NeURoscience | Vol 10 | 2021

NEUROSCIENCE University of Rochester | Ernest J. Del Monte Institute for Neuroscience Vol. 10 - 2021

The intersection of science and surgery PG 4

F R O M T H E D I R EC TO R ’ S D E S K

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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 Top right: Frank Garcea, Ph.D., in operating room ahead of surgery.

Left: In red is the left frontal aslant tract identified using high definition fiber tractography. This is an example of how structural brain mapping helps neurosurgeons avoid white matter fiber pathways when planning a patient's surgery.

Bottom right: Neurosurgery team working on patient in operating room.

Photography John Schlia Photography Adam Fenster Editor Kelsie Smith Hayduk Contributor Mark Michaud

e are marking the warmer months with a season of progress at the Del Monte Institute for Neuroscience.

Our researchers continue to push the boundaries of neuroscience. This year the annual Del Monte Pilot Program received 48 applications. Each application underwent a comprehensive NIH-level review from neuroscientists from around the globe, and we are deeply grateful to this independent board for their efforts on behalf of the institute. The program will soon award nearly $1 million in research support for new and innovative neuroscience research projects.

In our cover story, we explore a program that represents a unique nexus between science and neurosurgery to improve care and outcomes. The Program for Translational Brain Mapping brings together neuroscientists and neurosurgeons to create detailed structural and functional maps of patients with brain lesions that can guide surgeons in the operating room and measure recovery. At the same time, the program provides researchers access to a plethora of information about the various processes occurring in the brain on a daily basis.

Comparing this data with healthy individuals, the research team is able to develop models for the cognitive processes that underlie the ability to speak, think, and interact with the world.

The Neuroscience Diversity Commission (NDC) is making great strides in providing access and supporting the research pipeline for Black and Latino students. A group of high school students just completed the first year of the NEUROEAST program. This program was led by the NDC Chair Manuel Gomez-Ramirez, Ph.D. He provided several students from Rochester’s East High School with hands-on experience in his Haptics Lab in the Brian and Cognitive Sciences Department. In this issue, you will also learn more about NDC’s NEUROCITY program, a partnership between the University of Rochester and The

City College of New York (CCNY). Eight CCNY undergraduates are working in neuroscience labs in Rochester this summer. Both programs are examples of our goal to make research accessible and affirm our commitment to diversity, which is essential for excellence in science.

In this issue, you’ll meet Jennetta Hammond, Ph.D., she recently joined the institute as an assistant professor in Neurology and Neuroscience. Her research aims to understand interactions between the nervous system and the immune system and its impact on brain development.

Yanya Ding is a stand-out student who just completed her first year in the Neuroscience Graduate Program. She is dedicated to research with a focus on Batten disease. She will work directly with the folks in the University of Rochester Batten Center and aims to learn more about underlying neural circuity of the disease.

This fall we are looking forward to coming together for the first time in nearly two years for our annual symposium. In October, the Institute will partner with the University of Rochester Intellectual and Developmental Disabilities Research Center to host the event titled: Developmental emergence of neural circuit architecture and function. It will feature speakers from more than a dozen institutions and organizations.

I am energized by the work being done by our faculty, trainees, students, and staff. It is not lost on me the grind everyone undertakes daily for the reward of meaningful contributions to science. I am proud to be a part of such a team.

In Science,

John J. Foxe, Ph.D.

NEWS BRIEFS

Brain map will help identify risk factors for mental health problems New findings from the Adolescent Brain Cognitive Development Study (ABCD) provide researchers with a roadmap of brain activity that could be used to identify cognitive processing problems that could ultimately contribute to mental and physical health problems later in life.

“This study pushes us closer to the point where we can identify and ultimately prevent mental health problems later in life by identifying risk early,” said John Foxe, Ph.D., director of the University of Rochester Del Monte Institute for Neuroscience and co-author of the study, which appears in the journal Nature Neuroscience. “If we can identify these risks with a simple brain scan at a young age, then that gives us a long runway to intervene and potentially change outcomes.”

Using functional magnetic resonance imaging (fMRI) technology, the researchers observed brain activation during a battery of three different tasks and identified how differences in the patterns of activity related to individual differences in these processes. The findings demonstrate which brain regions are involved in a range of important psychological processes, including cognitive control, reward processing, working memory, and social and emotional function.

The ABCD study is the largest brain development study ever undertaken by the National Institutes of Health. The

study has enrolled almost 12,000 youths aged 9 to 10 and will follow them for 10 years. The University of Rochester Medical Center (URMC) is one of 21 sites in the U.S. participating in the initiative. The local study is led by Foxe and Ed Freedman, Ph.D.

New award explores intersection of infectious diseases and neurological disorders URMC neurologist Gretchen Birbeck, M.D., M.P.H., has received a $4.3 million award from the National Institutes of Neurological Disorders and Stroke (NINDS) to continue her research in sub-Saharan Africa on the neurological problems that arise in people recovering from malaria, HIV, and other infectious diseases, including COVID. Initially, her research will focus on two projects. The roles neuroinflammation in structural injury and neurologic morbidity play in cerebral malaria survivors, and HIVassociated accelerated aging of the nervous system, particularly in children. Researchers will also investigate the effects a COVID infection has in these populations as well.

The NINDS Research Program Award, which uses the R35 funding mechanism, is given to investigators whose record of research achievement demonstrates an ability to make major contributions to the field of neuroscience. The eight-year award is intended to provide recipients, like Birbeck, the freedom to embark on ambitious, creative, and longer-term research projects, without the constraints of specific aims.

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NEUROEAST NEUROEAST is a Del Monte Institute for Neuroscience Diversity Commission (NDC) program, designed to give underrepresented minority students at East High School in the Rochester City School District access to a neuroscience research lab at the University.

“Being able to provide these students a real world experience in a working research lab is setting the foundation for the future of science," Manuel Gomez-Ramirez, Ph.D., principal investigator of The Haptics Lab and NDC chair. "Progress in neuroscience depends on having the best researchers doing the work. And to find the best, we must provide access to all."

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 Lulu Abdullahi (right), a junior at East, practices soldering to repair an experiment

component with Gomez-Ramirez (center) in The Haptics Lab. Catalina Feistritzer (left), a University of Pittsburgh senior participating in UR's Summer Research Program, looks on.  Gomez-Ramirez conducts a lecture to small group including Abdullahi.

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NEUROCIT Y NEUROCITY is a partnership between the NDC and The City College of New York (CCNY). Eight undergraduate students are participating in this 10-week research intensive program designed to encourage underrepresented minority students to explore the field of neuroscience. Students are working under co-mentorship of faculty from UR and CCNY, and a UR graduate student. 

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 Yacinda Hernandez (center), CCNY senior, works with gradute

student mentor Emily Isenstein MD/PhD, (R) in the Duje Tadin Lab on accessing visual proprioceptive integration. Kerry O'Banion, M.D., Ph.D., (L) shows CCNY junior Nathalie Membreno how to look for proper staining of brain tissue samples. Kathryn-Mary Wakim (L), 5th year NGP student, teaches CCNY graduate Manuel Otero programming for EEG analysis. Julie Fudge, M.D., (L) shows CCNY senior Jancy Contreras Brightfield microscopy analysis of dopamine cells in the ventral tegmental area.

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F E AT U R E

Front: Webster Pilcher, M.D., Ph.D. Back from left: Emma Strawderman, Brad Mahon, Ph.D., Sam Haber, Max Sims, Frank Garcea, Ph.D.

It began when Webster Pilcher, M.D., Ph.D., the Ernest & Thelma Del Monte Distinguished Professor in Neuromedicine and chair of the University of Rochester Medical Center (URMC) Department of Neurosurgery, asked a simple question: How could the insights of cognitive neuroscience be more fully harnessed to help improve the outcomes of patients who undergo brain surgery?

Pilcher’s focus is surgical intervention for brain tumors and epilepsy, but the challenge is similar in other forms of brain injury – clinicians require more detailed information about the organization of the brain, particularly at the

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individual patient level, to help guide them in the operating room and emergency department, and predict functional deficits and recovery.

“As a surgeon, you see a patient in clinic with a tumor in an eloquent area of the brain, and

Garcea, Ph.D., prepares OR computers for surgery.

you're asking yourself can this tumor be removed safely?,” said Pilcher. “What's the risk if I go this way or that way, what's the risk if I map this function and move it aside?”

Surgery by its nature risks damaging tissue and breaking connections between different areas of the brain. While the average brain is organized in roughly the same way, the control centers for different functions such as expressive and receptive language, motor and sensory functions, visual processing and visual–spatial functions can vary by crucial millimeters or even centimeters from person to person. If a tumor is present, then the variation can be even more significant. A procedure called awake brain surgery, which utilizes intraoperative brain mapping, has long been used by neurosurgeons to probe the area around a tumor immediately prior to and during a resection, but there remain gaps in the surgeon’s understanding of the precise functional organization of an individual patient’s brain prior to their arrival in the operating room.

In 2011, Pilcher connected with University of Rochester cognitive neuroscientist Brad Mahon, Ph.D., whose research employs neuroimaging and behavioral analysis to study disruption and recovery in the brain. The two formed a partnership that would eventually become the Del Monte Institute for Neuroscience’s Program for Translational Brain Mapping, and the team grew to include other neurosurgeons, neurologists, ophthalmologists, and neuroscientists.

While the program has the clinical purpose of guiding neurosurgeons and measuring recovery over time, by studying individuals with brain lesions, researchers are also able to learn a great deal about sophisticated brain functions which occur on a daily basis. Comparing data in patients with brain tumors and epilepsy with healthy individuals, the team

is able to test models of the cognitive processes that underlie the ability to speak, think, and interact with the world.

The process starts when a brain surgery patient is referred into the program, at which point the neuroscience team performs a battery of cognitive tests and functional and structural MRI scans in the URMC Center for Advanced Brain Imaging and Neurophysiology. After the procedure, patients return for assessments and are followed for multiple years post-surgery to assess their recovery. These studies and the analysis of the data are supported by research grants from the National Institute of Neurological Disorders and Stroke, the National Eye Institute, the National Science Foundation, a partnership with Head for the Cure, and philanthropy from Norman and Arlene Leenhouts and others.

The researchers also build a profile that takes into account the patient’s occupation, expertise, and hobbies, and whether the surgery could impact parts of the brain important to their identity. The program has assessed a high school music teacher with a tumor in the area of the brain responsible for music processing, an accountant with one in the region responsible for mathematical cognition, and a carpenter with one in an area important for fine motor control, among others.

“You work backwards from the goal, which is to protect people's minds, and that's fundamentally what makes the brain mapping translational,” said Mahon. “The goal is to help determine what is safe and not safe from a neurosurgical perspective and from the standpoint of understanding how that patient will be doing neurologically six months after surgery.”

The end product is a detailed functional and structural map of the patient’s brain which surgeons can consult prior to and during the procedure in order to preserve critical brain tissue. During awake brain surgery, a team of neuroscientists

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in the operating room perform a cognitive assessment of the patient, collecting more data.

“I think what's so attractive to those of us who are clinicians is that by taking  the power of cognitive neuroscience and applying it directly to our clinical programs, we can generate benefit for patients in months and years, not in decades,” said Pilcher.

SURVIVING STROKE PROPELS CAREER IN BRAIN RESEARCH The impact of brain injury on function and cognition has long been a source of personal interest for Frank Garcea, Ph.D. In 2005, he suffered a hemorrhagic stroke from a ruptured brain aneurysm during a high school soccer practice. Reflecting on why he was able to make a quick recovery, while so many others who suffer from this type of stroke are faced with a lifetime of disability, shaped his future academic career.

Garcea went on to earn his Ph.D. in cognitive neuroscience from the University of Rochester, working closely with Pilcher and Mahon to assess brain surgery patients. In 2017 he left for a postdoctoral fellowship at the Moss Rehabilitation Research Institute in Philadelphia and returned to the University of Rochester earlier this year to rejoin the Program for Translational Brain Mapping team.

Garcea’s research interest harkens back to his brush with death almost 16 years ago. He is combining functional and  In blue are the regions

of the brain identified when participants performed a motor task during an fMRI scan.

This is an example of how functional brain mapping helps neurosurgeons avoid cortical areas supporting eloquent function when planning a patient's surgery.  From left: Garcea, Haber,

Strawderman

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structural MRI with angiography to understand how brain aneurysms in different vascular territories are associated with different kinds of cognitive deficits, with the goal of informing surgical care to maximize postoperative recovery of function. In ischemic and hemorrhagic stroke, his research is seeking to decipher how people recover language and motor function after injury, and identify the cognitive and neural factors associated with recovery vs. long-term disability.

“We can use these mapping techniques to get a better understanding of the factors that determine who will go on to make a full or partial recovery after an aneurysm, with the goal of using the information we collect pre-operatively to obtain a prediction of the extent to which a patient will recover post-operatively,” said Garcea.

THE NEXT PHASE: WHITE MATTER TRACTS AND MORE DATA A critical piece of a neurosurgeon’s task during a procedure is preserving the connections between different regions of the brain that work together to support complex functions like language processing. Over the last several years, there has been a boom in the development of sophisticated algorithms that can map white matter fibers in and around tumors. Garcea and Mahon, who is also an associate professor in psychology at Carnegie Mellon University, are applying a method called high-definition fiber tracking to map out white matter tracts that are in the proximity of a

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...by taking the power of cognitive neuroscience and applying it directly to our clinical programs, we can generate benefit for patients in months and years, not decades."

brain tumor. This additional data will allow the surgeons to get a better idea of where the tumor is in relation to these vital connections and plan a safer surgical approach.

With every patient, the researchers learn more about the brain’s organization and how different surgical approaches impact long-term outcomes. While the University of Rochester sees approximately 50 brain mapping patients per year, the predictive powers of the information collected would be amplified with a larger patient dataset. The team is in the process of building a consortium of major medical centers to contribute pre-operative mapping and surgical data to a centralized open source repository that will be managed by Carnegie Mellon University. To date, eight institutions and five medical centers have agreed to participate in the initiative. The data will provide researchers a richer set of data with which to develop predictions about surgical outcomes.

“We want to develop the next generation of algorithms, so that surgeons will be able to simulate patient outcomes for a given surgical plan prior to the first incision,” said Mahon.

“They will be able to test different surgical approaches using AI algorithms trained on outcomes from prior studied patients.”

The Program is helping draw new researchers to Rochester. Sam Norman-Haignere, Ph.D., a post-doctoral researcher at Columbia University, will be arriving early next year as an assistant professor of Biostatistics and Computational Biology and Neuroscience. He employs computational methods to study the organization of the human auditory cortex and the neural computations that

Neurosurgery team performs brain surgery on patient. Researchers provide the neurosurgery team with a detailed structural and functional map of each patient’s brain, which helps guide surgeons’ decisionmaking in the operating room.

allow people to understand natural sounds like speech and music. The long-term goal of the research is to understand the basic neural mechanisms that allow people to understand natural sounds in order to better understand and treat deficits in auditory perception caused by hearing loss and other sensory and cognitive deficits.

“The types of intracranial recordings made as a part of the Program for Translational Brain Mapping provide a rare opportunity to measure responses in the human brain with spatiotemporal precision, which is critical to understanding how the brain codes complex natural sounds like speech,” said Norman-Haignere.

The Program also provides a platform of core resources to support the research and training of graduate students, residents and fellows, and undergrads. Emma Strawderman, a Brain and Cognitive Sciences undergrad at the University of Rochester, is employing advanced brain imaging data collected by the program to study white matter pathways underlying the networks that support our ability to recognize and grasp everyday objects. The study of this process in the healthy brain sets the foundation to investigate how lesions to brain networks can lead to cognitive and motor deficits in patients.

She is in the process of applying to M.D./Ph.D. programs with plans to pursue research in the application of neuroimaging in neurosurgery and neurology cases.

“I’ve been doing research with diffusion MRI since I was a sophomore, and I’m grateful to have such excellent mentors like Drs. Mahon, Pilcher, and Garcea to support me in this pursuit,” said Strawderman.

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

inhibitors have a protective role against excessive complement activity and direct immune attacks on the adult brain.

You were recently rewarded an R01 with a focus on autism research. How will this fit into your research?

My R01 aims to understand the function of the Sez6 gene family, whose three members have genetic links to multiple neurodevelopmental and psychiatric disorders, including autism. The grant is based on the hypothesis that Sez6 proteins normally put the brakes on complement-mediated synaptic pruning in order to facilitate correct connectivity in the brain.

Disruptions in this process may contribute to the pathogenesis of neurodevelopmental disorders such as autism. This work actually began in 2018 when I was granted a $47,000 Harry T. Mangurian Jr. Foundation pilot award. That turned into an R21 from the NIH, which lead to this R01.

Q&A with Jennetta Hammond, Ph.D. Jennetta Hammond, Ph.D., joined the Del Monte Institute for Neuroscience as an assistant professor in Neurology and Neuroscience in July 2021. She received her B.S. in Zoology from Brigham Young University and went on to complete her Ph.D. in Cell and Developmental Biology at the University of Michigan. She first came to the University of Rochester as a post-doctoral trainee in 2012 and was hired as a research assistant professor of Neurology in 2018. Her research aims to understand interactions between the nervous system and the immune system that impact brain development or contribute to various autoimmune disorders.

Tell us a little bit about your research?

My lab is interested in learning how immune pathways, such as complement, play a role in normal and abnormal brain development. We have begun characterizing some novel, complement regulators that are expressed by neurons. These complement inhibitors may serve as protective factors during brain development when complement is engaged to clear away excess neuronal connections. In neurodevelopmental disorders, this pruning event may be poorly controlled leading to over – or under – pruning that could contribute to the disorders. We are also investigating whether these complement

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What brought you to the University of Rochester?

My career path has been somewhat atypical compared to most faculty. After I completed my Ph.D., I took four years off from research to raise my two young children. When my husband’s first faculty job brought us to Rochester, I was ready to start doing research full-time again and I obtained a post-doctoral position in the lab of Harris Gelbard, M.D., Ph.D. Once I was back at the bench, I found really supportive people and then funding for my projects. I think it is important for a robust and diverse workforce that we support families and continue to be open to different career paths.

Do you have any advice?

Stay focused on your big goals and just keep working. In my experience, working in basic research is like being on a slow moving roller coaster. It is easy to get discouraged during the slow and uncertain times, but hard work, good ideas, and smart decisions along the way usually yield productive results in the end. I think it is exciting to be the one asking questions about how the brain is built and working to extend our knowledge bit by bit into the unknown.

Image of Sez6L2 being expressed

by Purkinje and granular cells in the mouse cerebellum (Sez6L2 = green; vGlut1 = magenta).

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

Yanya Ding is starting her second year in the Neuroscience Graduate Program (NGP) at the Medical Center. Originally from China, she graduated from the University of Wisconsin with a B.S. in Neuroscience in 2019.

In June, Ding joined the Cognitive Neurophysiology Laboratory of John Foxe, Ph.D., and Ed Freedman, Ph.D., and she is also co-mentored by Kuan Hong Wang, Ph.D. Her current research is examining neuronal ceroid lipofuscinosis – the underlying neural circuity of Batten disease. Using in vivo imaging, she is attempting to identify brain areas with ceroid accumulation and will compare MRIs and electroencephalograms (EEGs) between animal models and human scans.

Access to the University of Rochester Batten Center is invaluable to Ding’s research. “Having human patients report from that center and participate in our research raises the

level of our understanding that we can’t get from just looking at animal models. This collaboration is a huge and important part of our research,” Ding said.

Batten disease affects at least one out of every 50,000 children in the United States, and can result in seizures, movement dysfunction, and cognitive impairment. The average life expectancy of someone diagnosed with the disease is less than 20 years. “I think it is really beneficial to study this disease and underlining process so we can help more people. There is much we do not understand about this disease, which gives me a lot of freedom to explore in my research,” Ding said.

Ding plans to continue to pursue research in an academic setting after graduation. She is looking forward to more in-person experiences and learning opportunities in the 20212022 school year.

Del Monte Institute for Neuroscience Executive Committee John 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

Bradford Berk, M.D., Ph.D.

Director, The University of Rochester Neurorestoration Institute Professor of Medicine, Cardiology

Robert Dirksen, Ph.D.

Lewis Pratt Ross Professorship of Pharmacology and Physiology Professor and Chair, Department of Pharmacology and Physiology

Diane Dalecki, Ph.D.

Distinguished Professor of Biomedical Engineering Chair, Department of Biomedical Engineering

Jennifer Harvey, M.D.

Paige Lawrence, Ph.D.

Wright Family Research Professorship - Dean's Office M&D Professor and Chair, Department of Environmental Medicine

Hochang (Ben) Lee, M.D.

John Romano Professorship in Psychiatry Professor and Chair, Department of Psychiatry

Shawn Newlands, M.D., Ph.D., M.B.A. Professor and Chair, Department of Otolaryngology

Webster Pilcher, M.D., Ph.D.

Ernest & Thelma Del Monte Distinguished Professor in Neuromedicine Professor and Chair, Department of Neurosurgery

Duje Tadin, Ph.D.

Professor and Chair, Department of Brain & Cognitive Sciences

Professor and Chair, Department of Imaging Sciences

Robert Holloway, M.D., M.P.H.

Edward A. and Alma Vollertsen Rykenboer Chair in Neurophysiology Professor and Chair, Department of Neurology 9

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SAVE THE DATE Del Monte Institute for Neuroscience and University of Rochester Intellectual and Developmental Disabilities Research Center Symposium

Developmental emergence of neural circuit architecture and function October 22 & 23, 2021 Memorial Art Gallery, Rochester, NY delmonte.urmc.edu