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It began when Webster Pilcher, M.D., Ph.D., the Ernest & Thelma Del Monte Distinguished Professor in Neuromedicine and chair of the Â鶹ÊÓƵ (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?

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

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 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 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.

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.

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 Â鶹ÊÓƵCenter 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 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

Garcea prepares computers in operating room prior to surgery.

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 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

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.

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 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 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.

Left: Garcea, Haber, Strawderman

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.