NeURoscience | Vol. 4 | 2020

NEUROSCIENCE University of Rochester | Ernest J. Del Monte Institute for Neuroscience Vol. 4 – 2020

New Frontiers in Neuroimaging Pg. 3

FROM THE DIRECTOR’S DESK

A

s I write, Rochester and the Northeast have plunged into winter.

It reminds us, as we transition between semesters, of all that has taken place and been accomplished since the summer.

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

Our large group of new graduate students have joined their peers in engaging fully with neuroscience, and we are thrilled to have them with us to begin their next career steps. I’m sure that you’ll be very pleased, as I was, to read here about the work of one of our outstanding students, Adnan Hirad, and his research on the neurological impacts of repetitive sub-concussive brain injury which was covered by The New York Times and many other news outlets.

Our cover story this edition details how neuroimaging technologies are advancing the study of the human brain. The piece profiles the groundbreaking research of Feng (Vankee) Lin, Giovanni Schifitto, and David Dodell-Feder as they harness new imaging technologies, data science, and AI to study neurological and psychiatric disorders.

This past October was filled with significant events and participation by our faculty and students in multiple activities. The Society for Neuroscience (S fN) conference in Chicago was a real success, with many of our students and faculty attending and presenting. We were also extremely pleased

to welcome many prospective students at the NGP booth at S fN, and to share with them the exciting work that is taking place here in Rochester. While in Chicago, we hosted a well-attended Rochester Neuroscience social for staff, students, alumni, and friends at Tapas Valencia. At that celebratory event, we also awarded our first Neuroscience Alumni Award to Nathan Smith, Ph.D. – congratulations Nathan!

Immediately following S fN, the Institute hosted its annual Symposium at the Memorial Art Gallery here in Rochester (Oct 24–26). This year’s theme was Manipulating Brain States – Invasive Mapping and Neuromodulation in Human Neurological Disease. As I mentioned in my last letter, since my arrival here at Rochester, I have had many conversations with our chair of Neurosurgery, Dr. Web Pilcher, about the role and promise of these techniques in clinical neuroscience. The Symposium exceed all of our expectations; we had 21 superb speakers from across the globe join a group of 150 faculty and students in a lively and exceptional few days of learning and collaboration.

We all wish you a wonderful transition into 2020! I look forward to connecting with you all again in the spring and reporting on the numerous exciting developments which continue to unfold here in Rochester.

On the cover Feng (Vankee) Lin, Ph.D., Giovanni Schifitto, M.D., M.S. , and David Dodell-Feder, Ph.D.

Photo by John Schlia Editor

In Science,

Mark Michaud Design by

m-print

2

John J. Foxe, Ph.D. NEUROSCIENCE

|

Vol. 4, 2020

NEWS BRIEFS

Image from Scientific Reports study shows protein marker (green) that indicates activation of microglia (red) after exposure to radiation.

Radiation breaks connections in the brain

Immune cells rewire, repair brain while we sleep

A Scientific Reports study by Kerry O’Banion, M.D., Ph.D., a professor in the Del Monte Institute, shows that radiation exposure triggers an immune response in the brain that severs connections between nerve cells. These findings may explain why patients often experience cognitive impairment after cranial radiotherapy.

The culprit is a cell in the immune system called microglia. In addition to fighting infection and repairing damage, microglia play a role in the rewiring of neurons by pruning the connections between nerve cells when they are no longer needed.

In the new study, researchers exposed the mice to radiation equivalent to the doses that patients experience during cranial radiotherapy. They observed that microglia in the brain went into overdrive and removed nodes that form one end of the synaptic juncture – called spines – which prevented the cells from making new connections with other neurons. The microglia appeared to target less mature spines, which the researchers speculate could be important for encoding new memories.

The research points to two possible approaches that could help prevent damages to nerve cells, including blocking a receptor called CR3 that is responsible for synapse removal by microglia or tamping down the brain’s immune response during radiotherapy.

Research by URMC neuroscientist Ania Majewska, Ph.D., in the journal Nature Neuroscience shows for the first time that important immune cells called microglia – which play an important role in reorganizing the connections between nerve cells, fighting infections, and repairing damage – are also primarily active while we sleep.

The findings have implications for brain plasticity, diseases like autism spectrum disorders, schizophrenia, and dementia, which arise when the brain’s networks are not maintained properly, and the ability of the brain to fight off infection and repair the damage following a stroke or other traumatic injury.

The study points to the role of norepinephrine, a neurotransmitter that signals arousal and stress in the central nervous system. This chemical is present in low levels in the brain while we sleep, but when production ramps up, it arouses our nerve cells, causing us to wake up and become alert. The study showed that norepinephrine acts on a specific receptor, the beta2 adrenergic receptor, which is expressed at high levels in microglia. When norepinephrine is present in the brain, the microglia slip into a sort of hibernation.

The research reinforces to the important relationship between sleep and brain health and could help explain the correlation between sleep disturbances and the onset of neurodegenerative diseases.

University of Rochester

| Ernest J. Del Monte Institute for Neuroscience

1

NEWS BRIEFS

Symposium explores brain mapping and modulation technologies In October, the Del Monte Institute welcomed more than 150 attendees to the Manipulating Brain States – Invasive Mapping and Neuromodulation in Human Neurological Disease Symposium in Rochester. The event featured 21 internationally renowned speakers and highlights included keynote addresses delivered by Helen Mayberg, M.D., with the Icahn School of Medicine (“Iterative Strategies to Refine and Optimize Deep Brain Stimulation for Depression”) and Itzhak Fried, M.D., Ph.D., with UCLA (“Neuromodulation of Human Memory”). Other speakers and panel discussions during the two days included topics such as deep brain stimulation in neuropsychiatric and neurological disease, non-invasive neuromodulation, electrocorticography, pre-operative and intra-operative brain mapping, and neuromodulation in epilepsy.

Smith receives URMC Neuroscience Alumni Award Nathan Smith, Ph.D., a principal investigator at Children’s National Research Institute and an associate professor at George Washington University School of Medicine and Health Sciences, was presented with the URMC Neuroscience Alumni Award at the SfN conference in Chicago.

Rett Syndrome Education and Research Day In November, the Del Monte Institute welcomed patients and families, clinicians, researchers, and community members to the inaugural Rett Syndrome Education and Research Day, led by Tufi Brima, Ph.D., a research assistant professor in the URMC Cognitive Neurophysiology Lab.

2

NEUROSCIENCE

| Vol. 4, 2020

FEATURE

Photo: John Schlia

A portfolio of imaging technologies are providing researchers with new insight into the human brain. Since it first became commercially available in the 1980’s, the MRI has been an invaluable tool to study the central nervous system.

(L to R) Feng (Vankee) Lin, Ph.D., David Dodell-Feder, Ph.D., and Giovanni Schifitto, M.D., M.S. with UR’s Siemens 3T whole-body horizontal-bore Prisma magnet.

In the ensuing decades, new sequences and modalities, and advances in computational science have transformed this technology, enabling researchers to study not only the structure, but the brain’s function and complex networks of connections.

Created in 2004, the University of Rochester (UR) Center for Advanced Brain Imaging and University of Rochester

Neurophysiology (CABIN) houses a state-ofthe-art Siemens 3T whole-body horizontal-bore Prisma magnet. CABIN, led by John Foxe, Ph.D., and Jianhui Zhong, Ph.D., serves as a hub for neuroscientists, technicians, biostatisticians, data scientists, and biomedical engineers.

These multidisciplinary teams are necessary to not only develop study protocols, but also

| Ernest J. Del Monte Institute for Neuroscience

3

other areas of the brain. ACC is associated with a broad range of behaviors and cognitive processes and its function deteriorates during both Alzheimer’s and the natural aging process. Her research has shown that a small population of older adults — known as “supernormals”— who are able to maintain memory and cognitive function as they age have higher levels of ACC activity and connectivity. Lin is testing whether a regimen of computerized tasks that are specific to ACC function and other non-invasive neuro-stimulation approaches can improve working memory, strengthen the connections between the ACC and other brain regions, and thwart cognitive decline.

Giovanni Schifitto, M.D., M.S., a professor in the Department of Neurology, is employing neuroimaging to study inflammation in the brain and its association with cerebral small vessel disease, stroke, and cognitive impairment.

While many factors – including hypertension and diabetes – can trigger damage in the vascular system in the brain, one of the culprits that Schifitto and his colleague are most interested in is the immune system. When the body’s immune response is triggered due to infection or injury, this can activate monocytes which then cross the blood brain barrier, promote inflammation, and damage the network of micro vessels that supply blood to the brain. This causes

Photo: John Schlia

interpret the mountains of data that are providing scientists with an ever more detailed portrait of the human brain.

More than 30 principal investigators are currently engaged in research using the imaging resources in CABIN to study a wide range of neurological disorders such as Batten disease, Alzheimer’s, Rett syndrome, schizophrenia, chronic pain, stroke, muscular dystrophy, traumatic brain injury, brain tumors, and seizure disorders. UR researchers are also employing neuroimaging technologies to understand brain development and sensory processing.

Feng (Vankee) Lin, Ph.D., an associate professor in the School of Nursing, is harnessing neuroimaging technologies in an effort to develop new diagnostic tools for early detection of Alzheimer’s disease and dementia, identify new therapeutic targets that hold the potential to slow the progression of the diseases, and understand the cognitive decline associated with normal aging.

The current gold standard for Alzheimer’s diagnosis is PET imaging, but the high cost of the technology severely restricts its use as a screening tool. One of the goals of Lin’s research is to identify cost-effective MRI-based imaging biomarkers that could detect the disease before cognitive symptoms appear.

Lin has zeroed in on the anterior cingulate cortex (ACC), a region that serves as a hub with connections to many

4

NEUROSCIENCE

| Vol. 4, 2020

New public and private initiatives are creating vast imaging resources for data sharing and machine learning and artificial intelligence are allowing research to accelerate the process of extracting information from images and data.”

Photo: John Schlia

“

local tissue damage and can disrupt communication between different areas of the brain, leading to cognitive problems.

Schifitto and his colleagues employ several MRI modalities, including diffusion weighted imaging (DWI) and resting state fMRI, to assess impact on the brain’s connections and integrity of the cerebrovascular system.

His lab also employs a new imaging modality called magnetic resonance elastography (MRE), which gently vibrates the head during an MRI scan and measures the relative stiffness of brain tissue. Changes in brain elasticity are the result of neuro-inflammation associated with diseases such as HIV, multiple sclerosis, vascular diseases, brain tumors, and neurodegenerative disorders such as Alzheimer’s. Collectively, these technologies enable researchers to measure changes in the brain and correlate these with cognitive performance. Further, by linking changes with inflammatory markers in the peripheral blood system, this research could lead to new methods to diagnose and measure the effectiveness of experimental therapies.

People with schizophrenia often have difficulty empathizing, recognizing, and responding to the unspoken cues that allow us to navigate the world around us and form social connections. David Dodell-Feder, Ph.D., an assistant professor in the Department of Psychology, is employing imaging technologies in the field of psychotic spectrum disorders, such as schizophrenia, to see if the social deficits in these patients can be overcome by “training” specific areas of the brain.

Dodell-Feder is focusing on a network of regions of the brain in the medial temporal cortex and medial prefrontal cortex that studies have shown to be important for allowing us to understand and interpret another person’s knowledge, beliefs, emotions, and intentions. His research, along with others, have found abnormalities in these brain networks University of Rochester

in people with schizophrenia, specifically they tend to be under recruited when performing social tasks. The most widely used behavioral intervention for people with schizophrenia is social skills training, typically performed in a group setting. While beneficial, this approach has limitations and does not address the underlying deficits in the brain.

The question that Dodell-Feder’s research is attempting to address is whether these areas of the brain can be targeted in a more direct and mechanistic way. He employs a technology called real time fMRI, which allows study subjects to view their own neural activity as it occurs. While in the scanner, participants are asked to focus on activating specific areas of the brain. The neural activity from the fMRI is gathered and displayed in real time, providing participants feedback during the exercises. The idea is that by giving someone a window into his or her own brain, they have the opportunity to gain control over these regions and that skill could lead to cognitive or behavioral changes in the real world.

A common thread across the field of neuroimaging is data – specifically, how to store, share, and analyze the vast quantities of information produced by a technology that is constantly advancing and yielding increasingly detailed images of brain structure and function. Zhengwu Zhang, Ph.D., an assistant professor of Biostatistics and Computational Biology, who collaborates with many CABIN investigators, identifies data as one of the greatest challenges and opportunities in the field of neuroimaging. New public and private initiatives are creating vast imaging resources for data sharing and machine learning and artificial intelligence are allowing researchers to accelerate the process extracting information from images and data. These advances, along with scanners that are producing ever-higher resolution images, are poised to revolutionize the field in the coming years. |

Ernest J. Del Monte Institute for Neuroscience

5

Photo: J. Adam Fenster / University of Rochester

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

Q&A with Farran Briggs, Ph.D.

“

Every time I study a neural circuit, I want to understand the cellular components of that circuit: what is the morphology and physiology of each component neuron? What is the conductivity among neurons?”

Farran Briggs, Ph.D., joined the Del Monte Institute for Neuroscience in 2017 as an associate professor in the Departments of Neuroscience, Brain and Cognitive Sciences, and the Center for Visual Sciences. She received her B.A. in Biology from Dartmouth College and Ph.D. in Biology from the University of California, San Diego. Her work focuses on neuronal circuits in the visual system, and how attention affects the brain’s ability to process visual information.

Tell us a little bit about your research.

FB: I am a vision neuroscientist. Broadly speaking, the questions that most interest me involve trying to understand how specific neuronal circuits in the early visual system encode visual information. I am also interested in how things like attention change the way that visual information is encoded in neuronal circuits. I am always interested in connecting structure with function. So every time I study

6

NEUROSCIENCE

Vol. 4, 2020

a neural circuit, I want to understand the cellular components of that circuit: what is the morphology and physiology of each component neuron? What is the conductivity among neurons? The ultimate goal is to understand the causal role of identified neuronal circuits in vision. Malfunctions in some of these neuronal circuits in the early visual system could be implicated in a variety of diseases including sensory hypersensitivity and even Autism Spectrum Disorder (ASD). Other potential translational applications pertain to attention deficits that are components to many neuropsychiatric disorders.

neurons. Again, insights gained from our animal models may inform better approaches to visual therapy for patients.

Do you have a favorite piece of advice from your own mentor, or someone who has inspired you in your career?

FB: Starting out as a new PI is really challenging. It’s trial by fire when you’re a new faculty member and sometimes you feel that if your experiments don’t work every day, you’re not going to make it. I went through a difficult phase during my first couple of years, where I would constantly question whether I was good enough to make this career work. At a particularly low point, I called up my postdoc advisor, Marty Usrey, for advice. He told me that he had no doubt that I have what it takes, but he also said that I needed to be sure that I felt the same about myself. He told me to evaluate whether what I was doing made me happy, because if I get to a point where I’m unhappy, then it’s time to consider alternatives. That was really good advice. In the end, what matters most is that you’re happy and that you’re doing something you love. I think I really needed to hear that in that moment.

What brought you to the University of Rochester?

FB: I was a faculty member at the Geisel School of Medicine at Dartmouth for six years before I came to UR. My reasons were simple: for vision research in highly visual animal models, UR is one of the best institutions in the world. The Center for Visual Science (CVS), which has one of the longest running core grants and training grants for vision research in the country, includes an unprecedented number of faculty studying vision at all levels from the optics of the eye to visual cognition. Additionally, there’s a concentration of research at UR involving similar animal models and techniques to those I use in my research. I’m surrounded by an amazing community of people who are doing similar things to me, which was not the case previously.

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

FB: That is a fun question, although my answer is a little sad because my participation in my non-work activities has dwindled over the years. I’ve always been an athlete and participated in different types of sports, and when I was a graduate student and a postdoc, I got excited about triathlons. I loved the training; long solo rides and runs are such a great antidote to science, which is cerebral and detail oriented. Those runs and rides were meditative, a fantastic way to switch my mind into a different mode over a long period. The downside was the amount of training required, up to 40 hours per week.

Partway through my postdoc, I realized this time commitment was not sustainable. I still love to ride my bike, run and swim, though, and I would love to get back into triathlons someday. Maybe when I’m 80.

Is there anyone at UR with whom you had been especially looking forward to collaborating?

FB: I am currently engaged in a couple of active collaborations with faculty in CVS, specifically Krystel Huxlin and Bill Merigan. One of our projects involves understanding the downstream effects of retinal disease. Diseases like glaucoma, for example, cause damage to retinal ganglion cells, the output neurons of the retina. There has been remarkable progress made in understanding glaucoma progression in the eye. However, we know very little about what happens when you deprive the rest of the visual system of its major input. You can envision a situation where retinal function is restored through a prosthetic or stem cell therapy in a patient who was blind for some period, but their visual perception has been altered. We know very little about how the visual system is altered by loss of retinal input, so it’s very difficult to comprehend how we might need to supplement retinal treatment in order to provide full vision restoration.

In addition to developing an animal model of glaucoma and we also want to produce an animal model of visual cortical stroke. We are interested in the thalamus because the visual cortex provides a robust input to the visual thalamus. If we can replicate vision loss in animal models of stroke that mimic what researchers have observed in their patients, we will be able to measure the functional changes that occur in individual University of Rochester

Any final thoughts you would like to share?

FB: I’m really excited about the great potential for new collaborations at UR. I want to test my hypothesis that even some of the early circuits in the visual system might be implicated in sensory hypersensitivity. At UR, we’re surrounded by experts on ASD and other developmental disorders and I would love to keep developing this project and potential collaborations with PIs studying these disorders in humans.

There’s a lot of potential.

|

Ernest J. Del Monte Institute for Neuroscience

7

Photo: Carnegie Mellon University

STUDENT SPOTLIGHT

Adnan Hirad Adnan Hirad, an M.D./Ph.D. trainee in the UR Medical Scientist Training Program, was first author of a study published in Science Advances in August that identifies a single region of the brain that can be used to examine the impact of a concussion or repeated hits to the head.

The New York Times and numerous other news outlets covered the study.

Data collected from 38 University of Rochester football players before and after three consecutive football seasons were analyzed for the study. The players’ brains were scanned in an MRI before and after a season of play, and the football helmets they wore throughout the season were equipped with impact sensors that captured all hits above 10g force sustained during practices and games.

The analysis showed a significant decrease in the integrity of the midbrain white matter following just one season of football as compared to the preseason.

The research supports the emerging idea that traumatic brain injury is not limited to people who sustain a concussion; it can result from repetitive head hits that do not produce visible signs or symptoms of a concussion. These sub-concussive hits have been increasingly recognized as a potential threat to long-term brain health and as a possible cause of chronic traumatic encephalopathy.

8

NEUROSCIENCE

Impact sensors inside the helmet

| Vol. 4, 2020

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

Webster H. Pilcher, M.D., Ph.D. Ernest & Thelma Del Monte Distinguished Professor in Neuromedicine; Professor and Chair, Department of Neurosurgery

Robert G. Holloway, M.D., M.P.H. Edward A. and Alma Vollertsen Rykenboer Chair in Neurophysiology; Professor and Chair, Department of Neurology

Diane Dalecki, Ph.D. Distinguished Professor of Biomedical Engineering; Chair, Department of Biomedical Engineering

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

Greg DeAngelis, Ph.D. Professor, Brain and Cognitive Sciences, Biomedical Engineering, Neuroscience; Center for Navigation and Communication Sciences

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

Robert T. Dirksen, Ph.D. Lewis Pratt Ross Professorship of Pharmacology and Physiology; Professor and Chair, Department of Pharmacology and Physiology

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

Del Monte Institute for Neuroscience

Executive Committee

University of Rochester

| Ernest J. Del Monte Institute for Neuroscience

9

University of Rochester Medical Center 601 Elmwood Avenue, Box 603 Rochester, New York 14642

10

Visit us online delmonte.urmc.edu

Follow us on Twitter @URNeuroscience

Del Monte Institute director John Foxe, Ph.D., (left end) and Neurosurgery chair Web Pilcher, M.D., Ph.D., (right end) joined by members of the Del Monte

family at the conclusion the Manipulating Brain States Symposium in October.

NEUROSCIENCE

Photo: @SliceofRye

|

Vol. 4, 2020