MR ANDREW ABERCROMBIE Bec LLB MBA (IMD)

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 Top 200 company on the ASX. Formerly a commercial lawyer, he now oversees a broad range of commercial interests. He is a former Chairman of the Melbourne Chapter of Young

Presidents’ Organisation. He 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).

PROFESSOR JAMES ANGUS

(Appointed 1 August 2012) AO FAA BSc PhD James Angus is Dean of the Faculty of Medicine, Dentistry and Health Sciences at the University of Melbourne. He is also a Fellow and former Member of Council at the Australian Academy of Science. Professor Angus is the Vice Chancellor’s nominee for appointment in accordance with the Constitution and was a non-executive Director of MHRI (appointed 2003).

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

Professor Geoffrey A Donnan AO

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Professor Graeme Jackson

(Florey Director) MBBS MD FRACP FRCP (Edin)

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 he was co-founder of the Australian Stroke Trials

BOARD OF DIRECTORS

(BRI Scientific Director & Florey Deputy Director) BSc (Hons) MBBS MD FRACP Network. He is immediate Past-President of the World Stroke Organisation. He received the American Stroke Association William Feinberg Award for Excellence in Clinical Stroke Research in 2007 and both the Karolinska Award for Excellence in Stroke Research and the World Stroke Organisation Leadership in Stroke Medicine Award in 2012.

Mr Craig Drummond

Professor Graeme Jackson is the Deputy Director of the Florey Institute of Neuroscience and Mental Health, Director of the Brain Research Institute (BRI), a practicing clinical neurologist specializing 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 prestigious Outstanding Achievement Award for research excellence in 2008.

Mr Mark Jones is a Partner in KPMG’s Advisory Services practice, with national responsibility for internal risk management. He 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.

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 Council of the National Health and Medical Research Council (NHMRC),

the Board of the Telethon Institute for Child Health Research and 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.

Mr Mark Jones

BComm (Melb) ACA SFFIN

BA (Hons) (Sheff) MBA (MBS) Mr Craig Drummond is Chief Executive Officer and Country Head of Bank of America Merrill Lynch Australia, and brings with him more than 25 years of banking and securities experience. He is a member of the Business Council of Australia, a Member of the University of New South Wales’ Australian School of Business Advisory Council, a Senior Fellow of FINSIA and is a Chartered

Accountant. He is a Director of the Australian Financial Markets Association (AFMA) and the Geelong Football Club.

Mr Rob Gerrand

Professor Anne Kelso AO

(Appointed 1 August 2012) BA FAICD

BSc (Hons) PhD (Melb) Mr Gerrand heads the marketing and communications consultancy Gerrand & Associates and is Chairman of Healthy Parks People Global Ltd, a Director of Inner North West Melbourne Medicare Local, Director of MHRI and Chairs an AICD Director Nexus group. He is a former General Manager of Group Public Affairs at ANZ. Previous board appointments include the Financial Planning Association of Australia, the

Koorie Heritage Trust, the Melbourne Convention and Marketing Bureau, the Alfred Hospital and Parks Victoria where he chaired the Board. He was the Founding President of the Monash Alumni Association, and in 1994 was appointed Adjunct Professor at Deakin University. He is also a published author.

Emeritus Professor Andrea Hull AO

Ms Jennifer Labourne

BA Dip Ed (Univ of Sydney) MBA (MBS, Univ of Melb) FAICD FAIM Professor Andrea Hull has had a distinguished career in CEO and executive roles, and also as a nonexecutive Board member in government and not-for-profit organisations. She is an Emeritus Professor at the University of Melbourne, and sits on the Boards of the National Museum of Australia, the Abbotsford Convent Foundation and the Breast Cancer Network of Australia.

(Appointed 1 August 2012) BBus, FCPA 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.

Jennifer Labourne is the Director of Finance & Business Services at Colac Area Health. 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). She is a former Director of MHRI.

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

BOARD OF DIRECTORS

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Laureate Professor Colin L. Masters

(Executive Director MHRI & Florey Deputy Director) (appointed 1 August 2012) BMedSc (Hons) MBBS MD Hon DLitt WAust FRCPath FRCPA FAA FTSE

former directors

Professor Colin Masters is a Laureate Professor at the University of Melbourne, Deputy Director of the Florey Institute of Neuroscience and Mental Health, Executive Director of MHRI, and a former Director of Prana Biotechnology Limited. He is one of the world’s best-known authorities on Alzheimer’s disease.

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Dr Brendan Murphy MBBS PhD FRACP FAICD

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 currently a member of the Board of Health Workforce Australia and a Professorial Fellow with the title of Professor at Melbourne University.

Mr D Charles K Allen AO (Former Chairman) (Resigned 31 July 2012) MA (Cantab) MSc Hon LLD (Monash) FTSE

Emeritus Professor Richard G Larkins AO

Professor James McCluskey

Mr Robert Trenberth AM

Dr Sandra Hacker AO

(Resigned 31 July 2012) MDBS LLD (Hon) (Melb) PhD (Lond) LLD (Hon) (Monash) FRACP FRCP (Lond) FRCPI FTSE

(Resigned 31 July 2012) BMedSci MBBS MD FRACP FRCPA

Mr Stephen Spargo LLB LLM

Mr Stephen Spargo is a solicitor practising in the financial services and projects department of Allens (Linklaters) where he has been a partner since 1983. 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 and a member of the Victorian State Council, Committee for the Economic Development of Australia.

Dr Thomas J Schneider

(Resigned 31 July 2012) AB magna cum laude with highest hons (Harvard) D Phil (Oxon) JD (Harvard) Hon D Laws (Deakin)

(Resigned 31 July 2012) BEng (Melb) MA Sc (Waterloo, Canada) MBA (Harvard) FAICD

(Former Chair) (Resigned 31 July 2012) MBBS, DPM, FRANZCP, FAICD

Mr Andrew Stripp

(Appointed 1 August 2012) MSc (Clinical Psychol), BBSc (Hons)

Mr Trevor Clark OAM (Former Deputy Chairman) (Resigned 31 July 2012) ACIS, FAMI, FAICD, CPM

Professor Ingrid Winship

(Resigned 31 July 2012) MBChB, MD, FRACP, FACD

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Andrew Stripp is the Deputy Chief Executive Officer and Chief Operating Officer at Alfred Health where he has worked for 9 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.

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

division heads

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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. Andrew 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.

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 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 Iceburgers.

Professor Graeme Jackson is the Deputy Director of the Florey, a practicing 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 prestigious Outstanding Achievement Award for research excellence in 2008.

Dr Amy Brodtmann

DIVISION HEADS

Behavioural Neuroscience

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Professor Seong-Seng Tan Brain Development and Regeneration

Professor Graeme Jackson Epilepsy

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

Associate Professor Steven Petrou

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Professor Philip Beart

Epilepsy

Associate 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 mice models for the study of human familial epilepsy. He

division heads

Neurodegeneration

Philip Beart (PhD ANU, DSc Melbourne) has been a NH&MRC Research Fellow for 30 years and is currently Professorial Fellow in the Florey Neuroscience Institutes and Adjunct Professor in Pharmacology, University of Melbourne. He worked at the Cambridge and Harvard Universities, before holding positions at the Austin Hospital and Monash University.

works closely with industry and has several patents for his discoveries. In addition to his many roles, he is the Deputy Director of the Centre for Neural Engineering at University of Melbourne, he serves on the editorial board of the Journal Neurobiology of Disease the Basic Science Committee for the International League Against Epilepsy and is Editor of the Australian and New Zealand Society for Neuroscience.

Professor Alan Connelly

Associate Professor Ross Bathgate

Imaging

Neuropeptides Professor Alan Connelly is an NHMRC Principal Research Fellow. He is the 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 researchonly 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

Laureate Professor Colin Masters

Professor Colin 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

Stroke

Associate 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 exercise-

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.

Professor Trevor Kilpatrick

based 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.

Associate Professor David W Howells

Multiple Sclerosis

Trevor Kilpatrick leads the MS Division at the Florey and is a neurologist and Head of the MS Unit at the Royal Melbourne Hospital, in addition to being Director of the Melbourne Neuroscience 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.

clinical trials 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 development of these peptides. 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 Julie Bernhardt

Mental Health

He 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.

Associate Professor Ross Bathgate is the Head of the Division of Neuropeptides, a NHMRC Senior Research Fellow and an Honorary Principle Research Fellow in the Department of Biochemistry and Molecular Biology at The University of Melbourne. His work focuses on the relaxin family of peptides and their G-protein coupled receptors. These peptide-receptor systems show enormous potential for therapeutic targeting and the hormone relaxin is currently in Phase III

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.

Stroke Professor Kilpatrick has been the recipient of the Sunderland Award, AMRAD Postdoctoral Award and the inaugural Leonard Cox Award. More recently, Professor Kilpatrick and his group were awarded the Australian Museum’s Jamie Callachor Eureka Prize for Medical Research (2008) in recognition of their extraordinary contribution to medical research into multiple sclerosis.

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.

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

EQUALITY IN SCIENCE

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Professor Robin McAllen Systems Neurophysiology

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 of cardiovascular and autonomic functions, and has published extensively of this topic.

More recently he has collaborated with the 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.

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.

Equality in science – gender balance at the bench ;

The Florey’s Equality in Science committee is made up of a range of staff, male and female, across all campuses and includes our Director, Professor Geoff Donnan. It aims to increase and retain females in the scientific workplace and to offer all employees encouraging career progression.

clear guidelines for the fair assessment of grants from female scientists who have had career interruptions due to the birth of children. The NHMRC has responded positively to the lobbying and we hope to be given the opportunity to take an active role in shaping the guidelines.

A staff mentoring scheme across all areas of the Florey was launched in 2012 accompanied by an e-learning training module and a joint workshop for mentors and mentees. The committee matched 23 pairs of mentors and mentees according to their experience, skills and career paths. The success of this program will be reviewed in May/June 2013. Mentoring has been available for students through the University of Melbourne but no formal program has been available to staff until now.

Professor Margaret Sheil (Provost, University of Melbourne) delivered the our career development seminar at the Austin campus and shared wonderful life experiences that shaped her career. She also discussed the impact various mentors and supporters had over the years. It was an inspiring lecture delivered with aplomb under challenging conditions.

Jhodie Duncan took on the role of project coordinator for the “Building effective career paths for women in science”, a valuable case study of the Florey’s workplace, conducted by Kate White from the University of Ballarat. The committee together with the Florey Executive will join forces over the coming year to work through the recommendations of the report. This review will inform initiatives and policies to improve gender equity across the institute.

We would like to acknowledge the work of the members of this committee throughout the year, a very committed core group has ensured that the committee continues to voice and proactively solve gender equity issues at the Florey. Karin Sitte and Wah Chin Boon EqIS co-chairs 2012

The committee has continued to lobby the National Health and Medical Research Council (NHMRC) to implement better processes on grant assessment panels that include

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

the science

the science

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To raise new questions, new possibilities, to regard old problems from a new angle, requires creative imagination and marks real advance in science.

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Albert Einstein

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

Brain development and regeneration

Brain development and regeneration division

A QUICK SNAPSHOT

RESEARCH HIGHLIGHT

The understanding of how new brain cells are generated, become connected together, and their survival during stress is pivotal to preventing and treating brain disorders. The underlying drivers of brain cell assembly are undoubtedly genetic, but the outcomes are also shaped by environmental influences. We want to learn which genes drive neuronal migration and understand how genes have shaped brain evolution. Such knowledge will also provide new understanding on the causes of mental illnesses such as autism, schizophrenia and epilepsy.

Our team has identified a number of survival pathways that are used by neurones to protect themselves from cell death. One survival pathway uses a new method that involves a well known anti-cancer protein called PTEN. We found that PTEN not only protect cells against cancer but can also protect neurones in the brain from death after injury. We are the first to identify the mechanism that PTEN employs to protect brain cells from death.

OUR RESEARCH OVER THE PAST YEAR HAS IDENTIFIED A NEW SURVIVAL MECHANISM IN THE BRAIN THAT CAN PROTECT AGAINST BRAIN CELL DEATH AFTER BRAIN INJURY.

 SENIOR STAFF Seong-Seng Tan, Division Head

We study how brain cells are born and wired together to understand how to prevent mental disorders such as autism and schizophrenia. We have discovered a new way to prevent neurones from dying after injury.

Joanne Britto, Senior Research Officer Jason Howitt, Senior Research Officer Ulrich Putz, Senior Research Officer Ley-Hian Low, Research Officer Choo-Peng Goh, Research Officer

Our laboratory uses a variety of modern techniques to study brain cell movement and brain cell biology. These include creation of new mouse strains with inserted genes, molecular cloning of brain genes and manipulation of brain proteins. We use transplantation methods to insert brain cells into animal models to study their movement and ultimate fates.

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Brain Development Group

Brain Survival Group

Formation of the brain is a complex process for the correct placement and connection of neurons. But what happens when things go wrong and neurones fail to be positioned correctly? This is believed to be the underlying cause of disorders such as schizophrenia and autism spectrum disorder. Our research is focussed on understanding how immature neurones move in the expanding brain, how they assembled correctly and wired up to each other. Our work using brain transplantation followed by video imaging allows us to study the behaviour of transplanted brain cells in the host environment, in real time. This information is of vital importance in an era where modern stem cell technology is being explored for repairing diseased brains.

How can we save neurones from dying after injury? Brain injuries, including stroke and head trauma, have limited treatment options and result in long-term physical, behavioural and cognitive deficits. Whilst rehabilitation is able to restore some patients to their previous level of functioning, clearly there are significant benefits if we can limit the degree of neuronal death occurring after brain injury. Our work aims to understand how neurones die after brain injury and how to activate defence mechanisms against cell death.

``Research highlights for 2012 An important class of nerve cells in the brain are known as interneurons. We have trained our sights on this class of neurones because they are the key drivers of mental processing and sensory experience. We previously discovered that interneurones have the ability to migrate vast distances to reach their final positions in highly specific addresses. We have been studying how they achieve this because certain mental disorders can arise when these neurones do not reach their destinations. To study these neurons, we have created special mice with artificial colours introduced into these neurones so that we can follow their movements under a laser microscope. The information from these studies allows us to pinpoint which types of interneurones are most at risk when something goes wrong. Going further, we have carried out transplantation of these neurones into other brains, to try and use these young interneurones for repair of diseased brains.

``Research highlights for 2012 Our team has identified a number of survival pathways that are used by neurones to protect themselves from cell death. One survival pathway uses a new method that involves a well known anti-cancer protein called PTEN. We found that PTEN not only protect cells against cancer but can also protect neurones in the brain from death after injury. We are the first to identify the method that PTEN uses to protect brain cells from death. We aim to take this further by manufacturing drugs to activate this cell survival pathway. In addition, we have employed a variety of techniques including cell culture, animal models and human tissue, to find a natural means of activating this pathway in the injured brain to prevent cell loss. In conclusion, our research over the past year has identified a new survival mechanism in the brain that can protect against brain cell death after brain injury.

Editorial positions •

Seong-Seng Tan Experimental Neurology (USA)

Journal of Anatomy (UK)

Journal of Cell Biology (Korea)

Frontiers in Neuroscience

Brain Communication Group Brain cells are in constant communication with each other for transmitting electrical and chemical signals during mental activity. However, we believe that certain chemicals are also exchanged between brain cells for purposes that are not related to mental processing, for example for brain repair after injury. Brain communication is also important for protection of nerve cells against brain stress. We are currently engaged in discovering the nature of these communications and under what circumstances are they being transmitted.

``Research highlights for 2012 We have discovered that there is a natural method of communication between cells in the body. This communication occurs by exchange of packaged compounds called proteins. The exchanged material contains important messages that can have important consequences for cells that receive them. For example, in cancer, the spread of cancerous cells can be either hastened or retarded depending on the nature of these messages. Recently, we found out how to include certain additional messages that are normally not found in these packages that are also called exosomes. We are excited to study how these new messages in synthetic can be used to repair brain cells after injury by boosting levels of repair proteins. In addition, we are enthusiastic about using these exosomes for transferring anti-cancer messages into brain tumours for reversing cancerous growth.

PUBLICATIONS 1.

Howitt J, Lackovic J, Low LH, Naguib A, Macintyre A, Goh CP, Callaway JK, Hammond V, Thomas T, Dixon M, Putz U, Silke J, Bartlett P, Yang B, Kumar S, Trotman LC and Tan SS, Ndfip1 regulates nuclear Pten import in vivo to promote neuronal survival following cerebral ischemia, J Cell Biol, 196:29-36,2012, PMID: 22213801

2.

Lackovic J, Howitt J, Callaway JK, Silke J, Bartlett P and Tan SS, Differential regulation of Nedd4 ubiquitin ligases and their adaptor protein Ndfip1 in a rat model of ischemic stroke, Exp Neurol, 2012, PMID: 22417925

3.

Putz U, Howitt J, Doan A, Goh CP, Low LH, Silke J and Tan SS, The tumor suppressor PTEN Is exported in exosomes and has phosphatase activity in recipient cells, Sci Signal, 5:ra70,2012, PMID: 23012657

4.

Tsunekawa Y, Britto JM, Takahashi M, Polleux F, Tan SS and Osumi N, Cyclin D2 in the basal process of neural progenitors is linked to non-equivalent cell fates, Embo J, 31:1879-92,2012, PMID: 22395070

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

Behavioural Neuroscience

Addiction Neuroscience Group

division

A QUICK SNAPSHOT

RESEARCH HIGHLIGHT

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 such as Alzheimer’s disease and other dementias from a clinical perspective.

2012 was a year of excellence for our scientists and students. Shaun Khoo, Doron Lavan, Sophia Luikinga and Isabel Zbukvic achieved first class Honours in 2012, with Ms Zbukvic on the Dean’s List for exceptional performance. Dr Heather Madsen graduated with her PhD, as did Dr Andrezza Kim. Dr Robyn Brown commenced her tenure as a NHMRC Doherty Fellow and travelled to the USA to learn new experimental techniques. Dr Jee Hyun Kim won the international D. G. Marquis Behavioral Neuroscience Award for Best Paper published in Behavioral Neuroscience, and an Asia-Pacific Society for Neurochemistry Young Investigator Award. Dr Kim also won the prestigious and historical Australian Psychological Society Early Career Research Award, only given to two people Australia-wide in 2012. Dr Jhodie Duncan won an Asia-Pacific Society for Neurochemistry Young Investigator Award. Dr Duncan is the Australian Scientific Coordinator for the River’s International SIDS Collaboration: philanthropic funding from the River’s Gift Memorial SIDS research fund, $150,000 (1st 18 months). Dr Emma Burrows graduated with her PhD and also won a Victoria Fellowship which she will use to visit international laboratories, gain expertise in cognitive testing of rodent models and establish new collaborative links. Dr Mark Ransome won an Early Career Researcher Grant from the University of Melbourne. Ms Christina Mo won awards for best oral presentations at the Students of Brain Research (SOBR) Symposium and the Biomed Link student conference in 2012.

 SENIOR STAFF Professor Andrew Lawrence Associate Professor Anthony Hannan Associate Professor John Drago Dr Amy Brodtmann Associate Professor David Darby

behavioural neuroscience

2012 was a year of consolidation for the Cognitive Neuroscience group. Interim analyses of the CANVAS study were published and findings presented both nationally and internationally. We are grateful for the ongoing support of the Collie Trust and the Sidney and Fiona Myer Family Foundation for this innovative study. Assoc Prof Darby launched the TREAD study, which has been greeted with great media interest, and continued his collaboration with the AIBL project. We received a Mason Trust philanthropic grant at the end of 2012, which will enable us to directly compare a number of brain imaging techniques in the early diagnosis of AD and FTD. Dr Brodtmann was one of the inaugural directors on the board of the Australian Frontotemporal Dementia Association (AFTDA), a charity for people affected by FTD. The launch of this charity represents years of lobbying by many carers and health professionals, and will be affiliated with the International FTD Association which was also launched in October 2012.

“It is a mistake to try to look too far ahead. The chain of destiny can only be grasped one link at a time.” Winston Churchill (1874-1965)

The Addiction Neuroscience Group studies how alcohol and drugs change the brain’s chemistry, structure and function. During 2012 we expanded our group and made a number of important findings, many of which are still being actively pursued. As part of her PhD, Heather Madsen delineated the neural circuitry in the mouse brain that underpins drug-seeking compared to natural reward-seeking. This study highlighted a number of commonalities, but importantly also a number of different nuclei implicated in food-seeking compared to drugseeking. Other significant new leads on treating addiction were discovered in 2012 by Dr Kim. One lead indicates that repeatedly exposing rats to an environment that was previously associated with drug-taking, but not allowing any drug to be consumed, produces a significant suppression of relapse behaviour when rats were mildly ‘high’ and allowed to seek drugs again. Another lead showed that adolescents are more susceptible to relapse because the cues that are associated with drug-taking are stronger, thus inducing a persistent ‘craving’ compared to adults taking the same amount of drugs. This finding explains for the first time in the world the widelyknown fact that adolescent exposure to drugs typically causes more severe (treatment resistant) addiction, allowing more in-depth analyses of treating drug abuse for the population of addicts in which drug exposure occurred early in life. The abuse of inhaled chemical vapours to produce selfintoxication is a significant concern, especially among adolescent and indigenous populations. Dr Duncan and her student Mr Alec Dick recently published work demonstrating that exposure to inhalants during adolescence results in abnormalities in the brain detectable by magnetic resonance imaging techniques. These abnormalities resolved when exposure ceased, suggesting there may be potential for recovery should intervention strategies be implemented in humans. This model has also shown that inhalant abuse during adolescence leads to metabolic dysfunction and altered dietary preference which may lead to an increased risk for adult onset disorders such as heart disease and diabetes. The results from this study may have a profound impact on our understanding of the high rate of nutrition related diseases in indigenous communities where inhalant abuse is prevalent.

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

39

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. Huntington’s disease (HD) is an inherited single-gene abnormality that causes neurones in the brain to become dysfunctional and eventually die. We are currently identifying molecular targets for ‘enviromimetics’: novel drugs which would mimic or enhance the beneficial effects of environmental stimulation. Dr Terence Pang was able to show for the first time that depression in HD can be modelled, and ameliorated by enhanced mental and physical activity. Dr Thibault Renoir then showed that exercise alone can be beneficial, as is chronic administration of the antidepressant drug sertraline. Dr Pang, along with PhD student Xin Du, also discovered an abnormal stress response in the mouse model of HD and identified key molecules involved in both the disease and the response to environmental stimuli. Investigation of the effects of stress on HD has been followed up by Dr Renoir and another PhD student, Christina Mo. This will have implications not only for HD, but for depression 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.

Cognitive Neuroscience Group 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. Dementia will overtake all other conditions as the greatest global burden of disease by 2015, greater than stroke, respiratory disease, and depression, the current leaders. The CANVAS project is a 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. Some of the publications from this group over the last year have been pilot data from this study, as well as editorialising on the mechanisms of stroke-related cognitive decline. An understanding of whether stroke is neurodegenerative, and in which patients, may be used to help guide the early delivery of disease-modifying therapies. The first study to show benefit in early Alzheimer’s disease was presented last year: a monoclonal antibody against amyloid. The benefit was only significant in patients with early AD, not advanced disease.

Together with a collaborator at the University of Melbourne, 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.

Assoc Prof David Darby (also MHRI) launched the TREAD Study in late 2012, with 670 enrolled participants at time of writing. We will track the cognitive trajectories of a group of community dwelling participants over months as they log in for their monthly test, identifying their earliest decline. These people will be offered early evaluation and possible intervention – an exciting innovation.

Schizophrenia involves 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

We continue to maintain an interest in how advanced imaging techniques, such as cortical thickness analyses, can improve the diagnosis of frontotemporal dementia (FTD), as well as the use of other techniques, including perfusion CT and MRI, in the early diagnosis of dementia.

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

{{Conferences 2012 1.

2nd Asia-Pacific Society for Alcohol and Addiction Research Conference, Bangkok, Thailand. Invited presentation, Professor Lawrence

2. Australasian Winter Conference on Brain Research, Queenstown, NZ. Plenary lecture, Professor Lawrence 3. Australasian Professional Society on Alcohol and Other Drugs (APSAD) Conference. Invited presentation, Professor Lawrence

21. DCRC Meeting Workshop on FTD Canberra, invited workshop presentation, Dr Brodtmann 22. Cognitive testing for movement disorders neurologists: potential pitfalls Asian Oceanian Congress on Neurology, Plenary session, Dr Brodtmann

behavioural neuroscience

Dr Thibault Renoir Frontiers in Neuropharmacology, Associate Editor Dr Amy Brodtmann Neurology, Editorial Board Member

{{Other academic invitations 2012

 Collaborations

1.

External Collaborations for Addiction Neuroscience Group

Dept of Psychiatry & Neuroscience, Lausanne University, Switzerland – guest lecture, Professor Lawrence

6. International Behavioral Neuroscience Society 21st Annual Meeting, Hawaii, USA. Invited presentation, Dr Kim

4. Centres for Neuroregeneration and Clinical Brain Sciences, University of Edinburgh, UK – guest lecture, Assoc Prof Hannan

7. International Stillbirth Alliance and International Society for the Prevention of Perinatal and Infant Death, Baltimore, USA, Oct 4th-7th

5. University of Melbourne Neuroscience PhD series: Neurodegenerative Diseases: current clinical research questions, invited presentation, Dr Brodtmann

Professor Alon Chen (Weizmann Institute, Israel); Professor Jian-Hui Liang (NIDD, Beijing, China); Professor Bernard Balleine (University of Sydney); Professor Tony Paolini (RMIT); Professor Peter Kalivas (MUSC, USA); Professor Rainer Spanagel (ZIMH, Germany); Professor Caroline Rae (UNSW); Professor Sarah Dunlop (UWA); Assoc Prof 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); Assoc Prof Colin Willis (UNE, Maine); Dr Sarah MacLean (Turning Point Alcohol and Drug Centre, Melbourne), Dr Silvia Cruz (Mexico); Dr Andrew Brunn (Melbourne); Dr Zane Andrews (Monash); Dr Michael Mathai (Victoria Uni)

 2012 students

External Collaborations for Neural Plasticity group

PhD

Professor Laurence Lanfumey (INSERM, Paris), Professor Robert Metcalf (Monash University), Professor Margaret Morris (UNSW), Professor Edna Hardeman and Dr Steve Palmer (UNSW), Dr Danny Hatters (Bio21 Institute), Dr Elisa Hill and Professor Joel Bornstein (Melbourne), Dr Jess Nithianantharajah (University of Edinburgh, UK), Dr Laura Gray (Deakin University), Dr Peter Crouch (Melbourne), Dr Nigel Jones and Professor Terry O’Brien (Melbourne), Professor Moira O’Bryan (Monash), Dr Andrew Jenner and Professor Brett Garner (Wollongong), Dr Trent Woodruff and Assoc Prof Peter Noakes (UQ), Assoc Prof Xiao-Jun Du (Baker-IDI), Dr Ghazelah Sadri-Vakili (MGH, Harvard University), Dr Tomris Mustafa (National Institute of Mental Health, USA), Professors Julie Stout and Nellie-Georgiou-Karistianis (Monash), Dr Dan Malone (Monash)

4. Addiction Research and Therapy, August 20th-22nd, Las Vegas, NV, USA. Invited presentation, Dr Duncan. 5. Young Investigator Colloquium, 11th Biennial meeting of the Asia Pacific Society for Neurochemistry, Kobe, September 30-Oct 2nd. Invited presentations, Dr Duncan & Dr Kim

8. Society for Neuroscience, New Orleans, USA, Oct 13th-16th. Multiple lab members 9. 8th Federation of European Neurosciences (FENS) Forum of Neuroscience, Barcelona, Spain. Multiple lab members 10. 32nd Australian Neuroscience Society meeting, Gold Coast, Aust., Jan 29th -Feb 1st. Multiple lab members 11. 3rd Schizophrenia International Research Society (SIRS) Conference, Florence, Italy. Invited presentation, Assoc Prof Hannan 12. Cognitive Enhancers: 22nd Neuropharmacology Conference, Official Satellite to the Annual Meeting of the Society for Neuroscience, New Orleans, USA. Invited presentation, Assoc Prof Hannan

2. Dept of Experimental Biology, University of Cagliari, Sardinia, Italy – guest lecture, Professor Lawrence 3. Scripps Research Institute, La Jolla, California, USA – guest lecture, Assoc Prof Hannan

Nicola Chen, Alec Dick, Rose Chesworth, Phil Ryan, Hanna Kastman, Andrezza Kim, Katherine Beringer, Xin Du, Christina Mo, Annabel Short, Dean Wright Masters Charlotte Handford, Shawn Tan, Sarah Gibbs, Faith Lamont Honours Doron Lavan, Sophia Luikinga, Isabel Zbukvic, Shaun Khoo, Martin Axelsson

13. 2nd International Congress on Neurology and Epidemiology, Nice, France. Invited presentation, Assoc Prof Hannan

Editorial boards

14. 6th Alzheimer’s Disease & Parkinson’s Disease (A&PD) Annual Meeting, Sydney. Invited presentation, Assoc Prof Hannan

The British Journal of Pharmacology, Senior Editor

External Collaborations for Cognitive Neuroscience Group

Neurochemical Research, Associate Editor

The Journal of Pharmacological Sciences, Associate Editor

Dr Tobias Loetscher (Flinders University, Adelaide); Professor John Hodges (FRONTIER, Sydney)

Addiction Biology, Editorial board member

16. Human Genetics Society of Australasia (HGSA) Neurogenetics Symposium, Adelaide. Invited presentation, Assoc Prof Hannan

The Open Neuropsychopharmacology Journal, Editorial board member

ISRN Addiction, Editorial board member

17. Invited Speaker, 7th World Congress for NeuroRehabilitation, Melbourne. Invited presentation, Assoc Prof Hannan

Associate Professor Anthony Hannan •

Journal of Huntington’s Disease, Associate Editor

18. Australasian Society of Clinical and Experimental Pharmacologists and Toxicoligists (ASCEPT) Annual Scientific Meeting (held jointly with APSA), Sydney. Invited presentation, Assoc Prof Hannan

European Journal of Neuroscience, Scientific Review Associate

19. Australian and New Zealand Neuropsychiatry and Behavioural Neurology Conference Examination of speech in neurodegenerative disease Melbourne, Dr Brodtmann, invited speaker

CNS & Neurological Disorders - Drug Targets, Editorial board member

Neural Plasticity, Editorial board member

Frontiers in Neuropharmacology, Review Editor

Neuroepidemiology, Editorial board member

20. AC4R Meeting Computerised testing for cognitive disorders, Canberra, Dr Brodtmann, invited speaker

Recent Patents CNS Drug Discovery, Editorial board member

15. 4th Brain Plasticity Symposium, Queensland Brain Institute, University of Queensland. Invited presentation, Assoc Prof Hannan

Professor Andrew Lawrence

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

behavioural neuroscience

PUBLICATIONS

PUBLICATIONS

43

1.

Badawy RA, Loetscher T, Macdonell RA and Brodtmann A, Cortical excitability and neurology: insights into the pathophysiology, Funct Neurol, 27:131-45,2012, PMID: 23402674

27. Klug M, Hill RA, Choy KH, Kyrios M, Hannan AJ and van den Buuse M, Long-term behavioral and NMDA receptor effects of young-adult corticosterone treatment in BDNF heterozygous mice, Neurobiol Dis, 46:722-31,2012, PMID: 22426399

2.

Brodtmann A, Pardoe H, Li Q, Lichter R, Ostergaard L and Cumming T, Changes in regional brain volume three months after stroke, J Neurol Sci, 2012, PMID: 22858417

28. Liu Q, Zhang M, Qin WJ, Wang YT, Li YL, Jing L, Li JX, Lawrence AJ and Liang JH, Septal nuclei critically mediate the development of behavioral sensitization to a single morphine injection in rats, Brain Res, 1454:90-9,2012, PMID: 22502977

3.

Darby DG, Pietrzak RH, Fredrickson J, Woodward M, Moore L, Fredrickson A, Sach J and Maruff P, Intraindividual cognitive decline using a brief computerized cognitive screening test, Alzheimers Dement, 8:95-104,2012, PMID: 22404851

29. Madsen HB, Brown RM and Lawrence AJ, Neuroplasticity in addiction: cellular and transcriptional perspectives, Front Mol Neurosci, 5:99,2012, PMID: 23162427

4.

Lim YY, Pietrzak RH, Snyder PJ, Darby D and Maruff P, Preliminary data on the effect of culture on the assessment of Alzheimer's disease-related verbal memory impairment with the International Shopping List Test, Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists, 27:136-47,2012, PMID: 22198565

30. Madsen HB, Brown RM, Short JL and Lawrence AJ, Investigation of the neuroanatomical substrates of reward seeking following protracted abstinence in mice, J Physiol, 590:2427-42,2012, PMID: 22393250 31.

Madsen HB, Navaratnarajah S, Farrugia J, Djouma E, Ehrlich M, Mantamadiotis T, Van Deursen J and Lawrence AJ, CREB1 and CREB-binding protein in striatal medium spiny neurons regulate behavioural responses to psychostimulants, Psychopharmacology (Berl), 219:699-713,2012, PMID: 21766169

5.

Loetscher T, Nicholls ME, Brodtmann A, Thomas NA and Brugger P, Disentangling input and output-related components of spatial neglect, Front Hum Neurosci, 6:176,2012, PMID: 22707937

32. Manning EE, Ransome MI, Burrows EL and Hannan AJ, Increased adult hippocampal neurogenesis and abnormal migration of adult-born granule neurons is associated with hippocampal-specific cognitive deficits in phospholipase C-beta1 knockout mice, Hippocampus, 22:309-19,2012, PMID: 21080410

6.

Batcha AH, Greferath U, Jobling AI, Vessey KA, Ward MM, Nithianantharajah J, Hannan AJ, Kalloniatis M and Fletcher EL, Retinal dysfunction, photoreceptor protein dysregulation and neuronal remodelling in the R6/1 mouse model of Huntington's disease, Neurobiology of Disease, 45:887-96,2012, PMID: 22198376

33. Nithianantharajah J and Hannan AJ, Dysregulation of synaptic proteins, dendritic spine abnormalities and pathological plasticity of synapses as experiencedependent mediators of cognitive and psychiatric symptoms in Huntington's disease, Neuroscience, 2012, PMID: 22633949

7.

Brown R, Lawrence A, Kim J, The role of mitogen-activated protein kinase in treatment strategies for fear and drug addiction, Xavier DGDS, editor. Advances in Protein Kinases, 2012, http://www.intechopen.com/books/advances-in-protein-kinases/the-role-of-mitogen-activated-protein-kinase-in-treatmentstrategies-for-fear-and-drug-addiction

34. Pang TY and Hannan AJ, Enhancement of cognitive function in models of brain disease through environmental enrichment and physical activity, Neuropharmacology, 2012, PMID: 22766390

8.

Brown R, Lawrence A, Intravenous Self-Administration of Drugs of Abuse in Mice, 2012, http://www.med-associates.com/medlines/Summer2012/InYourLabSummer2012.html

9.

Brown RM and Lawrence AJ, Compulsive use of dopamine replacement therapy in Parkinson's disease: insights into the neurobiology of addiction, Addiction, 107:250-1,2012, PMID: 22248133

10.

Brown RM, Duncan JR, Stagnitti MR, Ledent C and Lawrence AJ, mGlu5 and adenosine A2A receptor interactions regulate the conditioned effects of cocaine, Int J Neuropsychopharmacol, 15:995-1001,2012, PMID: 21816123

38. Renoir T, Pang TY and Hannan AJ, Effects of environmental manipulations in genetically targeted animal models of affective disorders, Neurobiol Dis, 2012, PMID: 22525570

11.

Brown RM, Mustafa S, Ayoub MA, Dodd PR, Pfleger KD and Lawrence AJ, mGlu5 Receptor Functional Interactions and Addiction, Front Pharmacol, 3:84,2012, PMID: 22586398

39. Renoir T, Pang TY, Mo C, Chan G, Chevarin C, Lanfumey L and Hannan AJ, Differential effects of early environmental enrichment on emotionality-related behaviours in Huntington's disease transgenic mice, J Physiol, 2012, PMID: 23045340

12.

Brown RM, Stagnitti MR, Duncan JR and Lawrence AJ, The mGlu5 receptor antagonist MTEP attenuates opiate self-administration and cue-induced opiateseeking behaviour in mice, Drug and alcohol dependence, 123:264-8,2012, PMID: 22129842

40. Renoir T, Pang TY, Zajac MS, Chan G, Du X, Leang L, Chevarin C, Lanfumey L and Hannan AJ, Treatment of depressive-like behaviour in Huntington's disease mice by chronic sertraline and exercise, British Journal of Pharmacology, 165:1375-89,2012, PMID: 21718306

13.

Du X, Leang L, Mustafa T, Renoir T, Pang TY and Hannan AJ, Environmental enrichment rescues female-specific hyperactivity of the hypothalamic-pituitaryadrenal axis in a model of Huntington's disease, Transl Psychiatry, 2:e133,2012, PMID: 22760557

41.

14.

Duncan JR and Lawrence AJ, The role of metabotropic glutamate receptors in addiction: evidence from preclinical models, Pharmacology, biochemistry, and behavior, 100:811-24,2012, PMID: 21443897

42. Smith CM, Hosken IT, Sutton SW, Lawrence AJ and Gundlach AL, Relaxin-3 null mutation mice display a circadian hypoactivity phenotype, Genes, brain, and behavior, 11:94-104,2012, PMID: 21899720

15.

Duncan JR, Dick AL, Egan G, Kolbe S, Gavrilescu M, Wright D, Lubman DI and Lawrence AJ, Adolescent toluene inhalation in rats affects white matter maturation with the potential for recovery following abstinence, PLoS One, 7:e44790,2012, PMID: 23028622

43. Tomiyama K, Drago J, Waddington JL and Koshikawa N, Constitutive and conditional mutant mouse models for understanding dopaminergic regulation of orofacial movements: emerging insights and challenges, J Pharmacol Sci, 119:297-301,2012, PMID: 22863668

16.

Gray LJ, Hannan AJ and Zhang X, Metabotropic glutamate receptors as targets for novel antipsychotic treatments, Curr Pharm Biotechnol, 13:1522-34,2012, PMID: 22283756

44. Wen RT, Zhang M, Qin WJ, Liu Q, Wang WP, Lawrence AJ, Zhang HT and Liang JH, The phosphodiesterase-4 (PDE4) inhibitor rolipram decreases ethanol seeking and consumption in alcohol-preferring fawn-hooded rats, Alcohol Clin Exp Res, 36:2157-67,2012, PMID: 22671516

17.

Griffiths RI, Kotschet K, Arfon S, Xu ZM, Johnson W, Drago J, Evans A, Kempster P, Raghav S and Horne MK, Automated Assessment of Bradykinesia and Dyskinesia in Parkinson’s Disease, Journal of Parkinson’s Disease , 2:47-55,2012,

45. Farid WO, Lawrence AJ, Krstew EV, Tait RJ, Hulse GK and Dunlop SA, Maternally administered sustained-release naltrexone in rats affects offspring neurochemistry and behaviour in adulthood, PLoS One, 7:e52812,2012, PMID: 23300784

18.

Hannan AJ, Tandem repeat polymorphisms as modulators of biological function and dysfunction, Hum Mutat, 33:v,2012, PMID: 22806976

19.

Hannan AJ, Tandem repeat polymorphisms: Genetic plasticity, neural diversity and disease, Springer series: Advances in Experimental Medicine and Biology, 769:1-208, 2012,

35. Ransome MI, Androgen function in the pathophysiology and treatment of male Huntington's disease patients, J Neuroendocrinol, 2012, PMID: 22672384 36. Ransome MI and Hannan AJ, Behavioural state differentially engages septohippocampal cholinergic and GABAergic neurons in R6/1 Huntington's disease mice, Neurobiol Learn Mem, 12:12,2012, PMID: 22261461 37. Ransome MI, Renoir T and Hannan AJ, Hippocampal Neurogenesis, Cognitive Deficits and Affective Disorder in Huntington's Disease, Neural plasticity, 2012:874387,2012, PMID: 22830053

Rezvani AH, Lawrence AJ, Arolfo MP, Levin ED and Overstreet DH, Novel medication targets for the treatment of alcoholism: preclinical studies, Recent Pat CNS Drug Discov, 7:151-62,2012, PMID: 22574676

20. Hannan AJ, Tandem repeat polymorphisms: Mediators of genetic plasticity, modulators of biological diversity and dynamic sources of disease susceptibility, Adv Exp Med Biol, 769:1-9,2012, PMID: 23560301 21.

Hannan AJ and Ransome MI, Deficits in spermatogenesis but not neurogenesis are alleviated by chronic testosterone therapy in R6/1 Huntington's disease mice, J Neuroendocrinol, 24:341-56,2012, PMID: 21988129

22. Howard ML, Palmer SJ, Taylor KM, Arthurson GJ, Spitzer MW, Du X, Pang TY, Renoir T, Hardeman EC and Hannan AJ, Mutation of Gtf2ird1 from the WilliamsBeuren syndrome critical region results in facial dysplasia, motor dysfunction, and altered vocalisations, Neurobiol Dis, 45:913-22,2012, PMID: 22198572 23. Jupp B, Williams J, Binns D, Hicks RJ, Cardamone L, Jones N, Rees S and O'Brien TJ, Hypometabolism precedes limbic atrophy and spontaneous recurrent seizures in a rat model of TLE, Epilepsia, 2012, PMID: 22686573 24. Kim AK, Brown RM and Lawrence AJ, The role of orexins/hypocretins in alcohol use and abuse: an appetitive-reward relationship, Front Behav Neurosci, 6:78,2012, PMID: 23189046 25. Kim JH, Lawrence AJ, The role of metabotropic glutamate 5 receptor in addiction, .J. Canales (Ed), Emerging Targets for Drug Addiction Treatment. Chapter 9, NOVA publishers: New York, 183-202, 2012, 26. Kiriazis H, Jennings NL, Davern P, Lambert G, Su Y, Pang T, Du X, La Greca L, Head GA, Hannan AJ and Du XJ, Neurocardiac dysregulation and neurogenic arrhythmias in a transgenic mouse model of Huntington's disease, J Physiol, 2012, PMID: 22890713

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

The Clinical Discovery Unit

the clinical discovery unit

HIGHLIGHTS NAC IN MAJOR DEPRESSION The team has just completed a double-blind, randomised placebo controlled trial of 2gm per day of NAC or placebo over four months for the treatment of major depressive disorder. Over 260 patients were randomised to this study, which was substantially in excess of recruitment targets. The study provides some support for the adjunctive use of NAC in the treatment of major depression. In individuals with more severe depressive symptoms, a beneficial effect of NAC was found, which was not clearly seen in individuals with mild depression, paralleling findings of recent antidepressant studies. Magnetic resonance spectroscopy conducted by Professor Malhi at our Sydney site, demonstrated a relationship between metabolite changes and treatment. Examination of the effect of NAC on biomarkers is currently underway.

PROFESSOR MICHAEL BERK

The Clinical Discovery Unit operates as a partner and component of the IMPACT (Innovations in Mental and Physical Health and Clinical Treatments) Strategic Research Centre at Deakin University. It aims to further understand the underlying pathology of mental illness and to assist in the discovery of better treatment for people with these illnesses. The Unit is a collaboration between Deakin University, Barwon Health, the Florey Institute of Neuroscience and Mental Health and the Cooperative Research Centre for Mental Health. It investigates novel biological pathways to identify new treatment targets, and seeks to understand the underlying factors involved in the development of psychiatric disorders. The current research focuses on oxidative stress, inflammation, mitochondrial dysfunction, psychiatric illnesses, and agents that might usefully modify these pathways. At present, the group is conducting clinical trials investigating adjunctive treatments for psychiatric illnesses and working together on laboratory-based projects to clarify the underlying mechanisms. As part of the Cooperative Research Centre for Mental Health (CRC), a number of trials developing novel therapies based on these pathways are underway. The Unit continues to be involved in a range of trials to test the benefits of the antioxidant N-acetyl cysteine (NAC) on bipolar depression and autism, as well as of minocycline for depression and a “mitochondrial cocktail” for the treatment of bipolar depression. In conjunction with these trials, magnetic resonance spectroscopy is being used to investigate changes in biomarkers following NAC treatment.

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NAC FOR BIPOLAR DEPRESSION Following our positive pilot study of N-acetyl cysteine in bipolar depression, which showed robust clinical effect, we have now begun a definitive NHMRC-funded study to confirm this signal. This is a three-site study conducted in Geelong, Melbourne and Sydney, which should be completed after two years. THE MITOCHONDRIAL COCKTAIL FOR BIPOLAR DEPRESSION There is now compelling evidence of mitochondrial dysfunction in bipolar depression with reduced energy generation in depression and increased energy generation in mania. Accordingly, we have commenced a CRC supported trial to examine the efficacy of a cocktail of mitochondriallyacting neutraceutical agents for the management of bipolar depression. This exploration will be conducted as a third arm of the NAC bipolar depression study.

 NAC AND AUTISM There are practically no useful and validated biological therapies for autism. As is the case with other neuropsychiatric disorders, autism is associated with oxidative stress, inflammation and mitochondrial dysfunction, all of which are NAC targets. We are currently completing a Simons Foundation and Rotary Health-funded study of NAC in autism. We have currently enrolled over 100 children, ahead of our recruitment targets, and results of this study should be available early in 2014. MINOCYCLINE FOR UNIPOLAR DEPRESSION Minocycline is an intriguing agent that has antiinflammatory and antioxidative properties and enhances neurogenesis. It is positive in many pre-clinical models of depression. Olivia Dean was successful in obtaining NARSAD funding to conduct a pilot study of minocycline for melancholic unipolar major depression, which has just commenced. Results of this study should be available in 2015. FUTURE DIRECTIONS In addition to the above studies, the Clinical Discovery Unit has embarked on a number of new initiatives. In partnership with Professor Ken Walder at Deakin University, who used the gene expression profile of a cocktail of anti-diabetic drugs to discover new therapies for diabetes, we are modifying this proven drug discovery paradigm to discover new agents for bipolar disorder. We are planning a study of NAC for anaestheticinduced cognitive dysfunction and have partnered with Professor John McNeil, head of the ASPREE study to examine the preventative effects of aspirin on the development of depression in the elderly. Our Unit produced in excess of 100 papers in 2012 in high impact journals including The Lancet and Molecular Psychiatry and we trust that 2013 will similarly produce a bountiful harvest.

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

clinical research group

Clinical Research Group

KEY RESULTS RETENTION OF AIBL SUBJECTS Since baseline, the AIBL inception cohort has maintained excellent retention rates at subsequent time points. At 18-months, 89.9% of the original cohort was re-assessed (18-month cohort; 317 NMC, 375 SMC, 82 MCI and 197 AD subjects). At 36-months, 78.0% returned (36-month cohort; 301 NMC, 309 SMC, 55 MCI and 154 AD subjects). Conversion from HC to MCI at 18-months was 2.5%, and 5.7% by 36-months, with 69% of converters previously being SMC. HC who converted to MCI over the initial 18-months showed greater decline on learning, short-term and long-term memory than HC whose clinical status remained stable. Conversion from MCI to AD was 24% at 18-months and 36% by 36-months.

DR KATHRYN ELLIS

The Clinical Research Group (CRG) aims to detect and understand biological, clinical and cognitive differences between healthy ageing and dementia, including Alzheimer’s disease. The group collects, stores and analyses data from human participants and human tissue samples. The multi-disciplinary team includes neuropsychologists, research nurses, molecular biologists, neuro imaging specialists and bioinfomaticians. The group is currently involved in: • Australian Imaging, Biomarkers and Lifestyle (AIBL) Flagship Study of Ageing • AIBL Active (exercise intervention trial) • the CRC for Mental Health • the Dementia Collaborative Research Centre (DCRC) - Early Risk Diagnosis and Prevention • the Dominantly Inherited Alzheimer’s Network (DIAN) study • the Rates of Change in Cognition (ROCS) study • the Older Australian Twin Study (OATS) • the Women’s Healthy Aging Study (WHAP)

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HIGHLIGHTS

THE AIBL STUDY In 2012, the AIBL study was close to completing the fourth (54 month) time point assessment of all study volunteers. AIBL also recruited new volunteers to enrich the cohort and 184 new participants have been screened at baseline. The longitudinal AIBL data has been analysed and presented at multiple international conferences. A number of key, high impact papers have been published in international journals in the last 6 months. The study has also been granted funding from Science and Industry Endowment Fund (SIEF) until 2013 which will assist to fund our operation of the study’s second phase.

Recently AIBL, in collaboration with a pharmaceutical industry partner, completed a targeted biomarker analysis of the baseline cohort and a panel of blood based analytes were identified that included markers that were significantly changed in AD (Doecke et al., 2012). Crossvalidated accuracy measures from the AIBL cohort reached a mean (SD) of 85% (3.0%) for sensitivity and specificity and 93% (3.0%) for the area under the receiver operating characteristic curve. Therefore, AIBL has identified a panel of plasma biomarkers that distinguish individuals with AD from cognitively healthy control subjects with high sensitivity and specificity. Cross-validation within the AIBL cohort and further validation within the ADNI cohort provides strong evidence that the identified biomarkers are important for AD diagnosis. Other molecular events being systematically investigated by the biomarker research group include; lipidomics, metalomics, proteomics, genomics and targeted analytes including Aß, tau and inflammatory proteins. AIBL have also expanded the collection of cerebrospinal fluid (CSF), focused on MCI and enrichment participants, to corroborate the imaging findings and cross-validate peripheral biomarker studies which will enhance diagnostic classification and characterization of the cohort.

⚿ SUMMARY The AIBL study has made considerable progress since its original goal to assemble a cohort of individuals who could be assessed at regular intervals and whose imaging, biomarkers and lifestyle factors could be compared in relation to their cognitive function (especially with respect to the presence or absence of AD symptoms) and risk factors. Molecular and structural imaging techniques coupled to neuropsychology, lifestyle factors and peripheral biomarker analysis are showing great potential for the preclinical detection of AD, and therefore open a critical window for intervention to prevent deterioration with novel therapeutic approaches. AIBL ACTIVE STUDY This study builds on previous work from AIBL to investigate the effectiveness of physical activity in delaying the progression of cognitive decline and cardiovascular disease (as measured by brain imaging). The group is collaborating with Professor Nicola Lautenschlager’s team at the National Ageing Research Institute and have recently completed the baseline collection with some 6 month follow-up assessments now underway. RATE OF CHANGE STUDY This study aims to improve future research design, so that studies are easier for participants and for assessors, as well as to improve our ability to detect subtle changes in memory at an earlier time point. The study measured cognitive function over the short (1-3 months) and long (18 months) term with repeated assessments conducted at relatively brief re-test intervals in a sub group of 205 well characterized patients currently enrolled in the AIBL cohort. ROCS is now in the final stages of analysis. As the study nears completion, data from these repeated assessments are being analysed.

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

KEY RESULTS (continued) DOMINANTLY INHERITED ALZHEIMER’S NETWORK Since its inception in 2008 DIAN has enrolled over 200 participants across sites in the USA and the UK, as well as Australia, making it the largest study worldwide examining familial Alzheimer’s disease. Results from the study have shown that in this population there are measurable changes in brain chemistry up to 20 years before clinical symptoms are detectable. The CRG is a leading site for data collection in Eastern state participants. INTERNAL GROWTH Due to growth in research activity, the group has now expanded its office and laboratory area, which has tripled the capacity to collect and process samples. THE WOMEN’S HEALTHY AGEING PROJECT (WHAP) WHAP is a study of women’s health over midlife, menopause and ageing lead by Associate Professor Cassandra Szoeke at the National Ageing Research Institute. This study is an extension of the Melbourne Women’s Midlife project Health Project performed during 1991-1998. WHAP has completed its 2012 assessments, this time with brain amyloid imaging, which will be a vital and complementary dataset in the CRG.

clinical research group

⚿ DEMENTIA COLLABORATIVE RESEARCH CENTRES The group continues to play a key role in phase two of the Dementia Collaborative Research Centres (DCRC), being a partner of DCRC Early Risk Diagnosis and Prevention. We have a number of projects focusing on blood biomarkers for Alzheimer’s disease, in addition to a study of a brain imaging compound which may have clinical utility in the coming years. This exciting work is being conducted in collaboration with the Australian National University, Austin Health and Edith Cowan University among other DCRC partners. KNOWLEDGE TRANSFER The information from the research is disseminated to both the scientific community and the general public. The CRG has presented its research at numerous scientific conferences through 2012 (as listed below). The group hold a yearly function in conjunction with Alzheimer’s Australia, Victoria for participants in the AIBL study. The session includes presentation from leading scientists and provides a forum for questions and discussion. Also, participants are updated with regular mail-out.

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PERSONNEL AND COLLABORATORS CLINICAL RESEARCH GROUP

Senior AIBL Study Scientists and Collaborators

Clinical and Neuropsychology Researchers

Professor Colin Masters (Mental Health Research Institute)

Dr Kathryn Ellis BSc (Hons), PhD (Cognitive Stream Leader) Jo Robertson BA(Psych)(Hons) Adrian Kamer BSc (Hons), Candidate DPsych (ClinNeuropsych) Carolina Restrepo (Psych) Fiona Lamb BASc(Psych)(Hons), DPsych(ClinNeuro) Harriet Downing BA, PGrad Dip Psych, Candidate DPsych (ClinNeuropsych) Karra Harrington BA Rachel Buckley BSc (Psych)(Hons) Stacey Walker

NEUROBIOLOGY RESEARCHERS Postdoctoral Fellows Dr Alan Rembach BSc (Hons), PhD Postdoctoral Research Fellow – Coordinator AIBL study

Research Assistants Brett Trounson BSc (Hons) AIBL Blood Processing Laboratory Manager

Professor David Ames (National Ageing Research Institute) Professor Kaarin Anstey (Australian National University) Professor Ashley Bush (Mental Health Research Institute) James Doecke (CSIRO Mathematical and Information Sciences) Dr Maree Farrow (Alzheimer’s Australia Victoria) Associate Professor Marc Budge (Australian National University) Associate Professor Jonathan Foster (Edith Cowan University) Norm Good (CSIRO Mathematical and Information Sciences) Associate Professor David Darby (CogState) Professor Nicola Lautenschlager (The University of Melbourne) Dr Lance Macaulay (CSIRO) Simon McBride (The Australian e-Health Research Centre) Professor Paul Maruff (Mental Health Research Institute)

Dr Christopher Fowler BSc (Hons) PhD – AIBL Biospecimen Manager

Professor Ralph Martins (Edith Cowan University)

Kelly Pertile BSc (Hons) – Recruitment and Biospecimen Coordinator

Lynette Moore (Alzheimer’s Australia Victoria)

Rebecca Rumble BBioSc (Hons) – CSF coordinator

Andrew Milner (Neurosciences Victoria) Dr Timothy O’Meara (CSIRO) Glenn Rees (Alzheimer’s Australia)

DIAN Study

Professor Chris Rowe (Austin Health)

Conferences & presentations

Tabitha Nash BA (Psych)(Hons) DipEd (Secondary)

Olivier Salvado (CSIRO e-Health)

• • • • •

Administration

Research and Standardisation in Alzheimer’s Disease Conference Melbourne, Australia (March 2012) Alzheimer's Association International Conference (AAIC), Vancouver, Canada (July 2012) 9th Annual Australia-China Symposium on Healthy Ageing, Canberra, Australia (July 2012) DCRC National Dementia Forum, Canberra, Australia (September 2012) The 11th International Conference on Alzheimer’s and Parkinson’s disease (AD/PD) Florence, Italy (March 2012) • Science of AIBL Day, Melbourne, Australia (November 2012)

Yumiko Matsumoto

Associate Professor Greg Savage (MACCS) Jack Sach (Alzheimer’s Australia Victoria) Dr Wichat Srikusalanukul (Australian National University) Associate Professor Cassandra Szoeke (CSIRO Preventative Health) Kevin Taddei (Edith Cowan University) Associate Professor Victor Villemagne (Austin Health) Associate Professor Michael Woodward (Austin Health) Associate Professor Olga Yatsrubetskaya (The University of Melbourne)

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

Epilepsy

Epilepsy

Epilepsy - Ion Channels and Human Disease Our research focus is in the understanding the pathology of ion channel disorders. We use a multidisciplinary approach spanning ion channel biophysics, mouse transgenesis, genetic analysis, computational modeling in vitro and in vivo physiology.

division

``Research highlights for 2012

A QUICK SNAPSHOT

SENIOR STAFF

Epilepsy is the most common serious neurological disorder of children and one of the major neurological conditions affecting the general population. Up to 10 percent of people will have a seizure at some time in their life. As one of the world leading centres for epilepsy research, the Florey Epilepsy Division specialises in imaging and molecular neurobiology in both humans and animal models. Our main academic collaborations are through a NHMRC program grant “Neurobiology of human epilepsy: Genes, cellular mechanisms, networks and whole brain” led by Professor Sam Berkovic, AM, and in cognitive neuroscience led by Assoc Prof Sarah Wilson and Professor Michael Saling. At the Florey’s Austin campus, researchers have been undertaking high impact research using Magnetic Resonance Imaging (MRI) for more than 15 years to understand the structural and functional basis of human epilepsy. At the Florey’s Parkville campus, research has revealed many of the fundamental neurobiological mechanisms by which genetic abnormalities 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.

This year we pioneered a new method that allows high spatial and temporal resolution imaging of neurone activity using quantum NV-diamonds – a collaboration with The University of Melbourne’s School of Physics.

Epilepsy Imaging

Dr Saul Mullen

Dr Elena Gazina

Professor Graeme Jackson

Dr Heath Pardoe

Dr Carol Milligan

Dr David Abbott

Professor Michael Saling (Honorary)

Dr Kay Richards

Dr John Archer (Honorary) Professor Sam Berkovic (Honorary)

Dr Robert Richardson

Professor Ingrid Scheffer Dr Chris Tailby

Dr Evan Thomas

Dr Meng Han Tsai

Dr Verena Wimmer

Dr David Vaughan

Synaptic Physiology

Steve Fleming

Associate Professor Sarah Wilson (Honorary)

Dr Christopher Reid

Dr Richard Leventer (Honorary)

Ion Channels and Human Disease Group

Dr Ernesto Vargas

Associate Professor Peter Brotchie (Honorary) Dr Patrick Carney

Dr Michael Makdissi Dr Simone Mandelstam Dr Richard Masterton Associate Professor Paul McCrory

Ion Channels and Epilepsy Lab Associate Professor Steve Petrou Dr Alison Clarke

Dr Han Shen Tae

Dr Marie Phillips Purinergic Signalling Dr Ben Gu Professor James Wiley

The NIH funded Epi4K program is revealing the fundamental genetic architecture of the epilepsies. A/Prof Petrou heads the Epi4K Functional Core and work is underway to understand the functional mechanisms that underlie genetic epilepsy to enable much needed translational outcomes for improved therapies. Deployment of a range of high throughput automated patch clamp and multielectrode array recording systems are the basis of a platform that is systematically deconstructing the function of epilepsy gene variants. Development of new iPS models and TALEN based genome editing is underway and will be used to create human neurones for network scale functional genomics analysis. Our dynamic clamp platform, a hybrid cellcomputer interface, is nearing full development and we are testing its utility for drug discovery in epilepsy.

RESEARCH HIGHLIGHT

MAIN AREAS OF RESEARCH

This year we completed development of a novel neuroimaging analysis method that dramatically improves our ability to map the location of epileptic activity in the brain. The method is called event-related independent components analysis (eICA), and when used in conjunction with acquisition methods previously developed by our group it has enabled us to map the precise location of abnormality in the most common childhood epilepsy syndrome (Rolandic epilepsy).

Epilepsy imaging Human brain structure and function Ion channels and disease Neurobiology of epilepsy Purinergic signalling

``Research highlights for 2012 Our basic work is to understand the networks that underlie epileptic disorders. In addition to the obvious symptomatology of epilepsy (i.e. seizures) cognition, memory and language disturbances are key cognitive areas affected by the disease. We are using EEG/fMRI, advanced diffusion techniques including tractography, functional connectivity and network analysis with EEG to investigate the underlying brain mechanisms responsible for the clinical symptoms. For example, we recently discovered that intrinsic functional brain networks are altered in childhood absence epilepsy (figure 1). We have also mapped the functional brain changes that occur during inter-ictal epileptiform activity in these patients and discovered changes are more complex than previously described (figure 2). These discoveries are likely to have significant phenotypic and genetic implications for understanding epilepsy syndromes.

 Collaborations •

Hertie Institute, University of Tubingen, Germany

University of Madison, WI, USA

Center for Human Genome Variation Duke University Medical Center, USA

Experimental Epileptology and Cognition Research University of Bonn Medical Center, Germany

Columbia University Medical Center, Department of Neurology, USA

Department of Human Genetics, University of Michigan, USA

Yale University School of Medicine, USA

Jackson Laboratories, Bar Harbour, USA

Editorial positions

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Neurobiology of Disease

Epilepsia

Epilepsy - Neuroimaging This group undertakes activities across both the imaging division and the epilepsy division. 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 Melbourne University teaching hospitals.

Figure 1: We discovered that cortical and thalamic intrinsic functional connectivity is altered in childhood absence epilepsy. The colour maps display the relative number of functional connections throughout the brain. Our findings suggest enduring changes in function of the thalamus and the cortex in these patients even when there is no overtly epileptic activity (either seizures or subclinical spikes) occurring. These human functional connectivity data support the findings in animal models of involvement of cortex as well as thalamus in absence epilepsy. Figure 2: Previous studies of absence seizures using EEG with fMRI (EEGfMRI) show a consistent network with prominent thalamic activation and a variety of cortical changes. However despite evidence suggesting a role of frontal cortex in seizure generation, group studies have not detected consistent absence seizurerelated changes in this region. We hypothesised that only a subgroup may show frontal cortical activation. We therefore examined individual activity maps in patients with absence epilepsy and discovered that generally they may be classified as having either increased or decreased frontal activity. The figure here shows group surface renderings for the positive and negative frontal activity groups. Our observations suggest that there may be at least two mechanisms underpinning absence epilepsy in individuals with this condition. This may have phenotypic and genetic implications for understanding epilepsy syndromes.

Epilepsy, and surgical interventions for its amelioration, can provoke reorganization of neurocognitive networks supporting functions such as language. We recently completed a functional

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

Epilepsy

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Figure 4. Cortical thickness mapping is increasingly being used for the analysis of neuroanatomical differences between subject groups. We demonstrate here that the sensitivity of the method can vary appreciably across the surface of the brain. This inflated surface view of the brain displays in colour the number of subjects required per group to detect a thickness difference of 0.25 mm. Lateral view in the top row, medial view on the bottom row. The standard deviation was estimated from 98 neurologically normal controls. We subsequently applied power analysis methods over a range of image processing parameters to derive a model that allows researchers to calculate the number of subjects required to ensure a well-powered cross-sectional cortical thickness study.

Figure 3. We developed a new method for data-driven (exploratory) analysis of event-related functional magnetic resonance imaging (fMRI) that can objectively identify brain activity that is consistently time-locked to events of interest. The method works particularly well in one of the most challenging applications: simultaneous EEG-fMRI of epilepsy. We use the EEG to identify when abnormal events occur (‘epileptic spikes’ detectable when many neurones fire together), and fMRI to map the location of neuronal networks responsible for these events. Existing analysis methods are poorly suited to this data because much of the abnormal neuronal activity is not detectable by the EEG. Our new method requires no prior knowledge of the hidden complex pattern of neuronal activity occurring in association with each spike, only that the pattern will be similar for each spike. This figure shows it identifying the origin of ‘epileptic spikes’ in patients with Rolandic Epilepsy, even though the events of interest only became visible on the EEG after the onset of relevant brain changes.

neuroimaging study of a trained singer with epilepsy before and after surgery. The surgery was successful in stopping seizures, and the patient subsequently showed improved performance on pitch accuracy tests. Neuroimaging revealed dramatic brain changes related to musical function, with an initially unusual pattern of extensive activity prior to surgery changing to a more focal pattern (more typical of expert singers,

including less overlap with language networks) after surgery. This case revealed that musical function can show reorganisation accompanied by improved behavioural performance following resection of a longstanding epileptogenic lesion. Recent methodological developments of our group include completion of a new model-free method for analysis of simultaneous EEG-fMRI that is able to detect abnormal brain

activity beyond conventional model based methods (figure 3). We are now applying this method to further investigate several different epilepsy syndromes. We have also completed a study of the sensitivity of a method used for mapping thickness of the cortex over the surface of the brain (figure 4). In this work we derived a model that can now be used prospectively to estimate the sample-size required to address hypotheses regarding abnormal cortical thickness.

Epilepsy Centre Kempenhaeghe, Oosterhout, the Netherlands

Institute of Breathing and Sleep, Austin Health, Australia

Institute of Child Health, University College London, Great Ormond Street Hospital, London, UK

Murdoch Childrens Research Institute, Melbourne, Australia

New York University, New York, USA

A particularly pleasing highlight of the year was the awarding of Laureate 2012 for Asia-Pacific in the L'Oréal-UNESCO Women In Science Award to Professor Ingrid Scheffer. This award recognised Professor Scheffer’s outstanding research achievements contributing to the identification of genes involved in some forms of epilepsy.

Royal Children's Hospital Melbourne, Australia

University of Adelaide, Australia

University of Antwerp and Antwerp University Hospital, Antwerp, Belgium

The University of Melbourne, Australia

University of Otago, Wellington, New Zealand

 Collaborations

University of Queensland, Australia

Boston Children’s Hospital, Harvard University, Boston, MA, USA

University of South Australia, Australia

University of Washington, Seattle, USA

Centre for Eye Research, Australia

Chicago Children’s Hospital, USA

Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

Comprehensive Epilepsy Program, Austin Health, Australia

Women & Children’s Hospital, Adelaide, South Australia

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

Editorial positions •

Associate Editor, Frontiers in Auditory Cognitive Neuroscience – Sarah Wilson

Member, Editorial Board, Annals of Neurology – Ingrid Scheffer

Member, Editorial Board, Epilepsy & Behavior – Sarah Wilson

Member, Editorial Board, Epileptic Disorders Graeme Jackson and Ingrid Scheffer

Member, Editorial Board, Progress in Epileptic Disorders Series - Ingrid Scheffer

{{Conferences 1.

Archer J, Stagnitti M, Masterton M, Abbott D, Jackson G, Lennox Gastaut Syndrome: a secondary network epilepsy. Proceedings of the American Epilepsy Society 66th Annual Meeting, San Diego, USA (December 2012) (oral presentation)

2. Patrick W Carney, Richard A J Masterton, Samuel F Berkovic, Graeme D Jackson. Familial patterns of BOLD activation. Proceedings of the American Epilepsy Society 66th Annual Meeting, San Diego, USA (December 2012) 3. Intusoma U, Stagnitti M, Masterton M, Abbott D, Newton M, Jackson G, Freeman J, Harvey AS, Archer J. The Tonic Seizures of Lennox Gastaut Phenotype: ictal SPECT shows a cortico-reticular network. Proceedings of the American Epilepsy Society 66th Annual Meeting, San Diego, USA (December 2012) 4. Abbott DF, Palmer SM, Low E, Jackson GD, Carey LM. An fMRI study of the relative laterality of dominant and non-dominant hand sensory function. Proc. Intl. Soc. Mag. Reson. Med. 20;2157 (2012) 5. Tailby C, Abbott DF, Jackson GD. Prior cognitive state can influence functional connectivity networks at the individual and group level. Proc. Intl. Soc. Mag. Reson. Med. 20;2124 (2012) 6. Pardoe, Heath R.; Jackson, Graeme D. Do Antiepileptic Drugs Affect Brain Structure? a Cross-Sectional Investigation of Morphometric Differences Associated with Sodium Valproate. Proc. Intl. Soc. Mag. Reson. Med. 20; 796 (2012) 7. Masterton, Richard; Jackson, Graeme. Network Analysis of Resting-State fMRI Reveals Increased Centrality in Regions Generating Focal Epileptiform Spikes. Proc. Intl. Soc. Mag. Reson. Med. 20; 372 (2012) 8. Brotchie, Peter; Seixas, Shaun; Ip, Shoane; Hughes, Mathew; Jackson, Graeme. Persistent Activity in Posterior Parietal Cortex Reflects Planned Changes in Orientation During Navigation. Proc. Intl. Soc. Mag. Reson. Med. 20; 2135 (2012) 9. Vaughan, David; Tournier, Jacques-Donald; Connelly, Alan; Jackson, Graeme. Spread of Discharges Through Tracks Identified with Diffusion Tractography May Explain Transient Splenial "lesions" in Epilepsy. Proc. Intl. Soc. Mag. Reson. Med. 20; 3734 (2012) 10. Mohamed A, Masterton R, Archer J, Abbott D, Kean M, Harvey S, Jackson G. Resting State Functional Connectivity in Tuberous Sclerosis Complex and Refractory Epilepsy. Proc. Intl. Soc. Mag. Reson. Med. 20;3666 (2012) 11. Calamante F, Masterton RAJ, Tournier JD, Smith RE, Willats L, Raffelt D, Connelly A. Super-Resolution Track-

Weighted Functional Connectivity (TW-FC): A Tool for Characterizing the Structural-Functional Connections in the Brain. Proc. Intl. Soc. Mag. Reson. Med. 20 (2012), Melbourne, Australia, p.139 12. Archer J, Stagnitti M, Masterton M, Abbott D, Jackson G. Lennox Gastaut Syndrome: a secondary network epilepsy. Proceedings of the Epilepsy Society of Australia 26th Annual Meeting, Hobart, Tasmania ( 31st Oct- 2nd Nov 2012) 13. Patrick W Carney, Richard A J Masterton, Deepak Gill, Graeme D Jackson. Nodular heterotopia and absence seizures: fMRI evidence of active nodule involvement. Proceedings of the Epilepsy Society of Australia 26th Annual Meeting, Hobart, Tasmania ( 31st Oct- 2nd Nov 2012) 14. Patrick W Carney, Richard A J Masterton, Samuel F Berkovic, Graeme D Jackson. Proceedings of the Epilepsy Society of Australia 26th Annual Meeting, Hobart, Tasmania ( 31st Oct- 2nd Nov 2012) 15. Intusoma U, Stagnitti M, Masterton M, Abbott D, Newton M, Jackson G, Freeman J, Harvey AS, Archer J. Tonic Seizures of Lennox Gastaut Syndrome: ictal SPECT shows a cortico-pontine network. Proceedings of the Epilepsy Society of Australia 26th Annual Meeting, Hobart, Tasmania ( 31st Oct- 2nd Nov 2012) 16. Carey LM, Abbott DF, Lamp G, Puce A, Seitz RJ, Donnan GA. Imaging neuroplasticity of touch after stroke: trainingfacilitated changes following intervention. Proceedings of the 18th Annual Meeting of the Organisation for Human Brain Mapping, Beijing, China. (2012) 17. Connor HR, Abbott DF, Hosking SL. Glaucoma patients with large optic disc size have reduced retrobulbar optic nerve diameter. Proc 20th International Visual Field and Imaging Symposium. Jan 22-25, Melbourne, Australia. Program# P28, p53 (2012) 18. Tailby, C., & Solomon, S. G. (2012). Hysteresis as a source of noise correlation. In Vision Down Under. Lamington, Qld, Australia 19. Martin, P. R., Tailby, C., Solomon, S. G., Cheong, S. K., & Pietersen, A. N. J. (2012). Contribution of short wavelength sensitive (S or “blue”) cones to visual responses in superior colliculus. In Proceedings of the Australian Neuroscience Society 20. Epilepsy Sub-Domain meeting Imaging of the preictal state 13th September 2012 21. Epilepsy Research Retreat 2012 Lancefield The Piriform Cortex and Epilepsy 2-4 August, 2012

Epilepsy

28. West Coast Leader’s Dialogue (Australian American Leadership Dialogue), Palo Alto & San Diego USA 29. Invited Lecture at NHMRC Forum and Roundtable: Innovation and the Research Virtuous Cycle: Enablers and Barriers to Commercial Development in Health and Medical Research. The Hotel Charsfield, Melbourne, Australia. Talk title: "A device for simultaneous continuous acquisition of EEG and MRI" 30. Invited talk: Surgical Symposium - EEG fMRI. Epilepsy Society of Australia, Hobart 31. Invited talk - special interest group meeting “Epilepsy Networks – resting state fMRI perspectives” American Epilepsy Society 66th Annual Meeting, San Diego, USA 32. Invited Lecture: “Update on the new organisation: where have the modifications taken us?” NAC/ILAE Symposium: Epilepsy classification: hot controversies in 2012, American Epilepsy Society Annual Meeting, San Diego, CA, US 33. Invited Lecture: “Dravet syndrome: what matters more, seizures or the underlying aetiology?” Outcome of Childhood Epilepsies: Progress in Epileptic Disorders Workshop, The Hague, The Netherlands 34. Invited Speaker: “Women in science: an exciting career filled with extraordinary rewards” Kobe University International symposium on Women in Science, Kobe, Japan 35. Invited Speaker: “Clinicopathological conference: The causes of epilepsy” Teaching course, 10th European Congress of Epileptology, London, UK 36. Invited Speaker: Dravet syndrome, Athena Diagnostics Webinar Series Two 37. Invited Plenary: “Vaccinations, gait and Dravet Spectrum Disorders: What medical professionals and caregivers need to know”, Dravet.org 2012 Biennial Conference, Minneapolis South, USA, (webinar) 38. Invited Lecture: “Glut1 epilepsies”, International Child Neurology Congress, Brisbane, Australia 39. Invited Lecture: “The girls only story”, International Child Neurology Congress, Brisbane, Australia 40. Invited Speaker: Dravet syndrome, Athena Diagnostics Webinar Series One 41. Plenary Laureate Lecture: L’Oreal-Unesco Awards 2012 For Women in Science, French Academy of Sciences, Paris, France

22. Neuroscience Centre of Clinical Research Excellence – Specialist Certificate in Clinical Research (Neuroscience) 2012 Frontiers of Neuroimaging 18th June, 2012

42. Plenary Lecture: “Epilepsy genetics: the impact on clinical practice”, 9th Asian & Oceanian Epilepsy Congress (AOEC), Manila, Philippines

23. ICNCN Pre Congress Symposium New and emerging imaging techniques to detect subtle MCD Malformations of cortical development Brisbane

43. Plenary Lecturer: "Cryptogenic epilepsies in young children revisited in the light of recent discoveries in genetics", Swiss Paediatric Neurology Society, Lausanne, Switzerland

24. ISMRM (International Society of Magnetic Resonance Medicine) 25. Moderator: Workflow Across Geography Melbourne 26. AOEC Chairman's Symposium, Manila “fMRI – how are we now?" 27. AOEC Chairman's Symposium, Manila "Functional and structural connectivity imaging"

44. Invited Lecture: "Epilepsy and deficit in GLUT1", Swiss Paediatric Neurology Society, Lausanne, Switzerland 45. Invited Lecture: “Epilepsy genetics: impact on clinical practice in 2012”, GlaxoSmithKline Luncheon Seminar, The 14th Annual Meeting of ISS: International Symposium on Surgery for Catastrophic Epilepsy in Infants, Tokyo, Japan

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46. Invited Lecture: “Genetic and autoimmune aetiologies of infantile epilepsies”, The 14th Annual Meeting of ISS: International Symposium on Surgery for Catastrophic Epilepsy in Infants, Tokyo, Japan 47. Invited Lecture: “Application of the new ILAE organisation to infantile epilepsy syndromes”, The 14th Annual Meeting of ISS: International Symposium on Surgery for Catastrophic Epilepsy in Infants, Tokyo, Japan 48. Invited Lecture: “Genetics of neonatal and infantile epileptic encephalopathies”, Translational Research Symposium, Epilepsy Society of Australia Annual Meeting, Hobart, Tasmania, Australia 49. Tracy Maund Orator: “A woman’s work is never done: Balancing scientific excellence with life’s challenges”, Royal Women's Hospital, Parkville, Melbourne, Australia 50. Invited Lecture: “Paroxysmal neurological events – the new genetics solves age-old questions”, ICT for Life Sciences Forum, Melbourne, Australia 51. Invited Lecture: “PRRT2: A gene for infantile convulsions and paroxysmal dyskinesia”, Second Annual Meeting of Melbourne Epilepsy, Melbourne, Australia 52. Invited Lecture: “Epilepsy genetics: exciting insights from molecular and phenotypic discoveries”, Human Variome Project Seminar Series, Melbourne, Australia 53. Invited Lecture: L'Oréal Australia and New Zealand For Women In Science Fellowships Award Ceremony, Melbourne, Australia 54. Invited Lecture: “Clinical research: What makes it real science?”, Women in Medical Research: Passionate Minds, Melbourne, Australia 55. Invited Lecture: “Genetics of Infantile Epileptic Encephalopathies”, Sydney Children’s Hospital, Sydney, Australia 56. Invited Lecture: “Taking Epilepsy Classification into the 21st Century”, Grand Rounds Sydney Children’s Hospital, Sydney, Australia 57. Invited Lecture: “Communicating Science”, SOBR From the lab to the layman: Communicating science to the public dinner, Melbourne, Australia, 24 May 2012 58. Invited Lecture: “How can lessons learned from epilepsy inform the autism-vaccination debate?” Walter and Eliza Hall Institute Celebratory Symposium Public Lecture: Translation – delivering the benefits of medical research to the community, Melbourne 59. Invited Lecture: “A woman’s work is never done: Balancing scientific excellence with life’s challenges”, Clinical and Public Health Seminar, Royal Children’s Hospital, Melbourne 60. Guest Speaker: The University of Melbourne Conferring Degrees Ceremony, Melbourne 61. Plenary Lecture: “Epilepsy genetics: impact on clinical practice in 2012", Hopkins Symposium Royal Children’s Hospital, Melbourne

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

Epilepsy

PUBLICATIONS

PUBLICATIONS

57

27. Kim TH, Richards K, Heng J, Petrou S and Reid CA, Two lines of transgenic mice expressing cre-recombinase exhibit increased seizure susceptibility, Epilepsy Res, 2012, PMID: 23196213

1.

Abbott DF, Pell GS, Pardoe HR and Jackson GD, Selecting appropriate voxel-based methods for neuroimaging studies, Neuroimage, 59:885-6,2012, PMID: 21763436

2.

Afawi Z, Bassan H, Heron S, Oliver K, Straussberg R, Scheffer I, Leventer R, Korczyn A and Berkovic S, Benign Neonatal Sleep Myoclonus: An Autosomal Dominant Form Not Allelic to KCNQ2 or KCNQ3, Journal of Child Neurology, 27:1260-1263,2012, PMID: WOS:000309078800003

3.

Arsov T, Mullen SA, Damiano JA, Lawrence KM, Huh LL, Nolan M, Young H, Thouin A, Dahl H-HM, Berkovic SF, Crompton DE, Sadleir LG and Scheffer IE, Early onset absence epilepsy: 1 in 10 cases is caused by GLUT1 deficiency, Epilepsia, 53:e204-e207,2012, PMID: WOS:000312218000003

4.

Arsov T, Mullen SA, Rogers S, Phillips AM, Lawrence KM, Damiano JA, Goldberg-Stern H, Afawi Z, Kivity S, Trager C, Petrou S, Berkovic SF and Scheffer IE, Glucose transporter 1 deficiency in the idiopathic generalized epilepsies, Ann Neurol, 72:807-15,2012, PMID: 23280796

30. Masterton RA, Carney PW and Jackson GD, Cortical and thalamic resting-state functional connectivity is altered in childhood absence epilepsy, Epilepsy Res, 2012, PMID: 22281064

5.

Badawy RA and Jackson GD, Cortical excitability in migraine and epilepsy: a common feature?, J Clin Neurophysiol, 29:244-9,2012, PMID: 22659718

31.

6.

Badawy RA, Jackson GD, Berkovic SF and Macdonell RA, Inter-session repeatability of cortical excitability measurements in patients with epilepsy, Epilepsy Res, 98:182-6,2012, PMID: 22018906

32. McIntosh AM, Averill CA, Kalnins RM, Mitchell LA, Fabinyi GC, Jackson GD and Berkovic SF, Long-term seizure outcome and risk factors for recurrence after extratemporal epilepsy surgery, Epilepsia, 2012, PMID: 22417071

7.

Badawy RA, Macdonell RA, Vogrin SJ, Lai A and Cook MJ, Cortical excitability decreases in Lennox-Gastaut syndrome, Epilepsia, 53:1546-53,2012, PMID: 22813348

8.

Barkovich AJ, Guerrini R, Kuzniecky RI, Jackson GD and Dobyns WB, A developmental and genetic classification for malformations of cortical development: update 2012, Brain, 2012, PMID: 22427329

33. Mohamed AR, Bailey CA, Freeman JL, Maixner W, Jackson GD and Harvey AS, Intrinsic epileptogenicity of cortical tubers revealed by intracranial EEG monitoring, Neurology, 2012, PMID: 23175730

9.

Berkovic S, Cossette P, Delanty N, Dlugos D, Eichler E, Epstein M, Glauser T, Goldstein D, Heinzen E, Johnson MR, Kuzniecky R, Lowenstein D, Marson T, Mefford H, O'Brien T, Ottman R, Poduri A, Scheffer I, Sherr E, Shianna K and Epi KC, Epi4K: Gene discovery in 4,000 genomes, Epilepsia, 53:1457-1467,2012, PMID: WOS:000308442800027

10.

Carney PW, Masterton RA, Flanagan D, Berkovic SF and Jackson GD, The frontal lobe in absence epilepsy: EEG-fMRI findings, Neurology, 78:1157-65,2012, PMID: 22459682

11.

Chambers B, Chambers J, Cameron H and Macdonell R., Chronic cerebrospinal venous insufficiency is not more prevalent in patients with mild multiple sclerosis: a sonographer-blinded, case-control ultrasound study, Mult Scler, 2012, PMID: 22961213

12.

Chambers JD, Bethwaite B, Diamond NT, Peachey T, Abramson D, Petrou S and Thomas EA, Parametric computation predicts a multiplicative interaction between synaptic strength parameters that control gamma oscillations, Front Comput Neurosci, 6:53,2012, PMID: 22837747

38. Petrou S, Reid CA. , The GABAAgamma2(R43Q) mouse model of human genetic epilepsy, Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, editors. Jasper's Basic Mechanisms of the Epilepsies. Bethesda MD: Michael A Rogawski, Antonio V Delgado-Escueta, Jeffrey L Noebels, Massimo Avoli and Richard W Olsen, 2012,

13.

Davis GA and Makdissi M, Concussion tests: clarifying potential confusion regarding sideline assessment and cognitive testing, British Journal of Sports Medicine, 46:959-960,2012, PMID: WOS:000310357900003

39. Reid CA, Phillips AM and Petrou S, HCN channelopathies: pathophysiology in genetic epilepsy and therapeutic implications, British Journal of Pharmacology, 165:49-56,2012, PMID: 21615728

14.

Dibbens LM, Hodgson BL, Helbig KL, Oliver KL, Mulley JC, Berkovic SF and Scheffer IE, Rare protein sequence variation in SV2A gene does not affect response to levetiracetam, Epilepsy Research, 101:277-279,2012, PMID: WOS:000309438000011

40. Rodda JM, Scheffer IE, McMahon JM, Berkovic SF and Graham HK, Progressive Gait Deterioration in Adolescents With Dravet Syndrome, Arch Neurol, 2012, PMID: 22409937

15.

Field M, Scheffer IE, Gill D, Wilson M, Christie L, Shaw M, Gardner A, Glubb G, Hobson L, Corbett M, Friend K, Willis-Owen S and Gecz J, Expanding the molecular basis and phenotypic spectrum of X-linked Joubert syndrome associated with OFD1 mutations, European Journal of Human Genetics, 20:806-809,2012, PMID: WOS:000305345900015

41.

16.

Gartland A, Skarratt KK, Hocking LJ, Parsons C, Stokes L, Jorgensen NR, Fraser WD, Reid DM, Gallagher JA and Wiley JS, Polymorphisms in the P2X7 receptor gene are associated with low lumbar spine bone mineral density and accelerated bone loss in post-menopausal women, Eur J Hum Genet, 20:559-64,2012, PMID: 22234152

17.

Gazina EV and Petrou S, Viral targets of acylguanidines, Drug Discov Today, 2012, PMID: 22580299

18.

Hall LT, Beart GC, Thomas EA, Simpson DA, McGuinness LP, Cole JH, Manton JH, Scholten RE, Jelezko F, Wrachtrup J, Petrou S and Hollenberg LC, High spatial and temporal resolution wide-field imaging of neuron activity using quantum NV-diamond, Sci Rep, 2:401,2012, PMID: 22574249

19.

Hao MM, Lomax AE, McKeown SJ, Reid CA, Young HM and Bornstein JC, Early development of electrical excitability in the mouse enteric nervous system, J Neurosci, 32:10949-60,2012, PMID: 22875929

20. Heinzen EL, Swoboda KJ, Hitomi Y, Gurrieri F, Nicole S, de Vries B, Tiziano FD, Fontaine B, Walley NM, Heavin S, Panagiotakaki E, Fiori S, Abiusi E, Di Pietro L, Sweney MT, Newcomb TM, Viollet L, Huff C, Jorde LB, Reyna SP, Murphy KJ, Shianna KV, Gumbs CE, Little L, Silver K, Ptacek LJ, Haan J, Ferrari MD, Bye AM, Herkes GK, Whitelaw CM, Webb D, Lynch BJ, Uldall P, King MD, Scheffer IE, Neri G, Arzimanoglou A, van den Maagdenberg AMJM, Sisodiya SM, Mikati MA, Goldstein DB, European Alternating H, Biobanca Registro C and European Network Res A, De novo mutations in ATP1A3 cause alternating hemiplegia of childhood, Nature Genetics, 44:1030-+,2012, PMID: WOS:000308491200015 21.

Heron SE, Grinton BE, Kivity S, Afawi Z, Zuberi SM, Hughes JN, Pridmore C, Hodgson BL, Iona X, Sadleir LG, Pelekanos J, Herlenius E, Goldberg-Stern H, Bassan H, Haan E, Korczyn AD, Gardner AE, Corbett MA, Gecz J, Thomas PQ, Mulley JC, Berkovic SF, Scheffer IE and Dibbens LM, PRRT2 Mutations Cause Benign Familial Infantile Epilepsy and Infantile Convulsions with Choreoathetosis Syndrome, American Journal of Human Genetics, 90:152-160,2012, PMID: WOS:000299409100016

22. Heron SE, Smith KR, Bahlo M, Nobili L, Kahana E, Licchetta L, Oliver KL, Mazarib A, Afawi Z, Korczyn A, Plazzi G, Petrou S, Berkovic SF, Scheffer IE and Dibbens LM, Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy, Nat Genet, 44:118890,2012, PMID: 23086396 23. Howell KB, Katanyuwong K, Mackay MT, Bailey CA, Scheffer IE, Freeman JL, Berkovic SF and Harvey AS, Long-term follow-up of febrile infection-related epilepsy syndrome, Epilepsia, 53:101-110,2012, PMID: WOS:000298790100017 24. Jackson GD, Badawy R and Gotman J, Functional magnetic resonance imaging: focus localization, Handb Clin Neurol, 107:369-85,2012, PMID: 22938983

28. Klein KM, O'Brien TJ, Praveen K, Heron SE, Mulley JC, Foote S, Berkovic SF and Scheffer IE, Familial focal epilepsy with variable foci mapped to chromosome 22q12: Expansion of the phenotypic spectrum, Epilepsia, 53:E151-E155,2012, PMID: WOS:000308442800004 29. Mandelstam SA, Challenges of the Anatomy and Diffusion Tensor Tractography of the Meyer Loop, AJNR Am J Neuroradiol, 2012, PMID: 22422189

McCrory P, Falvey E and Turner M, Returning to the golden age of boxing, Br J Sports Med, 46:459-60,2012, PMID: 22661694

34. Nangia S, Caraballo RH, Kang H-C, Nordli DR and Scheffer IE, Is the ketogenic diet effective in specific epilepsy syndromes?Epilepsy Research, , 100:252257,2012, PMID: WOS:000307530400009 35. Oliva M, Berkovic SF and Petrou S, Sodium channels and the neurobiology of epilepsy, Epilepsia, 2012, PMID: 22905747 36. Pardoe HR, Abbott DF and Jackson GD, Sample size estimates for well-powered cross-sectional cortical thickness studies, Hum Brain Mapp, 2012, PMID: 22807270 37. Pell GS, Lin A, Wellard RM, Werther GA, Cameron FJ, Finch SJ, Papoutsis J and Northam EA, Age-related loss of brain volume and T2 relaxation time in youth with type 1 diabetes, Diabetes care, 35:513-9,2012, PMID: 22301124

Rojo DC, Harvey AS, Iona X, Dibbens LM, Damiano JA, Arsov T, Gill D, Freeman JL, Leventer RJ, Vincent A, Berkovic SF, McMahon JM and Scheffer IE, Febrile infection-related epilepsy syndrome is not caused by SCN1A mutations, Epilepsy Research, 100:194-198,2012, PMID: WOS:000305591600024

42. Sadleir LG, Vears D, Regan B, Redshaw N, Bleasel A and Scheffer IE, Family studies of individuals with eyelid myoclonia with absences, Epilepsia, 53:21412148,2012, PMID: 23205932 43. Scheffer IE, Diagnosis and long-term course of Dravet syndrome, European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society, 16 Suppl 1:S5-8,2012, PMID: MEDLINE:22704920 44. Scheffer IE, Epilepsy: A classification for all seasons?Epilepsia, , 53:6-9,2012, PMID: WOS:000306138300003 45. Scheffer IE, GLUT1 deficiency: A glut of epilepsy phenotypes, Neurology, 2012, PMID: 22282642 46. Scheffer IE, Grinton BE, Heron SE, Kivity S, Afawi Z, Iona X, Goldberg-Stern H, Kinali M, Andrews I, Guerrini R, Marini C, Sadleir LG, Berkovic SF and Dibbens LM, PRRT2 phenotypic spectrum includes sporadic and fever-related infantile seizures, Neurology, 2012, PMID: 23077018 47. Tailby C, Cheong SK, Pietersen AN, Solomon SG and Martin PR, Colour and pattern selectivity of receptive fields in superior colliculus of marmoset monkeys, Journal of Physiology-London, 590:4061-4077,2012, PMID: WOS:000308128100032 48. Thammongkol S, Vears DF, Bicknell-Royle J, Nation J, Draffin K, Stewart KG, Scheffer IE and Mackay MT, Efficacy of the ketogenic diet: Which epilepsies respond?, Epilepsia, 2012, PMID: 22310062 49. Tomlinson SE, Bostock H, Grinton B, Hanna MG, Kullmann DM, Kiernan MC, Scheffer IE, Berkovic SF and Burke D, In vivo loss of slow potassium channel activity in individuals with benign familial neonatal epilepsy in remission, Brain, 135:3144-3152,2012, PMID: WOS:000310156700022 50. Ullmann JF, Keller MD, Watson C, Janke AL, Kurniawan ND, Yang Z, Richards K, Paxinos G, Egan GF, Petrou S, Bartlett P, Galloway GJ and Reutens DC, Segmentation of the C57BL/6J mouse cerebellum in magnetic resonance images, Neuroimage, 62:1408-14,2012, PMID: 22658976 51.

Vears DF, Tsai MH, Sadleir LG, Grinton BE, Lillywhite LM, Carney PW, Simon Harvey A, Berkovic SF and Scheffer IE, Clinical genetic studies in benign childhood epilepsy with centrotemporal spikes, Epilepsia, 5:1528-1167,2012, PMID: 22220564

52. Weckhuysen S, Mandelstam S, Suls A, Audenaert D, Deconinck T, Claes LRF, Deprez L, Smets K, Hristova D, Yordanova I, Jordanova A, Ceulemans B, Jansen A, Hasaerts D, Roelens F, Lagae L, Yendle S, Stanley T, Heron SE, Mulley JC, Berkovic SF, Scheffer IE and de Jonghe P, KCNQ2 encephalopathy: Emerging phenotype of a neonatal epileptic encephalopathy, Annals of Neurology, 71:15-25,2012, PMID: WOS:000299412200006

25. Kaye AH and McCrory P, Does football cause brain damage?Medical Journal of Australia, , 196:547-549,2012, PMID: WOS:000304518400004

53. Yang Z, Richards K, Kurniawan ND, Petrou S and Reutens DC, MRI-guided volume reconstruction of mouse brain from histological sections, J Neurosci Methods, 211:210-7,2012, PMID: 22981936

26. Kemp JL, Collins NJ, Makdissi M, Schache AG, Machotka Z and Crossley K, Hip arthroscopy for intra-articular pathology: a systematic review of outcomes with and without femoral osteoplasty, British Journal of Sports Medicine, 46:632-643,2012, PMID: WOS:000305482800004

54. Zheng TW, O'Brien TJ, Morris MJ, Reid CA, Jovanovska V, O'Brien P, van Raay L, Gandrathi AK and Pinault D, Rhythmic neuronal activity in S2 somatosensory and insular cortices contribute to the initiation of absence-related spike-and-wave discharges, Epilepsia, 2012, PMID: 23083325

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

A VOICE LIKE NO OTHER

59

A voice like no other Sally Watt’s story is extraordinary. It is a tale of perseverance and trust in the medical profession – as well as a story of a strong young woman who has undergone treatment on her own terms. Sally has also provided the Florey’s epilepsy team with some valuable knowledge about the workings of a singer’s brain.

An accomplished pianist and singer, Sally had planned to build her career around music, despite the impact of absence seizures which began when she was 16. She struggled with musical memory despite the obstacles presented by large doses of medication – loss of concentration and poor cognitive functioning - Sally made it into the Conservatorium of Music and The University of Melbourne. But her situation became intolerable and neurologists at the Royal Melbourne Hospital recommended invasive brain surgery. Sally undertook her own research and while she feared she would lose her highly trained singing abilities, she made the decision to go ahead. Enter Professor Graeme Jackson, a neurologist and division head of the Epilepsy Division at the Florey. Graeme is internationally renowned for his ability to steer surgeons around the brain, based on highly sophisticated magnetic resonance imaging which is conducted prior to surgery. “Sally’s case presented a rare opportunity to study how the brain works when singing and, in turn, whether we could gain new insight into the processes of language and song,” Graeme says. “We were perfectly positioned to conduct such a study with sophisticated imaging equipment, physicists, neurologists and radiographers able to analyse the scanned brain.” Sally was asked to lie in the MRI machine and to imagine she was singing while looking at a score of music. But the surgery posed a clear risk. The area of the brain affected by the seizures was right where her singing centre was located. The surgical team, led by Dr Andrew Kay, decoupled the language and singing networks in Sally’s brain during a right anterior temporal lobectomy. But most amazing of all, Sally now has improved pitch despite striking changes to her brain’s neural pathways.

According to Graeme: “The right temporal lobe has a wellestablished role in musical abilities with specific areas responsible for fine-grained pitch perception, pitch memory and representation of tunes.”

The surgery was unique, as is every case undertaken by Graeme and the surgeon, both of whom regularly makes crucial decisions. Pre-surgery, Graeme works to ensure functional reorganisation is possible on a patient-by-patient basis. “The aim is to spare functional tissue to preserve pre-surgical capacity of the patient. Cognitive risks are minimised but weighed-up against the chance of complete seizure freedom.” We know that in untrained singers, both hemispheres of the brain are involved indicating that language and singing are close to each other. Earlier research has also shown that trained musicians have improved language skills, tonal understanding and reading ability. Significantly, trained singers rely on the right side of their brains to sing, unlike non-singers. Sally’s case motivated a major research project in music which led to a new understanding of brain plasticity and how singers ‘find their voices’. It’s hard to imagine the risk Sally was prepared to take, prior to surgery. “I had an almost spiritual connection to singing which had helped me cope with adversity.” For five years after the surgery, Sally faced an arduous recovery with a strange mix of unexpected panic attacks and depression without a trigger or cause - and ‘emotionless’ singing. For a time she became dyslexic and couldn’t work with numbers. But the epilepsy was at last manageable. Today, Sally proudly reports she has rediscovered piano, her brain has reorganised itself and she can once again sing with emotion. Sight singing is now much more instinctive and remarkably accurate. She also has improved verbal memory and no longer struggles with reading or numbers. But most amazing of all, Sally now has improved pitch despite striking changes to her brain’s neural pathways. Sally performs at Trinity College in the Canterbury Fellowship, singing music from the Renaissance and other periods. As Graeme said at the photo shoot for this story: “I’ve seen Sally thinking about singing. Now I want to hear her sing”.

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Professor Graeme Jackson

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

imaging

IMAGING

Advanced MRI Development Group

“Chronic pain following traumatic brain injury” Robin Donald, Peter Fox, Research Imaging Institute, UTHSCSA, Texas (Department of Defense # D10IARJ8793 $1m USD)

MRtrix: software package to enable white matter fibre tracking to be done in the brain using our constrained spherical deconvolution algorithm. (>5500 downloads)

“Pain and motor brain activation in OA knee patients” Kim Bennell UM, Paul Hodges UQ (Student - Camille Shanahan)

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 testbed for the development and evaluation of tractography methods (>1200 downloads)

“Central cough networks in health and disease” Stuart Mazzone, UQ (Students - Jennifer Leech, Ayaka Ando)

“Regulation of salt and water” Derek Denton, Michael McKinley, Pascal Saker, The Florey (G. Harold and Leila Y. Mathers Charitable Foundation, New York)

Patent

 Neuroimaging research at the Florey involves the study of many disease states, including MS, stroke, epilepsy, tumours, dementia and in a range of mental health disorders such as schizophrenia. The MRI technical development program is world leading in the highly active field of diffusion MRI.

Software

DIVISION

61

Image processing system A method for generating super-resolution images of fibrous tissue (such as white matter), based on tractography output.

A QUICK SNAPSHOT The Florey Imaging Division encompasses the following research groups: Advanced MRI Development, Epilepsy Imaging, Small Animal MRI, and Interoception. 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. Most 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 HIGHLIGHTS

SENIOR STAFF

The Advanced MRI Development physics team at the Florey Heidelberg campus has an international reputation for innovative methodological development in a number of areas of magnetic resonance physics and of MR signal processing. One of the principal interests of this team is translational research, with the aim of applying new methods to important clinical and neuroscientific problems, in particular in the field of epilepsy.

Advanced MRI Development

Significant breakthroughs have been achieved in the field of diffusion MRI and perfusion MRI, and many ongoing projects are developing these strengths further. In particular, this group is one of the world leaders in diffusion MRI innovation, and the methodological advances made at the Florey have been adopted at many of the major centres around the world (eg the software package (MRtrix) developed by this group for diffusion image processing has been downloaded >5500 times worldwide). These advances have also provoked great interest from the world’s leading MRI scanner manufacturer, namely Siemens, who have contracted to have this approach developed as a Siemens software package for distribution on Siemens scanners when completed.

Dr Donald Tournier

The Animal MRI group benefitted greatly from a significant upgrade to the 4.7 T animal scanner at the Florey. While this entailed substantial disruption in the short term during 2012, it has greatly increased the capabilities of the MRI facility, and the research is now progressing in areas that were not previously possible (eg animal functional MRI). Following the scanner upgrade, and optimisation of the new scanner performance, many new scientific collaborations have been established and are currently underway (see below).

Animal MRI

International patent application no: PCT/AU2010/000257

 Collaborations In addition to a range of collaborations within the Florey, the MRI Development Group have both national and international collaborations with a wide range of institutions, including: Universities of Adelaide, Queensland, Sydney, and Melbourne; MCRI; CSIRO; University College London; Stanford University; Karolinska Institute; Leiden University; George Mason University; Neuroscience Research Institute, Incheon (S Korea); Max Planck Institute, Leipzig

Professor Alan Connelly

A novel MRI method known as super-resolution track density imaging (TDI) has been developed at the Florey. As part of a methodological validation study, superresolution track density maps of a mouse brain were compared to myelin stained histological sections obtained from the same mouse brain. Example coronal slices (at three different anatomical positions) corresponding to myelin stained histology (top row), super-resolution TDI maps (middle row) and super-resolution colour coded TDI maps (bottom row). The colour-coding indicates the local fibre orientation (red: left-right, green: dorsal-ventral, blue: cranial-caudal). The super-resolution maps have 20 µm isotropic resolution, which is 125 times greater resolution than the acquired MR images. The distance to Bregma for each histological slice is indicated in the figure. Attribution: F.Calamante et al. MRI Development group.

Associate Professor Fernando Calamante Dr Lisa Willats Dr David Raffelt Dr Xiaoyun Liang Robert Smith Steve Fleming

Dr Leigh Johnston (Honorary) Professor Roger Ordidge (Honorary) David Wright Dr Hong Wang

The Interoception Group’s research includes strong interests in the areas of brain (and brainstem) systems for central pain processing and central cough networks, the latter in particular in patients with cough hypersensitivity and in people with cystic fibrosis.

Dr Kelvin Layton

The work of the Epilepsy Imaging Group is described in detail in the Epilepsy Division section of this report, and will therefore not be repeated here. Nevertheless, it is important to note the significant cross-relations between these two divisions.

Dr Michael Farrell

Interoception Dr Leonie Cole

Example of whole-brain fibre-tracking results from a mouse brain. (Top-left) Surface view of the whole mouse brain. Coronal section (top-right), sagittal section (bottom-left) and horizontal section (bottom-right) of whole-brain fibre-tracking results; each section displays the tracks within a 200 µm thick slab from within the whole brain dataset. The colour-coding indicates the local fibre orientation (red: left-right, green: dorsalventral, blue: cranial-caudal). Attribution: F.Calamante et al. MRI Development group.

Animal MRI  Collaborations The Alfred Hospital, Baker IDI, Bionics Institute, CSIRO, Monash ARMI, Monash Richie Centre, Royal Victorian Eye and Ear Hospital, Royal Women’s Hospital, The University of Melbourne, MCRI

Interoception  Collaborations •

“Brainstem autonomic control” Robin McAllen, Systems Neurophysiology, The Florey

“Central pain processing in Parkinson’s Disease” Andrew Evans, Head, Movement Disorders Program, RMH, (Student – Simon Sung)

The MRI Development Group at the Florey has developed a novel approach to visualising the connecting fibres in the brain using diffusion MRI. The most commonly used approach to perform fibre tracking (diffusion tensor imaging (DTI)) has a systematic limitation that results in misleading visualisation of fibre tracts. This is due to the so-called crossing fibre problem, in which DTI cannot correctly estimate fibre orientations when there is more than one fibre in an image voxel (as is the case in >90% of brain white matter). The Florey MRI Development Group has produced a solution to this problem know as Constrained Spherical Deconvolution (CSD). This advance has many consequences in neuroscience, including in clinical neuroscience. For example, it is increasingly common practice for neurosurgeons to request images of the fibre tracts that subserve motor function in patients prior to resective neurosurgery, in order to minimise the risk of causing post-surgical loss of motor function due to damage to these tracts. In the example shown here of a 24 year old woman undergoing surgery for relief of epilepsy associated with a region of cortical dysplasia in the right posterior frontal region (lesion outlined in green), the extent of the cortico-spinal tract is underestimated using the DTI approach (blue tracks). The DTI-based tractography suggest that only the medial aspect of the lesion impinges on the corticospinal tract, whereas the CSD-based tractography results (red tracks) suggest that the lesion is enveloped by medial and lateral projections of corticospinal fibers. Attribution: S. Farquharson et al. MRI Development group.

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

IMAGING

Journal ArticleS

Animal MRI Publications 2012

63

1.

D.Raffelt, J-D.Tournier, S.Crozier, A.Connelly, O.Salvado. Reorientation of Fibre Orientation Distributions using Apodised Point Spread Functions. Magn. Reson. Med., 67, 844-855 (2012).

1.

Duncan J et al. Adolescent toluene inhalation in rats affects white matter maturation with the potential for recovery following abstinence, PLoS One. 2012;7(9):e44790.

2.

F.Calamante, J-D.Tournier, N.D.Kurniawan, Z.Yang, E.Gyengesi, G. J.Galloway, D.C.Reutens, A.Connelly. Super-resolution track-density imaging studies of mouse brain: comparison to histology. NeuroImage, 59, 286-296 (2012).

2.

Acharya DP et al. Cubic mesophase nanoparticles doped with superparamagnetic iron oxide nanoparticles: a new class of MRI contrast agent. RSC Adv., 2012, 2, 6655-6662

3.

D Raffelt, J-D Tournier, S.Rose, G.R.Ridgeway, R.Henderson, S Crozier, O Salvado, A Connelly. Apparent Fibre Density: A novel measure for the analysis of diffusion-weighted magnetic resonance images. NeuroImage, 59, 3976-3994 (2012).

3.

Lei P et al. Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export. Nature Medicine 2012;18(2):291-5

4.

F.Calamante, J-D.Tournier, R.E.Smith, A.Connelly. A generalised framework for super-resolution track-weighted imaging. NeuroImage, 59, 2494-2503 (2012).

4.

King EB, et al. Direct entry of gadolinium into the vestibule following intratympanic applications in Guinea pigs and the influence of cochlear implantation, J Assoc Res Otolaryngol. 2011;12(6):741-51.

5.

F.Calamante and A.Connelly. Comment on time-varying eddy currents effects on diffusion-weighting echo-planar imaging. NeuroImage, 59, 881-882 (2012).

5.

C. Davey et al. Filtering induces correlation in fMRI resting state data, NeuroImage, 64, 728-740, 2013

6.

Ma H, Parsons MW, Christensen S, Campbell BC, Churilov L, Connelly A, Yan B, Bladin C, Phan T, Barber AP, Read S, Hankey GJ, Markus R, Wijeratne T, Grimley R, Mahant N, Kleinig T, Sturm J, Lee A, Blacker D, Gerraty R, Krause M, Desmond PM, McBride SJ, Carey L, Howells DW, Hsu CY, Davis SM, Donnan GA. A Multicentre, Randomized, Double-Blinded, Placebo-Controlled Phase Iii Study to Investigate Extending the Time for Thrombolysis in Emergency Neurological Deficits (Extend). Int J Stroke, 7, 74-80 (2012).

6.

S. Kolbe, et al. Diffusion Tensor Imaging of the Optic Radiations after Optic Neuritis, Human Brain Mapping, 33, 2047-2061, 2012.

7.

K. Layton, et al. Performance analysis for magnetic resonance imaging with nonlinear encoding fields, IEEE Transactions on Medical Imaging, 31, 391-404, 2012.

8.

C. Davey, D.B. Grayden, G.F. Egan and L.A. Johnston, The equivalence of linear Gaussian connectivity methods, to appear Human Brain Mapping, accepted 26.12.2011.

7.

J-D.Tournier, F.Calamante, A.Connelly. MRtrix: diffusion tractography in crossing fibre regions. International Journal of Imaging Systems and Technology, 22, 53-66 (2012).

9.

C. Davey, D.B. Grayden, G.F. Egan and L.A. Johnston, Filtering induces correlation in fMRI resting state data, NeuroImage, 64, 728-740, 2013

8.

X.Liang, J-D.Tournier, R.Masterton, A.Connelly, F.Calamante. A k-space sharing 3D GRASE pseudo-continuous ASL method for whole-brain resting-state functional connectivity. International Journal of Imaging Systems and Technology, 22, 37-43 (2012).

10.

S. Kolbe, C. Bajraszewski, C. Chapman, T. Nguyen, L. Johnston, M. Kean, P. Mitchell, H. Butzkueven, M. Paine, T. Kilpatrick, G. Egan, Diffusion Tensor Imaging of the Optic Radiations after Optic Neuritis, Human Brain Mapping, 33, 2047-2061, 2012.

9.

L.Willats, A.Connelly, S.Christensen, G.A.Donnan, S.M.Davis, F.Calamante. The role of bolus delay and dispersion in predictor models for stroke. Stroke, 43, 1025-1031 (2012).

11.

K. Layton, M. Morelande, P.M. Farrell, W. Moran and L.A. Johnston, Performance analysis for magnetic resonance imaging with nonlinear encoding fields, IEEE Transactions on Medical Imaging, 31, 391-404, 2012.

10.

C.Butler, N.Kapur, A.Zeman, R.Weller, A.Connelly. Epilepsy-related long-term amnesia: Anatomical perspectives. Neuropsychologia, 50, 2973-2980 (2012).

11.

R.E.Smith, J-D.Tournier, F.Calamante, A.Connelly. Anatomically-Constrained Tractography: Improved diffusion MRI streamlines tractography through effective use of anatomical information. NeuroImage, 62, 1924-1938 (2012)

12.

G.B.Northam,F.Liegeois,J-DTournier,L. J Croft, P.N. Johns, W.K. Chong, J.S.Wyatt , T.Baldeweg. Interhemispheric temporal lobe connectivity predicts language impairment in adolescents born preterm. Brain 135: 3781-3798 (2012).

13.

X.Liang, A. Connelly, F.Calamante. Improved partial volume correction for single inversion time arterial spin labeling data. Magn. Reson. Med., 69, 531-537 (2013)

14.

R.E.Smith, J-D.Tournier, F.Calamante, A.Connelly. SIFT: Spherical-deconvolution Informed Filtering of Tractograms. NeuroImage, 67, 298-312 (2013).

15.

Interoception Publications 2012 1.

Fok, P., Farrell, M.J., McMeeken, J., Morris, M., The effect of dividing attention between walking and auxiliary tasks in people with Parkinson’s disease, Human Movement Science 31(1) (2012) 236-246

2.

McGovern, A.E., Davis-Poynter, N., Farrell, M.J., Mazzone, S.B., Transneuronal tracing of airways-related sensory circuitry using Herpes Simplex Virus 1, strain H129, Neuroscience 207 (2012) 148-66

3.

Hogg, M., Gibson, S., Helou, A., DeGabriele, J., Farrell, M., Waiting in pain: a systematic investigation into the provision of persistent pain services in Australia, Medical Journal of Australia 196(6) (2012) 386-90

A.Morgan, R.Masterton, L.Pigdon, A.Connelly, F.Liégeois. fMRI of chronic dysarthric speech after childhood brain injury: limited efficiency of a compensatory network. Brain, in press (accepted 29.10.12).

4.

Evans, A.E., Farrell, M.J., Gibson, S.J., Helme, R.D., Lim, S. Dyskinetic patients show rebound worsening of affect after acute L-dopa challenge, Parkinsonism and Related Disorders 18(5) (2012) 514-9

16.

F.Liégeois, J-D.Tournier, L.Pigdon, A.Connelly, A.T.Morgan. Corticobulbar tract changes as predictors for dysarthria in childhood brain injury. Neurology, in press (accepted 16.10.12).

5.

Farrell, M.J., Cole, L.J., Chiapoco, D., Egan, G.F., Mazzone, S.B., Neural correlates coding stimulus level and perception of capsaicin-evoked urge-to-cough in humans, Neuroimage 61(4) (2012) 1324-1335

17.

F.Calamante, R.A.J.Masterton, J-D.Tournier, R.E.Smith, L.Willats, D.Raffelt, A.Connelly. Super-resolution track-weighted functional connectivity (TW-FC): a tool for characterizing the structural-functional connections in the brain. NeuroImage, in press (accepted 23.12.12).

6.

Leech, J., Mazzone, S.B., Farrell, M.J., The effect of placebo conditioning on capsaicin-evoked urge-to-cough, Chest 142(4) (2012) 951-957

18.

S.Farquharson, J-D.Tournier, F.Calamante, G.Fabinyi, M.Schneider-Kolsky, G.D.Jackson, A.Connelly. Clinical fibre tracking: The need to move beyond diffusion tensor imaging. J Neurosurg, in press (accepted 18.9.12).

7.

Farrell, M.J., Age-related changes in the structure and function of brain regions involved in pain processing, Pain Medicine 13(s2) 2012 S37-S43

8.

19.

F.Calamante, S-H.Oh, J-D.Tournier, S-Y.Park, Y-D.Son, J-Y.Chung, J-G.Chi, G.D.Jackson, C-W.Park, Y-B.Kim, A.Connelly, and Z-H.Cho. Super-resolution trackdensity imaging of thalamic sub-structures: comparison to high-resolution anatomical MRI at 7.0T. Human Brain Mapping, published online: 14 NOV 2012 (DOI: 10.1002/hbm.22083)

Mazzone, S.B., McGovern, A.E., Yang, S., Phipps, S.2, Ando, A., Leech, L. Farrell, M.J. Sensorimotor circuitry involved in the higher brain control of coughing, Cough (in press)

9.

Farrell, M.J., Trevaks, D., Taylor, N., McAllen, R., Brain stem representation of thermal and psychogenic sweating in humans, American Journal of Physiology: Regulatory, Integrative and Comparative Physiology (in press)

10.

Smallwood, R.F., Ramage, A.E., Parkinson, A., Lewis, J., Clauw, D.J., Williams, D.A., Schmidt-Wilcke, T., Farrell, M.J., Laird, A., Eickhoff, S.B., Robin, D.A., Metaanalysis of voxel based morphometry studies of the effects of chronic pain on brain structure, Journal of Pain (in press)

20. B.Jeurissen, A.Leemans, J-D.Tournier, D. K. Jones,J.Sijbers. Investigating the prevalence of complex fiber configurations in white matter tissue with diffusion magnetic resonance imaging. Human Brain Mapping, in press (doi: 10.1002/hbm.22099).

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64

THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

mental health

MENTAL HEALTH

Neuropathology Laboratory This laboratory has been researching to understand the principle cause of neurodegeneration that occurs in Alzheimer’s disease. Recently a highlight has been our discovery of how to control the oligomeric status of amyloid beta (Aß). Amyloid beta is a 42 amino acid peptide that causes Alzheimer’s disease. Our discovery of how to modulate the self assembly of this neurotoxic peptide has allowed us to solve the first ever solution structure of oligomeric amyloid beta. This is a major advance in our understanding of Alzheimer’s disease and has provided us with a target against which to develop therapeutic compounds. The lab is feverishly screening drugs against our target that we hope will prove to be effective against the progression of Alzheimer’s disease.

DIVISION

A QUICK SNAPSHOT

RESEARCH HIGHLIGHT

The Mental Health Division conducts research to understand what causes psychiatric and neurodegenerative illness and to find better ways to diagnose, treat and ultimately cure them.

This division includes the Australian Imaging, Biomarker and Lifestyle (AIBL) study of ageing. The aim of this study is to discover which biomarkers, cognitive characteristics, and health and lifestyle factors determine subsequent development of symptomatic Alzheimer’s disease (AD), you can refer to the Clinical Discovery section for more information. This year, Professor Ashley Bush, as Chief Scientific Officer of the Cooperative Research Centre (CRC) for Mental Health, and with support from Postdoctoral Fellow, Dr Alan Rembach, the AIBL research team has identified a panel of plasma biomarkers that distinguish individuals with AD from healthy control subjects, which could prove important for AD diagnosis.

Our research groups use a variety of laboratory and clinical methods in order to achieve results that can be translated from benchtop to bedside.

As the world population ages, we know that better and earlier diagnosis for AD is an integral part of being able to treat people earlier and more effectively.

 RESEARCH OVERVIEW The Mental Health Division, led by Professor Colin Masters, undertakes high quality, basic scientific, clinical and public health research. This includes not only work our laboratories but also working with the community to run trials that help gather information about the illnesses we study. This work continues to enrich our understanding of both mental illness and neurodegenerative illness. Part of the division’s important work includes promoting the understanding of, and investment in, research through advocacy, attendance at international conferences and involvement in the community. An important role of this division is to provide expert commentary, on a scientific basis, on mental and psychiatric illness and dementia.

 The International Society for Zinc Biology conference was held in Australia for the first time. This event drew approximately 150 participants from around the globe and was a great success that spawned a number of collaborations.

SENIOR STAFF Professor Colin Masters Dr Paul Adlard, Head Professor Michael Berk Professor Ashley Bush Associate Professor Robert Cherny Professor Brian Dean Dr Kathryn Ellis Associate Professor David Finkelstein Dr Gawain McColl Associate Professor Suresh Sundram Associate Professor Maarten van den Buuse

Behavioural Neuroscience Laboratory The Behavioural Neuroscience Laboratory, headed by Associate Professor Maarten van den Buuse, uses behavioural animal models to study neuropsychopharmacological mechanisms involved in schizophrenia and depression. In rats or mice, behavioural tests are combined with specific genetic, neuropharmacological or surgical interventions. State-of-theart automated equipment is used for detailed behavioural analysis, including photocell activity meters, video-analysis, prepulse inhibition of startle and several models of learning and memory. This in-vivo work is complemented with receptor autoradiography and molecular studies on gene expression.

``Research highlights for 2012 Our recent studies are aimed at modelling gene-environment interactions in schizophrenia, focusing on the neurotrophins, brain-derived neurotrophic factor (BDNF) and reelin, the effects of young-adult stress, cannabis and methamphetamine, and the modulatory effects of sex hormones. Rats and mice heterozygous for a mutation in the BDNF or reelin genes were treated with either the stress hormone, corticosterone or chronic injection of a cannabis-like compound, or methamphetamine during young-adulthood. The effect of these ‘two hit’ treatments was assessed in adulthood in a battery of behavioural paradigms. We observed marked qualitative differences in the ‘two hit’ effects of young-adult stress, cannabis or methamphetamine. For example, against a background of reduced BDNF levels, the effects of corticosterone treatment were mostly seen in selected cognitive tasks. In contrast, the effect of a combination of BDNF deficiency and cannabis was seen mostly on affective and emotional behaviours. BDNF deficiency and methamphetamine interacted to produce altered psychosis-like behaviour and selected changes in social cognition. In all cases the effects were strikingly sex-specific and suggest a generally protective role of oestrogen or a facilitatory role of testosterone. In support of this, the adolescent/young adult developmental trajectory of BDNF signalling in different brain regions was markedly different between male and female mice and sensitive to altered circulating levels of these sex hormones. Furthermore, in animal and human studies we observed differential effects of oestrogen and testosterone in behavioural paradigms with relevance to schizophrenia. These findings may provide clues about the mechanism of new treatments to reverse or prevent the development of schizophrenia symptoms.

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Maarten van den Buuse was awarded a NHMRC Senior Research Fellowship, Level B (2013-2017) and a NHMRC Project Grant (CIA). Rachel Hill was also awarded a NHMRC Project grant as CIA.

 Collaborations •

Swinburne University of Technology, Melbourne, Australia

Department of Human Immunology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia

University of British Columbia, Vancouver, Canada

Department of Psychiatry, University of California at San Diego, San Diego, USA

Editorial positions Maarten van den Buuse Editorial Board Member: •

The International Journal of Neuropsychopharmacology (from 2011)

Psychopharmacology (from 2012)

Neuropharmacology (from 2011)

ISRN Pharmacology (from 2010)

President of the International Society for Serotonin Research after having been councillor for the past eight years.

{{Conferences 1.

32nd Annual Meeting of the Australian Neuroscience Society, Gold Coast, Australia (2012)

2. 3rd Schizophrenia International Conference, Florence, Italy (2012)

Research

Society

3. 21st Annual Meeting of the International Behavioural Neuroscience Society, Hawaii, USA (2012) 4. 2012 Serotonin Club Meeting, Montpellier, France (2012) 5. 8th FENS Forum of Neuroscience, Barcelona, Spain (2012) 6. 2012 Biological Psychiatry Australia Scientific Meeting, Melbourne, Australia (2012)

Oxidation Biology Laboratory The Oxidation Biology Laboratory is headed by Professor Ashley Bush and is dedicated to understanding the causes of Alzheimer's disease (AD), Parkinson's disease (PD) and other age-related neurodegenerative diseases, and in particular advancing the basic understanding of the interactions between cellular proteins and biologically important metals in health and disease.

``Research highlights for 2012 In addition to his position as Head of the Oxidation Biology Laboratory, Professor Ashley Bush is involved in clinical studies of predictive biomarkers for age-dependent degenerative disorders and other mental health diseases through his leadership role as Co-Director of Biomarker Development in the Australian Imaging, Biomarker and Lifestyle (AIBL) study, and as Chief Scientific Officer of the Cooperative Research Centre (CRC) for Mental Health. With support from Postdoctoral Fellow, Dr Alan Rembach, the AIBL research team has identified a panel of plasma biomarkers that distinguish individuals with AD from healthy control subjects, which could prove important for AD diagnosis.

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

mental health

The CRC study is also providing valuable information towards early detection and clinical monitoring of diseases such as AD, PD, and schizophrenia.

The Scientific World Journal (2009-2013)

National Grants

Neurotherapeutics (2010-2013)

Postdoctoral Fellow, Dr Gawain McColl established a new laboratory to explore ageing and age-dependent diseases, including AD, using worms (C.elegans) to model these processes. In 2012, he published the first quantitative 3D visualisation of biological metals in a whole animal. In addition, his laboratory published a new C elegans transgenic model developed for use in drug screens to rapidly identify, and assist in the development of, potential therapeutics for AD.

Current Psychopharmacology (2011-2013)

NHMRC “Identifying the mechanisms of action of a novel 8-hydroxy quinazolinone in models of Parkinson's disease”

Senior Editor:

Dr McColl was successful in obtaining a 2012 ARC Discovery Grant and a NHMRC Project Grant. This work focuses on understanding ageing, how it impacts on diseases such as AD, and how we can counter these effects with new therapeutics. Postdoctoral Fellow, Dr Ya Hui Hung, together with Professor Bush and Associate Professor Tony White, were successful in obtaining funding from Perpetual Trustees (Harry Secombe and Payne Foundations) to continue their research into lysosomal storage disorders such as Niemann-Pick type C disease, Batten disease and AD. This research aims to target zinc as a new approach to develop a novel therapy for these disorders, and to evaluate zinc manoeuvring drugs such as PBT2 for their potential to improve lifespan, motor and cognitive performance, metal balance and lysosomal function. A highlight for Peng Lei, in the final year of his PhD candidature, was the publication of a ground-breaking paper in the prestigious journal ‘Nature Medicine’. It reported that the loss of a protein (namely ‘tau’) may contribute to toxic iron accumulation in the brain cells of patients with AD and PD, and that this may be rescued pharmacologically. Peng was awarded an Epsilon Postdoctoral Fellowship in Dementia as well as a NHMRC Early Career Fellowship.

Journal of Alzheimer's Disease (2011-2013)

Editorial Advisory Board Member: •

Current Alzheimer Research (2013- )

James Duce Editorial Board Member: PLoS ONE (2010-2013)

{{Conferences 1.

17th University of Melbourne Symposium for the Academic Unit of the Psychiatry of Old Age, Melbourne, Australia (24 Feb, 2012)

2. 4th Scientific Symposium on Niemann-Pick Type C: The Expanding Universe of NP-C, Athens, Greece (24-25 March, 2012) 3. Alzheimer's Research UK Conference 2012, Birmingham, UK (27-28 Mar, 2012) 4. 2nd International Conference on The Science of Nutrition in Medicine and Healthcare, Melbourne, Australia (4-6 May, 2012) 5. Genetics Society of AustralAsia, Melbourne, Australia (15-18 July, 2012) 6. Neurobiology of Brain Disorders: Synaptic Dysfunction and Neurodegeneration, Boston USA (5-10 Aug, 2012) 7. Neurodegeneration Conference 2012, Cancun, Mexico (27 Nov - 1 Dec, 2012) 8. Free Radical and Metal Biology 2012, Brisbane QLD, Australia (28 Nov – 2012)

 Collaborations

Synaptic Neurobiology Laboratory

The Laboratory, headed by Associate Professor Paul Adlard and Associate Professor David Finkelstein, focuses on understanding the role of metals in both normal and pathological aging, with a specific focus on understanding the basic cellular requirements for normal learning and memory. These studies will help provide direction for future drug therapy into conditions such as Alzheimer’s disease (AD) and normal age-related cognitive decline.

Department of Genetics, The University of Melbourne, University of Tasmania, University of Technology, Sydney, Materials Engineering, Monash University, Illawarra Health and Medical Research Institute, University of Wollongong, Synchrotron Division, CSIRO, XFM beam line team, Australian Synchrotron. Melbourne Neuroscience Institute, The University of Melbourne, University of Western Australia, Centre for Cellular and Molecular Biology, School of Biological and Chemical Sciences, Deakin University, The Alfred, Melbourne, Materials Engineering, Monash University, Department of Biochemistry and Molecular Biology, Monash University, School of Chemistry and Physics, University of Adelaide

``Research highlights for 2012

Ashley Bush

Associate Professor Adlard successfully organised and helped to host the International Society for Zinc Biology conference, which was held in Australia for the first time. This event drew approximately 150 participants from around the globe and was a great success that spawned a number of collaborations. Associate Professor Adlard was also awarded an ARC Future Fellowship and had a number of publications accepted in high ranking journals in the field.

Editorial Board Member:

International Grants

Michael J Fox and Shake it Up Australia “Alpha synuclein and iron in Parkinson’s Disease”

United States, United Kingdom, Chile, Taiwan, Republic of Korea, Japan, Spain, Hungary, Israel

Editorial positions

Journal of Biological Chemistry (2003-2013)

Drug Design Reviews (2003-2013)

PLoS ONE (2007-2013)

International Journal of Alzheimer’s Disease (2009-2013)

Parkinson’s United Kingdom “Mechanism of new drugs to prevent degeneration in models of Parkinson’s”

NHMRC “Iron export protein failure in parkinsonism and dementia” 2012 Publications in high impact scientific journals including: Nature Medicine, Annals of Neurology, Journal of Experimental Medicine Total citations to published literature = 3005; h-index 32

 Collaborations UK, Spain, USA, Japan, Finland.

Editorial positions Paul Adlard •

PLoS One (2009- )

Frontiers in Aging Neuroscience (2012- )

Journal of Neurodegenerative Diseases (2012- )

Current Gerontology and Geriatrics Research (2011-2012)

Journal of Alzheimer's Disease (2012)

{{Conferences 1.

Society for Neuroscience, New Orleans, USA (2012)

2. Australian Neuroscience Society, Gold Coast, Australia (2012)

Molecular Psychopharmacology Laboratory / Northern Psychiatry Research Centre The Molecular Psychopharmacology Laboratory, led by Associate Professor Suresh Sundram is dedicated to understanding the molecular pathology of psychotic disorders such as schizophrenia, bipolar disorder and major depression. In achieving this, we aim to develop better and more effective markers and interventions for these illnesses. We investigate how psychotropic medications and drugs interact with receptors and intracellular signalling mechanisms in nerve cells (neurons) and then examine these systems in psychotic disorders. 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.

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We have been continuing to investigate our novel findings about the involvement of a growth factor signalling system in the brain, the epidermal growth factor (EGF) system, in the pathology of psychotic disorders. Avril Pereira and her team have carried on with their work investigating which proteins are activated in the brain consequent to clozapine treatment, in collaboration with Peter Crouch and David Bowser from The University of Melbourne, this work was also funded by a NHMRC Project Grant (commenced in 2010). Vaidy Swaminathan, in collaboration with Cyndi ShannonWeickert from University of New South Wales, is looking at how these genes and proteins of the EGF system may be disturbed in the brains of people with schizophrenia. These data were presented at the World Congress of Neuropsychopharmacology (CINP) in Stockholm in mid-2012 and showed that receptor for EGF was increased in the frontal brain region of people with schizophrenia. In addition there were differences between those people who had a history of suicidal behaviour compared to those without suggesting that the EGF system may be involved in mediating these behaviours as well. In parallel with the laboratory-based aspects of the project, Sujeevan Sinnatamby and the NPRC, in collaboration with Michael Berk and Seetal Dodd from Deakin University, have been collecting clinical data and biological samples from people who are receiving treatment with clozapine. In conjunction with our McIver Family Trust Fellow, Dr Rejhan Idrizi and the CRC for Psychosis, the NPRC samples were measured for EGF system markers. We found that two markers, EGF and betacellulin were lower in people with schizophrenia and that these levels changed with clozapine treatment. We are currently determining whether specific genetic variants and these markers can predict response to clozapine treatment. Biological samples are being collected with the help of funding from the Marian and EH Flack Trust. The aim of this type of screening test is to help prevent unnecessary exposure to the toxic effects of clozapine for many people, and streamline potential responders to earlier and more effective intervention. This work will enable us to understand the pathology of schizophrenia and hopefully develop more effective interventions. Our preliminary data have demonstrated results strongly supporting our hypothesis that the EGF system correlates with symptoms in people with treatment-resistant schizophrenia treated with clozapine. Sensory integration in schizophrenia

We are continuing our work to reveal how antipsychotic drugs work; these are the mainstay of treatment for psychotic disorders including schizophrenia, bipolar disorder and major depression. Although these agents have been in use for over 50 years there is still a lot to learn about how they work.

With the continued collaboration of Olivia Carter and students from The University of Melbourne, the group is examining sensory deficits in schizophrenia. Previous research showed that healthy individuals are both accurate and fast when it comes to integrating visual information in different areas of visual space. In contrast, people with schizophrenia tend to be selectively impaired on tasks that assess visual integration. This study has demonstrated that integration of sensory information is affected across a number of psychotic disorders and shows some correlation with psychotic symptoms such as delusions and hallucinations.

In particular, we continue research into why one antipsychotic drug, clozapine, is effective in people for whom other antipsychotic drugs are not. From this we hope to gain insight into the pathology of psychotic disorders and more effective ways of treating them.

Most intriguingly, in collaboration with Dr Ken McAnally from Defence Science and Technology Organisation (DSTO), we have shown that these changes also occur in audition. Such findings will inform us about the changes in brain function with reference to specific symptoms across the range of psychotic disorders.

``Research highlights for 2012

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68

THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

mental health

A Special Thank You The generous and ongoing support of One in Five continues to make much of our research possible. The One in Five group was formed by the friends and family of Mathew Wardlaw who lost his battle with mental illness on New Year’s Eve 2001. An entirely voluntary group and now formally established as an organisation they provide much needed funds for our work. Staff achievements Suresh Sundram continues to serve as Deputy Editor for the Asian Journal of Psychiatry and was invited onto the Scientific Committees of the Australasian Schizophrenia Conference and the World Psychiatric Association Human Factors in Crisis and Disasters Thematic Conference and was an invited keynote speaker at the Asian Congress of Schizophrenia Research and Australasian Schizophrenia Conference.

{{Conferences and presentations 1.

IndoGlobal Psychiatry Initiative Annual Meeting, Kochi, India (January 2012)

2. Royal Australian and New Zealand College of Psychiatrists Annual Meeting, Hobart, Australia (May 2012) 3. World Congress of Neuropsychopharmacology, Stockholm, Sweden (June 2012) 4. Biological Psychiatry Australia Meeting, Melbourne, Australia (October 2012)

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PUBLICATIONS 1.

Bellingham SA, Coleman BM and Hill AF, Small RNA deep sequencing reveals a distinct miRNA signature released in exosomes from prion-infected neuronal cells, Nucleic Acids Res, 2012, PMID: 22965126

2.

Berk M, Is Australian psychiatry getting SHIP shape?, Aust N Z J Psychiatry, 46:801-2,2012, PMID: 22956564

3.

Darby DG, Master CL and Grady MF, Computerized neurocognitive testing in the medical evaluation of sports concussion, Pediatr Ann, 41:371-6,2012, PMID: 22953983

4.

Doecke JD, Laws SM, Faux NG, Wilson W, Burnham SC, Lam CP, Mondal A, Bedo J, Bush AI, Brown B, De Ruyck K, Ellis KA, Fowler C, Gupta VB, Head R, Macaulay SL, Pertile K, Rowe CC, Rembach A, Rodrigues M, Rumble R, Szoeke C, Taddei K, Taddei T, Trounson B, Ames D, Masters CL and Martins RN, Bloodbased protein biomarkers for diagnosis of Alzheimer disease, Arch Neurol, 69:1318-25,2012, PMID: 22801742

5.

Gogos A, Kwek P and van den Buuse M, The role of estrogen and testosterone in female rats in behavioral models of relevance to schizophrenia, Psychopharmacology (Berl), 219:213-24,2012, PMID: 21800043

6.

Greenough MA, Camakaris J and Bush AI, Metal dyshomeostasis and oxidative stress in Alzheimer's disease, Neurochem Int, 2012, PMID: 22982299

7.

Gururajan A, Comment on: "Anxiogenic-like effects of chronic cannabidiol administration in rats" (Elbatsh MM, Assareh N, Marsden CA, Kendall DA, Psychopharmacology 2012), Psychopharmacology (Berl), 222:725-6,2012, PMID: 22760485

8.

Hammers D, Spurgeon E, Ryan K, Persad C, Barbas N, Heidebrink J, Darby D and Giordani B, Validity of a brief computerized cognitive screening test in dementia, J Geriatr Psychiatry Neurol, 25:89-99,2012, PMID: 22689701

9.

Klug M and van den Buuse M, Chronic cannabinoid treatment during young adulthood induces sex-specific behavioural deficits in maternally separated rats, Behav Brain Res, 233:305-13,2012, PMID: 22610052

10.

Kwek P and van den Buuse M, Modafinil disrupts prepulse inhibition in mice: Strain differences and involvement of dopaminergic and serotonergic activation, Eur J Pharmacol, 699:132-140,2012, PMID: 23219987

11.

Lim YY, Ellis KA, Ames D, Darby D, Harrington K, Martins RN, Masters CL, Rowe C, Savage G, Szoeke C, Villemagne VL and Maruff P, Abeta amyloid, cognition, and APOE genotype in healthy older adults, Alzheimers Dement, 2012, PMID: 23159043

12.

Lim YY, Ellis KA, Harrington K, Ames D, Martins RN, Masters CL, Rowe C, Savage G, Szoeke C, Darby D, Maruff P and The Aibl Research G, Use of the CogState Brief Battery in the assessment of Alzheimer's disease related cognitive impairment in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study, J Clin Exp Neuropsychol, 34:345-58,2012, PMID: 22248010

13.

Lim YY, Ellis KA, Harrington K, Pietrzak RH, Gale J, Ames D, Bush AI, Darby D, Martins RN, Masters CL, Rowe CC, Savage G, Szoeke C, Villemagne VL and Maruff P, Cognitive Decline in Adults with Amnestic Mild Cognitive Impairment and High Amyloid-beta: Prodromal Alzheimer's Disease?, J Alzheimers Dis, 2012, PMID: 23160011

14.

Lim YY, Ellis KA, Pietrzak RH, Ames D, Darby D, Harrington K, Martins RN, Masters CL, Rowe C, Savage G, Szoeke C, Villemagne VL and Maruff P, Stronger effect of amyloid load than APOE genotype on cognitive decline in healthy older adults, Neurology, 79:1645-1652,2012, PMID: 23071163

15.

Lim YY, Pietrzak RH, Ellis KA, Jaeger J, Harrington K, Ashwood T, Szoeke C, Martins RN, Bush AI, Masters CL, Rowe CC, Villemagne VL, Ames D, Darby D and Maruff P, Rapid Decline in Episodic Memory in Healthy Older Adults with High Amyloid-beta, J Alzheimers Dis, 2012, PMID: 23001710

16.

Moriarity JM, Pietrzak RH, Kutcher JS, Clausen MH, McAward K and Darby DG, Unrecognised ringside concussive injury in amateur boxers, Br J Sports Med, 46:1011-5,2012, PMID: 22547563

17.

Morris JC, Aisen PS, Bateman RJ, Benzinger TL, Cairns NJ, Fagan AM, Ghetti B, Goate AM, Holtzman DM, Klunk WE, McDade E, Marcus DS, Martins RN, Masters CL, Mayeux R, Oliver A, Quaid K, Ringman JM, Rossor MN, Salloway S, Schofield PR, Selsor NJ, Sperling RA, Weiner MW, Xiong C, Moulder KL and Buckles VD, Developing an international network for Alzheimer research: The Dominantly Inherited Alzheimer Network, Clin Investig (Lond), 2:975-984,2012, PMID: 23139856

18.

Pietrzak RH, Maruff P, Woodward M, Fredrickson J, Fredrickson A, Krystal JH, Southwick SM and Darby D, Mild worry symptoms predict decline in learning and memory in healthy older adults: a 2-year prospective cohort study, Am J Geriatr Psychiatry, 20:266-75,2012, PMID: 22354117

19.

Prakash A and Kumar A, Mitoprotective effect of Centella asiatica against aluminum-induced neurotoxicity in rats: possible relevance to its anti-oxidant and anti-apoptosis mechanism, Neurol Sci, 2012, PMID: 23224641

20. Rembach A, Doecke JD, Roberts BR, Watt AD, Faux NG, Volitakis I, Pertile KK, Rumble RL, Trounson BO, Fowler CJ, Wilson W, Ellis KA, Martins RN, Rowe CC, Villemagne VL, Ames D, Masters CL and Bush AI, Longitudinal Analysis of Serum Copper and Ceruloplasmin in Alzheimer's Disease, J Alzheimers Dis, 2012, PMID: 23168449 21.

Scarr E and Dean B, Altered neuronal markers following treatment with mood stabilizer and antipsychotic drugs indicate an increased likelihood of neurotransmitter release, Clin Psychopharmacol Neurosci, 10:25-33,2012, PMID: 23429852

22. Sona A, Zhang P, Ames D, Bush AI, Lautenschlager NT, Martins RN, Masters CL, Rowe CC, Szoeke C, Taddei K and Ellis KA, Predictors of rapid cognitive decline in Alzheimer's disease: results from the Australian imaging, biomarkers and lifestyle (AIBL) study of ageing, Int Psychogeriatr, 24:197-204,2012, PMID: 21749739 23. Villemagne VL, Okamura N, Pejoska S, Drago J, Mulligan RS, Chetelat G, O'Keefe G, Jones G, Kung HF, Pontecorvo M, Masters CL, Skovronsky DM and Rowe CC, Differential diagnosis in Alzheimer's disease and dementia with Lewy bodies via VMAT2 and amyloid imaging, Neuro-degenerative diseases, 10:161-5,2012, PMID: 22261520 24. Wu YW, Hill RA, Gogos A and van den Buuse M, Sex differences and the role of estrogen in animal models of schizophrenia: interaction with BDNF, Neuroscience, 2012, PMID: 23085218

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

Mental illness: the push to find some answers

Mental illness: the push to find some answers ;

The Florey is committed to improving the lives of the one in five Australian adults affected by mental illness

Mental illness

Substance use disorders

Some 3.2 million Australians each year live with a mental health difficulty.

5.1 %

45%

Three per cent will be seriously affected

About 45 per cent of Australian adults will be affected by mental illness at some time in life

Recent data suggests 1.4 million or 38 per cent of people with a mental disorder had two or more disorders

Substance use disorders, involving harmful use of, or dependency on, alcohol or other drugs affect 5.1 per cent of people aged 16-85 years

Substance use disorders are more common in men than in women and most prevalent in men aged 16-24 years (13 per cent)

Depression and anxiety disorders are the most common mental illnesses

15%

Women are more likely than men to have had symptoms. A higher rate of anxiety disorders among women is responsible for the higher figure.

26%

Around 26 per cent of adults are affected by anxiety disorders at some point in their life.

Around three per cent of adults are severely affected by mental illness. The more disabling mental illnesses include: this disorder affects approximately one per cent of Australians at some point in their lives.

Other forms of psychosis

3%

for example, drug-induced psychosis.

The cost

   

$20 Billion The annual cost of mental illness in Australia has been estimated at $20 billion, which includes the cost of lost productivity and labour force participation.

severely affected by mental illness

Schizophrenia

$ Up to one in ten people affected by mental illness commit suicide, compared to an average of one in a hundred for the whole population.

Depression and anxiety disorders

Around 15 per cent of adults are affected by depression at some point in their life.

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Some chronic forms of depression

Cannabis use may double the risk of schizophrenia development in vulnerable individuals.

 Mental disorders are identified as the leading cause of healthy years of life lost due to disability.

Bipolar disorder

this condition affects up to two per cent of Australians at some time during their lives.

Source: 2007 National Survey of Mental Health and Wellbeing

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

Do illicit drugs cause psychosis?

do illicit drugs cause psychosis?

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Fast facts on mental illness ;

;

Among the many studies into mental illness taking place at the Florey is one involving a link between drug abuse and psychosis.

Associate Professor Maarten van den Buuse studies the link between drug abuse and psychosis. Recently, members of his team published a review in the Australian and New Zealand Journal of Psychiatry. It investigated the available research findings on the link between drug abuse (particularly cannabis and methamphetamine) and psychosis development. “Our overview showed increasing evidence that illicit drugs play a causal role in at least some individuals with psychosis and/or schizophrenia,” Maarten said.

The review also highlights the complex and often conflicting nature of the evidence. For instance, the incidence or prevalence of psychosis has remained stable over the last two decades, despite significant increases in use of cannabis and stimulants. Nevertheless, multiple largecohort studies have found that drug use remains a risk factor for psychosis, supporting a link between drugs and psychosis which may involve both direct causative effects and shared vulnerabilities.

“Firstly, animal studies demonstrating the effects of cannabis or stimulant administration show that these effects are greatest when exposure to drugs occurs during critical developmental stages,” Maarten says. “There is also a ‘dose effect’, where a greater quantity of drug use is associated with more psychotic symptoms in experimental and clinical studies with recreational drug users.”

Associate Professor Maarten vn den Buuse is an NHMRC senior research fellow in behavioural neuroscience

Among other findings, research also demonstrates that cannabis use may double the risk of schizophrenia development in vulnerable individuals – in fact, it has been estimated that from seven per cent to 25 per cent of incident cases of schizophrenia may be attributable to cannabis.”

The relationship between stimulants and psychosis is probably at least as strong as that for cannabis. Amphetamines’ effects are linked to dopamine in the brain, and unlike many other drugs, these effects sensitize rather than habituate with repeated use. However, because of their less frequent use and almost universal overlap with cannabis and other substances, they have been less systematically studied, underlining the particular need for further research on stimulants.

In short, cannabis and stimulants do appear to play a causal role in psychosis. Evidence about the impact of drug use on psychosis is relevant to current debates on drug policy, and this review may help to inform some of the difficult trade-offs inherent in any position on this complex problem.

         Nearly half Australia's adult population will experience mental illness – including depression, bipolar disorder, anxiety disorder or alcohol or drug abuse – at some point in their lives, according to the National Mental Health Commission.

7.3 million It estimates that 7.3 million Australians aged 16 to 85 have already suffered mental illness, and 3.2 million will experience it in any year.

  Nearly one million Australians are using Medicare-subsidised counselling with a psychologist, psychiatrist or social worker each year.

☀ The number of patients in therapy is growing by 20 per cent annually – 10 times faster than the number on anti-depressant and anti-anxiety drugs.

$

Mood disorders, dementia, psychotic disorders, anxiety disorders and addiction account for a huge proportion of health costs because they are common, chronic and debilitating.

People with a mental illness die, on average, 25 years earlier than the general population with a staggering 70 per cent of deaths caused by cardiovascular disease.

$

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

Multiple sclerosis

Multiple sclerosis

Oligodendrocyte biology and neuronal-glial interactions 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.

DIVISION

``RESEARCH HIGHLIGHTS

A QUICK SNAPSHOT Multiple Sclerosis is the commonest neurodegenerative disease affecting young adults in our community. It is a complex disease involving disrupted interactions between the immune and nervous systems; one which results in the demyelination of neurons.

Our work has provided novel and important insights into how to promote nervous system repair, in particular remyelination.

 RESEARCH OVERVIEW 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 elusive. The MS division, which spans the Florey, University of Melbourne and Royal Melbourne Hospital is adopting a multifaceted approach to researching the disease. Our approach recognises that we need to understand the genetic determinants, environmental precipitants and molecular drivers of the disease if we are to prevent or reduce damage. We also recognise that it is essential to establish novel approaches to enhance nervous system repair if we are to reduce the disability of those with extant disease. With these aims in mind, we have developed strong collaborations with colleagues throughout Australia in order to assemble large cohorts of patients to interrogate the genetics and epidemiology of the disease and to access biological samples in order to adopt a fully integrated translational approach. These research projects have been highly productive, identifying novel susceptibility-genes, environmental risk factors and biological markers of disease severity. In addition, our laboratory work, detailed in this report, has provided novel and important insights into how to promote nervous system repair, in particular remyelination; an understanding that has been assisted via our research that has focussed on how myelinating cells behave during both development and in the healthy adult as well as in disease. Our work has also provided novel insights into how the immune cells in the brain interact with the myelinating cells during disease, thereby identifying approaches that have therapeutic potential.

RESEARCH HIGHLIGHT A major highlight of our work in 2012 is the identification that oligodendrocyte dysfunction in the absence of demyelination can rapidly generate axonal pathology and neurological deficits. This surprising result raises important issues that we are currently interrogating concerning the nature of the interactions between oligodendrocytes and neurons. In particular, we are assessing whether the observed deficits consequent to oligodendrocyte dysfunction arise due to deficits in energy transport and whether these deficits can be overcome by the provision of key energy metabolites. Such approaches may have profound implications for the treatment of diseases such as multiple sclerosis.

 SENIOR STAFF Professor Trevor Kilpatrick Dr Holly Cate Dr Simon Murray Dr Toby Merson Dr Ben Emery Dr Junhua Xiao Dr Judith Field Dr Michele Binder

In 2012 the Merson Laboratory published an important discovery concerning the function of oligodendrocytes in the brain. By genetically modifying mice we developed an approach to specifically deplete oligodendrocytes from the brain in a highly specific and targeted manner. This research has provided us with a fundamental new understanding of how oligodendrocytes interact with and support the function of nerve cells. Our research paper entitled “Targeted Ablation of Oligodendrocytes Induces Axonal Pathology Independent of Overt Demyelination” was published in the Journal of Neuroscience and has already had a significant impact in the field and for our understanding of the biology of Multiple Sclerosis. Work undertaken by final year PhD student Jo Stratton has also highlighted the role of Schwann cells in the maintenance of neuronal function in the peripheral nervous system. Using a genetic approach for depleting Schwann cells from the peripheral nerves Jo’s research has important implications for understanding disease course in peripheral neuropathies. Research by PhD student Lulu Xing investigating how oligodendrocytes are regenerated in the brain after injury has revealed that a particular type of brain stem cell plays a very important and previously unappreciated role in oligodendrocyte regeneration. Finally, research conducted by PhD student Philipp Röth is focusing on a detailed analysis of oligodendrocyte organisation in the brain. The study has provided fascinating new insights into the cellular processes responsible for establishing the unique topography of oligodendrocytes in white matter and how these processes facilitate the coordination of myelination during development and remyelination. The work has important implications for understanding how specific patterns of myelination restore neuronal function after injury and contribute to brain plasticity in adult life.

Myelin development and its application to demyelinating disease 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 In 2012, the Emery laboratory has shown that Myrf is essential for the maintenance of healthy myelin in the adult central nervous system. This has important implications for our understanding of myelin; although it is typically viewed as being an inert structure in the adult brain, these findings indicate it is subject to turnover and requires ongoing support. The team has also

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recently found that the Myrf gene encodes a novel example of a transmembrane transcription factor that directly coordinates a pro-myelination program. Current research focuses on trying to understand how to stimulate the expression and activity of Myrf to promote myelin repair in human diseases.

Promoting oligodendrogliogenesis to enhance myelin repair The Cate Laboratory aims to clarify the importance of BMP signaling in modulating the differentiation of oligodendrocyte precursor cells present within and surrounding myelin lesions and in modulating their potential for differentiation and remyelination in the context of demyelinating disease.

``Research highlights Augmenting regeneration of oligodendrocytes by enhancing differentiation of resident oligodendrocyte precursor cells is a promising therapeutic strategy for demyelinating diseases such as MS. Holly Cate and her staff have identified that BMP signalling is increased in demyelinated lesions in mice. The laboratory has also determined that increases in BMP signalling can transiently increase the population of myelin precursor cells. Furthermore, the laboratory has identified that inhibiting BMP signalling during demyelination can increase myelin repair. These results suggest that time specific modulation of BMP signalling could be utilized to enhance the population of cells needed for myelin repair and could ultimately increase remyelination of demyelinated lesions. The team is further investigating these processes in vitro and in vivo. Along these lines, we have most recently begun investigations to determine whether modulation of the BMP receptor, BMPRIa, enhances OPC differentiation and remyelination, and hence, whether it represents a bona fide therapeutic target. In addition, through collaboration, we have established the presence of BMP signaling within oligodendroglia in human MS lesions. This is an important precursor to undertaking translational research in this area. Our ultimate aim is for this work to provide important information concerning molecular mechanisms within oligodendrocyte precursor cells that could be targeted for therapeutic benefit in the treatment of MS.

Promoting remyelination The Murray and Xiao Laboratories aim to identify molecules and strategies that can be applied to promote repair in both MS and of other demyelinating diseases.

``Research highlights In 2012, our work continues to identify the molecular mechanisms that the neurotrophin BDNF utilises to regulate both central and peripheral nervous system myelination during development, and remyelination following a demyelinating insult. In collaboration with Associate Professor Tony Hughes of the Department of Pharmacology at the University of Melbourne, we have adopted a structure-based drug design approach that has yielded several classes of BDNF mimetics. One of these mimetics has proven to be extremely effective in promoting peripheral nervous system myelination both in vitro and in vivo. We are currently investigating the influence that this peptide exerts upon an in vivo model of peripheral demyelinating neuropathy.

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

Our work on central nervous system myelination has yielded substantial novel insights into the influence that BDNF and its receptor TrkB exert. This was the thesis topic of PhD candidate Agnes Wong. The results of Agnes’ work have prompted investigation into novel BDNF-based strategies for the treatment of CNS demyelinating diseases such as MS. We have also begun to dissect the molecular targets of BDNF signalling that regulate myelin formation at the transcriptional level.

Understanding immune-oligodendrocyte interactions We have identified an important set of receptors that is expressed on both the immune cells and oligodendrocytes in the brain and which influence the severity of demyelinating disease. Michele Binder and Judith Field are leading a team that is exploring how these receptors (the TAM family) and their ligands influence cellular behaviour in order to exert these influences.

``Research highlights Our recent research in this area has identified that animals deficient in one of the TAM ligands (Gas6) exhibit worse disease when immune attack of the nervous system is induced. We are currently exploring how this occurs and in particular whether TAMs exert their beneficial effects by influencing immune cell activation in the periphery or alternatively, within the central nervous system. We are also exploring strategies that involve activation of the TAM receptors to determine whether this might be a viable strategy to limit disease severity.

The genetic predisposition to MS Dr Judith Field and colleagues are focusing 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.

``Research highlights 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. The consequences of the genetic changes that have been shown to lead to increased risk of developing MS are also being investigated in immune cell subtypes isolated from people with MS and healthy volunteers, and has allowed us to identify gene expression and protein expression changes that provide us with excellent candidates for further investigation including as potential therapeutic targets.

Multiple sclerosis

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Conference presentations 1.

Ferner AH., Xiao J., Peckham H., Wong AW., Guiffrida L., Kilpatrick TJ, Murray SS. The intracellular signalling pathways that regulates oligodendrocyte myelination. Poster presentation, Australia Neuroscience Society Annual Meeting, Gold Coast, Australia, February 2012

2.

Fisher B.D., Sabo J.K., Merlo D., Kilpatrick T.J., Cate H.S. (2012) BMP signaling is increased in oligodendrocytes in chronic demyelinated lesions. Australian Neuroscience Society, Gold Coast, Australia.

3.

Homman-Ludiye J, Merson TD and Bourne JA. Do multipotent neural progenitor cells remain in the maturing primate neocortex? 32nd Annual Meeting of the Australian Neuroscience Society, Feb 2-6, 2012; Gold Coast, Australia.

4.

Merson TD. Establishing and maintaining oligodendrocyte topography in CNS white matter in health and disease. Symposium presentation. 32nd Annual Meeting of the Australian Neuroscience Society, Feb 2-6, 2012; Gold Coast, Australia.

5.

Stratton JAS, Kilpatrick TJ and Merson TD. Rapid functional recovery following Schwann cell apoptosis. 32nd Annual Meeting of the Australian Neuroscience Society, Feb 2-6, 2012; Gold Coast, Australia.

6.

Sabo J.K., Aumann T.D., Merlo D, Kilpatrick T.J., Cate H.S. (2012) Exogenous growth factor delivery to the demyelinated mouse brain modulates numbers of oligodendrocytes during remyelination. Australian Neuroscience Society, Gold Coast, Australia.

7.

Wong AW., Xiao J., Kemper D., Kilpatrick TJ, Murray SS. BDNF promotes CNS myelination in vivo via oligodendroglial TrkB receptors. Poster presentation, Australia Neuroscience Society Annual Meeting, Gold Coast, Australia, February 2012.

8.

Xing YL, Kilpatrick TJ and Merson TD. Minocycline treatment attenuates axonal pathology and motor deficits in a mouse model of inducible oligodendrocyte apoptosis. 32nd Annual Meeting of the Australian Neuroscience Society, Feb 2-6, 2012; Gold Coast, Australia

9.

Göttle P., Sabo J.K., Torres K., Heinen A, Tzekova N., Kremer D., Hartung H-P., Cate H.S., Küry P. (2012) Nucleocytoplasmic translocation of p57kip2 promotes oligodendroglial differentiation. Gordon Research Conference – Myelin, Lucca, Italy.

10.

Stratton JAS, Oluich LJ, Xing YL, Ng SW, Kilpatrick TJ and Merson TD. Targeted ablation of myelinating glia: structural and functional consequences for neuroglial interactions in the central and peripheral nervous systems. Gordon Research Conference on Biology and Pathobiology of Myelinating Glia, April 29 - May 4, 2012; Lucca, Italy.

11.

Wong AW., Xiao J., Kemper D., Kilpatrick TJ, Murray SS. Oligodendroglial TrkB is required for normal CNS myelin development. Poster presentation, Myelin Gordon Research Conference, Lucca, Italy, April 2012.

12.

Xiao J., Ferner AH., Wong AW., Guiffrida L., Kilpatrick TJ, Murray SS. Dissecting the role of Erk2 signalling in oligodendrocyte that regulates CNS myelination. Poster presentation, Myelin Gordon Research Conference, Lucca, Italy, April 2012.

13.

J. Field, L.J. Johnson, H. Butzkueven, T.J. Kilpatrick, Australia and New Zealand Multiple Sclerosis Genetics Consortium “Analysis of genotype–dependent CD40 expression in Multiple Sclerosis”. The 8th International Congress on Autoimmunity. Granada, Spain. May 9 -13, 2012. (Poster)

14.

G.Z.M. Ma, J. Stankovich, M. Gresle, G. Foo, L. Louise, M. Jordan, A. Baxter, J. Charlesworth, L. Johnson, H. Butzkueven, T.J. Kilpatrick, J. Field, M.D. Binder, The Australia and New Zealand Multiple Sclerosis Genetics Consortium (ANZgene). A multiple sclerosis-associated single nucleotide polymorphism in the MERTK receptor is correlated with altered MERTK expression. The 8th International Congress on Autoimmunity. Granada, Spain. May 9 -13, 2012.

15.

J. Field, M. Jordan, L. J. Johnson, L. Laverick, M. Gresle, G. Foo, J. Charlesworth, J. Stankovich, A. Baxter, H. Butzkueven. “Gene expression in immune cell subsets – A Risk Gene Study for Multiple Sclerosis.” The 8th International Congress on Autoimmunity. Granada, Spain. May 9 -13, 2012.

16.

Fielding, J., Kolbe, S., Kilpatrick, T., White, O., Clough, M., Egan, G. (2012). Brain imaging correlates of ocular motor dysfunction in MS. [17th Annual Conference on RIMS: Hamburg, Germany, May 31 Jun 02, 2012]. Multiple Sclerosis Journal, 18(5), 703 703.

17.

Gresle, M. M., Alexandrou, E., Wang, B., Egan, G., Ayres, M., Jokubaitis, V., Jonas, A., Friedhuber, A. M., Doherty, W., Achuthan, A., Shaw, G., Vacher, J., Sendtner, M., Kilpatrick, T. J., Butzkueven, H. (2012). Endogenous leukaemia inhibitory factor signalling reduces axonal damage in mice with EAE. [17th Annual Conference on RIMS: Hamburg, Germany, May 31 Jun 02, 2012]. Multiple Sclerosis Journal, 18(5), 692.

18.

Jonas, A. K., Gresle, M. M., Wagener, R., Aszodi, A., Kuhlmann, T., Kilpatrick, T. J., Butzkueven, H. (2012). Matrilin 2 expression is up regulated in murine Experimental Autoimmune Encephalomyelitis (EAE) and human Multiple Sclerosis lesions. [17th Annual Conference on RIMS: Hamburg, Germany, May 31 Jun 02, 2012]. Multiple Sclerosis Journal, 18(5), 698.

19.

Ma, G. Z. M., Stankovich, J., Kilpatrick, T. J., Binder, M. D., Field, J., & Australia New Zealand Multiple, S. (2012). Polymorphisms in the receptor tyrosine kinase MERTK gene are associated with multiple sclerosis susceptibility. [17th Annual Conference on RIMS: Hamburg, Germany, May 31 Jun 02, 2012].Multiple Sclerosis Journal, 18(5), 702.

20. Van der Walt, A., Kolbe, S., Wang, E., Shuey, N., Ahmadi, G., Marriott, M., Paine, M., Tsonis, S., Mitchell, P., Klistorner, A., Egan, G., Butzkueven, H., Kilpatrick, T. (2012). Baseline axial diffusivity predicts poor visual recovery at 6 months after acute optic neuritis. [17th Annual Conference on RIMS: Hamburg, Germany, May 31 Jun 02, 2012].Multiple Sclerosis Journal, 18(5), 700-701. 21.

Wang, Y., Van der Walt, A., Kolbe, S., Shuey, N., Ahmadi, G., Tsonis, S., Marriott, M., Paine, M., Mitchell, P., Klistorner, A., Egan, G. F., Butzkueven, H., Kilpatrick, T. J. (2012). Optic nerve MTR at 3 months reflect RNFL thinning 12 months after onset of optic neuritis. [17th Annual Conference on RIMS: Hamburg, Germany, May 31 Jun 02, 2012]. Multiple Sclerosis Journal, 18(5), 701.

22. Murray SS, Hughes RA, Hodgkinson SJ, Tran G, Wong AW., Peckham H., Ferner AH., Guiffrida L., Kilpatrick TJ, Xiao J. A putative modulator of the p75 neurotrophin receptor promotes peripheral myelin development and repair. Oral presentation, Melbourne Protein Group Symposium, Melbourne, Australia, November 2012.

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

associate professor anthony hannan

79

publications 1.

Curley M, Josey L, Lucas R, Dear K, Taylor BV, Coulthard A, Chapman C, Dwyer T, Kilpatrick T, McMichael T, Pender MP, Ponsonby AL, Taylor B, Valery P, van der Mei I and Williams D, Adherence to MRI protocol consensus guidelines in multiple sclerosis: an Australian multi-centre study, J Med Imaging Radiat Oncol, 56:594-8,2012, PMID: 23210577

2.

Gresle MM, Alexandrou E, Wu Q, Egan G, Jokubaitis V, Ayers M, Jonas A, Doherty W, Friedhuber A, Shaw G, Sendtner M, Emery B, Kilpatrick T and Butzkueven H, Leukemia Inhibitory Factor Protects Axons in Experimental Autoimmune Encephalomyelitis via an Oligodendrocyte-Independent Mechanism, PLoS One, 7:e47379,2012, PMID: 23077604

3.

Gu BJ, Duce JA, Valova VA, Wang B, Bush AI, Petrou S and Wiley JS, The P2X7-mediated scavenger activity of mononuclear phagocytes towards non-opsonized particles and apoptotic cells is inhibited by serum glycoproteins but remains active in cerebrospinal fluid, J Biol Chem, 2012, PMID: 22461619

4.

Gu BJ, Duce JA, Valova VA, Wong B, Bush AI, Petrou S and Wiley JS, P2X7 receptor-mediated scavenger activity of mononuclear phagocytes toward nonopsonized particles and apoptotic cells is inhibited by serum glycoproteins but remains active in cerebrospinal fluid, J Biol Chem, 287:17318-30,2012, PMID: 22461619

5.

Homman-Ludiye J, Merson TD and Bourne JA, The early postnatal nonhuman primate neocortex contains self-renewing multipotent neural progenitor cells, PLoS One, 7:e34383,2012, PMID: 22470566

6.

Koenning M, Jackson S, Hay CM, Faux C, Kilpatrick TJ, Willingham M and Emery B, Myelin gene regulatory factor is required for maintenance of myelin and mature oligodendrocyte identity in the adult CNS, J Neurosci, 32:12528-42,2012, PMID: 22956843

7.

Kolbe S, Bajraszewski C, Chapman C, Nguyen T, Mitchell P, Paine M, Butzkueven H, Johnston L, Kilpatrick T and Egan G, Diffusion tensor imaging of the optic radiations after optic neuritis, Hum Brain Mapp, 33:2047-61,2012, PMID: 21915943

8.

Kolbe SC, Marriott M, Walt A, Fielding J, Klistorner A, Mitchell PJ, Butzkueven H, Kilpatrick TJ and Egan GF, Diffusion tensor imaging correlates of visual impairment in multiple sclerosis and chronic optic neuritis, Invest Ophthalmol Vis Sci, 53:825-32,2012, PMID: 22247457

9.

Lai JK, Lucas RM, Banks E and Ponsonby AL, Variability in vitamin D assays impairs clinical assessment of vitamin D status, Intern Med J, 42:43-50,2012, PMID: 21395958

10.

Lill CM, Liu T, Schjeide BM, Roehr JT, Akkad DA, Damotte V, Alcina A, Ortiz MA, Arroyo R, Lopez de Lapuente A, Blaschke P, Winkelmann A, Gerdes LA, Luessi F, Fernadez O, Izquierdo G, Antiguedad A, Hoffjan S, Cournu-Rebeix I, Gromoller S, Faber H, Liebsch M, Meissner E, Chanvillard C, Touze E, Pico F, Corcia P, Dorner T, Steinhagen-Thiessen E, Baeckman L, Heekeren HR, Li SC, Lindenberger U, Chan A, Hartung HP, Aktas O, Lohse P, Kumpfel T, Kubisch C, Epplen JT, Zettl UK, Fontaine B, Vandenbroeck K, Matesanz F, Urcelay E, Bertram L and Zipp F, Closing the case of APOE in multiple sclerosis: no association with disease risk in over 29 000 subjects, J Med Genet, 49:558-62,2012, PMID: 22972946

11.

Liu Y, Mitchell PJ, Kilpatrick TJ, Stein MS, Harrison LC, Baker J, Ditchfield M, Li K, Egan GF, Butzkueven H and Kolbe SC, Diffusion tensor imaging of acute inflammatory lesion evolution in multiple sclerosis, J Clin Neurosci, 19:1689-94,2012, PMID: 23084347

12.

Martin KR, Corlett A, Dubach D, Mustafa T, Coleman HA, Parkington HC, Merson TD, Bourne JA, Porta S, Arbones ML, Finkelstein DI and Pritchard MA, Overexpression of RCAN1 causes Down syndrome-like hippocampal deficits that alter learning and memory, Hum Mol Genet, 21:3025-41,2012, PMID: 22511596

13.

Martinelli-Boneschi F, Esposito F, Brambilla P, Lindstrom E, Lavorgna G, Stankovich J, Rodegher M, Capra R, Ghezzi A, Coniglio G, Colombo B, Sorosina M, Martinelli V, Booth D, Oturai AB, Stewart G, Harbo HF, Kilpatrick TJ, Hillert J, Rubio JP, Abderrahim H, Wojcik J and Comi G, A genome-wide association study in progressive multiple sclerosis, Mult Scler, 18:1384-94,2012, PMID: 22457343

14.

Oluich LJ, Stratton JA, Lulu Xing Y, Ng SW, Cate HS, Sah P, Windels F, Kilpatrick TJ and Merson TD, Targeted ablation of oligodendrocytes induces axonal pathology independent of overt demyelination, J Neurosci, 32:8317-30,2012, PMID: 22699912

15.

Ponsonby AL, Lucas RM, van der Mei IA, Dear K, Valery PC, Pender MP, Taylor BV, Kilpatrick TJ, Coulthard A, Chapman C, Williams D, McMichael AJ and Dwyer T, Offspring number, pregnancy, and risk of a first clinical demyelinating event: the AusImmune Study, Neurology, 78:867-74,2012, PMID: 22402857

16.

Wang Y, van der Walt A, Paine M, Klistorner A, Butzkueven H, Egan GF, Kilpatrick TJ and Kolbe SC, Optic nerve magnetisation transfer ratio after acute optic neuritis predicts axonal and visual outcomes, PLoS One, 7:e52291,2012, PMID: 23272235

17.

Wiley JS and Gu BJ, A new role for the P2X7 receptor: a scavenger receptor for bacteria and apoptotic cells in the absence of serum and extracellular ATP, Purinergic Signal, 2012, PMID: 22476940

18.

Wu M, Hernandez M, Shen S, Sabo JK, Kelkar D, Wang J, O'Leary R, Phillips GR, Cate HS and Casaccia P, Differential Modulation of the Oligodendrocyte Transcriptome by Sonic Hedgehog and Bone Morphogenetic Protein 4 via Opposing Effects on Histone Acetylation, J Neurosci, 32:6651-64,2012, PMID: 22573687

19.

Xiao J, Neuroprotection on Multiple Sclerosis: a BDNF Perspective, Journal of Neurology and Neurophysiology, 3:e108,2012,

We have discovered an unexpected benefit from cognitive stimulation and physical activity – it can correct dysfunction in the adrenal gland and associated stress responses.

20. Xiao J, Ferner AH, Wong AW, Denham M, Kilpatrick TJ and Murray SS, Extracellular signal-regulated kinase 1/2 signaling promotes oligodendrocyte myelination in vitro, J Neurochem, 122:1167-80,2012, PMID: 22784206 21.

Yan J, Liu J, Lin CY, Anzgene AN, Csurhes PA, Pender MP, McCombe PA and Greer JM, Interleukin-6 gene promoter-572 C allele may play a role in rate of disease progression in multiple sclerosis, Int J Mol Sci, 13:13667-79,2012, PMID: 23202972

Associate Professor Anthony Hannan, commenting on a paper in Nature Publishing Group’s Translational Psychiatry. The findings will have wide-ranging implications for our understanding of stress responses and depression particularly for people living with Huntington's disease.

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Neurodegeneration

Neurodegeneration division

Motor neurone disease research

Molecular Neuropharmacology

Our research seeks to understand the primary pathological mechanisms of the protein misfolding disorder, motor neurone disease (MND), and translate these findings into effective biomarkers and therapeutic strategies. We employ a combination of biochemistry, cell and molecular biology to study the pathogenesis of MND in patient tissues, cell culture and mouse models.

The Molecular Neuropharmacology laboratory studies the cellular consequences of injury processes, especially oxidative stress and inflammation, which both contribute to brain pathologies. Our focus is on neurones and the main glial type, the astrocyte, which have an interdependent relationship essential to brain health. Our diverse experimental approaches reveal new strategies to rescue threatened neurones and to establish a supportive environment near an injury zone.

``Research highlights for 2012

THE BRAIN HAS A SIGNIFICANT CAPACITY FOR SELF-REPAIR AND PLASTICITY

RESEARCH HIGHLIGHT

SENIOR STAFF

Professor Malcolm Horne has been working on a wristwatch-like device for nearly 23 years that is, at last, making it to market. The Parkinson’s KinetiGraph is a system for measuring the motor symptoms, and disorders of sleep and impulse control in Parkinson’s disease. The device allows better management of treatments for Parkinson’s disease and is now in early commercial use in centres throughout Australia and internationally.

Professor Malcolm Horne Professor Bevyn Jarrott Dr Clare Parish Dr Lachlan Thompson Dr Wah Chin Boon Dr Tim Aumann Dr Bradley Turner

 A QUICK SNAPSHOT Our focus is on how neurones live, die and can be rescued to improve brain function in Parkinson’s and motor neurone diseases. We have made notable advances relevant to gene abnormalities, energy disturbance, debris accumulation and inflammation, as well as destructive processes producing toxic outcomes for neurones. We have found abnormal levels or mutations of proteins disrupt brain debris clearance leading to accumulation of toxic intracellular protein aggregates. Here important clues are being translated from cellular to animal disease models to obtain outcomes beneficial to disease pathology. The brain has a significant capacity for self-repair and plasticity, and these events are under study with cell-based replacement therapies. A notable success has been improved reconstruction of circuitry compromised in Parkinsonism. This approach is being interfaced with engineering strategies to activate reparative mechanisms. A further exciting outcome has been the development by Professor Malcolm Horne of the Parkinson’s KinetiGraph (PKG), a system for measuring the motor symptoms, and disorders of sleep and impulse control in Parkinson’s disease. The device allows better management of treatments for Parkinson’s disease and is now in early commercial use in centres throughout Australia and internationally. A notable success has been improved reconstruction of the brain’s circuitry compromised in Parkinsonism. This approach is being combined with engineering to activate reparative mechanisms.

Neurones die … during brain injury and we have been one of the first groups internationally to define the contributions of autophagy as a cell death process

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This group has identified that disruption of a vital protein homeostatic mechanism called autophagy occurs in motor neurones of MND patients and genetic mouse models. We have shown that key misfolded proteins in MND are normally cleared by autophagy which is impaired in MND. This group has identified novel compounds that stimulate autophagy in the brain and is currently evaluating these in mouse models of MND to determine whether autophagic clearance of misfolded proteins is beneficial for MND.

``Research highlights for 2012 Two specific research highlights for Neuropharmacology laboratory for 2012 are;

the

Molecular

Neurones die by diverse gene programmed mechanisms during brain injury and we have been one of the first groups internationally to define the contributions of autophagy as a cell death process. While autophagy is a general process whereby cells capture and degrade damaged components and may accompany neuronal death, autophagic cell death requires a direct contribution We are also collaborating with colleagues of autophagy to the death outcome, which we have documented in primary at the University of Oxford to test neurones. Further we recently published the therapeutic effects of survival in the journal Free Radicals in Biology and motoneurone (SMN) gene therapy Medicine that during extended trauma for MND. We have demonstrated that other modes of injury occur in parallel and SMN gene therapy ameliorates motor This image shows the delivery of therapeutic SMN may surpass autophagy. New work reveals symptoms and enhances motor neurone protein (green) to motor neurones (red) in an that mitophagy, a form of autophagy where adult mouse spinal cord. survival in mouse models of MND. damaged or dysfunctional mitochondria This has paved the way to develop new selectively undergo degradation, may be strategies for therapeutic delivery of SMN using viral and nonrapidly recruited during the energy dysfunction typically seen in viral systems for evaluation in MND mouse models. acute pathologies such a stroke.

 Collaborations •

Prof Neil Cashman, University of British Columbia, Canada

Prof Kay Davies and Prof Kevin Talbot, University of Oxford, UK

Prof Roger Pamphlett, University of Sydney, Australia

Dr Hakan Muyderman, Flinders University, Australia

Prof Andrew Hill, Bio21 Institute, Australia

Dr Julie Atkin, La Trobe University, Australia

{{Conferences 1.

23rd International Symposium on ALS/MND, Chicago, USA (2012)

2. 11th Biennial Meeting of Asia-Pacific Society for Neurochemistry, Kobe, Japan (2012) 3. 8th Federation of European Neuroscience Societies Forum, Barcelona (2012) 4. Inaugural Proteostasis and Disease Symposium, Wollongong, Australia (2012)

The biology of astrocytes and their involvement in neuroinflammation continues to be a topic of great interest. Work on the cytoskeletal effects of Rho kinase (ROCK) inhibitors led us to examine the molecular signature of astrocytes where our publication in the Journal of Cellular Physiology favoured ROCK inhibition producing a pro-survival phenotype. Given the success of this drug intervention, we turned our attention to bioengineering approaches where provision of a bioscaffold can assist by enabling a favourable environment near a traumatized zone and so encourage endogenous reparative mechanisms. Astrocytes flourished on 3D biomatrices: expression of the glutamate transporter EAAT2 and BDNF was elevated relative to 2D astrocytes and immunoblotting showed GFAP expression was reduced. When we repeated this study using a ROCK inhibitor there extensive progress outgrowth relative to vehicle with GFAP expression again reduced. AHNAK expression was elevated indicative of extensive outgrowth activity. The combination of bioengineering and ROCK inhibition produced synergism decreasing cytoskeletal stress, elevating glutamate transport and process outgrowth, reflecting a “good” biology beneficial for brain repair.

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

Neurodegeneration

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publications

Autophagic vesicles (green) produced by ecstasy around a serotonin neuron (orange).

 Collaborations

{{Conferences

Dr David Nisbet, Research School of Engineering, Australian National University

Philip Beart

Dr Hakan Mudyerman, Department of Biochemistry, Flinders University

Dr Steve Cheung, School of Life and Environmental Sciences, Deakin University

3. ISN Advanced School “New Approaches in Glial Cell Research”, Barcelona, Spain (2012)

Prof Phillip Nagley, Department of Biochemistry and Molecular Biology, Monash University

4. 5th ISN Special Conference, Buenos Aires, Argentina (2012)

Prof Rod Devenish, Department of Biochemistry and Molecular Biology, Monash University

5. 2nd ISN Latin American School of Advanced Neurochemistry, Buenos Aires, Argentina, and Montevideo, Uruguay (2012)

Prof Lars Nilsson, Department of Chemistry, University of Lund

6. Joint APSN-JSN Meeting, Kobe, Japan (2012)

Editorial positions •

Philip Beart, Editorial Board Member, British Journal of Pharmacology, 2000-2013

Philip Beart, Associate Editor, Neurochemistry International, 2011-2013

1.

1.

Aumann T and Horne M, Activity-Dependent Regulation Of The Dopamine Phenotype In Substantia Nigra Neurons, J Neurochem, 2012, PMID: 22356203

2.

Aumann T, Boon WC, Horne M, Axelsson A, Rosengren A, Petkovic-Duran K, Zhu Y and Manasseh R, Using acoustic microstreaming to improve detection of gene expression in single cells, J Acoust Soc Am, 131:3337,2012, PMID: 22501706

3.

Bye CR, Thompson LH and Parish CL, Birth dating of midbrain dopamine neurons identifies A9 enriched tissue for transplantation into Parkinsonian mice, Experimental Neurology, 2012, PMID: 22524988

4.

Czech DP, Lee J, Sim H, Parish CL, Vilain E and Harley VR, The human testis determining factor SRY localizes in midbrain dopamine neurons and regulates multiple components of catecholamine synthesis and metabolism, J Neurochem, 2012, PMID: 22568433

5.

Denham M, Bye C, Leung J, Conley BJ, Thompson LH and Dottori M, GSK3beta and Activin/Nodal Inhibition in Human Embryonic Stem Cells Induces a PreNeuroepithelial State that is Required for Specification to a Floor Plate Cell Lineage, Stem Cells, 2012, PMID: 22911885

6.

Denham M, Parish CL, Leaw B, Wright J, Reid CA, Petrou S, Dottori M and Thompson LH, Neurons derived from human embryonic stem cells extend longdistance axonal projections through growth along host white matter tracts after intra-cerebral transplantation, Frontiers in cellular neuroscience, 6:11,2012, PMID: 22470319

7.

Farg MA, Soo KY, Walker AK, Pham H, Orian J, Horne MK, Warraich ST, Williams KL, Blair IP and Atkin JD, Mutant FUS induces endoplasmic reticulum stress in amyotrophic lateral sclerosis and interacts with protein disulfide-isomerase, Neurobiology of Aging, 2012, PMID: 22459602

8.

Hewitson TD, Zhao C, Wigg B, Lee SW, Simpson ER, Boon WC and Samuel CS, Relaxin and castration in male mice protect from, but testosterone exacerbates, age-related cardiac and renal fibrosis, whereas estrogens are an independent determinant of organ size, Endocrinology, 153:188-99,2012, PMID: 22028442

9.

Higgins GC, Devenish RJ, Beart PM and Nagley P, Transitory phases of autophagic death and programmed necrosis during superoxide-induced neuronal cell death, Free Radic Biol Med, 53:1960-7,2012, PMID: 22982049

10.

Kauhausen J, Thompson LH and Parish CL, Cell intrinsic and extrinsic factors contribute to enhance neural circuit reconstruction following transplantation in Parkinsonian mice, J Physiol, 2012, PMID: 23045338

11.

Lau CL, Perreau VM, Chen MJ, Cate HS, Merlo D, Cheung NS, O'Shea RD and Beart PM, Transcriptomic profiling of astrocytes treated with the Rho kinase inhibitor Fasudil reveals cytoskeletal and pro-survival responses, Journal of Cellular Physiology, 227:1199-211,2012, PMID: 21604263

12.

Soo KY, Atkin JD, Farg M, Walker AK, Horne MK and Nagley P, Bim Links ER Stress and Apoptosis in Cells Expressing Mutant SOD1 Associated with Amyotrophic Lateral Sclerosis, PLoS One, 7:e35413,2012, PMID: 22523592

13.

Sui Y, Horne MK and Stanic D, Reduced proliferation in the adult mouse subventricular zone increases survival of olfactory bulb interneurons, PLoS One, 7:e31549,2012, PMID: 22363671

14.

Wallis N, Zagami CJ, Beart PM and O'Shea RD, Combined excitotoxic-oxidative stress and the concept of non-cell autonomous pathology of ALS: Insights into motoneuron axonopathy and astrogliosis, Neurochem Int, 2012, PMID: 22421531

15.

Wang TY, Forsythe JS, Nisbet DR and Parish CL, Promoting engraftment of transplanted neural stem cells/progenitors using biofunctionalised electrospun scaffolds, Biomaterials, 2012, PMID: 23022345

16.

Wilkins EJ, Rubio JP, Kotschet KE, Cowie TF, Boon WC, O'Hely M, Burfoot R, Wang W, Sue CM, Speed TP, Stankovitch J and Horne MK, A DNA resequencing array for genes involved in Parkinson's disease, Parkinsonism & related disorders, 2012, PMID: 22243833

17.

Yap YW, Chen MJ, Peng ZF, Manikandan J, Ng JM, Llanos RM, La Fontaine S, Beart PM and Cheung NS, Gene expression profiling of rotenone-mediated cortical neuronal death: Evidence for inhibition of ubiquitin-proteasome system and autophagy-lysosomal pathway, and dysfunction of mitochondrial and calcium signaling, Neurochem Int, 2012, PMID: 23186747

43rd Annual Meeting of American Society for Neurochemistry, Baltimore, US (2012)

2. 8th FENS Forum of Neuroscience, Barcelona, Spain (2012)

7. Linda Lau Joint APSN-JSN Meeting, Kobe, Japan (2012) 8. APSN School of Neurochemistry, Kyoto, Japan (2012) Linda Lau 1.

Joint APSN-JSN Meeting, Kobe, Japan (2012)

2. APSN School of Neurochemistry, Kyoto, Japan (2012)

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

Confronting dementia head-on

Why is dementia a global problem?

Confronting dementia head-on ;

Dementia is a growing problem internationally. Here, Associate Professor David Darby, the principal investigator of a major study explores the issue.

Currently it is estimated that there are 35 million people in the world with dementia. Not only is this a staggering figure, but it is predicted to double every 20 years. And even here in Australia the figures are shattering. Whilst there were an estimated 234,000 people with dementia in 2009, this will rise to 1 million people by 2050 if the current increase in dementia continues. According to the World Health Organisation, dementia will also overtake both depression and HIV related illness as the leading cause of global disease burden within the next two years. These figures are for patients with dementia, which is the most severe stage with more than twice this number of people estimated to be in earlier stages of the disease.

Why is dementia prevalence increasing?

But aren’t there treatments for dementia? There have been huge advances in the understanding of the molecular, genetic and cellular basis for dementias at the Florey and around the world. In Alzheimer’s disease, accumulation of a brain protein called “amyloid” occurs and it forms components that are toxic to cellular membranes and synapses, and seems to lead to a cascade of cellular events that result in progressive cognitive decline over many decades. Therapies using chemicals found in neuronal signalling have shown heartening improvements in symptoms, and are available to patients with dementia. However, the real challenge has been to find a therapy that prevents or slows the rate of decline in patients with Alzheimer’s disease. Such therapies should work, but so far they have been disappointing or with only modest success, and it has caused a re-evaluation of what could be done to redress this.

Early detection may be the key

Currently there are 150 times more clinical trials focusing on treating people in the late stages of cancer than Alzheimer's disease. One in three people over the age of 65 will die with dementia. More funding for research is urgently needed if we are to defeat the condition once and for all.

British Alzheimer’s Society

to 30 years before dementia is diagnosed. Although there are some novel research efforts currently aiming to use these to find high-risk individuals, these techniques are probably not suitable for wide scale screening, being too expensive or with significant potential risks (e.g. radiation or infection).

Cognitive screening using the internet

One of the earliest known changes is Alzheimer’s disease is declining memory. Persistent decline in memory is not healthy, but it’s also not specific for Alzheimer’s disease, and can be caused by anxiety, depression, medical, neurological or other causes. But it can be used to flag individuals who might need more detailed assessment. Hence, regular testing of memory is a possible strategy for These studies, including those detecting individuals who could undergo from our own AIBL study, have the more expensive or invasive diagnostic shown changes up to 30 years techniques mentioned above. In addition, before dementia is diagnosed individuals who are concerned about their memory as they get older can be reassured by regular testing if it shows no such decline.

Age is by far the largest risk factor for dementia. The incidence rises from about one per cent at age 60, doubling every five years. At age 85 years and older, about 45 per cent of survivors will be afflicted by dementia, the majority of whom will have Alzheimer’s disease. And there is an increasing number of us who are in these older age groups, due to a “balloon of babyboomers” born just after the Second World War. Instead of looking forward to a golden age of retirement, many are quite reasonably concerned about their risk of getting dementia.

Associate Professor David Darby

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One of the most obvious possibilities is that therapies are most effective in animal models when given very early or even before the disease develops. Most trials have been in patients with established Alzheimer’s disease when it’s very unlikely any therapy is capable of reversing neuronal loss and other changes. So how do we detect people harbouring this very early disease? There are technological solutions that can detect “biomarkers” or abnormalities in living people that reflect brain pathology due to specific dementias. In Alzheimer’s disease, new PET scanning imaging techniques at the Florey show the presence of amyloid and other protein accumulations in the brain, and there are also changes in the cerebrospinal fluid that reflect early disease. These studies, including those from our own Australian Imaging Biomarkers and Lifestyle (AIBL) study, have shown changes up

Research done in Melbourne has shown that about 10 per cent of people over the age of 50 years may show persistent decline in memory, and about half of these will show Alzheimer’s disease pathology on biomarker imaging studies. Hence, such surveillance with cognitive tests is a potentially useful initial screening process. Computerization of these not only makes it possible to detect subtle changes in memory (often before the individual is aware themselves), but also to serve these to individuals remotely using modern web-browsers. This is the approach of our own TREAD (“Trajectory-Related Early Alzheimer’s Database”) study being conducted at The Florey utilizing technology developed by a Melbourne based company, CogState Ltd.

The TREAD Study This study is currently enrolling people aged 50 years or older who are willing to test their memory and thinking using their own computer and web-browser. They are asked to consent, register and test themselves without supervision at monthly intervals for about 6 months prior to 3 monthly testing. They also are required to provide the contact details of their local medical practitioner and to agree to being informed if they are found to have decline in their memory or thinking. The study started recruiting in Dec 2012, and with minimal publicity has attracted about 600 participants who have helped us to understand the issues of such an endeavour. We will aim to recruit at least 10,000 participants over the next few months. Participants that show decline in their memory will be offered medical evaluation and if suitable enrolled in therapeutic trials which involve performing the newer biomarker studies. In this way, we hope to cost-effectively identify individuals with very early Alzheimer’s disease pathology and more importantly offer them involvement in clinical trials of promising therapies aiming to slow the rate of decline and in future prevent progression to dementia. We are currently recruiting for the TREAD study. Interested participants can learn more about the study by going to the web site at www.tread.florey.edu.au. It is our hope that this sort of effort will help to accelerate the discovery of truly diseasemodifying therapies for Alzheimer’s and other dementias.

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

Welcome Charlotte Ermine

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Welcome Charlotte Ermine The Florey welcomes Charlotte Ermine, 25, who has decided to do her PhD a long way from home.

Originally from Paris where she worked at the Institut du Cerveau et de la Moelle èpiniére, Charlotte Ermine has quickly settled since arriving with the support of her supervisors, Dr Lachlan Thompson and Professor Phil Beart. Professor Beart is the head of the Florey’s Neurodegeneration Division and has recently returned from a visit to the French institute where he developed further links. As a result, the Florey has signed a memorandum of understanding to collaborate with scientists at Institut du Cerveau et de la Moelle èpiniére. The new institute is about the same size as the new Florey Parkville building and is situated on the site of the Hopital de la Salpetriere in the 13th arrondissement of Paris where Jean-Marie Charcot (1825-1893) conducted historic work as one of the pioneers of neurology. Charcot, who played a key role in defining motor neurone disease and multiple sclerosis, is considered the founder of modern neurology. He also made important contributions to Parkinson’s disease.

Charcot was a figure of renown and some notoriety for soirees he held involving patients, hypnosis and hysteria. According to Charlotte, the research at both institutes is complementary, especially in stem cell science, an area she is keen to pursue. “I am interested in Parkinson’s disease, cognitive symptoms and where they originate in the brain,” Charlotte says. “In Paris, I was working on Parkinson’s but in genetics. I’ve always been interested in the disease as my grandfather had it before he passed away.” Of all the therapeutic approaches to Parkinson’s, Charlotte believes stem cells hold the most potential. “I am also interested in the symptoms other than the motor problems – things like depression which is not looked into so much.” Charlotte is here on a four-year Melbourne Engagement International Award scholarship.

Charlotte Ermine, with her supervisors, Dr Lachlan Thompson and Professor Phil Beart

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

Neuro-ethics with Neil Levy

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Neuro-ethics with Neil Levy ;

Here’s how I understand luck. I think something is lucky (or unlucky) for a person if two things are true of it: it matters (somehow) to them, and it might easily not have happened. Neil Levy Author of Hard Luck: How Luck Undermines Free Will and Moral Responsibility

WHAT’S IN THE MIND?

PAPERS (SELECTED):

Professor Neil Levy is the Florey’s resident neuro-ethicist.

1.

He has published extensively in the last 12 months in journals, books and in the public sphere. Professor Levy travels extensively and has presented on ‘free will and the brain’, ‘consciousness and moral responsibility’, ‘addiction and self-control’ and other fascinating topics. You can read more on neuro-ethics by Neil Levy by visiting The Conversation (http://theconversation.com/profiles/ neil-levy-4379/activities?filter=articles)

LEVY, N. Skepticism and Sanction: The Benefits of Rejecting Moral Responsibility. Law and Philosophy, 31 (2012), 477-493.

2. LEVY, N. The Use Of Animals As Models: Ethical Considerations. International Journal of Stroke 7 (2012), 440-442. 3. Kadosh, R., C. LEVY, N., O’Shea, J., Shea, N. and Savulescu, J. (joint first author). The Neuroethics Of Non-Invasive Brain Stimulation. Current Biology, 22 (2012), R108-R111.

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

Neuropeptides

Neuropeptides

Peptide Neurobiology Our laboratory conducts ‘systems neuroscience’ research, with a primary interest in the role of neuropeptide signalling in the control of complex behaviours - arousal, stress and mood, and associated memory processes - under normal and pathophysiological conditions. We conduct experimental studies in animal models of psychiatric disorders, using a range of biomolecular tools, including receptor-selective peptides, viral-vector delivered ‘designer’ receptors and transgenic mice.

division

``Research highlights for 2012

A QUICK SNAPSHOT

RESEARCH HIGHLIGHT

The Neuropeptides Division 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 the peptides and their G protein-coupled receptors. The aim of this research is to develop therapeutics which target these peptide receptors to treat vascular, fibrotic, metabolic and psychiatric diseases.

The Neuropeptides Division was thrilled in 2012 by the successful completion of Phase III trials by the Swiss pharmaceutical company Novartis using the hormone relaxin for the treatment of acute heart failure. This work demonstrates how fundamental research on the mechanism of action of a hormone, in this case that of relaxin which was pioneered at the Florey more than thirty years ago by Professor Geoffrey Tregear, can lead to its ultimate use in patients to treat disease.

 We continue to make significant progress in the identification of the key structural features of the insulin-like peptides, relaxin and relaxin-3.

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

Ascending relaxin-3/RXFP3 networks and state-dependent modulation of affective behaviour: potential for treatment of psychiatric disorders It is clear that brain neuromodulatory systems play a key role in the control of affective behaviour and cognition, and that their monoamine and peptide transmitters are often altered in psychiatric pathology. Our experiments are aimed at identifying the potential of this novel but underexplored molecular target, the relaxin-3 receptor, for the treatment of specific psychiatric and neurodegenerative disorders such as clinical anxiety disorders, major depression, and related psychiatric illnesses. In our laboratory, we research an extensive network of inhibitory peptide neurones that modulate interrelated behaviours such as stress responses, arousal/sleep, anxiety/fear and related cognition. In important recent studies, we have documented how relaxin-3 neurones are activated by the stress hormone, CRF (Figure), and observed the behavioural effects of altered brain RXFP3 activity. Acute central activation of RXFP3 in adult rats increases feeding (Shabanpoor F et al., 2012), and reduces anxiety-like behaviour in elevated plus maze and light/dark box tests (Ryan PJ et al., 2012). By contrast, central blockade of RXFP3 reduces alcohol self-administration and cue-induced relapse in alcohol-preferring rats; and reduces food intake in mice exposed to a mildly-stressful environment and food restriction prior to food access. We have also identified an important phenotype in relaxin-3 and RXFP3 gene-deletion ‘knockout’ mice, reflected by highly fragmented circadian activity, which is commonly observed in a number of sleep/wake disturbances including major neurodegenerative disorders and clinical depression. Current studies are attempting to elucidate the neural targets of RXFP3 and mechanisms involved. Further, we have identified a major relaxin-3/RXFP3 pathway from the midbrain ‘medial central grey’ to the thalamic ‘intergeniculate leaflet’ (Blasiak A et al., 2012), an area which contributes to the control of circadian rhythms.

 Collaborations

It took 37 years, five clinical trials, collaboration with six biotechnology companies and a lot of faith. Professor Geoff Tregear can now relax knowing an obscure hormone - his life's work - has finally delivered. A synthetic version of relaxin – first described in 1929 – is the key ingredient in a new class of medicine for acute heart failure. It has been shown to improve symptoms and reduce deaths among sufferers.

All relaxin-3 neurones (stained red) also contain CRF-R1 (stained green), indicating that they would be capable of being activated by the stress hormone, CRF. A raw trace of relaxin-3 neuron firing and activation by CRF in an anesthetised rat. Following recording, the neuron was filled using ‘juxtacellular-labeling’ and neuron morphology reconstructed digitally. Average phase histograms of relaxin-3 and non-relaxin-3 neurones illustrating the strong modulation of these neurones in phase with theta oscillations in contrast to non-relaxin-3 neurons. Recording of a relaxin-3 neuron firing during hippocampal theta activity illustrates spiking occurs preferentially during the early phase of theta oscillations. Synchronized firing supports a role of relaxin-3 neurones in modulating memory processing.

International •

Department of Neurophysiology and Chronobiology, Jagiellonian University, Poland

Diabetes Center, University of California, San Francisco, USA

Department of Neurobiology, Weizmann Institute of Science, Israel

Department of Pharmacology, National University of Singapore, Singapore

Department of Pharmacology and Toxicology, University of Innsbruck, Austria

Department of Human Anatomy and Embryology, University of Valencia, Spain

Editorial positions Andrew Gundlach Editorial Board Member: •

Journal of Chemical Neuroanatomy

Frontiers in Molecular Neuroscience

NeuroSignals

Frontiers in Neuroanatomy

Neuropeptides

Chair, IUPHAR Database Committee on Galanin Receptors

{{Conferences 1.

Australian Neuroscience Society Annual Scientific Meeting, Gold Coast, Australia (2012)

2. 5th Annual European Molecular and Cellular Cognition (EMCCS) Meeting, Barcelona, Spain (2012) 3. FENS 8th Forum of European Neuroscience, Barcelona, Spain (2012) 4. 4th Brain Plasticity Symposium: Circuits, Synapses and Behaviour, Brisbane, Australia (2012)

School of Psychological Science, La Trobe University

School of Biomedical Sciences, University of Queensland

5. 11th Biennial Meeting Asian Pacific Society for Neurochemistry, 55th Annual Meeting Japanese Society for Neurochemistry, 34th Annual Meeting Japanese Society of Biological Psychiatry (Combined Meeting), Kobe, Japan (2012)

Faculty of Pharmacy and Pharmaceutical Sciences, Monash Institute of Pharmaceutical Sciences, Monash University

6. Frontiers in Stress and Cognition: From Molecules to Behavior, Ascona, Switzerland (2012)

Department of Medicine, Austin Health, The University of Melbourne

7. 6th International Conference on Relaxin and Related Peptides, Florence, Italy (2012)

National

Photo: The Age

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

8. 2012 Cell (Press) Symposia - Neuromodulatory Mechanisms, New Orleans, USA (2012) 9. 42nd Society for Neuroscience Annual Scientific Meeting, New Orleans, USA (2012) 10. Students of Brain Research (SOBR) Symposium, Melbourne, Australia (2012)

Insulin Peptides Peptide drugs with their low toxicity profile offer viable alternatives to small molecule drugs. Insulin and insulin-like peptides being large in size are difficult to manufacture. Once administered to patients, peptide drugs are quickly degraded and cleared from the body. Dr Hossain's laboratory focuses on developing novel chemical methods for efficient preparation of better insulin-like peptide drugs that will stay longer in blood.

Editorial positions

 Collaborations

Dr Mohammed Akhter Hossain, Editorial Board Member, Modern Chemistry (Science Publishing Group)

IBM Research Collaboratory for Life Sciences & IBM Australia Research Laboratory

The University of Melbourne, Australia

Victor Chang Cardiac Research Institute, Australia

University of Zurich, Switzerland

Monash University, Australia

CSIRO Parkville, Australia

Australian Synchrotron, Australia

{{Conferences 5th International Conference on Relaxin and Related Peptides (Relaxin 2012), Florence, Italy, Oct 8-12, 2012. “Towards the development of relaxin-RXFP1 agonist and antagonist analogues”

Membrane Protein Engineering Many membrane proteins are located on the surface of our cells where they are involved in processes such as sensing neurotransmitters, driving neural impulses and responding to drug treatment. However, the instability of membrane proteins makes them difficult to study. Our laboratory engineers stabilised membrane proteins to facilitate novel drug discovery.

``Research highlights for 2012

Cartoon representation of the GPCR stabilisation technology employed in our laboratory. We screen hundreds of millions of nano-capsules, each containing a different GPCR variant, in a fluidic stream using fluorescent activated cell sorting (FACS). The most fluorescent capsules contain stable GPCR variants that can be sorted from the capsule population by the FACS instrument.

``Research highlights for 2012 H2 relaxin exerts its biological function through its own receptor, Relaxin Family Peptide Receptor 1 (RXFP1; also known as LGR7). However, it also activates other receptors, including RXFP2 (native receptor for the related insulin-like peptide 3, INSL3). Thus, it would be beneficial to have a highly selective RXFP1 analogue to avoid potential undesired side effects mediated through RXFP2. We have recently developed such an analogue and published this work in the prestigious Journal of Biological Chemistry: Linda J. Chan, K. Johan Rosengren, Sharon L. Layfield, Ross A.D. Bathgate, Frances Separovic, Chrishan S. Samuel, Mohammed Akhter Hossain* and John D. Wade* Journal of Biological Chemistry 2012 287(49), 41152-64. [*Equal contribution]

2012 was the inaugural year for the Membrane Protein Engineering Laboratory. We have established our core G protein-coupled receptor (GPCR) stabilisation technology at the Florey, the first of its kind in Australia. So far this has allowed the stabilisation of two GPCRs, which are drug targets for hypotension, drug abuse and psychosis. The generation of these stabilised receptors will provide new avenues for discovering treatments for these diseases. Furthermore we are currently stabilising a further five GPCRs that are drug targets for conditions ranging from anxiety and chronic pain to neurodegenerative diseases. The laboratory is also working on the application of our technology to other membrane proteins such as ion channels, which are responsible for driving neural impulses and are drug targets in many neurological disorders.

University of Melbourne, Australia

Takeda Cambridge Ltd., UK

University of Queensland, Australia

Monash University, Australia

Monash University, Australia

Austin Health , Australia

University of Adelaide, Australia

1 patent application describing the membrane protein stabilisation technology mentioned above.

Major Collaborative Links

Department of Biochemistry and Molecular Biology, University of Melbourne

Department of Pharmacology, Monash University

Baker Heart Research Institute, Melbourne

4. Daniel Scott, keynote speaker

Department of Pharmacology, University of Melbourne

5. Relaxin 2012: 6th International Conference on Relaxin and Related Peptides, October 2012, Florence, Italy

School of Biomedical Sciences, University of Queensland

The 37th Lorne Conference on Protein Structure and Function, February 2012, Lorne, Victoria, Australia

2. Daniel Scott, poster presentation 3. Australian Society for Medical Research Student Symposium, June 2012, Melbourne, Australia

6. Daniel Scott, invited speaker 7. Kelvin Yong, poster presentation 8. 7th International meeting on the Molecular Pharmacology of G Protein-Coupled Receptors, December 2012, Melbourne, Australia 9. Daniel Scott, invited speaker

International •

Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, Florida International University, USA

Department of Psychiatry, University of North CarolinaUnemori Corthera (owned by Novartis), San Mateo, USA

Guo Institute of Protein Research, College of Life Sciences and Technology, Tongji University, Shanghai, China

10. Kelvin Yong, poster presentation

Neuropeptide Receptor The Neuropeptide Receptor Laboratory studies G proteincoupled receptors (GPCR) 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. Studies by the group have demonstrated the unique mechanism by which the hormone relaxin binds to and activates its receptor, RXFP1. This work was recently published in the journal 'Molecular Endocrinology' and is an essential part of our ongoing studies designed to understand the interaction between relaxin and RXFP1 to enable new drug design. The hormone 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.

Published the invention of a novel protein engineering method that was used to stabilise two GPCRs (Scott et al., J Mol Biol 2013). This technology allows us to engineer membrane proteins that can be easily manipulated in the laboratory, with applications in structural biology, pharmacology and drug discovery. This publication has already received international recognition, being recommended by the Faculty of 1000 (Sexton P & Furness, S. F1000 Prime Recommendation of [Scott DJ and Plückthun A, J Mol Biol 2012]. Faculty of 1000, (2012)).

 Collaborations

1.

months. This important work demonstrates that drugs targeting this GPCR can be utilized to modulate feeding disorders and was recently published in the journal 'Gene Therapy'. Ongoing studies on the RXFP3 receptor by our group will lead to smaller orally active drugs that will be able to cross the blood brain barrier and target RXFP3 to treat neurological disease.

National

``Research highlights for 2012

Published research describing the engineering of an insulinlike peptide 3 binding site into the relaxin receptor (Scott et al., Mol Endo 2012). This work helped us to understand the molecular mechanisms underlying the specificity of these receptors for different hormones, which is important for the development of drugs targeting the relaxin receptor.

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{{Conferences

Specific research highlights include:

 Collaborations •

Neuropeptides

Studies by Despina Ganella in collaboration with the Peptide Neurobiology Group have utilized viral delivery of a relaxin-3 peptide analog into the brain to modulate its receptor RXFP3. We were able to show that targeting RXFP3 led to increased feeding in rats and this effect was sustained over a period of two

Editorial positions Ross Bathgate •

Associate Editor of Frontiers in Molecular and Structural Endocrinology

Editorial Board Member of Journal of Pharmacological Sciences

Associate Editor of Molecular and Cellular Endocrinology

Member – IUPHAR subcommittee on relaxin receptors

{{Conferences Ross Bathgate Invited Speaker; Relaxin 2012: 6th International Conference on Relaxin and Related Peptides; Florence, Italy, October 2012. Despina Ganella •

Invited Speaker; Relaxin 2012: 6th International Conference on Relaxin and Related Peptides; Florence, Italy, October 2012

Poster; Australian Neuroscience Society 32nd Annual Meeting, Gold Coast, Australia, February 2012

Poster; 42nd Society for Neuroscience (SfN) Meeting, New Orleans, USA, November 2012

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

Roy Kong •

Poster; Relaxin 2012: 6th International Conference on Relaxin and Related Peptides; Florence, Italy, October 2012

Poster; 7th International meeting on the Molecular Pharmacology of G Protein-Coupled Receptors, Melbourne, Australia, December 6th - 8th, 2012

led to the development of a novel relaxin analogue which is selective for its own receptor and which has no cross reactivity for the receptor, RXFP2, of a related peptide INSL3.

Editorial positions John Wade

Neuropeptides

95

publications 1.

Bathgate RA, Zhang S, Hughes RA, Rosengren KJ and Wade JD, The structural determinants of insulin-like Peptide 3 activity, Front Endocrinol (Lausanne), 3:11,2012, PMID: 22654853

2.

Callander GE, Ma S, Ganella DE, Wimmer VC, Gundlach AL, Thomas WG and Bathgate RA, Silencing relaxin-3 in nucleus incertus of adult rodents: a viral vector-based approach to investigate neuropeptide function, PLoS One, 7:e42300,2012, PMID: 22876314

3.

Poster; 38th Lorne Conference on Protein Structure and Function, Lorne, Australia, 5th-9th Feb 2012

Editor in Chief, International Journal of Peptide Research & Therapeutics 2005-

Chan LJ, Rosengren KJ, Layfield SL, Bathgate RA, Separovic F, Samuel CS, Hossain MA and Wade JD, Identification of key residues essential for the structural fold and receptor selectivity within the A-chain of H2 relaxin, J Biol Chem, 2012, PMID: 23024363

Editor in Chief, Biochemical Compounds 2012-

4.

Poster; Melbourne Protein Group student symposium, 5th July 2012

Editor, Journal of Peptide Science, 1999-

Chow BS, Chew EG, Zhao C, Bathgate RA, Hewitson TD and Samuel CS, Relaxin Signals through a RXFP1-pERK-nNOS-NO-cGMP-Dependent Pathway to UpRegulate Matrix Metalloproteinases: The Additional Involvement of iNOS, PLoS One, 7:e42714,2012, PMID: 22936987

Editor, Protein & Peptide Letters, 2002-

5.

Poster; 7th International meeting on the Molecular Pharmacology of G Protein-Coupled Receptors, Melbourne, Australia, December 6th - 8th, 2012

Ganella DE, Callander GE, Ma S, Bye CR, Gundlach AL and Bathgate RA, Modulation of feeding by chronic rAAV expression of a relaxin-3 peptide agonist in rat hypothalamus, Gene Ther, 2012, PMID: 23135160

6.

Ganella DE, Ryan PJ, Bathgate RA and Gundlach AL, Increased feeding and body weight gain in rats after acute and chronic activation of RXFP3 by relaxin-3 and receptor-selective peptides: functional and therapeutic implications, Behav Pharmacol, 23:516-25,2012, PMID: 22854307

7.

Gundlach AL, Ryan PJ. , Galanin, The Handbook of Biologically Active Peptides [Internet]. San Diego: Elsevier, 766-75, 2012,

8.

Gundlach AL, Smith CM, Ryan PJ, Blasiak A, Olucha-Bordonau FE, Ma S., Relaxins, The Handbook of Biologically Active Peptides [Internet]. San Diego, USA: Elsevier, 2012,

9.

Hossain MA, Wade JD and Bathgate RA, Chimeric relaxin peptides highlight the role of the A-chain in the function of H2 relaxin, Peptides, 35:102-6,2012, PMID: 22414484

10.

Nair VB, Samuel CS, Separovic F, Hossain MA and Wade JD, Human relaxin-2: historical perspectives and role in cancer biology, Amino Acids, 2012, PMID: 22855207

Natalie Witteveen •

Editor, Amino Acids, 2008-

Editorial Board Member, Chemical Biology & Drug Design, 2006-

Maria Oh

Poster; 7th International meeting on the Molecular Pharmacology of G Protein-Coupled Receptors, Melbourne, Australia, December 6th - 8th, 2012

Editorial Board Member, International Journal of Peptides, 2006-

Editorial Board Member, Frontiers in EndocrinologyMolecular and Structural Endocrinology, 2010-

Peptide and Protein Chemistry

{{Conferences

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 ovarian peptide, relaxin, and the neuropeptide, relaxin-3.

11.

2. 12th International Chinese Peptide Symposium, Shenyang, China (2012)

Olucha-Bordonau FE, Otero-Garcia M, Sanchez-Perez AM, Nunez A, Ma S and Gundlach AL, Distribution and targets of the relaxin-3 innervation of the septal area in the rat, J Comp Neurol, 520:1903-39,2012, PMID: 22134882

12.

3. 7th British Peptide & Protein Symposium, Cambridge, UK (2012)

Scott DJ and Pluckthun A, Direct Molecular Evolution of Detergent-Stable G Protein-Coupled Receptors using Polymer Encapsulated Cells, J Mol Biol, 2012, PMID: 23164568

13.

Scott DJ, Rosengren KJ and Bathgate RA, The Different Ligand-Binding Modes of Relaxin Family Peptide Receptors RXFP1 and RXFP2, Mol Endocrinol, 2012, PMID: 22973049

14.

Shabanpoor F, Akhter Hossain M, Ryan PJ, Belgi A, Layfield S, Kocan M, Zhang S, Samuel CS, Gundlach AL, Bathgate RA, Separovic F and Wade JD, Minimization of human relaxin-3 leading to high-affinity analogues with increased selectivity for relaxin-family peptide 3 receptor (RXFP3) over RXFP1, Journal of Medicinal Chemistry, 55:1671-81,2012, PMID: 22257012

15.

Shabanpoor F, Bathgate RA, Belgi A, Chan LJ, Nair VB, Wade JD and Hossain MA, Site-specific conjugation of a lanthanide chelator and its effects on the chemical synthesis and receptor binding affinity of human relaxin-2 hormone, Biochem Biophys Res Commun, 420:253-6,2012, PMID: 22425984

16.

Wade JD, Lin F, Hossain MA and Dawson RM, Chemical synthesis and biological evaluation of an antimicrobial peptide gonococcal growth inhibitor, Amino Acids, 2012, PMID: 22555649

17.

Zhang WJ, Luo X, Liu YL, Shao XX, Wade JD, Bathgate RA and Guo ZY, Site-specific DOTA/europium-labeling of recombinant human relaxin-3 for receptorligand interaction studies, Amino Acids, 43:983-92,2012, PMID: 22187146

``Research highlights for 2012 Our laboratory has continued to make significant progress in the identification of the key structural features of the insulinlike peptides, relaxin and relaxin-3, that are responsible for the binding and activation of their respective primary G-protein coupled receptors, RXFP1 and 3. Both peptides possess an insulin-like structure in which two peptides chains are linked together by three disulfide bonds. 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 possesses a similar overall structure but is a neuropeptide that is expressed by the brain and which appears to have a critical role in regulating mood and stress systems. Because of their similar global structures, relaxin-3 can cross react with the receptor for relaxin; this can potentially complicate our attempts to better understand the role of relaxin-3 in the brain because the relaxin receptor is also present in this organ.

1.

1st International Bachem Peptide Symposium, Basel, Switzerland (2012)

4. 32 European Peptide Symposium, Athens, Greece (2012) 5. Relaxin & Related Peptides 2012 Symposium, Florence, Italy (2012)

However, by using chemical peptide synthesis, selective amino acid mutation together with sequential truncation was undertaken on each of the two chains that make up each of relaxin-3 to produce novel mimetics. These were shown to possess relaxin-3 receptor selectivity while retaining nearnative potency. Importantly, these new analogues are much simpler structurally and therefore easier to make which will greatly facilitate the neurobiological studies that are being undertaken by our colleagues in the laboratory of Andrew Gundlach. Such studies will determine whether these analogues possess clinical potential for treating psychiatric disorders such as anxiety and depression. Parallel chemical methods have also

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

Psychotropic Drug Advisory Service

Psychotropic Drug Advisory Service

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.

HEAD, PROFESSOR NICHOLAS KEKS

The Psychotropic Drug Advisory Service 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 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. Professor Nicholas Keks, Deputy Chair of Rehabilitation, Psychiatry and Pain Clinical Institute, Epworth Hospital, provides clinical support to pharmacist Christine Culhane who manages the service. The service responds to approximately 2000 enquiries each year. Funding is provided by the Department of Human Services Victoria, Mental Health Division and is auspiced to the Florey Institute of Neuroscience and Mental Health.

CONFERENCES AND PRESENTATIONS  Society of Hospital Pharmacists of Australia Victorian Branch Summit, Melbourne, Australia (August 2012) Society of Hospital Pharmacists of Australia Annual Meeting, Canberra, Australia (November 2012)

Presentations Presentations to both professional and consumer groups are also part of the work undertaken by the service. Presentations have been requested by and provided to a number of professional and lay audiences. Ms Culhane 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 practising psychiatrists and trainees. Tutorials and online discussions for undergraduate and post graduate pharmacists have also been provided. Ms Culhane has also been to a number of carer and consumer support organisations to provide information on medications in a patient sensitive forum.

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HIGHLIGHTS

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. 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.

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

Delivering STROKE rehab through play ;

Using your body to guide a ball through a maze or shoot fish with bubbles is not the first thing that springs to mind when thinking about stroke recovery but it’s getting results.

Delivering stroke rehab through play

Fast facts on sTROKE $49.3 BILLION

;

The burden of disease cost was estimated at $49.3 billion putting it on par with 2010 burden of disease costs for depression and anxiety.

Stroke is the second most common cause of death and disability.

Florey Honorary and Melbourne Health physiotherapist, Kelly Bower, is working with Assoc Prof Bernhardt of the Florey’s Stroke Division, to study whether video games could assist in stroke rehabilitation. After originally working with existing technology, such as Nintendo Wii and Xbox Kinect, the research team quickly realised some of their limitations. “We realised the games could be too difficult, either cognitively or physically, and they might be giving inappropriate feedback – for example, being very negative when the user failed to win,” Ms Bower says. This prompted a switch to a customised product that was created by the research team and game developer, Current Circus. “We produced a suite of four mini-games that operate using a low-cost, depth-sensing camera that can track body movements without needing markers on the body or controllers,” Ms Bower says. “Three of the games involve moving the torso to do things like hitting or dodging things in the environment, and the other one involves upper limb movement to shoot bubbles at fish.”

Forty patients undergoing rehabilitation participated in the study and initial results are promising. “A lot of the people in the study are elderly and had never played video games before but most seemed to really enjoy them.” “We’re still analysing the data but in general terms, it appears these games challenge people both physically and cognitively in a different way than some traditional physiotherapy exercises. “Also, we can’t underestimate the importance of fun and enjoyment. If people are really engaged, they are more likely to learn and keep it up, so you might see them repeating the movements hundreds of times instead of the ten or 20 times like they might do it in traditional rehab.” Ms Bower said the study showed the enormous opportunity that was still untapped in the area of game-based rehab.

Internationally, about 15 million people have a stroke each year, six million die and about 30 per cent of the survivors have significant neurological impairment.

50,000

Associate Professor Julie Bernhardt (left), physiotherapist Julie Louie and Kelly Bower use a video game to help patient Brian in his recovery after a stroke

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There were about 50,000 strokes in Australia during 2012.

 There were 420,000 survivors of stroke in Australia in 2012. This will rise to 709,000 by 2032.

The cost of stroke is high due to immediate health care costs and long-term disability. In Australia, the Florey’s Associate Professor Dominique Cadilhac estimates first-year costs of approximately $25,000 for an ischemic stroke, and once long-term treatment costs, carer time costs and productivity loss are included, the lifetime costs for a first-ever event is conservatively estimated to be $65,000

The powerful acute therapy, thrombolysis with tissue plasminogen activator, is proving to be very useful but only a small proportion of stroke patients receive this potent drug.

 The Florey is leading the way in researching risk reduction through blood pressure control, clotting control and cholesterol lowering.

$

9%

Costs of stroke are largely borne by individuals ($2.2 billion) and federal government ($1.5 billion)

Australia spends on average nine per cent of our GDP on health care, or $4,900 per person. The rate is steadily climbing as our population ages.

“The games we have developed are still in a basic stage and we have really only looked at the physical side but there is also great potential in the area of cognitive training. It’s definitely an exciting field with enormous opportunity for further research.”

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Stroke

stroke

Stroke Preclinical Science The Stroke Preclinical Science team of 18 staff and students investigates the mechanisms and therapeutic potential of neuroprotection and neuroregeneration, the use of biomarkers to improve stroke management, and development of tools to improve drug development. The latter include use of stem cell-derived human neurones for high throughput screening of novel pharmaceutical agents, refinement of animal models of stroke, systematic review and meta-analysis of published data to understand past translational failure and provide evidence based selection of agents for clinical trial.

division

A QUICK SNAPSHOT

RESEARCH HIGHLIGHT

15 million strokes and 6 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, optimize existing therapies and develop new treatments to both prevent and reduce the impact of stroke.

Country patients suffering a suspected stroke can now receive expert neurological opinion from Melbourne – without leaving their hospital bed thanks to the Florey's Stroke Telemedicine program. The program attracted $7.9 million from state and federal governments in 2012. Patients with a suspected stroke now receive time-critical specialist neurological assessment from Melbourne – via high speed and quality broadband. Other funding partners include Telstra, Monash University and Department of Health through the Victorian Stroke Clinical Network. The result? A greater number of treatment options for patients with stroke, giving the best chance for a successful outcome.

The Division has five main research teams, Stroke Preclinical Science, the AVERT Early Intervention Research Program, the Neurorehabilitation and Recovery Laboratory, Epidemiology and Public Health, and Clinical Trials.

We led a worldwide review of both the weaknesses and strengths of internationally published data to help improve the rigour and reporting of preclinical neuroscience. These efforts have now been reported in Nature. The results press for greater transparency in science and describe how we should avoid wasting the estimated $85 billion a year lost in the production and reporting of research evidence.

 SENIOR STAFF Dr Amy Brodtmann Associate Professor David Howells Associate Professor Dominique Cadilhac Professor Geoff Donnan Associate Professor Julie Bernhardt Professor Leeanne Carey

``Research highlights for 2012 In 2012 we took on responsibility for running the worldwide CAMARADES collaboration which uses systematic review and meta-analysis to document both the weaknesses and strengths of our existing published data to help improve the rigor and reporting of preclinical neuroscience. These efforts have now been reported in Nature. An October 2012 meeting in London with the Editors of The Lancet agreed to the 2013 publication of a special edition edited by Sir Iain Chalmers to continue to press for greater transparency in science and detail how we should avoid wasting the $85 billion/year estimated to be lost in the production and reporting of research evidence each year. Using these tools has also been particularly important in identifying the facets of disease pathophysiology and model use which most critically determine outcome and identifying which classes of drug and which individual members of those classes are most worthy of future study. To allow screening of new chemical entities our program uses stem cell-derived human tissue culture assays to detect drugs which prevent ischemic injury or promote recovery. To ensure that subsequent in vivo testing is robust, we are developing new models of stroke designed to avoid the confounding effects of anaesthesia and technically demanding surgery. We have also played a lead role in establishing the Multi-PART (Multicentre Preclinical Animal Research Team; www.multi-part.org) consortium which will conduct preclinical experiments across multiple sites using the same rigor as demanded in randomized controlled clinical trials. To closely link outcome assessment in preclinical and proof of concept clinical trials we have developed a panel of ischemia responsive blood biomarkers These biomarkers also have the potential to provide a biological 'Stroke Clock' which can be used to safely maximize recruitment of patients to existing thrombolytic therapy.

 Collaborations •

International cooperation in preclinical stroke research: Multi-PART (Multicentre Preclinical Animal Research Team; www.multi-part.org)

The CAMRARADES collaboration (http://www.camarades.info)

Harvard, USA

Emory University, USA

CSIRO, Australia

Centre for Research Excellence in Stroke Rehabilitation and Brain Recovery, Australia

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Editorial positions •

International Journal of Stroke

Virtual Medical Centre

Journal of Experimental Stroke Translational Medicine

Translational Stroke Research

{{Conferences 1.

Hypothermia in animal stroke models. Stroke Society of Australia Meeting 2012 Sydney, Australia

2. Quality Control for Translational Stroke Research , World Congress of Neurology, 2012 Brasilia, Brazil 3. 1st International Symposium and Workshop on Systematic Reviews in Laboratory Animal Science Nijmegen, Netherlands 2012 4. Stroke genetics. International Stroke Genetics Conference Newcastle, Australia

AVERT Early Intervention Research Program 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 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 will be 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 aim to identify key mechanisms by which early exercise may improve the outcome of people affected by stroke.

``Research highlights for 2012 AVERT, an international, multicentre (52), randomised controlled trial. This is a single blind, Phase III trial with planned recruitment of 2104 patients (1052 each arm) and intention to treat analysis. Eligible patients are those admitted to hospitals with a stroke unit within 24 hours of stroke symptom onset. Patients over 18 years with confirmed stroke, who meet physiological entry criteria for safety are eligible. Patients who are treated with thrombolysis (rtPA) are also eligible. Those admitted directly to intensive care, or with pre-morbid disability (mRS>2) or other life threatening illness are excluded. Randomisation is completed online, and patients are stratified by stroke severity on admission (NIHSS) and by site. Those randomised to very early rehabilitation commence out of bed training within 24 hours of stroke, delivered by nurses and physiotherapists. This continues until 14 days or discharge (whichever comes first). Primary outcome is mRS at 3 months post stroke. Secondary outcomes include cost effectiveness, walking recovery, ADL, mood, cognitive function and quality of life. Follow up is completed at 12 months post stroke. Blinded assessors gather all follow up data. Recruitment at December 2012 was 1500 patients from 5 countries (Australia, New Zealand, Malaysia, Singapore, Northern Ireland, Wales, England, Scotland). This trial meets international clinical trials standards

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

and is overseen by an international Steering Committee, Data Safety and Monitoring Committee, with adverse events independently adjudicated by an Outcomes Committee. Further information about the trial can be found at the ANZCRT trials register: http://www.anzctr.org.au/trial_view.aspx?ID=1266

``Major research projects Factors influencing the decision to mobilise after treatment with thombolysis in AVERT: This was a retrospective audit of medical records from over 200 patients admitted to Austin Hospital, Melbourne and treated with thromoblysis. We explored patient, stroke and system (time/day of admission) factors in those patient recruited to the trial and those not recruited. One of the goals of this study was to determine whether the patients recruited into AVERT and treated with this drug were representative of the broader stroke population. We found that both groups were similar and this holds promise for the generalisation of data from the larger trial. *Changes in bone, glucose and muscle in the first 6 months after stroke: Having a stroke often leads to physical inactivity, and the combination of these two things can have a range of negative physiological effects. This study tracks changes in bone density, glucose metabolism and lean muscle mass after stroke and investigates the effect of physical activity on these physiological outcomes. The study has been extended in a subgroup who are being followed out to 2 years post stroke. Finding a valid screening tool for cognitive impairment after stroke: Cognitive impairment is a common and important consequence of stroke, yet cognitive outcomes are often ignored in stroke research trials. In this study, we established that the recently developed short screening tool (the Montreal Cognitive Assessment) is a valid measure of cognitive impairment after stroke. *Measuring cognitive function in acute stroke patients: Assessing cognitive function in those with recent stroke can be challenging. In this study we tested whether a simple computer based task that uses playing cards can be used within days of stroke to measure cognitive function and the relationship between early cognitive deficits and later problems. *Exercise preferences after stroke: Following on from a pilot study that found that stroke survivors had different and more variable exercise preferences than a group of age and sex-matched controls, we are undertaking the next phase of developing an exercise preference measurement tool for people with stroke. Understanding an individual’s preferred mode of exercise should help the design of rehabilitation programs that promote long term adherence to exercise. *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. Exploring the patterns of inactivity and use of time in people living with stroke related disability (EPIPS): Long periods of sedentary behaviour in daily activity can increase risk of further stroke and other cardiovascular events. This study explores sedentary behaviour in stroke survivors as baseline to developing an intervention that will aim to change inactivity.

Stroke

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 Collaborations

Neurorehabilitation and Recovery

Sweden, St Olav’s University Hospital, Norway, Melbourne Health, Australia

The Neurorehabilitation and Recovery Research Program • Washington University, St. Louis, USA focuses on stroke recovery: in particular how the brain • University of Haifa, Israel adapts and how we can harness that potential in rehabilitation. • La Trobe University, Melbourne, The research involves development Australia of novel rehabilitation approaches • CSIRO e-health flagship, Hunter based on neuroscience. MRI is used to Medical Research Institute, investigate how changes in the brain Newcastle, Australia can help target rehabilitation most • Centre for Brain and Mental Health optimally to individual stroke survivors. Research, University of Newcastle Our research includes the impact of • Assoc Prof Thomas Linden. depression and cognition on stroke Neurologist/psychiatrist, recovery. An important focus is to Gothenburg, Sweden translate these discoveries into clinical • University of Newcastle, Australia practice and better outcomes for Brain activation pre and post sensory treatment known as • University of Nottingham, UK stroke survivors. SENSe. Patient with lesion of primary sensory cortex showed

Editorial positions •

International Journal of Stroke, currently lead guest Editor of special ‘Rehabilitation’ edition

Topics in Stroke Rehabilitation

International Journal of Therapy and Rehabilitation

Journal for Neurologic Physical Therapy

Guest editor for special edition of Stroke Research and Treatment on ‘Physical activity, exercise and fatigue’

American Heart Association writing group “Physical Activity and Exercise Recommendations for Stroke Survivors.” (2012)

{{Conferences 1.

World Stroke Conference. Early mobilisation. More than just getting out of bed. Brazil

2. Sino-Australia Stroke Congress 2012: Clinical trials and Practice. Shanghai, China 3. Stroke Society of Australasia Scientific Meeting. Optimising mobility outcomes after stroke: Neuroscience bench to bedside stroke recovery. Sydney, Australia 4. Stroke Rehabilitation Research Satellite Meeting. Validity and standardisation in stroke rehabilitation research. Hunter Valley, Australia 5. Western Health. Allied Health & Nursing Keynote Address: Clinical Research - The joys, the challenges, the future. Melbourne, Australia 6. National Broadband Network Company (NBNCo). Sharing a knowledge of Stroke. Melbourne, Australia 7. Victorian Stroke Clinical Network Forum. Early Mobilisation – we’re not there yet! Melbourne, Australia 8. Victorian Clinical Research Network - Research Challenges Forum Attracting funding as an allied health clinician. Melbourne, Australia 9. The Florey Institute of Neuroscience and Mental Health, Stroke Division. Annual Scientific Meeting. Optimising neural plasticity in stroke rehabilitation and brain recovery. Melbourne, Australia 10. Austin Health, Department of Physiotherapy Research Symposium, Melbourne, Australia 11. Allied Health Research Forum: a showcase of published work. Eastern Health. Melbourne, Australia 12. Allied Health Research Forum: a showcase of published work, Austin Health. Melbourne, Australia 13. The changing face of stroke rehabilitation. Surgical Synergies, Melbourne, Australia

``Research highlights for 2012

 Collaborations •

Heinrich Heine University, Germany

return of activation in sensory regions of the ‘stroke’ hemisphere following a novel sensory rehabilitation program that is based on neuroscience. Change in brain activation was associated with improved touch sensation.

The Neurorehabilitation and Recovery Group, headed by Professor Leeanne Carey, has received support from the National Health and Medical Research Council in 2012 for the research project Effective sensory rehabilitation after stroke: Targeting viable brain networks. We will compare brain networks involved in recovery of touch sensation under two new training conditions and in individuals with interruption to different parts of the sensory network. 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. A second major focus has been the START longitudinal stroke cohort study. This study is being conducted in collaboration with the CSIRO Preventative-Health Flagship Program. Our aim is to identify biological factors, molecular and imaging, associated with poststroke depression and recovery that may be used to guide more targeted interventions. In 200 stroke survivors we will examine the relationship between gene expression, depression and functional outcome. A subgroup will also be investigated for functional and structural changes in putative depression-related brain networks, and for additional cognition and activity participation outcomes.

• Neurology, Austin Health, Melbourne, Australia

• Department of Psychological and Brain Sciences, Indiana University, USA

Department of OT Education, Kansas Medical Centre, USA

Dept of Occupational Science and Occupational Therapy and Graduate Dept. of Rehabilitation Science, University of Toronto, Canada

Dept of Clinical and Biological Neurosciences, Unversity. Hospital, Grenobel, France

School of Paediatric and Child Health, University of Western Australia, Australia

Faculty of Health Sciences, La Trobe University, Melbourne, Australia

Editorial positions •

Neurorehabilitation and Neural Repair

Occupational Therapy International

Australian Occupational Therapy Journal

Brain Impairment

{{Conferences

Following the success of our randomised controlled trial of sensory rehabilitation, published in 2011, in 2012 we developed a clinical practice manual, DVD and ran training workshops to 'up-skill' therapists in the application of this effective approach to sensory rehabilitation. This has been complemented by the development of evidence-based sensory assessments and training equipment to support therapists. Development of this multi-media package has been supported by philanthropic organisations and has received attention and demand worldwide. The therapy has been described as ‘life changing’ from stroke survivors.

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In 2012 Professor Carey edited the successful book Stroke Rehabilitation: Insights from Neuroscience and Imaging published by Oxford University Press. The aim is to inform and challenge rehabilitation specialists to adopt more restorative and scientific approaches to stroke rehabilitation based on evidence from neuroscience.

4. An fMRI study of the relative laterality of dominant and nondominant hand sensory function. International Society for Magnetic Resonance and Imaging (ISMRM)

We congratulate Drs Brian Hoare, Louise Bannister and Michaela Pascoe who have successfully completed their PhD studies in 2012 and welcome Brendan Haslam, Belinda Mclean and Essie Low who have started their PhD studies.

Neuroscience to Neurorehabilitation: Connecting new networks for everyday contact through touch. 7th World Congress of Neurorehabilitation. Melbourne, Australia, 16-19 May

2. Imaging neuroplasticity of touch after stroke: trainingfacilitated changes following intervention. Organization for Human Brain Mapping. Beijing China, June 10-1 3. An RCT of differing intensities of early upper limb training post stroke: Evidence of delayed neuroplastic changes in the ipsilesional SMA. 7th World Congress of Neurorehabilitation. Melbourne, Australia, May

5. Stroke Rehabilitation: Insights from Neuroscience and Imaging. 7th World Congress of Neurorehabilitation. Melbourne, Australia, May 6. Proprioceptive Perception: A behavioural and functional MRI study of its Hemispheric Dominance. 7th World Congress of Neurorehabilitation. Melbourne, Australia, May

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7. Impaired proprioceptive perception after stroke: A functional MRI study. World Congress of Neurorehabilitation. Melbourne, Australia, May 8. START-PrePARE – PREdiction and Prevention to Achieve Optimal Recovery Endpoints after stroke: Study rationale and protocol. 7th World Congress of Neurorehabilitation. Melbourne, Australia, 16-19 May

Public health and epidemiology Our group conducts various projects related to improving the clinical management of stroke, as well as having a focus on understanding and modifying risk factors to prevent 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 2012 2012 has been a year of growth and transition for the Public Health team overseen by Assoc Prof Cadilhac. One of our major achievements was the transfer of data custodianship of the Australian Stroke Clinical Registry (AuSCR) from The George Institute for Global Health. The expansion of AuSCR has continued under the leadership of the Florey with 34 hospitals approved in 2012. This work is also facilitated by a successful NHMRC Partnership grant received for the Stroke123 study, a 4-year project that commenced in 2012. The main aim of Stroke123 is to demonstrate that integrated and comprehensive stroke data coupled with an active and evidenced-based clinical practice improvement program is more effective than when compared to the status quo. This outcome will be facilitated by ensuring better use of existing stroke data in Australia to routinely monitor and improve the quality of care. The grant is being led by Assoc Prof Cadilhac and colleagues and the main partner organisations involved are the Florey Institute, National Stroke Foundation, Queensland Health and Monash University. We also welcomed Professor Chris Bladin to a more substantial role in our team whilst he is on sabbatical from Eastern Health until June 2013. Professor Chris Bladin, along with Assoc Prof Dominique Cadilhac, is directing our efforts in establishing Stroke Telemedicine across regional Victoria following successful grant funding from the Victorian government and the federal government Department of Health and Ageing. The initial Victorian Stroke Telemedicine program, conducted since 2010 with Bendigo Health, successfully completed recruitment of participants in 2012 and the final report will be released in 2013. In the area of Epidemiology, we also congratulate Dr Wen Wen Zhang who completed her PhD on BAT24, a study of BP patterns and outcomes in patients with TIA, compared to age and sex matched controls.

 Collaborations National The George Institute for Global Health; La Trobe University; Monash University; Hunter Stroke Service, NSW; New South Wales Health; National Stroke Foundation; Australian Catholic University; Centre for Translational Excellence in Neuroscience; St Vincent’s Hospital, NSW; Southern Clinical School; Queensland Statewide Stroke Clinical Network; Victorian Stroke Clinical

Network; Victorian Statewide Stroke Clinical Network; Edith Cowan University, Western Australia; University of Western Australia; Stroke and Ageing Research, Southern Clinical School, Monash University; South Australian Statewide Stroke Clinical Network; NSW Statewide Stroke Clinical Network; Queensland Health; Southern Clinical School, Monash University; Telehealth Connect; NBNCo; Loddon Mallee Rural Health Alliance; Bendigo Health, Australia; Telstra, Australia; Polycom. International Michigan State University, USA; Ottawa Hospital Research Institute, Canada; Stroke and Ageing Research.

Editorial positions •

Cadilhac: Clinical Audit, Dove Medical Press and World Journal of Hypertension

Dewey: Stroke journal and International Journal of Stroke

Bladin: Current Neurology and Neuroscience Reports and British Journal of Sports Medicine

{{Conferences 1.

Evaluating the outcomes of the Victorian Stroke Clinical Network (VSCN) placements of Stroke Network Facilitators in selected health services. The Australasian Clinical Networks Conference, Sydney, Australia, 21-23 November

2. Transfer of patients between small and large rural hospitals: experience from the rural stroke project, Australia. 8th World Stroke Congress, Brasilia, Brazil 3. Enhancing stroke care in Australian hospitals: experience from the Victorian Stroke Clinical Network program. 8th World Stroke Congress, Brasilia, Brazil 4. How to survive and thrive in medical research. Heathcote Diabetes Support group: Understanding stroke and diabetes. Alfred Medical Research Precinct Early Career Researcher retreat, Dandenong Ranges, Australia 5. Establishment of a counsellor education program for stroke: a National Stroke Foundation (NSF) initiative. Stroke Society of Australasia, Sydney, Australia 6. Is it worthwhile to measure diabetes risk in the community as part of the Know your numbers (KYN) Program. Stroke Society of Australasia, Sydney, Australia 7. The effectiveness of the Rural Stroke Project: impact on clinical care and patient outcomes. European Stroke Conference, Lisbon, Portugal 8. Health economics – cost of health practice change. Melbourne Brain Centre at the Royal Melbourne Hospital, Partnership Strategies Forum, Melbourne, Australia 9. Research and Translation – Major Concepts and Strategies. Australian Prostate Cancer Research Centre Planning Conference. Geelong, Australia 10. The Australian Stroke Clinical Registry: contributing to the quality of care & treatment outcomes in stroke. AuSCR Management Committee. Austin Hospital Research Week, Melbourne, Australia

Stroke

13. Clinical use of telemedicine for acute stroke care in a regional area: pilot results from the Victorian Stroke Telemedicine (VST) project. Stroke Society of Australasia 2012 Annual Scientific Meeting. Sydney, Australia 14. Development of a telemedicine program for acute stroke: The Victorian Stroke Telemedicine (VST) project. 2nd International Conference on Global Telehealth, Sydney, Australia 15. What are the factors that influence low thrombolysis rates in a regional hospital. Stroke Society of Australasia Annual Scientific Meeting. Sydney, Australia 16. The Australian Stroke Clinical Registry – 2012 update, Registries Special Interest Group 17. Women's Public Health Research Presentation: A taste of Translational Public Health Unit (Stroke & Ageing Research): Research into prevention, clinical care and outcomes of stroke, SPHPM, Monash University, Monash Health Research Precinct, Melbourne, Australia 18. 3rd Annual Reducing Hospital Readmissions and discharge planning conference: identify, predict and prevent unplanned readmissions: Hospital readmission after Stroke. Melbourne Rendezvous Hotel The value of random blood glucose testing as part of diabetes risk assessments in the Know your numbers (KYN) Diabetes Program. Stroke Society Australasia Meeting. Sydney, Australia 19. Improvements in quality of care for stroke patients between 2009 and 2011. Stroke Society Australasia Meeting. Sydney, Australia 20. StrokeSafe Education Program: Delivering stroke prevention messages to raise community awareness and the profile of stroke. Stroke Society Australasia Meeting. Sydney, Australia 21. Blood pressure variability post-TIA or minor stroke. Stroke Society of Australasia Scientific Meeting 2012 22. Agreement between clinic BP and 24-hour ambulatory BP measurements. Hypertension Sydney 2012 meeting, 24th scientific meeting of the International Society of Hypertension 23. Comparison of circadian blood pressure patterns between patients with TIA or minor stroke and controls. Hypertension Sydney 2012 meeting, 24th scientific meeting of the International Society of Hypertension 24. Circadian BP pattern and recurrent stroke risk post-TIA or minor stroke. International Society of Hypertension new investigators symposium 25. The emergence of stroke rehabilitation in China: A systematic review, 5840 patients, positive effect but questionable quality. 26. Smart Strokes/Annual Scientific Meeting Stroke Society of Australasia, ‘Endovascular therapy for acute ischaemic stroke: should it only be offered in the clinical trial setting?’

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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 9 hours from 4.5 hours and that clot removal with the SOLITAIRE device may improve outcomes. A further study in which the hypothesis that administration of tranexamic acid (a clot promoting agent) may improve outcomes in patients with haemorrhagic stroke by minimising further bleeding into the brain has just commenced. Analysis is being completed on two earlier trials (ARCH trial - prevention of second stroke events in patients with stroke caused by clots coming from the main artery from the heart; DICE trial - Minimising complications post removal of narrowing of the carotid artery (endarterectomy) using the agent dextran given intravenously) and will be submitted for publication.

 Collaborations 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 at Newcastle, Greg Albers at Standford University USA, Pierre Amarenco, Paris, France and Werner Hacke, Heidelberg, Germany.

Editorial positions •

Journal of Neuroimaging, American Society of Neuroimaging, 2001-

International Advisory Board, Lancet Neurology, 2002-

Editor-in-Chief, International Journal of Stroke (Blackwell Publishing), 2005-

Editorial Advisory Board, Annals of Indian Academy of Neurology, 2006-

Editorial Board, Stroke Research and Treatment, 2009-

{{Conferences 1.

Ensuring quality care and support after stroke, 7th World Congress for Neurorehabilitation, Melbourne, Australia

2. Advances in stroke research, Australian E-Health Research Colloquium, Adelaide, Australia 3. The burden of stroke, Sino-Australia Stroke Congress, China 4. Treatment of acute ischaemic stroke: current status and future perspectives, Japanese Stroke Society, Tokyo, Japan 5. Coordination of stroke research for NINDS for the next five years, NINDS Planning Meeting, Bethesda, USA

Clinical Trials

6. How to write a paper, World Stroke Congress, Brasilia, Brazil

The Clinical Trials Platform crosses an array of clinical trial initiatives in stroke. The platform services of Neuroscience Trials Australia (NTA) which is housed within the Florey are utilised. These include statistical, data storage and management, regulatory and monitoring issues.

8. Extending the time window for ischaemic stroke therapy, Karolinska Stroke Meeting, Sweden

11. Development of a telemedicine model: The Victorian Stroke Telemedicine Project (VST). Austin Health Research Week, Melbourne, Australia

``Research highlights for 2012

12. Development of a telemedicine model: The Victorian Stroke Telemedicine Project (VST). 21st European Stroke Conference Lisbon, Portugal

The main focus of clinical trial activity has been around the extended time window for neurological deficits (EXTEND) series of trials. This is in partnership with Professor Stephen

7. Extending the time window for stroke, World Stroke Congress, Brasilia, Brazil

9. Atrial fibrillation and stroke, Israel Neurological Society, Eilat, Israel 10. Neuroscience in Victoria, Israel Neurological Society, Tel Aviv, Israel 11. Stroke in Asia, Asian Oceanic Congress of Neurology, Melbourne, Australia

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

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publications

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Abbott AL, Adelman MA, Alexandrov AV, Barnett HJ, Beard J, Bell P, Bjorck M, Blacker D, Buckley CJ, Cambria RP, Comerota AJ, Connolly ES, Jr., Davies AH, Eckstein HH, Faruqi R, Fraedrich G, Gloviczki P, Hankey GJ, Harbaugh RE, Heldenberg E, Kittner SJ, Kleinig TJ, Mikhailidis DP, Moore WS, Naylor R, Nicolaides A, Paraskevas KI, Pelz DM, Prichard JW, Purdie G, Ricco JB, Riles T, Rothwell P, Sandercock P, Sillesen H, Spence JD, Spinelli F, Tan A, Thapar A, Veith FJ, Zhou W. Why the United States Center for Medicare and Medicaid Services (CMS) should not extend reimbursement indications for carotid artery angioplasty/stenting. Eur J Vasc Endovasc Surg. 2012;43:247-251

24. Cosgrave L, Bernhardt J, Churilov L, Indredavik B and Cumming T, Gender and being born overseas influences the amount of acute stroke therapy, J Rehabil Med, 2012, PMID: 23223859

Abbott AL, Adelman MA, Alexandrov AV, Barnett HJ, Beard J, Bell P, Bjorck M, Blacker D, Buckley CJ, Cambria RP, Comerota AJ, Sander Connolly E, Davies AH, Eckstein HH, Faruqi R, Fraedrich G, Gloviczki P, Hankey GJ, Harbaugh RE, Heldenberg E, Kittner SJ, Kleinig TJ, Mikhailidis DP, Moore WS, Naylor R, Nicolaides A, Paraskevas KI, Pelz DM, Prichard JW, Purdie G, Ricco JB, Riles T, Rothwell P, Sandercock P, Sillesen H, David Spence J, Spinelli F, Tan A, Thapar A, Veith FJ, Zhou W. Why the United States Center for Medicare and Medicaid Services should not extend reimbursement indications for carotid artery angioplasty/stenting. Vascular. 2012;20:1-7

26. Davis SM and Donnan GA, Clinical practice: Secondary prevention after ischemic stroke or transient ischemic attack, N Engl J Med, 366:1914-22,2012, PMID: 22591297

Abbott AL, Adelman MA, Alexandrov AV, Barnett HJ, Beard J, Bell P, Bjorck M, Blacker D, Buckley CJ, Cambria RP, Comerota AJ, Sander Connolly E, Davies AH, Eckstein HH, Faruqi R, Fraedrich G, Gloviczki P, Hankey GJ, Harbaugh RE, Heldenberg E, Kittner SJ, Kleinig TJ, Mikhailidis DP, Moore WS, Naylor R, Nicolaides A, Paraskevas KI, Pelz DM, Prichard JW, Purdie G, Ricco JB, Riles T, Rothwell P, Sandercock P, Sillesen H, David Spence J, Spinelli F, Tan A, Thapar A, Veith FJ, Zhou W. Why the United States center for Medicare and Medicaid Services (CMS) should not extend reimbursement indications for carotid artery angioplasty/ stenting. Brain and Behavior. 2012;2:200-207 Abbott AL, Adelman MA, Alexandrov AV, Barnett HJ, Beard J, Bell P, Bjorck M, Blacker D, Buckley CJ, Cambria RP, Comerota AJ, Connolly ES, Jr., Davies AH, Eckstein HH, Faruqi R, Fraedrich G, Gloviczki P, Hankey GJ, Harbaugh RE, Heldenberg E, Kittner SJ, Kleinig TJ, Mikhailidis DP, Moore WS, Naylor R, Nicolaides A, Paraskevas KI, Pelz DM, Prichard JW, Purdie G, Ricco JB, Riles T, Rothwell P, Sandercock P, Sillesen H, Spence JD, Spinelli F, Tan A, Thapar A, Veith FJ, Zhou W. Why the US Center for Medicare and Medicaid Services should not extend reimbursement indications for carotid artery angioplasty/stenting. Angiology. 2012;63:639-644 Abbott AL, Adelman MA, Alexandrov AB, Barnett HJ, Beard J, Bell P, Bjorck M, Blacker D, Buckley CJ, Cambria RP, Comerota AJ, Sander E, Davies AH, Eckstein HH, Fraedrich G, Gloviczki P, Hankey GJ, Harbaugh RE, Heldenberg E, Kittner SJ, Kleinig TJ, Mikhailidis DP, Moore WS, Naylor R, Nicolaides A, Paraskevas KI, Pelz DM, Prichard JW, Purdie G, Ricco JB, Riles T, Rothwell P, Sandercock P, Sillesen H, Spence JD, Spinelli F, Tan A, Thapar A, Veith FJ, Zhou W. Why the United States Center for Medicare and Medicaid Services (CMS) should not extend reimbursement indications for carotid artery angioplasty/stenting. Int. Angiology. 2012;31:85-89

6.

Abbott AL. Carotid surgery or stenting following neck irradiation: Time to address the assumptions. Eur J Vasc Endovasc Surg: 2012;43:8-9

7.

Abbott AL. Proximal internal carotid artery stenosis: Time to capitalise on current knowledge. In: Davies AH, ed. Fast facts. 2012.

8.

Ankolekar S, Rewell S, Howells DW and Bath PM, The influence of stroke risk factors and comorbidities on assessment of stroke therapies in humans and animals, Int J Stroke, 7:386-97,2012, PMID: 22712740

9.

Antonic A and Howells DW, Human in vitro models of ischaemic stroke: A test bed for translation, Translational Stroke Research, 3:306-309,2012,

10.

Artto V, Putaala J, Strbian D, Meretoja A, Piironen K, Liebkind R, Silvennoinen H, Atula S and Happola O, Stroke mimics and intravenous thrombolysis, Ann Emerg Med, 59:27-32,2012, PMID: 22000770

11.

Askim T, Bernhardt J, Loge AD and Indredavik B, Stroke patients do not need to be inactive in the first two-weeks after stroke: results from a stroke unit focused on early rehabilitation, Int J Stroke, 7:25-31,2012, PMID: 22103927

12.

Banks G, Bernhardt J, Churilov L and Cumming TB, Exercise preferences are different after stroke, Stroke Res Treat, 2012:890946,2012, PMID: 21860809

13.

Bivard A and Parsons M, ASPECTaSaurus (a dinosaur)?, Int J Stroke, 7:564,2012, PMID: 22989390

14.

Bladin C, Victorian Stroke Telemedicine [Guest editorial], Pulse+IT Magazine, 8-10,2012,

15.

Borschmann K, Exercise protects bone after stroke, or does it? A narrative review of the evidence, Stroke Research and Treatment, 2012:103697,2012, PMID: 22007349

16.

Borschmann K, Pang MY, Bernhardt J and Iuliano-Burns S, Stepping towards prevention of bone loss after stroke: a systematic review of the skeletal effects of physical activity after stroke, Int J Stroke, 7:330-5,2012, PMID: 21967614

25. Cumming TB, Brodtmann A, Darby D and Bernhardt J, Cutting a long story short: Reaction times in acute stroke are associated with longer term cognitive outcomes, J Neurol Sci, 2012, PMID: 22819353

27. Donnan GA, Celebrating research!, Int J Stroke, 7:605,2012, PMID: 23134545 28. Donnan GA, Mentors, Int J Stroke, 7:443,2012, PMID: 22805572 29. Donnan GA, Multidisciplinary stroke management, Int J Stroke, 7:275,2012, PMID: 22583521 30. Donnan GA, Translational research: a critical point in time, Int J Stroke, 7:367,2012, PMID: 22712736 31.

Donnan GA, Why should you support the WSO?, Int J Stroke, 7:103,2012, PMID: 22264363

32. Donnan GA and Davis SM, IST-3: a major contribution to thrombolysis research, Int J Stroke, 7:566-7,2012, PMID: 22989392 33. Donnan GA and Davis SM, Stroke: Expanded indications for stroke thrombolysis-what next?, Nat Rev Neurol, 2012, PMID: 22847384 34. English C, Thoirs K, Coates A, Ryan A and Bernhardt J, Changes in fat mass in stroke survivors: a systematic review, Int J Stroke, 7:491-8,2012, PMID: 22594664 35. English CK, Thoirs KA, Fisher L, McLennan H and Bernhardt J, Ultrasound is a reliable measure of muscle thickness in acute stroke patients, for some, but not all anatomical sites: a study of the intra-rater reliability of muscle thickness measures in acute stroke patients, Ultrasound Med Biol, 38:368-76,2012, PMID: 22266233 36. Goh C, Churilov L, Mitchell P, Dowling R and Yan B, Clopidogrel Hyper-Response and Bleeding Risk in Neurointerventional Procedures, AJNR Am J Neuroradiol, 2012, PMID: 23275598 37. Graven C, Sansonetti D, Moloczij N, Cadilhac D and Joubert L, Stroke survivor and carer perspectives of the concept of recovery: a qualitative study, Disabil Rehabil, 2012, PMID: 22889405 38. Greving JP, Schonewille WJ, Wijman CA, Michel P, Kappelle LJ and Algra A, Predicting outcome after acute basilar artery occlusion based on admission characteristics, Neurology, 78:1058-63,2012, PMID: 22442438 39. Hakkennes S, Hill KD, Brock K, Bernhardt J and Churilov L, Accessing inpatient rehabilitation after acute severe stroke: age, mobility, prestroke function and hospital unit are associated with discharge to inpatient rehabilitation, Int J Rehabil Res, 2012, PMID: 22728683 40. Hakkennes S, Hill KD, Brock K, Bernhardt J, Churilov L., Selection for inpatient rehabilitation after severe stroke: what factors influence rehabilitation assessor decision-making? , Journal of rehabilitation medicine, Oct 25, 2012, 41.

Hankey GJ, Eikelboom JW, Yi Q, Lees KR, Chen C, Xavier D, Navarro JC, Ranawaka UK, Uddin W, Ricci S, Gommans J and Schmidt R, Antiplatelet therapy and the effects of B vitamins in patients with previous stroke or transient ischaemic attack: a post-hoc subanalysis of VITATOPS, a randomised, placebo-controlled trial, Lancet Neurol, 11:512-20,2012, PMID: 22554931

42. Head R and et al, Stroke study seeks to improve therapeutic window, Medical Journal of Australia, 196:552,2012, 43. Helsinki Stroke Thrombolysis Registry Group, Cerebral edema in acute ischemic stroke patients treated with intravenous thrombolysis, Int J Stroke, 2012, PMID: 22405327 44. Helsinki Stroke Thrombolysis Registry Group, Does time of day or physician experience affect outcome of acute ischemic stroke patients treated with thrombolysis? A study from Finland, Int J Stroke, 7:511-6,2012, PMID: 22494345 45. Helsinki Stroke Thrombolysis Registry Group, Intravenous thrombolysis for acute ischemic stroke patients presenting with mild symptoms, Int J Stroke, 2012, PMID: 22568877 46. Howells DW and Macleod MR, Translational research, Int J Stroke, 7:367-8,2012, PMID: 22712735

17.

Cadilhac DA, The economics of atrial fibrillation: a time for review and prioritization, Int J Stroke, 7:477-9,2012, PMID: 22805574

47. Howells DW, Sena ES, O'Collins V and Macleod MR, Improving the efficiency of the development of drugs for stroke, Int J Stroke, 7:371-7,2012, PMID: 22712738

18.

Cadilhac DA, Amatya B, Lalor E, Rudd A, Lindsay P and Asplund K, Is there evidence that performance measurement in stroke has influenced health policy and changes to health systems?, Stroke, 43:3413-20,2012, PMID: 23185049

48. Hubbard IJ, Harris D, Kilkenny MF, Faux SG, Pollack MR and Cadilhac DA, Adherence to Clinical Guidelines Improves Patient Outcomes in Australian Audit of Stroke Rehabilitation Practice, Arch Phys Med Rehabil, 2012, PMID: 22480546

19.

Cadilhac DA, Carter R, Thrift AG and Dewey HM, Organized Blood Pressure Control Programs to Prevent Stroke in Australia: Would They Be Cost-Effective?, Stroke, 2012, PMID: 22363058

49. Kilkenny MF, Harris DM, Ritchie EA, Price C and Cadilhac DA, Hospital management and outcomes of stroke in Indigenous Australians: evidence from the 2009 Acute Care National Stroke Audit, Int J Stroke, 2012, PMID: 22299773

20. Campbell BC, Christensen S, Levi CR, Desmond PM, Donnan GA, Davis SM and Parsons MW, Comparison of Computed Tomography Perfusion and Magnetic Resonance Imaging Perfusion-Diffusion Mismatch in Ischemic Stroke, Stroke, 2012, PMID: 22858726

50. Kim J, Gall SL, Dewey HM, Macdonell RA, Sturm JW and Thrift AG., Baseline smoking status and the long-term risk of death or nonfatal vascular event in people with stroke: a 10-year survival analysis, Stroke, 43:3173-8,2012, PMID: 23103491

21.

51.

Campbell BC, Christensen S, Parsons MW, Churilov L, Desmond PM, Barber PA, Butcher KS, Levi CR, De Silva DA, Lansberg MG, Mlynash M, Olivot JM, Straka M, Bammer R, Albers GW, Donnan GA and Davis SM, Advanced imaging improves prediction of hemorrhage after stroke thrombolysis, Ann Neurol, 2012, PMID: 23444008

22. Carey LM and Matyas TA, Response to Four weeks (10 sessions) of individual sensory discrimination training produced clinically important changes in upper limb sensation after stroke, Aust Occup Ther J, 59:168-9,2012, PMID: 22448999 23. Churilov L, Liu D, Ma H, Christensen S, Nagakane Y, Campbell B, Parsons MW, Levi CR, Davis SM and Donnan GA, Multiattribute selection of acute stroke imaging software platform for Extending the Time for Thrombolysis in Emergency Neurological Deficits (EXTEND) clinical trial, Int J Stroke, 2012, PMID: 22812698

Landis SC, Amara SG, Asadullah K, Austin CP, Blumenstein R, Bradley EW, Crystal RG, Darnell RB, Ferrante RJ, Fillit H, Finkelstein R, Fisher M, Gendelman HE, Golub RM, Goudreau JL, Gross RA, Gubitz AK, Hesterlee SE, Howells DW, Huguenard J, Kelner K, Koroshetz W, Krainc D, Lazic SE, Levine MS, Macleod MR, McCall JM, Moxley RT, 3rd, Narasimhan K, Noble LJ, Perrin S, Porter JD, Steward O, Unger E, Utz U and Silberberg SD, A call for transparent reporting to optimize the predictive value of preclinical research, Nature, 490:187-91,2012, PMID: 23060188

52. Lees JS, Sena ES, Egan KJ, Antonic A, Koblar SA, Howells DW and Macleod MR, Stem cell-based therapy for experimental stroke: A systematic review and meta-analysis, Int J Stroke, 2012, PMID: 22687044 53. Lenggenhager B, Loetscher T, Kavan N, Pallich G, Brodtmann A, Nicholls ME and Brugger P, Paradoxical extension into the contralesional hemispace in spatial neglect, Cortex, 48:1320-8,2012, PMID: 22115281

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local and international prize winners during 2012

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publications 54. Ly JV, Rowe CC, Villemagne VL, Zavala JA, Ma H, Sahathevan R, O'Keefe G, Gong SJ, Gunawan R, Churilov L, Saunder T, Ackerman U, Tochon-Danguy H and Donnan GA, Subacute Ischemic Stroke Is Associated With Focal 11C PiB Positron Emission Tomography Retention But Not With Global Neocortical Abeta Deposition, Stroke, 2012, PMID: 22492514 55. Ma H, Parsons MW, Christensen S, Campbell BC, Churilov L, Connelly A, Yan B, Bladin C, Phan T, Barber AP, Read S, Hankey GJ, Markus R, Wijeratne T, Grimley R, Mahant N, Kleinig T, Sturm J, Lee A, Blacker D, Gerraty R, Krause M, Desmond PM, McBride SJ, Carey L, Howells DW, Hsu CY, Davis SM and Donnan GA, A multicentre, randomized, double-blinded, placebo-controlled Phase III study to investigate EXtending the time for Thrombolysis in Emergency Neurological Deficits (EXTEND), Int J Stroke, 7:74-80,2012, PMID: 22188854 56. Magnus A, Cadilhac D, Sheppard L, Cumming T, Pearce D and Carter R, The Economic Gains of Achieving Reduced Alcohol Consumption Targets for Australia, Am J Public Health, 2012, PMID: 22594720 57. Meretoja A, [Stroke--an expensive public health issue in Finland], Duodecim, 128:139-46,2012, PMID: 22372069 58. Meretoja A and Kaste M, Pre- and in-hospital intersection of stroke care, Ann N Y Acad Sci, 1268:145-51,2012, PMID: 22994234 59. Meretoja A, Strbian D, Mustanoja S, Tatlisumak T, Lindsberg PJ and Kaste M, Reducing in-hospital delay to 20 minutes in stroke thrombolysis, Neurology, 79:306-13,2012, PMID: 22622858 60. Meretoja A, Strbian D, Putaala J, Curtze S, Haapaniemi E, Mustanoja S, Sairanen T, Satopaa J, Silvennoinen H, Niemela M, Kaste M and Tatlisumak T, SMASH-U: A Proposal for Etiologic Classification of Intracerebral Hemorrhage, Stroke, 2012, PMID: 22858729 61.

Meretoja A, Strbian D, Putaala J, Kaste M and Tatlisumak T, Hemiplegia and thrombolysis, European journal of neurology : the official journal of the European Federation of Neurological Societies, 2012, PMID: 22519602

62. Nagakane Y, Christensen S, Ogata T, Churilov L, Ma H, Parsons MW, Desmond PM, Levi CR, Butcher KS, Davis SM and Donnan GA, Moving Beyond a Single Perfusion Threshold to Define Penumbra: A Novel Probabilistic Mismatch Definition, Stroke, 2012, PMID: 22499579 63. Noonan K, Carey LM and Crewther SG, Meta-analyses Indicate Associations between Neuroendocrine Activation, Deactivation in Neurotrophic and Neuroimaging Markers in Depression after Stroke, J Stroke Cerebrovasc Dis, 2012, PMID: 23149149 64. O'Collins VE, Macleod MR, Donnan GA and Howells DW, Evaluation of combination therapy in animal models of cerebral ischemia, J Cereb Blood Flow Metab, 2012, PMID: 22293990 65. Pascoe MC, Crewther SG, Carey LM, Noonan K, Crewther DP and Linden T, Homocysteine as a potential biochemical marker for depression in elderly stroke survivors, Food Nutr Res, 56:2012, PMID: 22509143 66. Phan TG, Thrift A, Cadilhac D and Srikanth V, A plea for the use of systematic review methodology when writing guidelines and timely publication of guidelines, Intern Med J, 42:1369-71,2012, PMID: 23253008 67. Randall M, Imms C and Carey L, Further evidence of validity of the Modified Melbourne Assessment for neurologically impaired children aged 2 to 4 years, Dev Med Child Neurol, 54:424-8,2012, PMID: 22390189 68. Sahathevan R, Brodtmann A and Donnan GA, Dementia, stroke, and vascular risk factors; a review, Int J Stroke, 7:61-73,2012, PMID: 22188853 69. Said CM, Morris ME, Woodward M, Churilov L and Bernhardt J, Enhancing physical activity in older adults receiving hospital based rehabilitation: a phase II feasibility study, BMC Geriatr, 12:26,2012, PMID: 22676723 70. Seitz RJ, Sukiennik J and Siebler M, Outcome after systemic thrombolysis is predicted by age and stroke severity: an open label experience with recombinant tissue plasminogen activator and tirofiban, Neurol Int, 4:e9,2012, PMID: 23139853 71.

Sena ES, Jeffreys AL, Cox SF, Sastra SA, Churilov L, Rewell S, Batchelor PE, Vander Worp HB, Macleod MR and Howells DW, The benefit of hypothermia in experimental ischemic stroke is not affected by pethidine, Int J Stroke, 2012, PMID: 22759525

72. Sharma V, Ling TW, Rewell SS, Hare DL, Howells DW, Kourakis A and Wookey PJ, A novel population of alpha-smooth muscle actin-positive cells activated in a rat model of stroke: an analysis of the spatio-temporal distribution in response to ischemia, J Cereb Blood Flow Metab, 2012, PMID: 22805872 73. Strbian D, Engelter S, Michel P, Meretoja A, Sekoranja L, Ahlhelm FJ, Mustanoja S, Kuzmanovic I, Sairanen T, Forss N, Cordier M, Lyrer P, Kaste M and Tatlisumak T, Symptomatic intracranial hemorrhage after stroke thrombolysis: the SEDAN score, Ann Neurol, 71:634-41,2012, PMID: 22522478 74. Strbian D, Meretoja A, Ahlhelm FJ, Pitkaniemi J, Lyrer P, Kaste M, Engelter S and Tatlisumak T, Predicting outcome of IV thrombolysis-treated ischemic stroke patients: the DRAGON score, Neurology, 78:427-32,2012, PMID: 22311929 75. Thrift AG and Arabshahi S, Is stroke incidence in low- to middle-income countries driven by economics?, Int J Stroke, 7:307-8,2012, PMID: 22583522 76. Thrift AG, Srikanth VK, Nelson MR, Kim J, Fitzgerald SM, Gerraty RP, Bladin CF, Phan TG and Cadilhac DA, Risk factor management in survivors of stroke: a double-blind, cluster-randomized, controlled trial, Int J Stroke, 2012, PMID: 23231528 77.

van Wijk R, Cumming T, Churilov L, Donnan G and Bernhardt J, An early mobilization protocol successfully delivers more and earlier therapy to acute stroke patients: further results from phase II of AVERT, Neurorehabilitation and neural repair, 26:20-6,2012, PMID: 21807984

78. West T and Bernhardt J, Physical activity in hospitalised stroke patients, Stroke Res Treat, 2012:1-13,2012, PMID: 21966599 79. Wright L, Hill KM, Bernhardt J, Lindley R, Ada L, Bajorek BV, Barber PA, Beer C, Golledge J, Gustafsson L, Hersh D, Kenardy J, Perry L, Middleton S, Brauer SG and Nelson MR, Stroke management: updated recommendations for treatment along the care continuum, Intern Med J, 42:562-569,2012, PMID: 22616960 80. Yoo AJ, Sheth KN, Kimberly WT, Chaudhry ZA, Elm JJ, Jacobson S, Davis SM, Donnan GA, Albers GW, Stern BJ and Gonzalez RG, Validating Imaging Biomarkers of Cerebral Edema in Patients with Severe Ischemic Stroke, J Stroke Cerebrovasc Dis, 2012, PMID: 22325573 81.

Dr Ben Emery (MS), Shawna Farquharson (Imaging), Dr Jee Hyun Kim and Dr Emma Burrows (Behavioural Neuroscience) - local and international prize winners during 2012

Zheng AS, Churilov L, Colley RE, Goh C, Davis SM and Yan B, Association of Aspirin Resistance With Increased Stroke Severity and Infarct Size, Arch Neurol, 1-6,2012, PMID: 23165316

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the future of our science

THE FUTURE OF OUR SCIENCE ;

The future of brain research lies in the hands of our upcoming generations. It is they who will spark the next breakthroughs and innovations in medical research. At the Florey, this falls in the capable hands of our undergraduate and postgraduate students, and early-career researchers who are already showing great initiatives in leading the next generation. Our young researchers are an active, collegial group, supported by the Florey Postdoctoral Association (FPA) and Students of the Florey Institute (SOFI) programs. These associations organise events to promote networking, mentoring as well as seminars and scientific activities. In addition to these internal Florey programs, 2012 saw the rise of two notable Melbourne-wide brain research ventures; the THINK ABOUT IT School Outreach Program, and the SOBR Network. The THINK ABOUT IT School Outreach Program came to light with the simple objective of bringing awareness about the brain to Victorian secondary school students. A packed school curriculum means little time for exposure to neuroscience-related learning and our outreach program fills this gap. We send volunteer researchers to share their experiences to enlighten school students and teachers about the wonders of the brain. Dr Joanne Britto (Florey Research Fellow) pioneered the program and coordinates schools and speakers to meet during International Brain Awareness Week in March every year. In 2012, the outreach program has grown to reach over 2500 teenagers at 24 schools across metropolitan Melbourne and country Victoria. This year 26 Florey researchers devoted time to this cause and also spoke very positively of the experience. Following great feedback, the program has, and will continue to, educate and promote brain awareness in the hope of inspiring students to be involved with neuroscience. For more information, or to get your high-school involved, please see www.florey.edu.au/news-events/ news/2012-12-06

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The SOBR (Students of Brain Research) network is a Melbourne-wide scientific affiliation dedicated to career development and support for early-career neuroscience researchers. Since its conception by Floreybased researchers, Jo Stratton, Christina Mo and Lizzie Manning, the network has hosted many academic and networking events to promote the development of scientific rigor and effective communication in an encouraging environment. In only its second year, SOBR has gathered great momentum in 2012 with the membership base from approximately 15 institutes and universities in Victoria doubling to over 400. The network encompasses many domains within neuroscience from the cellular, molecular and behavioural neuroscience to neurophysiology, psychology, psychiatry and neuroengineering. In 2012, the Student Brain Symposium hosted approximately $4000 in prize money, 85 student presenters and just over 180 attendees. The success of the SOBR network has been demonstrated not only by these highly-regarded annual events, but has also drawn recognition from the University of Melbourne Graduate Student Association with Lizzie Manning, the SOBR cofounder, winning the inaugural Graduate Student of the Year award. A special thanks goes to Florey-based student researchers Ayaka Ando and Annabel Short who, in addition to non-Florey committee members, have been instrumental on the SOBR committee in 2012. The network is only in its infant years, but is expected to continue to grow and support even more early career brain researchers in the future. For more information please visit www.studentsofbrainresearch.blogspot.com.au Florey champions who speak as representatives of our outreach program as well as founders and members of professional associations for emerging neuroscientists across Melbourne

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Alzheimer's disease doesn't only affect older adults. I have personally experienced how it can cripple an entire family. It doesn't only rob memories, it also hijacks our personality. It will become the greatest health burden that we will face, and I am proud to be part of a team that is committed to understanding and hopefully curing this devastating disease.

dr Yen Ying Lim

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dr Yen Ying Lim ;

Dr Yen Ying Lim is about to begin a post-doctoral position in the US having completed a remarkably successful PhD.

Back in October, Dr Yen, 26, enjoyed her first 15 minutes of fame when she appeared on TV and in newspapers around the world, following the publication of her research in the prestigious journal, Neurology. Dr Yen’s paper was the first study to show that we
may be able to detect the earliest signs of the pathological process of
Alzheimer's disease (brain plaques) in healthy older adults,
in people who appear to be mentally and clinically
healthy. According to Dr Yen, healthy people with high levels of brain plaques
show greater rates of memory decline than healthy people with low levels
of brain plaques. As well, carrying the risk gene for Alzheimer's
 disease (the apolipoprotein E E4 allele) does not modify the rate of
memory decline associated with high levels of brain plaques. “This
provides us with great hope and opportunity that with the ability to
detect the disease early, we may be able to investigate the effects of
therapeutics designed to halt or alter these brain plaques early, and
prevent people from progressing to the more severe stages of Alzheimer's
disease,” Dr Yen says. Dr Yen is also a registered psychologist with an interest in both clinical psychology and neuropsychology.

Dr Yen Ying Lim

“I chose to do my PhD in Alzheimer's disease research for several
reasons. Alzheimer's is likely to become one of the greatest
health burdens globally. As well, the Australian Imaging, Biomarkers and Lifestyle (AIBL) study,
where I have conducted my PhD in, is at the forefront of Alzheimer's
disease research. “The final reason is a bit more personal. I have
 relatives who have been affected by this debilitating disease.” Dr Yen will leave in June to start a postdoc with the Dominantly Inherited Alzheimer's Network Trials Unit, which is being run out of Washington University in St. Louis.

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

Systems neurophysiology

Systems neurophysiology

Autonomic Neuroscience 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.

division

``Research highlights for 2012

A QUICK SNAPSHOT

RESEARCH HIGHLIGHT

The Neuropeptides Division 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 the peptides and their G protein-coupled receptors. The aim of this research is to develop therapeutics which target these peptide receptors to treat vascular, fibrotic, metabolic and psychiatric diseases.

The electrical changes in the brain which give rise to epilepsy remain poorly understood. Using transcranial magnetic stimulation (TMS) we have shown that the increased excitability of the motor cortex occurs in both sides of the brain in generalised epilepsies whereas this hyperexcitability is confined to the side containing the seizure focus in partial epilepsies.

 “Learning and memory mechanisms in the brainstem may explain how we modify breathing during vocalisation. In other words we all have to learn how to speak and therefore we also have to learn how to breathe. Our research suggests that these learning and memory mechanisms are imprinted into the brainstem from birth until puberty.”

SENIOR STAFF Professor Robin McAllen Professor Richard Macdonell Dr Bradford O Bratton Associate Professor Mathias Dutschmann Dr Davide Martelli Associate Professor Clive May Professor Michael McKinley Dr Rohit Ramchandra Dr Hari Subramanian Dr Mutsumi Tanaka Dr Song Yao, Song Dr Stuart McDougall Dr Tara Bautista

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. Prof Richard Macdonell heads the clinical arm at the Austin Hospital which researches the physiological changes underlying epilepsy and those that occur in multiple sclerosis and the effect of treatments on them.

Dr Lindsay Booth Dr Dan Tao

One of our most exciting projects is an investigation of how the brain, acting through sympathetic nerves, regulates the function of the immune system. The mechanism that we are studying is referred to as the ‘inflammatory reflex’. Inflammation is the first stage of the body’s defence mechanisms to invasion by infectious agents, but this process needs to be tightly controlled. Too weak a response risks inadequate defence against infection, too strong a response leads to organ damage and even death. In the inflammatory reflex, the brain responds to blood-borne chemical signals of infection or inflammation (inflammatory cytokines), and activates a nervous pathway to immune tissues such as the spleen; this pathway damps down the inflammatory process. This is interpreted as a self-limiting, or negativefeedback, response. In the past year we have published our findings that challenge the current model for this reflex. In experiments on rats we found no anatomical or electrophysiological basis for the existence of a pathway from the vagus to the splenic (sympathetic) nerves. Such a pathway has been proposed, without direct evidence, to mediate the inflammatory reflex. Follow-up studies in our laboratory have confirmed that the inflammatory reflex is not mediated by the vagus, but instead by a purely sympathetic nerve pathway.

Clinical Brain Function in Health and Disease Our investigations study the ways that disease processes such as epilepsy change the excitability of neurons. A second focus is on neurorehabilitation and neural repair in multiple sclerosis.

``Research highlights for 2012 Nocturia is a common problem in patients with multiple sclerosis (PwMS). We studied patterns of nocturia in PwMS and its relationship to nocturnal BP and heart rate (HR). Urine production was measured by self-completed 72-hour diary and 24-hour ambulatory BP and HR were compared with age and sex matched controls We found that nocturia in ambulatory MS patients is contributed to by both reduced bladder capacity and instability and greater nocturnal urine production. The latter was not related to measurably higher BP and HR overnight and the mechanisms behind this require further study. The electrical changes in the brain which give rise to epilepsy remain poorly understood. Using transcranial magnetic stimulation (TMS) we have shown that the increased excitability of the motor cortex occurs in epilepsies. We were interested in exploring whether seizure control using antiepileptic drugs (AED) could be predicted using this technique. The TMS findings in patients who successfully responded to drugs returned to normal within a few weeks of starting AEDs but in patients where AEDs failed the motor cortex remained hyperexcitable. TMS may be a tool which could be developed to test for likely individual responsiveness to an AED or in the development of new drugs for epilepsy.

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In further studies transcranial magnetic stimulation was used to study the effect of recurrent seizures on cortical excitability over time in epilepsy. 77 patients with firm diagnoses of idiopathic generalized epilepsy (IGE) or focal epilepsy were repeatedly evaluated over three years. At onset, all groups had increased cortical excitability. At the end of follow-up the refractory group was associated with a broad increase in cortical excitability. Conversely, cortical excitability decreased in all seizure free groups after introduction of an effective medication. This study shows that chronic epilepsy and recurrent seizures are associated with changes within inhibitory intracortical networks that can be prevented or reversed by the successful use of AEDs.

Neurophysiology 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 2012 A research highlight from the laboratory is the identification of a specific area of the brainstem that is able to learn and recall breathing patterns. Such learning and memory mechanisms may explain how we modify breathing during vocalisation. In other words we all have to learn how to speak and therefore we also have to learn how to breathe. Our research suggests that these learning and memory mechanisms are imprinted into the brainstem from birth until puberty. Any gene-mutations or other insults affecting the brainstem can result in the inability to breathe correctly and more importantly to coordinate breathing with other behaviour, the latter often resulting is speech disorders. Our most recent research project is linked to our discovery that the same brainstem area appears to be very susceptible to nerve cell degeneration in dementia and aging. Here, an important clinical feature is swallowing disorder and aspiration of food or fluid, which often causes fatal pneumonia in the elderly. Our results indicate that degeneration of our brainstem area indeed can result in malfunction of swallowing and breathing.

Neurocardiovascular The Neurocardiovascular Laboratory looks at the nerve activity that is transmitted by the brain to the heart, and how this is affected in disease conditions such as heart failure. The laboratory further examines cell death in heart attack and is looking at novel drugs to minimise damage to the heart and other organs.

``Research highlights for 2012 In heart failure there is a large increase in the activity of the cardiac sympathetic nerves from the brain to the heart. This is an attempt to increase the output of the heart, which has frequently been damaged by a heart attack. The problem is that long-term activation of these nerves causes damage to the heart and causes the heart to beat irregularly, leading to deterioration of cardiac function and sudden death. We have shown that administration of a blocker of angiotensin into the brain of sheep with heart failure substantially reduces cardiac sympathetic nerve activity (CSNA), demonstrating that the

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

brain determines this high level of nerve activity to the heart. Our aim is now to determine where in the brain is the origin of the drive to increase CSNA in heart failure. There is evidence that an area called the paraventricular nucleus of the hypothalamus (PVN) mediates the increase in nerve activity to the kidneys in heart failure. In initial experiments, we examined the effect of increasing blood volume, which inhibits renal nerve activity via the PVN. Interestingly, we found that the PVN did not mediate the changes in CSNA to volume expansion, and also that it does not drive the increased CSNA in heart failure, in contrast to its important role in causing the increased activity to the kidney. These findings demonstrate that the level of sympathetic nerve activity to the heart and kidney are controlled by different sites in the brain. Current projects are investigating which sites control the normal level of CSNA and the increased activity in heart

 Collaborations •

University of Lyon, France

University of Bristol, UK

University of Iowa, USA

University of Leuven, Belgium

Case Western Reserve University, USA

Editorial positions •

American Journal of Physiology

Clinical and Experimental Pharmacology and Physiology

Faculty of 1000

Frontiers in Neuroscience, Respiration Physiology and Neurobiology

Systems neurophysiology

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publications 1.

Bratton BO, Martelli D, McKinley MJ, Trevaks D, Anderson CR and McAllen RM, Neural regulation of inflammation: no neural connection from vagus to splenic sympathetic neurons, Exp Physiol, 13:13,2012, PMID: 22247284

2.

Ishikawa K, Calzavacca P, Bellomo R, Bailey M and May CN, Effect of selective inhibition of renal inducible nitric oxide synthase on renal blood flow and function in experimental hyperdynamic sepsis, Crit Care Med, 2012, PMID: 22622397

3.

Ishikawa K, Wan L, Calzavacca P, Bellomo R, Bailey M and May CN, The effects of terlipressin on regional hemodynamics and kidney function in experimental hyperdynamic sepsis, PLoS One, 7:e29693,2012, PMID: 22355305

4.

Martelli D, Luppi M, Cerri M, Tupone D, Perez E, Zamboni G and Amici R, Waking and Sleeping following Water Deprivation in the Rat, PLoS One, 7:e46116,2012, PMID: 23029406

5.

May CN, Calzavacca P, Ishikawa K, Langenberg C, Wan L, Ramchandra R and Bellomo R, Novel targets for sepsis induced kidney injury: the glomerular arterioles and the sympathetic nervous system, Exp Physiol, 2012, PMID: 22689445

6.

May CN, Ishikawa K, Wan L, Williams J, Wellard RM, Pell GS, Jackson GD and Bellomo R, Renal bioenergetics during early gram-negative mammalian sepsis and angiotensin II infusion, Intensive Care Med, 2012, PMID: 22302028

7.

Ramchandra R, Hood SG, Watson AM, Allen AM and May CN, Central Angiotensin Type 1 Receptor Blockade Decreases Cardiac But Not Renal Sympathetic Nerve Activity in Heart Failure, Hypertension, 2012, PMID: 22311902

8.

Cohen JA, Coles AJ, Arnold DL, Confavreux C, Fox EJ, Hartung HP, Havrdova E, Selmaj KW, Weiner HL, Fisher E, Brinar VV, Giovannoni G, Stojanovic M, Ertik BI, Lake SL, Margolin DH, Panzara MA and Compston DA., Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial, Lancet, 380:1819-28,2012, PMID: 23122652

9.

Coles AJ, Twyman CL, Arnold DL, Cohen JA, Confavreux C, Fox EJ, Hartung HP, Havrdova E, Selmaj KW, Weiner HL, Miller T, Fisher E, Sandbrink R, Lake SL, Margolin DH, Oyuela P, Panzara MA and Compston DA., Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial, Lancet, 380:1829-39,2012, PMID: 23122650

10.

Devonshire V, Havrdova E, Radue EW, O'Connor P, Zhang-Auberson L, Agoropoulou C, Haring DA, Francis G and Kappos L., Relapse and disability outcomes in patients with multiple sclerosis treated with fingolimod: subgroup analyses of the double-blind, randomised, placebo-controlled FREEDOMS study, Lancet Neurol, 11:420-8,2012, PMID: 22494956

11.

Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, Tornatore C, Sweetser MT, Yang M, Sheikh SI and Dawson KT., Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis, N Engl J Med, 367:1098-107, PMID: 22992073

12.

Tsang BK, Crump N and Macdonell RA., Subacute combined degeneration of the spinal cord despite prophylactic vitamin B12 treatment, J Clin Neurosci, 19:90810,2012, PMID: 22342235

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

Victorian Brain Bank Network

Victorian Brain Bank Network

HIGHLIGHT 02 New grants obtained

Parkinson's Victoria $6,500 (2012)

HEAD, PROFESSOR CATRIONA MCLEAN

We have a total of

1,009 brains

available for research, with 64 new donations received in 2012

AIMS The Victorian Brain Bank Network collects, processes and stores post-mortem human brains and related samples from individuals who have had neurological diseases (i.e. Alzheimer's disease, Motor neuron disease and Parkinson’s disease), psychiatric disorders (i.e. bipolar mood disorder, depression and schizophrenia) as well as normal ‘control’ cases. We support research into the study of brain diseases by providing tissue to researchers who, using current technologies, aim to unlock our understanding of how brain diseases occur. This will hopefully lead to improvements in diagnosis, the development of early diagnostic tests, therapeutic interventions and development of preventative strategies. We also provide a vital neuropathological diagnostic service and support continued education of medical and allied health professionals.

HIGHLIGHT 01

BRAIN AND BRAIN-SPINAL CORD DONATIONS The network has a total of 1,009 cases available for research, with 64 new donations received in 2012. The new donations included cases diagnosed with Alzheimer’s disease, frontotemporal dementias, Huntington’s disease, Lewy body disease, motor neuron disease, multiple sclerosis, Parkinson’s disease, schizophrenia, and control ‘normal’ cases. Our collection makes up 36 per cent of the cases available for research within Australia.

We provided

4,984 diseased and ‘control’ samples to researchers around the world

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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 Assistants Mr Geoff Pavey BSc (Hons) Ms Leanne Taylor BSc (Hons) Consultant Histologist Dr Ian Birchall BAppSc, MSc, PhD Collaborators 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.

TISSUES PROVIDED TO RESEARCHERS During 2012, we provided tissue to 41 Australian and international new or continuing research projects, with the main research focus being Alzheimer's disease, motor neuron disease, schizophrenia and bipolar disorder. This equates to 4,984 diseased and ‘control’ samples being provided to researchers. Research groups at The Florey Institute of Neuroscience and Mental Health are among the recipients of this tissue. Three new research groups have accessed tissues from the network this year with research being performed at the Murdoch Children’s Research Institute, The University of Tasmania and Chungbuk National University, South Korea. During 2012 research using tissue from the network has resulted in 49 Australian and international publications and presentations.

ACKNOWLEDGMENT The network would like to acknowledge the generosity shown by the donor and donor families in donating tissue. 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. We would like to acknowledge the support of the following funeral directors, Bethel, Jensen, Allison Monkhouse, Le Pine, Nelson Bros, Tobin Brothers and WD Rose & Joseph Allison.

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

GOVERNORS, BOARD COMMITTEES & FOUNDATION COUNCIL

GOVERNORS

BOARD COMMITTEES Commercialisation Committee

Andrew Abercrombie

Jerry de la Harpe

Peter Jopling

Hugh Niall

John Alexander

David de Rothschild

Bruce Kean

Kerin O'Dea

Charles Allen

David de Souza

John Kearney

Simon Parker-Bowles

James Angus

Derek Denton

Anne Kelso

Lady Primrose Potter

Professor Geoffrey Donnan

Etienne Baulieu

Peter Doherty

Bruce Kemp

Dr Steven Petrou

Samuel Berkovic

Ralph Doherty

John Poynter

Jennifer Labourne

Chris Blake

Suzanne Downes

Ian Renard

Frank Larkins

Neal Blewett

Craig Drummond

Richard Larkins

Graeme Bowker

George Fink

Di Bresciani

Alan Finkel

Alec Broers

John Finlay-Jones

Graham Brooke

Roger Flynn

Malcolm Broomhead

Malcolm Fraser

John Brumby

Tamie Fraser

Tom Buchan

Peter Fuller

Geoffrey Burnstock

John Funder

Richard Buxton

Rob Gerrand

Edward Byrne

Charles Goode

Hon Jim Carlton

Susan Greenfield

Peter Castaldi

Helen Groves

Jean-Pierre Changeux

Sandra Hacker Michael Hamson

Trevor Clark

Arnold Hancock

Peter Clemenger

John Lill Paul Little Bernard Lochtenberg Dr Ray Marginson Lina Marrocco Jim McCluskey Elspeth McLachlan George McMaster Fred Mendelsohn

Mr Stephen Spargo (Chair) Dr Henry De Aizpurua

Mr Andrew Stripp Dr Ross Macdonald

Geoffrey Ripper

Dr Ergad Gold

Eda Ritchie

Mr Wayne McMaster

John Rose Thomas Schneider David Scott Richard Smallwood

Mr Gary Gray

Finance & Investment Committee Mr Craig Drummond (Chair) Ms Jennifer Labourne

Loti Smorgon

Mr Mark Jones

Stephen Spargo

Professor Andrea Hull

Andrew Stripp Boris Struk

Professor Geoffrey Donnan Professor Graeme Jackson

Audit Committee Mr Mark Jones (Chair) Ms Jennifer Labourne Professor Andrea Hull Professor Geoffrey Donnan Professor Graeme Jackson

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External Scientific Advisory Committee Professor Sam Berkovic Professor Alastair Buchan Professor Seth Grant Professor Seong-Seng Tan

Professor Colin Masters Mr Gary Gray

Nomination Committee Mr Harold Mitchell (Chair) Andrew Abercrombie Professor James Angus Professor Geoffrey Donnan Rob Gerrand Professor Anne Kelso

Project Committee Disbanded

Professor Colin Masters

Naomi Milgrom

Robert Trenberth

Pamela Miller

Gad Trevaks

Richard Miller

Anne Ward

Harold Mitchell

Andrew Wardlaw

Peter Mitchell

Elizabeth Wardlaw

Pamela Hauser

Brendan Murphy

Brian Watson

Florey Foundation council

John Coghlan

Caroline Hogg

Baillieu Myer

Ingrid Winship

Mr Stephen Spargo (Chair)

David Copolov

Andrea Hull

Martyn Myer

Mr Charles K Allen (Ex officio)

Philip Cornish

Thomas Hurley

Louise Myer

Marelyn WintourCoghlan

Charles Curwen

Margaret Jackson

A H (Buck) Myers, Jr

Meredith Woods

Andrew Cuthbertson

Bevyn Jarrott

Allan Myers

Michael Wooldridge

Tim Daly

Barry Jones

Maria Myers

John Wylie

Stephen Davis

Mark Jones

Mark Nelson

Harrison Young

Mr Gary Gray

;

FOUNDATION COUNCIL

Mr Andrew Darbyshire Professor Geoffrey Donnan Ms Michelle Jablko Mr Simon Peck Mr Nicholas A Terry

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122

THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

FACULTY AND SENIOR POSITIONS

THE FLOREY FACULTY

FACULTY AND SENIOR POSITIONS

Faculty members

Board of management

123

Mr Charles Allen (Chairman until July 31)

Andrew Lawrence (Chair)

Mr Harold Mitchell (Chairman from August 1)

David Abbott

Helen Dewey

Jee Hyun Kim

Paul Anthony Adlard

Geoffrey Donnan

Richard Macdonell

Henry De Aizpurua

John Drago

Colin Masters

Timothy Aumann

Jhodie Duncan

Kevin Barnham

Mathias Dutschmann

Ross Bathgate

Ben Emery

Philip Beart

Jenny Favaloro

Julie Bernhardt

David Finkelstein

Stephanie Bissiere

Andrea Gogos

Clare Parish

Mr Mark Jones

Wah Chin Boon

Ben Gu

Steven Petrou

Professor Anne Kelso

Nathalie Braussaud

Andrew Gundlach

Rohit Ramchandra

Joanne Britto

Jenny Gunnersen

Chris Reid

Professor Colin Masters (from August 1)

Amy Brodtmann

Vicki Hammond

Ingrid Scheffer

Professor James McCluskey (until July 31)

Ashley Ian Bush

Anthony Hannan

Maarten Van Den Buuse

Malcolm Horne

Dominique Cadihac

Mohammed Hossain

Fernando Calamante

David Howells

Leeanne Carey

Jason Howitt

Leonid Churilov

Graeme Jackson

Bradley Turner

Florey Deputy Directors

Alan Connelly

Bevyn Jarrott

John Wade

Dr Henry De Aizpurua

Brian Dean

Trevor Kilpatrick

Jim Wiley

Clive May

Mr Craig Drummond (Honorary Treasurer) Professor Geoffrey Donnan (Scientific Director)

Directors Mr Andrew Abercrombie

Robin McAllen

Professor James Angus (from August 1)

Gawain Mccoll

Mr Rob Gerrand (from August 1)

Michael McKinley

Suresh Sundram Seong-Seng Tan Lachlan Thompson Donald Tournier

Professor Andrea Hull Professor Graeme Jackson

Ms Jennifer Labourne (from August 1) Professor Richard Larkins (until July 31)

Dr Brendan Murphy Dr Thomas Schneider (until July 31) Mr Stephen Spargo Mr Andrew Stripp (from August 1) Mr Robert Trenberth (until July 31)

Professor Graeme Jackson Professor Colin Masters Associate Professor Steve Petrou

Florey Associate Directors Professor Alan Connelly Associate Professor David Howells Professor Andrew Lawrence

Chief Operating Officer Mr Gary Gray

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124

Andrew Abercrombie David Abraham W J Absalom I D Ada Alex Adam Christine Adams Dawn M Adams Peter Adams Valerie Adams D Adcock Adland Horticultural Pty Ltd Joan Adler Douglas Agnew Michael Aitken Aziz Albazzaz Richard Alcock Charles K Allen AO Frances Allen R G Allen Keith & Winifred Allen Alma Hazel Eddy Trust Rod Alsop James Alymer Lorna Ames Katherene Anderson Angela Anderson Keith Anderson R Andre Sylvia Andrew William Angliss (Vic) Charitable Fund Judith Anketell Michael Annetta ANZ Banking Group Limited ANZ Trustees Limited Thambipillai Aran A M Arbuckle Frank Archer Marilyn Armstrong Richard Armstrong E Arthur Barbara Ashton Robert Atkins Jamie Atkinson Robert Audsley Patrick Aughton Australian Productivity Council Pt Cabe Ayton V Baguley W J Bailey Bruce Baird Peter Baird Ursula Baird Anne-Marie Baker

THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

DONORS

OUR DONORS

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David N Balcombe Rosemary Ball Joyce Bambery William E Bamford Iranganie Bandaranayake Gabriella Baré David Barkley Philip Barlow Colin J Barnes Jennifer Barnes Melvyn Barnett E Jane Barrett Mark Barrett Simon Barrett G Bartle Sarah Bartlett John & Lorraine Bates Terence Bates J L Bath Elizabeth Batt Vera Baudinette Margaret Bayliss William R Baxter Walter Beale John Beard M P Beard Marge Beardall Richard Bearman Anita Bearzatto Josephine Beatson Beaucorp Pty Ltd Judith Beaufort Tony J Beddison AO Enid Beeton Joyce Begg Carmel Behan Bell Charitable Fund Doreen Bell Sandra R Benjamin OAM Diana F Benefield Colin & Barb Benson Sally Benson Valerie F Benson Kelly Bertram Berwick Opportunity Shop Incorporated Emily Betteridge Pasqualina Bevinetto Jeff Beynon Fay Bice V Bicknell C Billinghurst Bio-balance Health Ian Birchall Katie Bird

Rudy Birsa Frederick K Bishop R H Bitcon E Bitsikas Lyn Black E Bladeni G R Blair Margaret Blanden Emilio Blasetti Betty Blaskett Gordon Blatchford Neal Blewett AC Sidney & Felicity Bloch Alex Bory Graeme Bowker Jean Bowles Roslyn Boyce Bob Boyd Jonathan Boyd Philip Bracanin Hugh Bradlow Judy Brady David Bramley Brian J Brand Bronwen Bray A Brecknell Kerry Breheney B M Brennan Marie C Brennan William Brennan Lino & Di Bresciani Kezia Brett Kash Briggs John Britcliffe Ingrid Brooks Janette Broom Ellis Brover Belinda Brown Rene Brown Linda Bruce Wendy Bruce Jacqueline Bryan Dennis J Bryant Alfio Bucceri Jim A Buchanan Alison Buck Michael Buckley Hans Bufe John Bugg M J Bugg Margaret Bullen Ed Bulog A B Bunnett Heather Bunning Ian Burgher Margaret Burke

Justin Burmeister June Burrell Maurice Burstin Ellen M Burt Kathy Burt Norman Bury Andrew J Butler E M Butt Ronald Butters Sheila Byard R I Byers Jarrod Byham Janet Caflisch Liz Cairns Peter Callaghan Rosemary Callow June Cameron Ian Campbell Ross Campbell Jacqui Cant Elaine Canty Jevon Carding C M Carrigan Sue Carroll June Carter P Carter Robert F Carter Susan Carter Wilma Carter Lucia Cartia The L E W Carty Charitable Fund Denise Catchlove B K Cates Keith Cattach Suzanne Cecil Diana Cerini Ashley Chaleyer Anthony E Chaloner Beth Chamberlain Graeme Chamberlain Jennifer Chambers W A Chamley Rodney Champness Jill Chapman Kerrie Chapman S P & J J Charles Sylvia Charlton Margaret Chatswood I G Chenoweth Diana M Cherry Lorraine F Chessells Jeen Sern Chew Feliks Chiczewski Beryl Childs Polly Choi

Joseph Chow Ahnya Chuah Enid Churcher Betty Clark Charles Clark Di Clark Frank Clark Faye Clarke Grace Clarke Jasmine Clarke Robert J Clarke Florence Clarridge Heather Clay J L & E S Cleland Joan and Peter Clemenger Trust Barbara Clifford John Xavier Clifton Arthur C Close Christine Clough F J Coates Susan Coates Jan & Michael Cody Catherine J Coghlan Sally Cohen S M Cohen R F Colbourne Neil Cole John Collingwood A Collins Barbara Coltman Frank & Dorothy Colwell Lyn Comar Tony & Geraldine Conabere Geoffrey & Joan Conron Consolidated Property Services Aust Pty Ltd V A Cooke B B & S H Cooling John Cooper The Rebecca L Cooper Medical Research Foundation Ltd David Copolov Helen Corben J M Corden Bruce Corlett Aine Corrigan Kevin J Cosgrave Richard G Cotton AM Peter Coughlan Brett Cousins Andrew Coventry Anne Cowan Helen Cowan

Peter Cowen James Craven Ruth Crawley Mary Crean Simon F Crean Donalda Crofts Andrew Cronin Pamela Crosthwaite Heather Crow Crown Melbourne Limited Frederick Cruz Graeme CumbraeStewart OAM Ken Cuming Robyn Curnow Joy M Curtis Ros Curtis Jessie Cush CWA High Country Branch CWA Hopetoun Branch CWA Victoria Gormandale Branch Frederick D'Agostinio Ann Daff Daimz Trading Pty Ltd Judith Dalley Pam Dalrymple John Dalton Michael Daly Lois Dalziel Domenic & Lydia Danastasio Phuong Dang Anthony Daniel June Danks L Gordon Darling AC CMG Barbara Darvall Arthur Davey Geoffrey Davey Ron Davies Frances Davis Ernest F Dawes OBE FTS Mavis Dawson Ineke De Graaf Ann De Paul Chitra De Silva Margaret Deacon Dorothy Deason Harry Debney Decor Corporation C M Deeley S Deeves Matthew Delasey Maree Delbridge

Verna Dempster Bill Denholm P J Devlin Tom Dewhurst G Di Pietro Mark Dick Marion Dickinson John & Margaret Dickman Jacqueline Digby Mr & Mrs Dillemente Disha Saul Dishon J & D Dixon D R Dobbie S & E Dobrenko Barbara Dodson Billie Donaldson J G Donaldson Matthew Donazzan Patricia Donges Geoffrey A Donnan AO Sarah Donnan Tim Donnellan Diana Donohue Patricia Donovan Jill Douglas James Douglass The Dowd Foundation H Dowd David & Karen Dowdle John M Dowling Michael Dowling The Downes Family Audrey Doyle Rosemary Drenen Anne Drew Anne Driesen Alison Driver Craig M Drummond George Dryen Janet Duke Jan Dunbar Kimiko Duncan R M Duncan Sir Edward Dunlop Medical Research Foundation Anne Dunstone Jenny Dwyer Andrew R Dyer Dierdre Dyer Luke Dynan East Family Trust Geoffrey & Pauline Eastmure Michael Edgar

Wilma Edgoose Betty Edington Marina Edmond Wilma Edwards Marie Einoder Lilian Ekselman D M Elias Alan Ellery Carl Elliott Jenni Elliott Lloyd Elliott Marie Ellis Peg Elmore Jo Elvins Maria & Merinda Epstein Equity Trustees Limited Andrew Erikson Essendon Parkinson's Support Group Lesley Evans Nicholas Evans Samuel Evans Graeme Ewart James O Fairfax AO Fairlane Images Jack Fajgenbaum Desmond Fanning David Farnsworth K Farrell Janne Faulkner AM Evelyn Fawcett David Feldman Christien Fender John Fenwick Prue M Ferguson Fiona Ferrington Thelma Fiddyment L & P Field Karen Filo Leo & Mina Fink Fund The Finkel Foundation Jodie Fisher Tony Fisher Doreen Fitzpatrick Marian & E.H. Flack Trust Jennifer Flanagan Charles Fleetwood Anthea Fleming Brian Fleming Randyl G Flynn Roger B Flynn Karen & Mark Foelz Anne Foote Bramac Forbes Clark Forbes

125

Ian A Forbes Arthur Ford Wilma Foreman Forest Hill Woodturners Inc David Forrest Jeff Forrest Steve Forster Isolde Forstmanis Cathy Foster Katrina Francis Maria Frangou Jasna Franich Ann Fraser Simon Fraser Nick Fratangelo Andrea Free Valmae Freilich Frank Freschi Shirley Fricke Ronald Friedman Norman Frost A K Fryday April Fuller J A Gabb Colin R Galbraith David & I M Gallwey Saki Ganella Desmond Gannon Dorothy M Gannon Neilma Gantner Anna Ganz Bronwyn Gardiner Frances R Gardiner David Gawler G R K Gay R Gehrig Sylvia Gelman Generation Investments Doug George Lesley Gerrish Roshan Ghadamian Narelle Gibbons Keith Gibbs Gillian Gibson Stuart Gilbert Isabel & John Gilbertson Charitable Trust Janet Gilbertson Peter Gill Jean Gillard Norman J Gilmore Silvio Gionfriddo William Gobbart Janice Godden

Alan Goldberg Andrea Goldsmith John Gordon-Kirkby Kevin Gossip R N Gotch James Goth Dirk E Goudberg Louise Gourlay OAM Anna Gouttmann Ian Goy Debbie Grace M R Grady E M Graham Peter Graham Marilyn Grant Susan V Grant Ian Gray M L Gray Peter & Colette Gray David Grbin Greatorex Foundation Pty Ltd John C Griffin Lesley Griffin Edwin Griffith Betty Griffiths The Grocer James Guest Heather Gulson Lucia Gurciullo Rosa Gurciullo J Guthrie H W I Electrical Ltd Alice Halasz John Hales Ronda Hall Shirley Hallows Olive M Hamilton Sylvia Hammond James Hancock James A Hancock OBE Geoff & Helen Handbury Foundation Hanlons Barristers & Solicitors Hartley R Hansen Richard E Harbig Roy Hardcastle Andrew T Hardie V E Harding Geoff Hardy G B Hargreaves Jane Hargreaves Joan M Harman David L Harper Lucy M Harper Yvonne Harper

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126

Judy Harradence Lynette Harris Peter & Elaine Harris Peter Harrison Hart Charities Pty Ltd Simon Harvest Chris Harvey Kathleen Hatch Dorn Hawking Paul Hawksley Carolyn Haywood Brian Head Peter Headlam Peta Heffernan Rosemary Heide Elizabeth M Heinze Gordon Hellsten William Henderson Susanna Henry Wilma J Herschell Margaret Heselev David F Hewett John Hewison Harold Hibbert Katherine Hickey Annette Hicks Donald Higgins Margaret Higgs Margaret Hilton Alex Hill Alistair Hillier Simon Himson Rhyl Hinwood W E Hirst Lily Ho Janelle Hoban John Hodgkisson Jean Hofmaier Beryl Hogben Barbara Holden Judith Holden Allan Holoyda Pip Holloway Holt & Macdonald J Homewood I Y Hoolihan S Hopwood Simon Hopwood Lucinda Horne Peter Horwood Susan Hosken W J Hosking Lesley Howard J F Howell Elizabeth Howcroft Jill & Gregor Howie

THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

DONORS

OUR DONORS

OUR DONORS

Bremda Huckstepp Maria Hudson Heather Hughes Miss L Hughes Mr L Hughes Su Hughes Wayne Hughes Human Variome Project International Limited Eric Hunter B Hurst Alex Husson Keith R Hutchison Michael Hutchison Pieter Huveneers Joan E Ikin Rowan V Ingpen Interpath Services Pty Ltd Intralot Australia Elspeth Irving Lorilee Irwin Arnold Izzard A S Jackson K Jackson K A & N J Jackson Martyn Jackson Masumi Jackson Robert P Jackson David Jacobson G Jacobson Jalna Dairy Foods Pty Ltd Brian D James George R James Norman James Elcahnan H Januszewicz Andrea Jeffress Barbara E Jenkins Dianne Jenkins Graeme & Rosemary Jenkins Nola Jennings Cliff Johnson L & R Johnson Campbell Johnston H & K Johnston Family Foundation Peter Johnston Alan & Joy Johnstone C L Jones Derrick Jones Joan E Jones Lorraine Jones Robert L Jones Shirley A Jones

Ronald Jordan Brian Joseph JSGF Pty Ltd Elizabeth Judd Shirley Judd Richard A Juska Danielle Kairouz Rachel Kalman Margaret Kamensky Anne Kantor Karingal Bowling Club Inc H Karsen Elliott Katz D & M Kaufmann Sumiko Kawabe James Kay Sue Keable John Kear J F Kearney Peg Keast Maree Keating Francis C Keen Keilor Retirement Village Margaret Kelleher Kelvin Kellett A P Kelly Belinda Kelly Anne Kelso AO Jennifer Kelso Michael Keniger Stephen Kenmar C R Kennedy & Company Pty Ltd Fiona Kennedy Ian Kennedy Pat & Alvin Kenwood Bryan & June KeonCohen Anne Kerr John Kerr Kirsten Kerr Janice D Kesterton Fen Kho Judy Kiefer Joseph Kiers Wesley Kilham Pamela Killer Cornelia Kimstra Brian King Margaret King Guy Kingham J Kingham Robyn Kingston Ellen Kinkel Terry Kinsella

A J Kirkham John Krikhope M C Kirkland Paul Kirton Caleb Kleinig Val Knaggs Jenny Kneipp Betty S Knight Gail Knight Peggy I Knight Rodney Knight Allan Knights Pam Knott Donald E Knox Lily Kocins Kristina Koenig P Kolliner D Kormas Paul Korner W Kottek Geoff Kroker Marie Ku G Kuran Samanthika Kuruppu David V La Fontaine Betty Laidlaw Meriel Laird Alice Landau The Landman Foundation Doug J Lane James Lang Gina Langlands R Lanini Mildred Lapthorne Harry Laspas The Law Institute of Victoria Valerie Laszlo Peter Lauritsen Law Comfort Claire Lawrence Judith Lawrence Alexander Lazare Jane Lazare Veronica Lazarou J & B Le Boeuf Le Pine Funerals Glen Waverley Doug Lean Harold Lean Joseph Lederman Sayma Lederman Edwin Lee Lois Lee Maxwell H Lee Claude Lefeuvre

Darren Leishman Maureen Leishman Peter Lemon G F Lenton D W & W I Leslie Stuart Leslie Foundation Alison Leslie Robert Lesnjak Lewis Lester Jackson Leung Emily Levin Geoff Levy Darren Liddell Ambrose Linke Antonio Linossi E Linton Lions Club of Somerville Edith Lipka Rob & Anne Litchfield Bruce Lithgow Brian Little I Little Paul A Little AO Algirdas E Liubinas Margaret M Livermore Winifred M Livingstone The Lochtenberg Foundation Kah Seong Loke P Long Robert Long Shirley Long Elizabeth Loorham Elisabeth N Lord Lord Mayor's Charitable Foundation Anna Louey Naomi Loughhead Heather J Low Nette Lowe Hugh Lowy Pearl Lubansky The Eirene Lucas Foundation Joan Lucas L Luce Mary Lugton William S Luke Judith Lukeis Marjorie Lund J A Lunt Kevin Luscombe AM Frances Luxon Irene Lynch Kim Lyons

Sylvia Lyons John R MacDougall Michael Macgeorge Gary Mackenzie Macquarie Group Foundation Lindy & Roger MacRaild Heather Macwhirter Warren Madsen R & M Maeder Patrick Maguire Janet Mahaffey Darrell Mahoney Lescil G Maidment Christine Malesic Don Maloney D Mann Andrew Manning Andrew Mansour Bridget Mar Margaret D March The Marchris Family Charitable Gift Margarete Pty Ltd Bruno Mariani Ian J Marks Reg Marlow Joel Marsden Anne Marshall B E Marshall Christopher Marshall Helen Marshall Matthew Marshall Marjory-Dore Martin George Mason Heather Mason Stephen Mason Carmel Mastwyk Carol Matthews F M Matthews Kay Matthews Mariana Matthews Tom Matthews Christopher Maxwell Betty May Shirley Mayes C G & P V McAleer Brian & Carmel McAllister Gwen McAllister M McAllister Peter McArdle Val McCallum Gwen & Peter McCarthy J McCauley

Ian W McCay L M McClelland P T McColl Andrew McComas Ben J McConchie Naomi McConchie V McCormack John McCredie Jennifer McCrohon Adam McCubbin D McCullough Denys McCullough David McDonald Lois McDonald John McDonell Mr & Mrs McElligott Zina McEnnally Marion McEwin Emmeline McFadyen Ann C McFarling Elizabeth McGarry Caroline McGhee Albert J McGill Shirley McGill Katherine McGloin Emma McGrady Joan McHardy David McHugh Pamela McIntosh Beris McKemmish Mr & Mrs McKenry Bruce McKenzie Margaret McKenzie Judith McKenzieMcHarg H A McKinnon Scobie & Claire MacKinnon Trust Roslyn McKnight Anne McLachlan Elizabeth A McLaren Ken McLaren Barry McLean P A McLean Raymond J McLean Wallace McLean Adrienne McMahon Graham McMahon Michael McManus Theresa McManus Alexander J McMillan Alan & Maureen McPhate Janice Medway R J Meggs Lawrence Melgaard Jean Melzer

Steven Mercer Elizabeth Meredith Jonathan Metcalfe John Meyer John Michaux Judith Middlemass Phillip A Miechel Donald Mierisch John & Dorothy Milburn Len & Barbara Miller Glenda Mills John Milne Roslynne Milne Mir Bros Group of Companies Ethel Mirams Harold Mitchell Foundation Helen Mitchell John Mitchell Kerry Mitchell Lyn Mitchell Heather Mitchener Peter & Andrea Moeser Moira Moffett Moir's Investment Service P/L Catrina Moller Ian Moller Margaret Moller Irene Moloney Vincenzo Monitto Vito & Fia Monitto Gillian Montgomery Sean Mooney Graham J Moore Judith Moore Christine Moran G A & C R Morgan Russell Morgan Steve Moriarty Geoffrey Morley Tony & Sue Morrison Arthur Morton Richard Moshinsky Laura Moss Rachel Mostacci Shirley Mottram N Moulden John Mountjoy B J & M P Moylan N B Mower Hazel Moyes Ann Muffatti Bob Muirhead

127

Munday Des & Son Bruce Munro Ian & Pat Munro William Munro Richard A Munt J M Muntz Peter Murray S Baillieu Myer AC Myer Foundation Seiji Nagakura Tania Nahum B J Nankervis Nano Technology Systems Michael & Atida Naphtali Rodney Nash Dennis Nassau P D & J G Nave Rob & Christine Nave Frank Naylor I T & B M Naylor Mark A Nelson Margot Newall Heather Newbegin Mel Newberry Next Step Recruitment Company Helen Ng Alison Nghiem K Nicholas G Nickas Greg Nielsen John & June NixonSmith Helen Nolan Gustav Nossal AC CBE R M & D Nossbaum Robert Nossbaum G Notley H M Oakes Elizabeth Oakley Ian T Oakley Joy Oaten Lorraine Oatley Aileen Oberegger Jarrad Oberhardt Doreen O'Brien Doris Enid O'Brien Peter O'Brien R O'Connor Sara O'Connor Rosalind O'Hagan S Ohl Lisa Olive Dianne Olston Kerry O'Meara

One in Five Association inc Sue O'Neill K Oram Mona Osborne Sue Osborne Valerie Osbourne Damien O'Shea Marcia O'Shea Greg O'Sullivan Mary O'Sullivan Judith A Overbeek Richard Oxborrow Paccar Australia Andrew Page G M Pallot Enza Panuccio Justine Paragreen Kamala Paramanathan G Parham Ashley J Parker Elizabeth Parker Scott Parker Geoffrey T Parkes Parkinson's Victoria Inc Ann C Parris Partek Ted Pask Jeremy Paterson D Patisteas Patsy Patten Julian Paul Janet Pavlakis Peter John Payne Payne L & Heather Medical Research Foundation David Pearson Diana Peatt Nigel & Patricia Peck Mark Peden Elizabeth Pender S Perelstein Perfect Events Perpetual Trustees Australia Ltd Nancy L Pescod Phillip Pesnikas H Peters Judith Peterson Mary Phiddian Catherine Philps Lucy Piccoli Michelle Picker Jennifer Picking Pierce Armstrong Foundation

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128

Dorothy Pill Miriem Pinczower D M Pinkerton Lois Pinkerton Pirovich Industries P/L R G Pitcher Lynn Pittard Jennifer Pitts Vivienne Player I & J Pleming Roland Pless Margaret Poh Kam Chan Cathy Pol Bodetto Christina Port Audrey Potts Norah Powell Jillian Pratt J W R Pratt Ed Prendergast The Prendergast Family Joan Preston Leonard Price S Pullen Kalli Pulos Jana Purcell Alan Purton Sue Pyke The Lynne Quayle Charitable Trust Lois Racca Margaret Rafferty John Ralph Ravi Ramjas Alan Ramsay Erin Ramsay A B Rasmussen Judith Raymond R Rayner Richard Read John Redman Reece Australia Ltd Lydie Reeve Ann Reid Barbara Reid Simon Remington Ralph & Ruth Renard Susan Rennie Grace Rew Tony Rich Ronald Richards Maureen Rigby L Rimington Joanne Rinaldi Ringwood Secondary College Joyce E Risstrom

THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

DONORS

OUR DONORS

OUR DONORS

Aneta Ristovski Ritchies Expense Company Ken Ritter Estate of L I Roach Marion Roberts Ray H Roberts Ann Robertson Arthur & Janet Robertson RobMeree Foundation Margaret Robson Joan Rodriguez Keith Rodwell Ivy E Roebuck Betty Rogers David W Rogers Gwen Rogers John Rogers Kitty Rohan Jim Rooks Barbara Rose Bruce & Judy Rose Robert Rosenzweig Leora Ross Margot Roth M Rothman Gwyneth Rothols Henriette Rothschild Paul & Sam Rovis Cynthia & John Rowe The Rowley Foundation Helen Rumbold E Rundell Margaret & Roger Rush Russell Family Trust Lorenn Ruster Ann Ryan Mary Ryan P & E Ryba Gina Sabto Martin Sachs Ron Sacks-Davis Michael Saclier Laurie & Connie Sadler Ramesh Sahathevan Owen James Saleeba Gayle Salisbury Josy Salomon Jeremy Samuel Donald N Sanders AO Janice Sanders Anne Sanderson Robert Sanderson Colin J Sando Lauren Sanford

Peter Sank Debbie Sapountzis Norman Sargeant Robert Sartori Francis G Saunders Jacy Saunders nee Fellows Lois Savage Jim Sawyer Say Family Foundation Pamela Sayers Michael & Jeanette Scales Quin Scalzo Margaret Schafter Peter & Deb Schembri Jane Schmeiszl Julie Schoff Barbara Schultz Donald Scott Heather Scott Ian Scott David Seaman Harry Secomb Foundation Shirley Seary Frances Seidel Ramesh Selva Ilya Serov S Seward Seyam Holdings Ian Seymour Robert Seymour SGF Laboratories Pty Ltd Neena Shanks Jaya Sharman Margaret Sharp John Sharwood Michael Sharwood Alan Shaw David Shaw Frances Shaw Gwen Shaw Terence Shelden Charlie Shen Andrew Shenton Joy Sherwin Alan Sherwood Lorna Sherwood George Siapantas Siky Siapantas Spiro Siapantas Dianne Sides Sietel Limited Mark Simcocks M & J Simmons

Vida Simmons George Simonsen Dorothy Simpson Kenneth J Sims Ralph Sinclair Robert Sinclair M A Sincock Barry Singleton Nell & Hermon Slade Trust Lynne Slade Sandra Sloane Justine Sloane-Lees Isabel M Sloman Slome-Topol Family Charitable Trust Maurice Slonim Andrew Slutzkin Michael Small P Smart Betty M Smith Carol A Smith Catherine J Smith Davina Smith G M Smith Keith S Smith Luke Smith Marie Smith Ross & Judy Smith Samuel Smorgon Marie Smyth Graham Snell Sylvia Solinski June & Edwin Solly Nicholas Soloway F B Sommervelle Anne Soosai Joy Sorel Mavis Sorensen Rona Soulsby Southern Peninsula Masters Athletics Venue Pauline Speedy Yvonne L Spencer Alex Spremic Barrie Squires Glenda Stacey Miriam Stackhouse Jane Standish Tony & Barbara Standish Ralph Stavely Beryl Steinke Frances Stephen A W Stephens P Stephenson

Jennifer Stevens Margaret Stevens Margaret Stewart Robert Stewart Russell Stewart Louise Stewart-Scott Gary Stiliano Betty Stinson Robert Stinson Susie Stock W E Stone Stonnington Probus Club Samuel Stopnik Caroline Storm Fay Strachan Patricia Strachan Richard Stradwick Susan Streat A A Street Shirley Strossa Patricia M Stuart Stephen Stuart Takako M Subocz Greg Sullings Lyndall Sullivan Yvonne Sullivan Eleanor Sumner David Sun Dot Surtees Nella Sutera Eric Sutherland Celia Sutterby Rene Sutton Ian A Swain Christine R Sweeney Bruce Sykes Stephen Szental Michael Taft Gregory Taggart Tahbilk Pty Ltd Margaret Tailby Angela Taranto P Taranto Elaine Targett Magdee Taryan Rowan Tatchell Ann Tauber Adrian Taylor Anne Taylor Bernadette Taylor Margaret Taylor Robin Taylor Warren Taylor Wendy Taylor Mona Templeton

Bruce Thomas Elisabeth Thomas Jean Thomas Mervyn Thomas Andrea & Paul Thompson Barbara Thompson Derek Thompson Karlene Thompson A & M Thomson Dougal & Virginia Thomson L Thomson Susan Thomson Bruce Thorley Wendy Thorpe Robert C Thrower J G Thrum Grace C Tivendale Marjorie Todd V Tolliday Jean Tom Joan Tomlin Blanche Toohey Mitchell Toole Lynette Torrens Norma Torriero Nino Totino Graham Towers Evelyn Townsend Moshe Trebish Mary Trembath Valda Trenberth J & E Treverton Andrew Trimble Doreen Trinham Michael Troy Trust Company Ltd Eugenia Tsaclidis Peter Tsanteeskis Margaret Tse Vince & Angela Tudini Katrina Tull Joan Tullo Bruce Turnbull Valerie Turnbull Brad Turner Howard Turner Jack B Turner Jacqui Turner Patricia Turner Margaret J Ullin George L Upston Marjorie Upton Pat Ure Eleanor U'Ren

Urquhart Charitable Fund Robert Utter Lisa Valenti Christine Vallence Sally van Doonr Anne Van Erp Cinnamon Van Reyk Peter Vassallo Luke Vaughan Hessel Verbeek D E Vernon David Vernon Victorian Medical Insurance Agency Dorothy Viskovic Hans Von Strokirch Paul R Voumard G W Vowell Foundation Ltd Ben Wadham Wendy Wagstaff Lorraine Wakefield Barry & Christine Wakelin J R Walker Richard Wall Colin Wallace Lisa Wallace Peter L Waller Stan Wallis James Walter Gary Walters R N Walters Peter Ward Ralph & Barbara WardAmbler Keith Warren Tim Watkin Joan Watmough A D Watson Barbara Watson Jean Watson Taryn Watson Gwen Webb OAM Beryl Webster James J Webster Jean M Webster Peter J Webster Lesley Weekes Meghan Weekes Cydni Weichert Philip Weickhardt Rosemary Weir D A Wells Wallace R Werrett Rachela H West

West Gippsland Healthcare Group Neil M Westaway Kathleen Westlake Richard Weston James White Mary White Peter & Lindy White Foundation Pty Ltd Robert White Trevor White Lesley Whitehead Leonard Whitehouse Robyn Whiteley Jean Whitla A J Whittle Helen Whyte Kaaren Whyte John A Wicks James S Wiley Karin Wiley John & Robyn Wilkins Marjorie Wilkins J Wilkinson K P & M M Wilks Paul A Willee QC Carol Willenberg Margaret Williams R Williams Tony Williams Valerie J Williams Tony Willigen Lyn Willis Ian Wilmoth Elizabeth Wilson Lydia Wilson Margaret Wilson Margery Wilson Robin Wilson William P Wilson Prunella Winterton Tom C Wise Doris L L Wisniewski Juen Witheford Claire Withers Keith Witney Arnold Wittner David J Wluka John Wong Alex Wood Jessica Wood Yvonne Wood F Woodcock George Woods Josephine Woods Meredith Woods

129

Gerrand & Associates

John Woodward Geoffrey S Wratten Grant Wright Matthew Wright Rosemary D Wright E M Wurf Linday Wyse Tom Yates L & E Yoannidis Bruce Young Harrison Young Sandy Young Belinda Yow Barbara Yuncken G F Zambelli Filippo & Vincenza Zappulla Robin Zeidler Victor Ziccone Marianne Zsifko Floriana Zuccarelli Goldie Zyskind

Graeme Samuel AO Intercontinental Melbourne James Andronis Jane Willson Janne Apelgren Jaques Reymond Jill Dupleix Joanna Savill John Moller Justin North Katrina Kanetani Ladelle Linda Karafilli Lisa Hudson Melbourne Theatre Company Middletons Lawyers Mona Museum Monash University

IN-KIND SUPPORTERS Andrew McConnell Ann Peacock Anthony Puharich Audi Penfold Belinda Ramsay Ben Shewry Block Arcade Bolt Blowers Briner Signs Brook Angove Carat Advertising Carpet Court Cavalier Bremworth Carpets Ceas Cedar Hospitality Clamms Seafood Coopers Creative Ingredients Crown Ltd Crowne Plaza Surfers Paradise David Hoath David Seaman Department of Human Services, Mental Health Branch Des Speakman Di Rolle Publicity Dr Di Bresciani Dulux Electrolux Fairfax Media -The Age Geoff Jansz

One in Five Association Inc Pacific Broadcasting Peninsula Hot Springs Peter Gilmore Philippa Sibley Philippe Mouchel Pinc Pearls Radisson Ross Lusted Ross Oakley Royal Yacht Club of Victoria Ryan Wavish San Pellegrino Seven Eleven Signed and Framed Southern Star Observation Wheel Staging Connections Terry Durack The Good Guys The University of Melbourne Treasury Wine Estates Trevor Clark OAM Vic's Meat Victoria Racing Club Vivienne Ulman Walter Wagner Wardlaw Family Warringal Financial Services Whybin/TBWA

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

FINANCIAL STATEMENTS

FINANCIAL STATEMENTS

FINANCIAL STATEMENTS

Consolidated Statement of Comprehensive Income (For the year ended 31 December 2012)

Consolidated Statement of Financial Position (As at 31 December 2012)

;

;

DEC 2012 DEC 2011 $’000 $’000

REVENUES FROM ORDINARY ACTIVITIES

42,666

28,770

(27,947)

(20,728)

Raw materials and consumables used

(4,170)

(3,794)

Conferences and collaborations

(1,854)

(1,372)

Buildings maintenance

(3,439)

(1,723)

Salaries and employee benefits

Research support services

(1,504)

(263)

General administration

(2,532)

(1,403)

Other expenses from ordinary activities

(1,770)

(209)

Distribution of grant funds

(2,153)

(1,884)

NET OPERATING (DEFICIT) BEFORE DEPRECIATION

(2,703)

(2,606)

Depreciation and amortisation

(7,379)

(3,544)

NET OPERATING (DEFICIT) AFTER DEPRECIATION Income contributed for building project Expenses related to building project Allocation of building space to third parties NET SURPLUS / (DEFICIT) FOR THE YEAR

131

(10,082)

(6,150)

593

39,338

(6,254)

(12,779)

-

(4,506)

(15,743)

15,903

ASSETS Current Assets Cash and short-term deposits Trade and other receivables Available-for-sale financial assets Prepayments Inventory

36,885 36,496 3,462 5,665 11,791 10,905 254 164 - 7,753

Total Current Assets

52,469

53,283

Property, plant and equipment Investment property Assets under construction Other Assets

14,949 6,635 - 100,141

13,989 79 81,356

Total Non-Current Assets

121,725

95,424

TOTAL ASSETS

174,194

148,707

Non-Current Assets

LIABILITIES Current Liabilities Trade and other payables Provisions Income in advance TOTAL LIABILITIES

OTHER COMPREHENSIVE INCOME Net gain / (loss) on revaluation of financial assets

710

(969)

OTHER COMPREHENSIVE INCOME FOR THE YEAR - SURPLUS / (DEFICIT)

710

(969)

TOTAL COMPREHENSIVE INCOME FOR THE YEAR - (DEFICIT) / SURPLUS

(15,033)

14,934

Total comprehensive income attributable to members of the entity

(15,033)

14,934

DEC 2012 DEC 2011 $’000 $’000

6,312 2,371 6,393 4,774 - 45 12,705

7,190

Non-Current Liabilities Provisions

700 540

Total Non-Current Liabilities

700

540

12,705

7,190

160,789

140,977

Retained surplus Unrealised investment reserve Merger/reorganisation reserve

100,020 (270) 61,039

115,763 (980) 26,194

TOTAL FUNDS

160,789

140,977

TOTAL LIABILITIES NET ASSETS FUNDS

OPERATING INCOME

ACTUAL $'000

Government & statutory bodies

% OF TOTAL

27,053

63.4%

Private donors & foundations

4,831

11.3%

Other peer review funding

3,254

7.6%

Miscellaneous income

2,653

6.2%

Commercial collaborations

2,567

6.0%

Investment income

2,308

5.4%

42,666

100%

TOTAL

We acknowledge the Victorian Government's strong support, particularly through funding from the Operational Infrastructure Support Grant. All funding received through the Department of Business and Innovation (now 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 in the building of our new facilities.

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Director's Office Geoffrey Donnan Maryanne Borg Colleen Buchhorn

Division of Behavioural Neuroscience Addiction Neuroscience Laboratory Robyn Brown Jhodie Duncan Bianca Jupp Jee Hyun Kim Elena Krstew Andrew Lawrence Liubov Lee-Kardashyan Heather Madsen Antonio Paolini Christina Perry Students Katherine Beringer Nicola Chen Rose Chesworth Alec Dick Shawn Tan Martin Axelsson Shaun Khoo Doron Lavan Isabel Zkukvic

Molecular Neurobiology Laboratory John Drago Jim Massalas

Neural Plasticity Laboratory Emma Burrows Anthony Hannan Xu Hou Monique Howard Caitlin McOmish Terence Pang Mark Ransome Thibault Renoir Students Xin Du Christina Mo Annabel Short Dean Wright

THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

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Division of Brain Development and Regeneration Joanne Britto Anh Doan Choo Peng Goh Jason Howitt Jenny Lackovic Ean Lee Ley-Hian Low Alison Macintyre Ulrich Putz Seong Tan Michelle Tang Students Paul Eleftheriou Yijia Li Hui-Xuan Ng

Division of Epilepsy Epilepsy David Abbott Patrick Carney Theresa Dang Carly Fitzgerald Danny Flanagan Jewell Gardner Graeme Jackson Michael Makdissi Simone Mandelstam Richard Masterton Paul McCrory Saul Mullen Heath Pardoe Ingrid Scheffer Mira Semmelroch Christopher Tailby Students Kaushik Bhaganagarapu Laura Bird Dawn Merrett Genevieve Rayner David Vaughan

Imaging Fernando Calamante Alan Connelly Steven Fleming Xiaoyun Liang Donna Parker David Raffelt Farnoosh Sadeghian Jacques-Donald Tournier Lisa Willats Students Heather Conor Elizabeth Smith Robert Smith

Imaging MRI Platform Saba Ansari Shawna Farquharson Adam Heyde Mary Macmillan Claire Mulcahy

Ion Chanels and Human Diseases Alison Clarke Lynley Cordeiro Elena Gazina Baijun Gu Carol Milligan Steven Petrou Alison Phillips Christopher Reid Kay Richards Evan Thomas Chantel Trager Ernesto Vargas Delgado Verena Wimmer Students Rosemary Harty Robert Hatch David Kaplan Tae Hwan Kim Bryan Leaw Melody Li Megan Oliva

Purinergic Signalling Laboratory Kelsey Dalton James Wiley

CJD - Clinical Research Group ANCJDR Qiao-Xin Li Amelia McGlade Shannon Sarros Christiane Stehmann Tian Zhao

Clinical Research Group (AIBL) Nicola Briggs Katherine Burn Kathryn Ellis Carly Copolov Harriet Downing Belinda Dridan Noel Faux Brian Fleming Christopher Fowler Jacqueline Giummarra Karra Harrington Adrian Kamer Fiona Lamb Xuelei Li Renee Lichter Lucy Mackintosh Maree Mastwyk Yumiko Matsumoto Ursula May Claire Montague Kelly Pertile Alan Rembach Joanne Robertson Rebecca Rumble Brett Trounson Students

Division of Mental HEALTH Professor Colin L Masters Emily Cuningham Brenda Huckstepp

Rachel Buckley Yen Ying Lim Carolina Restrepo

Clinical Research Group (aiblWHAP)

Behavioural Neuroscience Laboratory

Katherine Campbell Jasmin Grigg

Laetitia Buret Andrea Gogos Anand Gururajan Rachel Hill Szerenke Kiss von Solly Sally Martin Shane Thwaites Maarten van den Buuse

Katherine Campbell

Students Ye Sul (Yen) Kim Elizabeth Manning Anna Schroeder Shane Twaites Candace Wu

Student

Clinical Research Group (DIAN) Tabitha Nash Alicia Rooney

CRC for Mental Health Melanie Carew Ian Cooke Lauren Kelly Simone Quin Donna Staunton Kathryn Taylor Michael Wooldridge

CT Suite David Baxendale

Laboratory Services Mhairi Donohoe Anna Sellens Elsa Tsui

Property & Maintenance (Oak Street) Michael Kent

Animal Facility (Oak Street) Jason Verde Elissa Wells

Molecular Psychiatry Laboratory Daniel Bennett Brian Dean Alison Dean Andrew Gibbons Thien-Kim Le Ting Ting Lee Jaclyn Neo Geoff Pavey Myoung Suk Seo Madhara Udawela Aradhana Upadhyay Students Won Je Jean Nahed Tawadros Natalie Thomas Shaun Hopper Rebecca Worthing

Molecular Psychopharmacology Laboratory Rejhan Idrizi Peter Malcolm Avril Pereira Suresh Sundram Students Sujeevan Sinnatamby Vaidy Swaminathan Alexander Barty Ye-Sol An

Neurodegeneration Laboratory- Bio21 Kevin Barnham Jacky Chan Lin Wai Hung Xiang Liu Keyla Perez

Neuropathology Laboratory Katherine Ganio Vijaya Kenche Scott Laffoon Monica Lind Colin Masters Blaine Roberts Anne Roberts Tim Ryan

Oxidation Biology Laboratory Paul Adlard Scott Ayton Lisa Bray Ashley Bush Robert Cherny James Duce Bruce Etherton CHEN Feng David Finkelstein George Ganio Jessica George Mark Greenough Kali Hubbert Ya Hui Hung Charlotte Jordan Eoin Kelly Linh Lam Peng Lei Antonia Lynch Gawain McColl Elizabeth McNicol Lydia Nugroho Carlos Opazo Martinez Ashley Portbury Amelia Sedjahtera Brian Stevens Ambili Thoppuvalappil Appukuttan Irene Volitakis Bruce Wong Students Yifat Biran Deniece Fon Adam Gunn Sara Hancock He (Olivia) Xu Luz Fernanda YevenesUgarte Shih Min Chiu

Psychotropic Drug Advisory Service

133

Division of Multiple Sclerosis

Neurodegeneration Laboratory

Michele Binder

Malcolm Horne Katya Kotschet Davor Stanic

Holly Cate Bernard Chuang Ben Emery Judith Field Lauren Giuffrida Alison Hamlett Rex Huang Laura Johnson Anna Jonas Trevor Kilpatrick Daniel Merlo Tobias Merson Sze Woei Ng Maria Papaioannou

Students Susan Ilic Wendy Lang Shoshanah Longmuir Nirma Perera Yi Sui John Tran

Neurogenesis and Neural Transplantation Laboratory Lachlan Thompson Mong Tien

Jerome Staal

Student

Krutika Wikhe

Fahad Somaa

Students

Stem Cells and Neurodevelopment Laboratory

Brett Fisher Zhi-Ming (Gerry) Ma Philipp Roth Jo-Anne Stratton Yao (Lulu) Xing

Christopher Bye Chathurini Fernando Jonathan Niclis Clare Parish Ting Yi Wang

Division of Neurodegeneration

Students

Adult Neurogenesis Laboratory

Steriod Neurobiology Laboratory

Timothy Aumann Anupa Dey Doris Tomas

Molecular Neuropharmacology Laboratory Philip Beart

Jessica Kauhausen Jordan Wright

Wah Boon Hui Kheng Chua Lee Ng Students Heena Mulchandani Kristina Vacy Jessalyn Chia

Cecilia Cederfur Chew Lau Linda Mercer Student

Division of Neuroimaging Animal MRI Laboratory

Christine Culhane

Yea Seul Shin

Victorian Brain Bank Network

Motor Neuron Disease Laboratory

Leigh Johnston Hong Wang David Wright

Rebecca Sheean

Student

Bradley Turner

Bob Tran

Fairlie Hinton Catriona McLean Leanne Taylor

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THE FLOREY INSTITUTE OF NEUROSCIENCE & MENTAL HEALTH ANNUAL REPORT 2012

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Interoception Laboratory Leonie Cole Michael Farrell Gelareh Ahmadi Ayaka Ando Jennifer Leech Camille Shanahan

Division of Neuropeptides Insulin Peptides Mohammed Hossain

Membrane Protein Engineering Laboratory Natasha Lam Daniel Scott Students Fabian Bumbak Kelvin Yong

Molecular and Cellular Cognition Laboratory Stephanie Bissiere Timothy Hast Student Ellie Blackwood

Neuropeptide Receptor Laboratory Ross Bathgate Tania Ferraro Sharon Layfield Students Bryna Chow Natalie Diepenhorst Despina Ganella Roy Kong Shoni Bruell Brad Hoare Maria Oh Amber Ou

Peptide and Protein Chemistry Laboratory Feng Lin Fazel Shabanpoor Julien Tailhades John Wade

Students

Neuro Rehabilitation

Alessia Belgi Linda Chan John Karas Vino Nair

Leeanne Carey Gemma Lamp Christine Marsh Mary Mastos Susan Mary Palmer Emily Ramage Laura Scott Anne Marie Tan Tamara Tse

Peptide Neurobiology Laboratory Sherie Aizen Berenice Chua Andrew Gundlach David Hawkes Philip Ryan Qian Sang Craig Smith Melanie White Students Giancarlo Allocca Ihaia Hosken Hanna Kastman Emma Ong-Palsson Andrew Walker Sze Ong Annie Yang Cary Zhang

Division of Stroke Avert Julie-Ann Bernhardt Karen Borschmann Jan Chamberlain Janice Collier Toby Cumming Shefali Kalpushu Sharon Kramer Cecilia Li Tara Purvis Anne Rohrer Sally Speare Students Louise Craig Nathalie Fini Heidi Janssen Julie Luker Renee Trigg

Cognitive Neuroscience Amy Brodtmann Qi Li Renee Lichter Hugh Pemberton Audrey Raffelt Emile Werden

Students Isobel Hubbarb Sze CHeen Low Kate Noonan Michaela Pascoe Barbara Wolfenden

Public Health Dominique Cadilhac David Carey Sonia Denisenko Adele Gibbs Brenda Grabsch Francis Kung Natasha Moloczij Karen Moss Kate Paice Steven Street Emma Tod Nicole Wallis

Stroke- Basic Science Kathryn Ardipradja Heidi Ho David Howells Sarah McCann Victoria O'Collins Sarah Rewell Naoshi Sasaki Emily Sena Liem Vo Students Marie Dagonnier Candace Loy Charlotte Krenus Henry Ma Mark Mackay

Division of Systems Neurophysiology Autonomic Regulation in Health and Disease Bradford Bratton Mutsumi Tanaka David Trevaks

Breathing Control in Health and Disease Tara Bautista Mathias Dutschmann Hari Subramanian Student Sarah Jones

Central Control of Cardiovascular Physiology

Corporate Services Administration Alistair Kittson Ihaia Hosken Kristina Mary Vacy

Information Technology

Genomic Disorders Research Centre

Rat Facility

Timothy Brewer

Genomic Disorders Research Centre

Johanna Henry

Ayaka Ando Richard Cotton Asha Herten-Crabb Rania Horaitis Heather Howard Timothy Smith Alfreda Soetopo

Thomas Vale

Ricardo Casama Gary Eaton Kenny Jao

Building Management

Simon Miller

Effie Christofilopoulos

Occupational Health and Safety

Eugenia Lontos Michael Stirling Peter Ward

Corporate Services Gary Gray Lisa Keam

Gena Shoykhet

Damian Carroll Frances Tait

Operations Management Rita Alampi

Finance

Tina Bertelle

Rohit Ramchandra Tao Xing

Nick Catton

Danielle Di Sarno

Students

Karen Dent

Christine Corbett

Yonis Abukar Marcus Matear

Brian Fleming

Neurocardiovascular Laboratory

Irina Kouchnareva

Lindsea Booth Anthony Dornom Sally Hood Clive May Song Yao

Peter Plecher

Students Paolo Calzavacca Simon Leversha Emily Kong Kam Wa Gary Lazarovski Natasha Mitchell

Systems Neurophysiology Melinda Goga Robin McAllen Richard Macdonell Lesley Walker Frank Weissenborn Stuart McDougall

Viscerosensory Laboratory

Ross Humphreys

Krysten Donaldson Peta Hodgson Connie Jacobs Hannah Soulaiman Julia Watt

Anita Pejic

Li Wan Tan

Amanda Place Jade Sarna Margit Simondson Jane Standish Astrid Sweres Gemma Turvey Hazel Westbury

Human Resources

Janet Finn Karin Sitte-Meagher

International Journal of Stroke International Journal of Stroke Carmen Lahiff-Jenkins

Neuro Ethics Ayla Barutchu Neil Levy

Core Services Nathalie Braussaud Timothy Brown Travis Featherby Jacqueline Mills Brett Purcell

Neuroscience Trials Australia Lisa Brauman Fiona Ellery

Scientific Services

Julie Andrew Anita Thompson Melanie Hurley Su Cox

Bradley Hoare

Animal Services

Christine Johnston-Balls YiJia Li

Mile Petrovski

Anna Marcon

Henry De Aizpurua

Jacqueline House

Neil Cole

Ross Johnstone

Business Development

Purchasing

Jeremy Musolino

Anita Gowers

Gregory Thomas

BioResources

Fundraising and Marketing Jennifer Elliott

Maria Bastias

Michael Vovos

Carmel Jacobson

Patricia Lew

Bill Ristevski

135

Steven Oliphant

Reception Parkville Giancarlo Allocca Margaret Black Sarah Fisher Curtis Hay Matthias Koenning Ting Ting Lee Zhi-Ming Ma Christina Mo Vera Phipps Philipp Roth Jennifer Sabo

Stroke- Clinical Trials

Stuart McDougall Haoyao Guo

Cara Cortese

Annabel Short

Rachel Mostacci

Boon Siang Tan

Sandra Petrolo

Student

Rodi Neri

Agnes Wong

Lisa Walker

David Carter

Monica Parris

Luz Yevenes-Ugarte

Craig Thomson

Animal House Compliance Cristian Bustos Helen Huckle

Embryo Services Fiona Christensen Taryn Knight Rian Mackenzie

Mouse Facility Krista Brown Leah Catalano Blair Dowding Daniel Drieberg Elke Goettlicher Jessica Hartley Ana-Kiwa Hudson Maddison Ible Roxanne Monaghan Mathew Salzone Kim Schafers Ryan Kylie Williams

Kathy Skoff Robynnee Stevenson Sue Bates Sandra Petrolo Tina Soulis

Quality Systems/ Histology Ian Birchall Mirjana Bogeski Angela Vais

Scientific Services Georgia Giannakis Helen Mansour Alan McDonald

Statistics Leonid Churliov Li-Chun Quang Mahsa Keshtkaran

Stem Cells Martin Pera

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Front cover: Dr Mathias Dutschmann, recruited from Leeds University in the UK, is developing an understanding of the fundamental brain mechanisms associated with breathing during speech and swallowing. Adaptive breathing is impaired in lung disease, dementia and autism. He won a lucrative Australia Research Council Future Fellowship in 2012.

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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 four sites rest on this precious land. austin Campus melbourne Brain Centre

oak street Campus

Howard Florey laboratories

30 Royal Parade Parkville Victoria 3052, Australia

245 Burgundy Street Heidelberg Victoria 3084, Australia

155 Oak Street Parkville Victoria 3052, Australia

Gate 11, Royal Parade University of Melbourne Victoria 3010, Australia

T +61 3 9035 6789 F +61 3 9035 3107

T +61 3 9035 7000 F +61 3 9035 7301

$

Head office

FLOREY.EDU.AU ABN: 92 124 762 027

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Florey Institute of Neuroscience and Mental Health, 2012 Annual Report  

The Florey Institute of Neuroscience and Mental Health is the largest brain research group in the Southern Hemisphere. With more than 500 r...

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