Neuroscience | Summer/Fall 2019

NEUROSCIENCE University of Rochester | Ernest J. Del Monte Institute for Neuroscience Vol. 3 – 2019

Here come the engineers: developing multi-disciplinary research labs spanning engineering & neuroscience Pg. 4

FROM THE DIRECTOR’S DESK

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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

Photo by John Schlia Editor

Samantha Jean Design by

m-print

Contributing Writer

Mark Michaud

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here’s a creeping chill in the air as we say goodbye to Rochester’s summer and prepare for a very busy fall term.

Despite the dipping temperatures, both campuses are abuzz with new and returning students and faculty. Our incoming neuroscience grad-student class is one of the largest in the program’s history and we’re excited to welcome these young vibrant minds to our growing institute and to the incredible intellectual playground that is Rochester Neuroscience.

Manuel Gomez-Ramirez is one of these new faces, joining us from Brown University as an Assistant Professor in the Departments of Brain and Cognitive Sciences and Neuroscience. Manny’s Haptics Lab aims to understand the mechanisms that mediate object sensing and grasping with the hands.

In this issue, we talk to Manny about his arrival in Rochester, the establishment of his new lab, and the major scientific questions he intends to tackle in the year ahead.

You’ll also meet our cover stars: Ed Lalor and Ross Maddox, and the Chair of the Biomedical Engineering Department, Professor Diane Dalecki. Neuroscience stands at the interface of many branches of science, drawing on skills and expertise from molecular biology to cognitive psychology.

One key nexus in our approach allies the skills of biomedical engineering with fundamental understanding of neurophysiology and neuroanatomy. These young scientists sit at this crucial and exciting interface, bridging between neurobiology and the implementation of neural engineering solutions. You will also get to know Emily Isenstein, a standout MD-PhD student who received a summer scholarship from the Child Neurology Foundation to support her autism research.

Neuroimaging at the University is growing rapidly, and so I’d like to share some of the great news coming out of the Center for Advanced Brain Imaging and Neurophysiology (UR CABIN). We are delighted to report that in just the last three years, CABIN has more than doubled the number of studies it supports, and continues to grow its research portfolio at an accelerating rate. Also, Mada-

lina Tivarus, Assistant Professor of Imaging Sciences and Neuroscience, and Director of the 3D Post-Processing Laboratory, recently passed her MR Safety Expert exam.

We’re heading into a very busy season and October will be a full month for the Institute with many of our students and faculty attending and presenting at the Society for Neuroscience (SfN) conference in Chicago. There, on Monday October 21st at 6:30 pm, we will host a Rochester Neuroscience social for staff, students, alumni and friends. Join us at Tapas Valencia, 1530 South State Street, to raise a glass to a great year. We very much look forward to a great turnout and to meeting friends old and new.

Immediately following SfN, the Institute will host its annual symposium at the Memorial Art Gallery here in Rochester (Oct 24th to 26th). This year’s theme is “Manipulating Brain States – Invasive Mapping and Neuromodulation in Humans Neurological Disease.” Since my arrival here at Rochester, I’ve had many conversations with our Chair of Neurosurgery, Web Pilcher, about the role and promise of these techniques in clinical neuroscience.

We are both profoundly fascinated by the potential of these methodologies, and we want to learn more about their application.

Certainly, the role of deep brain stimulation in movement disorders such as Parkinson’s Disease, is already well-established, but what of conditions such as depression, PTSD, Tourette’s syndrome, or chronic pain?

The only solution was to invite 20 of the world’s most prominent and renowned neuroscientists working on these techniques right here to Rochester. It promises to be an exceptional few days of learning and collaboration. Please visit delmonte. urmc.edu/symposium for more information and to register—all are welcome!

I hope everyone had a wonderful summer and offer my warmest welcome to the new students and faculty.

In Science,

John J. Foxe, Ph.D.

NEWS BRIEFS

New Funding Boosts URMC Biotech Start-Up for Neurological Disorders

Oscine Therapeutics, a new biotechnology company based on discoveries made and developed at URMC, has received a significant multi-year investment to support both research and development of cell-based therapies for neurological disorders. The funding represents the largest-ever investment in a URMC start-up company. The venture is based on decades of research in the lab of Steve Goldman, M.D., Ph.D., co-director of the URMC Center for Translational Neuromedicine. Goldman’s work has focused on understanding the basic biology and molecular function of support cells in the central nervous system, devising new techniques to precisely manipulate and sort these cells, and studying how cell replacement could impact the course of neurological diseases. The investment in Oscine is being made by Sana Biotechnology, a new company focused on creating and delivering engineered cells as medicines for patients. The research will be conducted at URMC under a sponsored research agreement and will support 21 fulltime staff, with researchers in Rochester and additional staff in Seattle and New York City.

Steve Goldman, M.D., Ph.D.

Oscine Therapeutics is focusing on glia (astrocyte) replacement therapies in diseases like Huntington’s and MS. 1

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NEWS BRIEFS

New grants will accelerate clinical trials in rare neurological disorders

New gene therapy poised to transform care for Spinal Muscular Atrophy (SMA)

Two new grants from the National Institute of Neurological Disorders and Stroke (NINDS) will pave the way for new treatments for neuronal ceroid lipofuscinoses and Charcot Marie Tooth diseases, two groups of rare neurological disorders. The funding, which totals $10 million, will support new research programs led by URMC neurologists Erika Augustine, M.D., and David Herrmann, M.B.B.Ch., and involve an international team of scientists and clinicians.

The funding comes from the NINDS Clinical Trial Readiness for Rare Neurological and Neuromuscular Diseases program, which was created to support studies that lay the groundwork for the next generation of treatments – including gene replacement therapies – currently under development. URMC researchers play leading roles in three of the five NINDS clinical trial readiness programs. URMC neurologist Rabi Tawil, M.D., is a co-director of an existing program that focuses on facioscapulohumeral muscular dystrophy.

URMC has been tapped as one of the first institutions in the U.S. to offer Zolgensma, a new gene replacement therapy to treat spinal muscular atrophy (SMA). The new treatment can be delivered within weeks of birth and clinical trials have shown that it dramatically changes the course of the disease.

The therapy, which is administered in the form of a one-time IV infusion, was recently approved by the Food and Drug Administration under a “fast track” review process. URMC is one of only 17 medical centers in the U.S., and the only one in New York State, that will initially offer the treatment.

Liam Fabrizi (right) is one of two infants treated with Zolgensma at URMC since December 2018 under compassionate use provisions, which allows use of an experimental therapy prior to FDA approval. Liam’s parents call the gene replacement therapy a “gamechanger.”

New multi-institutional partnership to focus on stroke rehabilitation URMC, Burke Neurological Institute, and Wadsworth Center of the New York State Department of Health (NYSDOH) have been awarded a $5 million grant from the Empire State

Development Corporation to speed the development of ground-breaking neurological treatments for those disabled from stroke.

The project is a part of the NeuroCuresNY initiative, a new non-profit formed by the three institutions to accelerate the discovery of novel treatments for chronic neurological impairment and disability. The new state funding will support a two-year pilot study that will be launched in January 2020. This study design will be unique because it will test the efficacy of state-of-the-art robotic2

assisted rehabilitation technology combined with drugs to improve the functional recovery of stroke patients.

The study will be conducted at the UR Neurorestoration Institute, led by Bradford C. Berk, M.D., Ph.D., and the Burke Neurological Institute. The National Center for Adaptive Neurotechnologies at the Wadsworth Center will configure the technology that collects and analyzes the research data. Clinical and research faculty from URMC Departments of Neurology, Neurosurgery, and Physical Medicine & Rehabilitation will collaborate with the UR Neurorestoration Institute during the pilot study.

NEWS BRIEFS STUDENT SPOTLIGHT

Emily Isenstein Emily Isenstein, a student in the Medical Scientist Training Program at URMC, is the 2019 recipient of the Child Neurology Foundation Neurodevelopmental Disabilities (NDD) Summer Research Scholarship.

This scholarship is given to medical students interested in training as child neurologists, and Emily plans to use this project as the foundation for her Ph.D. research.

With support from the NDD scholarship, Emily is conducting research on visual-proprioceptive integration in autism using a combination of perceptual, behavioral, and virtual reality experiments. Emily has worked with individuals with neurodevelopmental disabilities for more than ten years and has long been fascinated by the role that proprioceptive awareness plays in autism etiology and presentation.

She hopes that by further understanding variability in proprioceptive functioning, the field will move closer toward developing personalized therapeutics and care for populations with neurodevelopment disabilities.

Perfect timing: making the ‘switch’ from juvenile to adult

Very little is known about how the onset of puberty is controlled in humans, but the discovery of a new gene in the roundworm C. elegans could be the “missing link” that determines when it’s time to make this juvenile-to-adult transition. Two genes, LIN28 and MKRN3, are known to be associated with precocious puberty in humans, where juveniles as young as six may start developing adult features.

These genes are found in all animals, including C. elegans, in which they also control the juvenile-to-adult transition.

Until the new discovery, it was unclear how these two genes are connected. Two new studies in the labs of Douglas Portman, Ph.D. at the URMC and David Fitch, Ph.D.,

at New York University, published in Developmental Cell and eLife, identified a new developmental timing mechanism involving a long non-coding RNA in the microscopic roundworm C. elegans.

Their research revealed a surprising new molecular mechanism that controls the timing of sex-specific changes in body shape, the maturation of neural circuits, and behavior.

The researchers identified a new gene that, when disrupted, delays the transition from the juvenile to the adult stage.

C. elegans adult hermaphrodite (lower) and male (upper), with two individual neurons fluorescently labelled (red and green) in the adult male’s head.

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Engineers Walk into a Cocktail Party ‌

(L to R) Diane Dalecki, Ed Lalor, and Ross Maddox.

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It’s a typical scene: you’re at a party, it’s crowded, and there’s people talking all around you in various volumes and tones. Your friend is speaking directly to you, and even with all of the surrounding chatter, you can still hear and understand what they’re saying, almost as if the background noise doesn’t exist.

This phenomenon is called the “cocktail party problem,” which humans solve through selective listening. How do our brains do this? And what happens when someone’s brain can’t cut out the clutter? These are the questions that a few biomedical engineer-neuroscientist hybrids at URMC are trying to answer.

For Ross Maddox, Ph.D., an assistant professor in the Departments of Biomedical Engineering and Neuroscience with a lab in the University of Rochester Center for Advanced Brain Imaging & Neurophysiology (UR CABIN), research begins long before anyone is old enough to “party.”

All newborn babies in the U.S. are screened with a hearing test, and if potential issues are found they are referred for an auditory brainstem response (ABR) exam. Several pitches need to be evaluated in each ear, and the test can only be done when the infant is sleeping and still. Needless to say, it’s time consuming. A recent study by Maddox’s lab, published in Trends in Hearing, developed a new method for measuring ABR in infants to test all frequencies in both ears all at once. Rough estimates from the study say the test may become two to four times faster than current methods, meaning it could be possible to get a much better diagnosis in the same amount of time, or confirm normal hearing in a much shorter time. Further testing is required before it becomes an industry standard, but Maddox has big aspirations: “My main goal is for my grandkids’ hearing to be tested with my technique, in whatever hospital they’re born in. I want it to be the technique that is used everywhere.”

The work of Maddox and his colleagues resides at the intersection of neuroscience and engineering, and emerging collaboration that holds the potential to unlock the complexity of human cognition, understand neurological diseases, and develop new technologies that help researchers and clinicians study, diagnose, and treat these disorders.

Another way that Maddox’s lab merges neuroscience and engineering is with their work to develop ways of processing speech for studying the brain. They’ve engineered new tools for analyzing brainwaves to try and get a good match between the speech that’s coming in, and the brainwaves that are coming out that correspond to the earliest parts of the auditory system. “What I really like about being split between BME and Neuroscience is that I feel like I have free rein to research in a broad realm,” said Maddox.

A music lover who went to undergrad as a sound 5

engineering major and wanted to run a recording studio someday, Maddox eventually found himself in grad school, interested in how the brain processes sound. Though he ultimately traded science for music academically, a recent grant from the National Science Foundation is taking him back to his roots. Along with fellow BME professor Anne Luebke, Ph.D., and Elizabeth Marvin, Ph.D., at the Eastman School of Music, Maddox is investigating whether formal musical training is associated with enhanced neural processing and perception of sounds, including speech in noisy backgrounds. Rochester was perfectly primed to be one of six universities running the study with its pool of auditory neuroscientists that span several departments and schools.

Working with professors in electrical engineering and computer science, Maddox is developing assistive

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more naturalistic and closer to the real world than has been traditionally done, they look to find how humans perceive and pay attention to objects and integrate information from different senses to help them navigate the world.

“We try to look at human brains and how they process naturalistic stimuli—music, speech, language, video, and how we actually deal with that kind of stuff,” he explains.

“That’s where engineering comes in—there’s lots of data to make sense of, and we come in with slightly more sophisticated signal processing techniques to analyze and interpret those data.”

Because Lalor’s work can be applied to multiple cohorts, he has several collaborators across the University. He’s currently working with Feng Vankee Lin, Ph.D., R.N., in the School of Nursing on language processing in older people

Ross and Ed have developed exciting multidisciplinary research labs spanning neuro-engineering and neuroscience. Such collaborations between the Department of Biomedical Engineering and the Del Monte Institute for Neuroscience offer opportunities to build a truly unique research and innovation environment at the UR to lead new break–throughs in technologies to understand the brain and treat neurological diseases.” — Diane Dalecki technology that is sort of a ‘visual hearing aid.’ Their focus is to accurately represent the speech sounds visually to improve understanding. “Being able to see someone talking is really helpful for understanding, which is especially true for people who are hard of hearing or use hearing aids or cochlear implants. But, there’s a lot of situations like talking on the phone or listening to a podcast where we don’t have a face to see,” Maddox explains. “We’re working on a project that takes in speech and renders a talking face saying that speech in real time.”

With too many additional collaborators across the University to list, Maddox stresses that this is the most collaborative university he’s ever been affiliated with: “It’s fun to work with people who are way smarter than you at other things. It’s a really exciting place to do science.”

Maddox is only one of several faculty members across the University merging engineering with neuroscience. Just down the hall in the CABIN sits fellow engineer, Ed Lalor, Ph.D., an associate professor in the Departments of BME and Neuroscience. Lalor took a non-traditional path to academia, first working as an electrical engineer and then an elementary school teacher before accepting a job analyzing EEG data in kids with attention problems. His lab is interested in how humans process the world around them. Focused on trying to understand how human brains operate in scenarios that are 6

as a potential way to detect Alzheimer’s disease early on.

The idea is that if people are just slightly sluggish in processing the meaning of words in their context, it could be a sensitive way to detect decline early on. Lalor’s lab is also looking to work with the CABIN’s top floor resident, the Cognitive Neurophysiology Lab, led by John Foxe, Ph.D., and Ed Freedman, Ph.D. They’re hoping to ramp up work looking at how perception might go awry in children with autism. Additionally, they’re beginning a new collaboration with David Dodell-Feder, Ph.D., an assistant professor in the Psychology department, on speech production.

“Ross and Ed have developed exciting multidisciplinary research labs spanning neuro-engineering and neuroscience.

Such collaborations between the Department of Biomedical Engineering and the Del Monte Institute for Neuroscience offer opportunities to build a truly unique research and innovation environment at the UR to lead new break– throughs in technologies to understand the brain and treat neurological diseases,” said Diane Dalecki, Chair of the UR Department of Biomedical Engineering. As for what the future holds for these ever-changing fields at the University?

“We’re all anticipating fantastic new discoveries at the intersection of neuroscience and engineering by this collaborative, multidisciplinary team,” said Dalecki.

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

Q&A with Manuel Gomez-Ramirez, Ph.D. This summer, Manuel Gomez-Ramirez arrived from Brown University to join the University of Rochester (UR) as an assistant professor in the Departments of Brain and Cognitive Sciences (BCS) and Neuroscience. His Haptic Perception Lab will focus on developing mechanistic models of how objects are perceived and manipulated with our hands, with the ultimate goal of using these models to optimize neural stimulation strategies for brain-computer interfaces and neuroprosthetics. We sat down with Manny, the guitarplaying, cocktail-making neuroscientist, to talk about what he’s most looking forward to at UR. Tell us a little bit about your research and what you’ll be doing at the University?

MG-R: My lab’s main interest is to understand the neural mechanisms that mediate haptic perception and control, that is, study the brain mechanisms that enable us to grab and manipulate objects with our hands. My lab employs a variety of tools to understand these mechanisms in different animal models. We utilize a comprehensive approach, in that we use electrophysiology, coupled with novel genetic-based optical methods, such as optogenetics and calcium-based imaging, which enable us to look at a variety of different cells in one picture. And, very importantly, manipulate those cells in a more fine-tuned than most neural stimulation methods.

In our lab, we’ll be using the mouse and non-human primate model. The idea is to tap into the best use of these animals for the research question that we need to address.

Non-human primates are phenomenal for understanding the brain mechanisms of how we grab objects because they, just like humans, use the hands to directly manipulate objects in the world. Mice, on the other hand, (no pun intended) don’t necessarily scan and manipulate objects with their paws.

Yet, they’re phenomenal for studying cell-type specific neural circuits in an awake-behaving mammal, which can potentially lead to fundamental findings about general brain principles that can later be tested in a non-human primate model.

One of the overall goals of my lab is to develop techniques that can be of use to clinical populations, such as amputees and tetraplegic. One example is developing strategies that integrate brain signals with prosthetic devices in order to control these devices directly. I think that tools like chemogenetics and optogenetic tools, in combination with electrophysiology, which is the main tool that is used in the field right now, is a good way to go about this.

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Prior tactile stimulation

During tactile stimulation

Image provided by Manuel Gomez-Ramirez, Ph.D.

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Firing Rate (Hz)

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The number of great resources and researchers that one can tap into [at UR] is so diverse in terms of discipline, even within my own department.… It’s just a great community for brain science, tapping into different techniques and different domains that I can then use in my own research.”

— Manuel Gomez-Ramirez, Ph.D.

Neural responses to touch depend on hand positioning: The brain responds differently to the same tactile stimulus on the skin depending on the conformation of the hand.

Is there anyone here that you’re looking forward to collaborating with?

I’ve actually already started some collaborations. I’ve put in a grant with Marc Schieber in the Departments of Neurology, Neuroscience, Center for Visual Science, and Biomedical Engineering, and with Greg DeAngelis in BCS to look at the idea of how can we use combined optogenetics and electrophysiology as a way to provide tactile information to the brain, and elicit motion percepts on the hand. The ultimate goal is to use this technique for brain-machine interface solutions. I’m also collaborating with Marvin Doyley in the Department of Electrical and Computer Engineering on a project to increase bio-availability of luciferins (bioluminescent drivers) to the brain, and perform non-invasive neural stimulation studies in non-human primates using bioluminescent light that drive optogenetic elements expressed in selective circuits of the brain.

I think it’s going to be a great experience, a new adventure.

It’s something that I’ve always dreamed of, having my own lab, mentoring students and personnel. Starting a project from the very beginning and teaching them all the basics about the methodology that we’re going to use, the research that we’re going to do—it’s something that I’m very, very excited about.

What drew you to the University of Rochester?

The number of great resources and researchers that one can tap into is so diverse in terms of discipline, even within my own department. I can go in and talk to people like Ralf Haefner about computational collaborations, or go in and talk to people like Marc Schieber, and Greg DeAngelis about neural stimulation methods. Or Duje Tadin about psychophysics and cross model perception. It’s just a great community for brain science, tapping into different techniques and different domains that I can then use in my own research. During my short time here, I’ve found that everybody has been very welcoming and supportive of my plans.

What are you most excited about during your first year?

I am really looking forward to starting my own project with the grad students that I’ve already committed.

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

My former supervisor mentioned something really interesting to me recently. He said to me, “Manny, you’re going to be a junior PI, and you’re going to get advice from many different people, and you’re going to be getting it constantly, and you should listen to it. But ultimately, you should always stay true to yourself.” Meaning, if you’re not comfortable with it, then you’re not going to be fully happy implementing that piece of advice. So, try and find a good marriage between the advice that you’re given and what you fundamentally believe in.

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

I love to cook; I’m most recently focused on cooking French and Spanish dishes. If I eat something at a restaurant that I enjoy, I will try to replicate it at home. I really love the culinary field in general, including experimenting with cocktail recipes. Music is another big part of my life...going to concerts, playing guitar—mostly classic jazz and bossa nova, but also grunge rock and punk music from the 70’s and 80’s. I went into college as a musician before I learned about neuroscience and quickly switched my major. I’ve heard great things about the Rochester Jazz Festival so I’ll want to check that out next year.

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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

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

Visit us online delmonte.urmc.edu

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