Neuroscience | Spring 2019

NEUROSCIENCE University of Rochester | Ernest J. Del Monte Institute for Neuroscience Spring 2019

Anyone, Anywhere Erika Augustine and Ray Dorsey on using tech to transform neurological research PG 4

University of Rochester | Winter 2019

Winter 2019

D I R EC TO R ’ S N OT E

Neuroscience in full bloom at the Del Monte Institute As Spring starts to make its way to Rochester (at last), another exceptional school year is wrapping up. As we go to print, three of our Neuroscience Graduate Program (NGP) doctoral candidates are about to defend their theses, and we have confirmed another superb incoming class: eight Ph.D. students, two M.D./M.S. students, and one Medical Scientist Training Program (MSTP) student for the Fall 2019 semester. NGP students published eight papers this year, five of which were first authorships. In this issue, in our Student Spotlight profile, you’ll read about the exceptional work of Uday Chockanathan, a third-year MSTP and NGP student, which has just appeared in Computers in Biology and Medicine. Uday’s work is directed at bringing much needed precision to the ways in which clinicians and neuroscientists can measure and track neural function in patients with HIV.

John J. Foxe, Ph.D. Kilian J. and Caroline F. Schmitt Chair in Neuroscience Director, The Ernest J. Del Monte Institute for Neuroscience Professor & Chair, Department of Neuroscience

On the cover: Photo by John Schlia Editor: Samantha Jean Art Director: Kara Austin

Our NGP also just wrapped a hugely successful retreat at the Memorial Art Gallery where 175 attendees experienced a full day of presentations on the latest in brain science from across the University. The student-led event was, as always, a great time to recognize the inspiring work our students do throughout the year. It could not have happened without the tireless efforts of the organizing committee, who deserve special recognition: Monique Mendes, Katherine Andersh, Alexandra McHale, Yunpeng Pang, Brendan Whitelaw, Kathleen Gates, Victoria D’Agostino, and their faculty mentor, Professor Krishnan Padmanabhan.

This issue’s cover story features two brilliant young scientists, Erika Augustine and Ray Dorsey, two of the dynamic leaders of one of our flagship programs—the Center for Health + Technology (CheT). You will learn about the exciting work they’re doing to transform research and care of neurological disorders through innovative technology. You’ll also meet our newest neuroscience faculty member, Paul Geha, M.D. Paul, who originally hails from Lebanon, is joining us from Yale University. Paul is a joint recruit between our Psychiatry Department and the Neuroscience Institute, and he will be based in our Center for Advanced Brain Imaging and Neurophysiology (UR CABIN), where he will conduct neuroimaging work in patients with chronic pain conditions.

I continue to be amazed by the camaraderie here at UR, the deep spirit of collaboration and the drive toward discovery. The energy in our Neuroscience community is palpable. Right now, we are in the throes of the external review process for our annual Del Monte Institute Pilot Grant Program, and I am both delighted and amazed to report that we received 58 applications this year, a new record. I have been on NIH study sections with fewer grant applications than that! To say growth is happening right before our eyes would be an understatement.

In Science,

Contributing Writer: Mark Michaud

John J. Foxe, Ph.D.

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NEWS BRIEFS

Grant Marks Two Decades of NIH Support for Muscular Dystrophy Research URMC has received $8 million from the National Institutes of Health (NIH) to support pioneering research on muscular dystrophy. The grant, which is a renewal of the Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, will fund ongoing work to investigate the genetic mechanisms and progression of this complex multi-system disease, research that has led scientists to the threshold of potential new therapies for myotonic dystrophy.

URMC is home to one of six NIH-designated Wellstone Centers in the nation and was selected in the first cycle of funding when the program launched 16 years ago. It is the only Wellstone Center that has been continuously funded since the program’s inception and with the current award, URMC has received a total of $29.8 million in NIH funding to study the disease since 2003.

Deposits of toxic RNA (red) are seen here inside muscle cell nuclei (blue) from an individual with myotonic dystrophy

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NEWS BRIEFS

Common test of mental state understanding is biased

In the Reading the Mind in the Eyes Task (RMET), recommended by the National Institutes of Mental Health, participants view 36 black and white photographs then decide which of four adjectives best describes the mental state expressed in the eyes.

Research published in Psychological Medicine by psychology and neuroscience professor David Dodell-Feder, Ph.D., finds flaws in a National Institute for Mental Health-recommended test, calling it “biased against the less educated, the less intelligent, and against ethnic and racial minorities.”

The test, called the Reading the Mind in the Eyes Task has participants view 36 black and white photographs, originally selected from magazine articles, of solely the eyes of Caucasian female and male actors. Participants then decide which of four adjectives—such as panicked, incredulous, despondent, or interested—best describes the mental state expressed in the eyes (the correct answer has been generated through consensus ratings). Using data from more than 40,000 people, researchers concluded that the test may be unduly influenced by social class and culture, hence posing a serious challenge to assessing correctly the mental state understanding in clinical populations, especially given the strong link between social status and psychiatric illness.

Studies show how blood pressure and sleep impact brain’s ability to clean itself

In the left panel, superimposed particle tracks reveal that cerebrospinal fluid flows through wide perivascular spaces, which are approximately as large as the adjacent artery. Averaging together hundreds of thousands of measurements produces a velocity field, shown in the green arrows in the right panel, which demonstrates that the net cerebrospinal fluid flow is in the same direction as the blood flow. (University of Rochester illustration / Jeff Tithof)

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New research studies led by Maiken Nedergaard, M.D., D.M.Sc., co-director of the Center for Translational Neuromedicine at URMC, show how high blood pressure and the depth of sleep impact the brain’s ability to efficiently wash away waste and toxic proteins. The first study, reported in Nature Communications, finds that the brain’s system for removing waste is driven primarily by the pulsations of adjoining arteries and shows that changes in the pulsations caused by high blood pressure slow the removal of waste, reducing its efficiency. This might explain the association between high blood pressure and Alzheimer’s disease, the researchers say. The second study, published in the journal Science Advances, reinforces and potentially explains the links between aging, sleep deprivation, and heightened risk for Alzheimer’s disease. The findings may also explain why some forms of anesthesia can lead to cognitive impairment in older adults.

S T U D E N T S P OT L I G H T

Udaysankar Chockanathan Udaysankar Chockanathan, a third-year neuroscience graduate student in the Medical Scientist Training Program, is the lead author of a new study that has been published in Computers in Biology and Medicine. The research explores automated approaches to detect biomarkers of a set of complications known as HIV-associated neurocognitive disorders (HAND). More than 25 percent of HIV-positive individuals experience HAND, but symptoms are often subtle and dynamic, which renders diagnosis of the condition challenging. Researchers trained a machine learning model using brain network properties derived from functional MRI (fMRI) data. They then applied the learned model to predict HIV-status and cognitive performance at the level of individual subjects. Prediction of both variables was better with large-scale Granger causality (lsGC), a novel method developed from an algorithm initially deployed in economics, than with Pearson correlation, a widely used technique for comparing the similarity between two variables. Down the line, Chockanathan would like to understand how biological and socioeconomic variables, such as age, sex, education level, drug use, and antiretroviral medications, affect the brain networks of individuals with HAND, and, ultimately, to find biomarkers that can be used to identify HIV-positive individuals at risk for HAND, before neurocognitive decline begins.

The images above shows the top 10 brain regions that were most informative at distinguishing HIV-negative from HIV-positive subjects.

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Do the Unprecedented: Harnessing Technology to Improve Research and Care

Smartphone data collected from a group of study participants was analyzed using a machinelearning algorithm which the researchers used to generate a mobile Parkinson disease score that uses a scale of 1-100 – with a higher number indicating a greater severity of symptoms.

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ay Dorsey, M.D., the director of the URMC Center for Health + Technology (CHeT) and David M. Levy Professor of Neurology is fond of the phrase “anyone, anywhere” and this mantra has become the guiding principal behind the Center’s efforts to create new technology-driven platforms to study neurological disorders and expand access to specialized care.

“The goal of the Center is to allow anyone, anywhere to participate in research, enable anyone, anywhere to benefit from the resulting advances, and allow anyone, anywhere to receive the care they need,” said Dorsey.

This convergence of technology and healthcare is possible due to the recent explosion of digital tools­—such as smartphones, remote and wearable sensors, telemedicine, and artificial intelligence—that enable researchers and clinicians to develop a more robust understanding of the daily lives of patients with complex neurological diseases, like Parkinson’s, Huntington’s, and Autism. These efforts have taken on a greater sense of urgency, as new studies show that neurological disorders are the leading source of disability in the world today and there is a growing demand to accelerate the development of new treatments by employing clinical studies that involve a smaller number of people, are shorter in duration, and cost less.

“These technologies provide us with sensitive and objective measures and new insight into what was previously unmeasurable,” said Dorsey. “Until recently, we had no window, or a limited window, into understanding how people with these diseases function in the real world environment, which is 99 percent of the time that they're not in the clinic.”

A prominent example of the power of technology to transform health research is the mPower iPhone app for Parkinson’s disease which was developed by Dorsey, Max Little, Ph.D., with Aston University in the U.K., and Sage Bionetworks. The app – which allows Parkinson’s patients to track dexterity, balance and gait, voice, and memory on a daily basis – was highlighted by Apple during a project launch event in 2015. More than 2,000 people downloaded the app and signed up to participate in a Parkinson’s study on the first day it was available. By comparison, the largest clinical trial ever conducted for the disease involved 1,700

people and it took more than two years for the study to meet its recruitment goals.

To date, 19,000 people have downloaded mPower and the app has served as a tool for multiple clinical studies.

The success of the mPower app was an “aha” moment for the team at CHeT. Not only did it demonstrate the research potential of the suite of smartphone technologies that reside in our pockets, but also the ability to reach large numbers of study volunteers when participation can be accomplished remotely and on their own terms.

“There are clear parallels between the way technology is now integrated into every aspect of our daily lives, and the potential that technology holds for being able to make care and research accessible and integrated into our daily lives, from common diseases to very rare diseases,” said Erika Augustine, M.D., the Robert Joynt Associate Professor of Neurology and associate director of CHeT. Over the ensuing years, CHeT has blossomed into one of the nation’s leading centers for innovation and the application of new technologies to study neurological disorders, an effort that has brought together researchers from a wide swath of academia and industry.

CHeT can trace its origins back to 1987 when URMC neurologists Ira Shoulson, M.D., and later Karl Kieburtz, M.D., M.P.H., formed what would eventually be called the Clinical Trials Coordination Center (CTCC). The Center remains one of the only academic-based organizations with the expertise and infrastructure necessary to conduct multisite clinical trials. Since its inception, the CTCC has played a pivotal role in bringing seven new drugs to market – four for Parkinson’s, two for Huntington’s, and one for periodic paralysis. This history, along with the leadership of Cynthia Casaceli, M.B.A. (director of the CTCC), Cornelia Kamp, M.B.A. (director of the Clinical Materials Services Unit), and Elise Kayson, M.S., R.N.C., A.N.P. (director of Clinical and Strategic Initiatives)—who between them have more than 60 years of experience in building international networks of researchers, working with industry, government, and foundation sponsors, and designing and managing clinical trials— has provided the foundation for current efforts to build new technology-based health tools.

In many respects, the digital transformation of research and care at the Medical Center began more than a decade ago with the creation of telemedicine programs in the Departments of Neurology and Pediatrics. Dorsey and Kevin Biglan, M.D., M.P.H., began connecting with nursing homes in upstate New York via web cameras to conduct

“THE GOAL OF THE CENTER IS TO ALLOW ANYONE, ANYWHERE TO PARTICIPATE IN RESEARCH.” RAY DORSEY, M.D.

virtual house calls with Parkinson’s patients. Over the years the program has expanded and support from Greater Rochester Health Foundation and the Edmond J. Safra Foundation helped create the Parkinson’s Disease Care, New York (PDCNY) initiative which connects movement disorders specialists in Rochester with 400 patients from across New York State.

When Dorsey assumed leadership of CHeT in 2014, he championed the potential of technology to overcome the barriers of distance and disability and complement, accelerate, and improve traditional investigations into new drugs.

The name was changed from the original Center for Human Experimental Therapeutics to better reflect this expanded mission. Augustine, who studies rare neurological diseases, and Chad Heatwole, M.D., who focuses on neuromuscular disorders, were subsequently appointed associate directors.

CHeT also created new collaborations with Ehsan Hoque, Ph.D., and Gaurav Sharma, Ph.D., in the University of Rochester Goergen Institute for Data Science to develop new analytical tools and machine learning algorithms to help research sift through the large sets of data being generated by these technologies.

The Del Monte Institute for Neuroscience, in collaboration with CHeT, has developed a targeted pilot grant program to support technology-driven research projects. David Dodell-Feder, Ph.D., in the UR Department of Clinical and Social Sciences and Psychology and Hoque received support for a project that will create computational models of human behavior. Katy Eichinger, Ph.D., D.P.T., in the Department of Neurology, received a grant to employ wearable sensors to track the activity of patients with myotonic dystrophy.

It also became clear that these efforts would require close partnerships with other academic intuitions and industry. In 2014, Dorsey and Avi Seidmann, Ph.D., the Xerox Professor of Computers and Information Systems and Operations Management at the Simon Business School, partnered to create the d.health Summit, an annual gathering now in its fifth year that brings together leading healthcare executives, physicians, entrepreneurs, policymakers, and technology

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H A R N E S S I N G T EC H N O LO GY TO I M P R OV E R E S E A R C H A N D C A R E

“THERE'S A REAL AND GROWING NEED TO PAIR CLINICAL CARE WITH CLINICAL RESEARCH, TO REACH ALL INDIVIDUALS AFFECTED WITH A DISEASE, INCLUDING THOSE WITH PHYSICAL OR GEOGRAPHIC ISOLATIONS...”

ERIKA AUGUSTINE, M.D.

pioneers to exchange ideas, develop partnerships, and foster disruptive technological and process innovations to improve the lives of the nation’s aging population.

The Medical Center’s long and successful track record in experimental therapeutics for neurological disorders, the emphasis on technology-enabled research, and the academic and industry relationships that were painstakingly created at the d.health Summit and in other forums culminated in URMC’s designation as a Morris K. Udall Center of Excellence in Parkinson's Disease Research by the National Institute of Neurological Disorders and Stroke in 2018.

Parkinson’s disease is poised to reach pandemic proportions. By 2040, it is estimated that more than 14 million people across the globe will have the disease and its rate of growth will outpace Alzheimer’s. “In the face of this looming health care crisis, it is clear the status quo is not working,” said Dorsey. “The medical community desperately needs to develop new approaches to better understand this complex disease, expand access to specialized care, and increase the speed and efficiency in how we bring new treatments to the market.”

Unlike other Udall Centers which focus primarily on basic science, the Medical Center’s emphasis is on the development of digital tools to enhance understanding of the disease, engage broad populations in research, and accelerate the development of new treatments. URMC Udall Center projects will involve multi-institutional academic-industry research collaborations with: • •

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23andMe to identify and follow individuals with a rarer inherited form of the disease; GNS Healthcare and Origent Data Sciences to develop advanced machine learning to create models that identify and predict the progression of the disease and the potential impact of new therapies;

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Johns Hopkins University, Aston University, and Sage Bionetworks to develop the next generation mPower app; The Goergen Institute of Data Science, MIT, the University of Michigan, Intel, and MC10 to develop and evaluate several remote monitoring and wearable technologies.

CHeT has forged a number of additional research partnerships across the University and the application of digital technologies is providing new insight into diseases. Dorsey is collaborating with David Mitten, M.D., with the Department of Orthopedics and the UR Health Lab, to develop a wearable device that is activated when someone speaks and counts the number of words they say over the course of a day. The device will be used to measure cognitive impairment in Huntington’s, Parkinson’s, and Alzheimer’s diseases.

Research involving wearable sensors developed by MC10 has revealed that patients with Huntington’s disease often spend half the day lying down, potentially due to depression, social separation, or sleep disturbances, an occurrence that researchers would have never discovered through traditional clinical evaluations.

“There's a real and growing need to pair clinical care with clinical research, to reach all individuals affected with a disease, including those with physical or geographic isolations, and to enhance the patient voice in care and research,” said Augustine. “Emerging technologies are placing the patient at the center of information, decision-making, and choice, whether that is genetic test diagnostics ordered directly by patients, or a new wearable sensor for heart monitoring that ties in with your smartphone. And as clinicians and scientists, we have a lot of catching up to do with respect to how we harness this new information, how we leverage data and research to improve care, and how we meet people where they are.” Q

F A C U LT Y P R O F I L E

Q&A with Paul Geha, M.D. This spring, Paul Geha, M.D., joins the University of Rochester as an assistant professor in the Departments of Psychiatry and Neuroscience. Geha went to medical school in Lebanon before completing a post-doctoral fellowship at Northwestern University and going on to Yale University for a fellowship, residency, and faculty appointment. His Pain and Perceptions laboratory at UR will focus largely on chronic pain and understanding how patients’ brains change as a result of prolonged exposure to pain. We caught up with Geha before his arrival on campus to find out what drew him to Rochester.

Del Monte: Where do your research interests lie and what will you will be focused on when you arrive at UR? PG: My main area of research is chronic pain, branching out into the interaction of chronic pain and addiction. I'm hoping by joining the faculty at Rochester to be able to continue to work on understanding how the brain of patients with chronic pain changes as they experience the chronic pain, or as they transition from acute to chronic pain. We have accumulated a lot of evidence over the years, thanks to advances in imaging, that the brain does not just sit there and receive the pain signals from the periphery; it changes with the experience of pain over time. This can teach us a lot about the nature of the experiences that patients are going through and help us understand how the chronic pain experience is generated. It also helps us identify areas of the brain that we could target with treatments like psychotherapy or drug therapy, and understand the vulnerabilities that these patients run into, such as overeating or getting hooked on opioid pills.

How did you initially become interested in science, and then more specifically in chronic pain research?

Before medical school, I went into philosophy for a year, and I was really interested in the Philosophy of Mind. In medical school, I was very drawn to understanding how the brain comes up with the mind.

My interest in chronic pain happened by accident. I had a professor in medical school that was working on pain and neuroimaging in Chicago, and so I ended up in Dr. Apkar V Apkarian’s lab at Northwestern University for five years. At the time, brain imaging was still in its early years, and we were doing all these cross-sectional studies just to understand what's going on in the brain of patients with chronic pain. I did some of the first open label imaging studies on the brain’s response 7

“The different departments [at the University] offer crucial and critical collaboration that will help me translate some of my ideas into the clinic. ” – Paul Geha, M.D. to analgesia, where you give a patient a drug and look at how their pain changes with time, imaging them before and after.

And, interestingly enough, almost 15 years ago, we started noticing that the areas of the brain that respond the most to analgesic drugs were also involved in emotion processing, or what we call the limbic system.

Are there any departments or centers at UR that you're looking forward to collaborating with?

Definitely. Neurosurgery, Orthopedics, Neurology, the Eastman Institute for Oral Health (EIOH)… Pain is a complaint that is common to many, many different diseases, and chronic pain can occur in multiple systems in the body. Despite almost 25 years of brain imaging, we still don't understand a lot of chronic pain conditions. Since I focus a lot on chronic back pain, I will be working closely with Dr. John Markman in Neurology and Neurosurgery, and Dr. Robert Dworkin in Anesthesiology. The different departments offer crucial and critical collaboration that will help me translate some of my ideas into the clinic. Another collaboration I'm really looking forward to is working with people who have chronic temporomandibular joint (TMJ) pain, which is a chronic pain of the joint between the cranium and the mandible (lower jaw).

EIOH cares for thousands of patients and a lot of them come for treatment of chronic TMJ pain. We have some hypotheses about the role of a specific area or circuit in the brain that could actually identify someone as at risk for chronic TMJ pain.

What really drew you to UR when you decided to make the move?

I worked closely with the chair of UR’s Psychiatry Department, Dr. Hochang (Ben) Lee during his time at Yale as director and chief of Psychological Medicine Service. He understands what kind of infrastructure team research needs and clearly this can be done at the University of Rochester given all the departments and their efforts in clinical pain research.

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Back pain patients show altered brain connectivity within the limbic system (i.e. emotional brain). Areas in red to yellow exhibit increased correlation with the nucleus accumbens (NAc), a hot spot of the limbic brain, and areas in blue to light blue exhibit decreased correlation to the NAc. And, of course, being a part of the Del Monte Institute, where I can collaborate with a lot of cognitive neuroscientists who are working on the brain and imaging other conditions.

What do you like to do for fun outside of your lab?

I’m very into soccer. I'm not a professional in any way, but I really like the sport and I watch it a lot. I also like to hike and one thing I'm looking forward to doing in Rochester is to learn how to ski. People have told me it’s the place to be if you want to ski in the winter. Another thing that was very attractive about the city is that there is a good cultural scene.

I love to go to the theater and music festivals, and my wife is actually a filmmaker—she created a festival for short movies before moving to the U.S.—so she's also looking forward to exploring the arts and culture scene. Q

Del Monte Institute for Neuroscience Executive Committee John J. Foxe, Ph.D. Director, The Ernest J. Del Monte Institute for Neuroscience Kilian J. and Caroline F. Schmitt Chair in Neuroscience Professor and Chair, Department of Neuroscience Diane Dalecki, Ph.D. Distinguished Professor of Biomedical Engineering Chair, Department of Biomedical Engineering

Webster H. Pilcher, M.D., Ph.D. Ernest & Thelma Del Monte Distinguished Professor in Neuromedicine Professor and Chair, Department of Neurosurgery S AV E T H E D AT E Robert G. Holloway, M.D., M.P.H. Edward A. and Alma Vollertsen Rykenboer Chair in Neurophysiology Professor and Chair, Department of Neurology

Gregory C. DeAngelis, Ph.D. George Eastman Professor Chair, Brain and Cognitive Sciences

Del Monte Symposium Manipulating Brain States:

Invasive Mapping and Neuromodulation in Human Neurological Disease K E Y N OT E S P E A K E R

Bradford Berk, M.D., Ph.D. Director, The University of Rochester Neurorestoration Institute Professor of Medicine, Cardiology

Helen Mayberg OCTOBER 24-26, 2019 MEMORIAL ART GALLERY ROCHESTER, NY

Hochang B. (Ben) Lee, M.D. John Romano Professorship in Psychiatry Professor and Chair, Department of Psychiatry

delmonte.urmc.edu

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NEUROSCIENCE TEACHING FACULTY IN THE DIVISION OF NEURAL AND ANATOMICAL EDUCATION 10

Pictured left to right: David R. Kornack, Ph.D., John A. Olschowka, Ph.D., John J. Foxe, Ph.D., Sarah McConnell, Ph.D., Sergiy Nadtochiy, Ph.D., Martha J. Gdowski, Ph.D., Linda Callahan, Ph.D. Not pictured: Diane Piekut, Ph.D.