Brian Sweis, MD, PhD, logging his clinical rounds notes while keeping an eye on the mice in his latest experiment.
The past few decades have seen a surge in neuroscience breakthroughs, but translating those findings into better outcomes for patients has been slow and, in some cases, non-existent. Neuroscientists who train as clinicians can narrow that interdisciplinary divide.
Brian Sweis, MD, PhD, a second-year psychiatry resident and post-doctoral researcher at The Mount Sinai Hospital, is learning that discoveries in the lab can help inform how psychiatrists conceptualize the biology underlying complex emotions. In his most recent experiments, he investigated where in the brain emotions like regret stem from, and how this could go awry in mood disorders.
“We learned that there may be two distinct types of regret in the brain: one linked to depression, and another linked to resilience, which differ based on how people view their own mistakes and what could have been done differently,” he said. “I realized that we may even be able to access the root of some of these seemingly similar but fundamentally distinct thought processes if we structure psychiatric interviews with patients more precisely. This could help us identify which type of regret a patient is experiencing—either an emotion that is healthy and adaptive (and should be reinforced) versus one that may be pathological (and targeted for treatment).”
Dr. Sweis anticipates that as he continues to grow as a budding psychiatrist, the connections between his research and clinical experience will help him better bridge the worlds of science and medicine.
An indirect path to psychiatry
Dr. Sweis was first introduced to neuroscience as an undergraduate at Loyola University in Chicago, where he worked in a research lab studying how stress can affect the body and brain in rodents. At the same time, he was drawn to a psychology professor who was studying similar concepts in humans. He realized that neuroscience lay at the intersection of the two. “I fell in love with neuroscience when I learned that something as intangible and abstract as a psychological concept could have concrete biological underpinnings,” he said.
He decided to double major in psychology and biology, and minored in neuroscience and philosophy. “I was a total nerd about everything neuroscience,” he said. “I remember thinking at one point that I definitely didn’t want to go to medical school. Instead, I wanted to be a professor, run a research lab, train my own students, and be a full-time scientist.”
He was most interested in areas of science where multiple fields overlapped. “That’s where the most exciting innovation happens,” he said. Towards the end of college, he learned he could pursue his research passions while in medical school and work at the intersection of two often separated career paths as a physician-scientist.
Dr. Sweis enrolled in the dual degree MD-PhD program at the University of Minnesota Medical School (UMN), which splits the four years of medical school and adds a four-year PhD program in the middle. For his PhD in neuroscience, he explored the complex cognitive processes around how the brain makes decisions. “I was fascinated by how we could take abstract concepts like thought, memories, and imagination, and boil them down to the physical properties of a brain cell that you can touch and directly measure,” he said.
Most of the breakthroughs in basic neurobiology occur in animal studies because the technologies available in that space are more advanced, but this is often far removed from affecting patient care. However, Dr. Sweis set out to work across species with rodent and human subjects in parallel in order to accelerate the “bench to bedside” process of translational research.
At UMN, Dr. Sweis was part of the first group of researchers to discover that humans are not the only species that are capable of experiencing regret. Combining elements from decision neuroscience with behavioral economics, he found that even rodents are sensitive to the mistakes they’ve made when realizing that alternative actions could have led to better outcomes. He also found that avoiding future regret can be a strong motivator for learning—mice will even sacrifice food to do so.
Related to this work, Dr. Sweis was first author on a Science paper showing that rodents also tend to overvalue rewards they’ve already invested in, even when it’s clear they should cut their losses. This well-studied cognitive bias is known as the sunk cost fallacy, and it was thought to be a psychological phenomenon unique to humans. Importantly, Dr. Sweis helped craft a way to study these concepts so that they could translate to animal models of psychiatric disorders. His work in comparative biology and evolutionary neuroeconomics landed him on the 2020 Forbes 30 Under 30: Science list. He has also received best PhD awards through UMN, nationally through the Council of Graduate Studies, and internationally through the Society for Neuroscience.
As a clinician, Dr. Sweis originally planned to train in neurology. But over the course of his PhD, he learned that the applications of what he was studying aligned more with the depth of training he could gain from a residency program in psychiatry.
“I realized psychiatry was more in line with the questions I found to be the most fascinating, and tied back to my philosophy interests in undergrad,” he said. “How does the mind work? Where does motivation come from? What happens when the machinery in our brain that controls the way we make decisions starts to physically break down? Whether it’s the result of a neurological insult like a stroke or psychiatric event like trauma, I wanted to know more about the biology that causes us to behave and think the way we do. To fully unpack all of the ways a clinician can deconstruct the origins of behavior, I knew I needed to be formally trained as a psychiatrist.”
Mount Sinai’s physician-scientist residency track
Dr. Sweis chose The Mount Sinai Hospital because “the institution as a whole values research at every level, not just a certain department or an individual or two,” he said. “Mount Sinai was built around accelerating and providing robust training experiences and research opportunities, and that’s one of its biggest strengths toward innovating new treatments for patients.”
The Mount Sinai Hospital was also a good fit because the training directors, Antonia New, MD, Asher Simon, MD, and Mercedes Perez-Rodriguez, MD, PhD, wanted to accelerate his research momentum concurrent with his clinical training as a physician.
“They readily identified that my talents lie with being a scientist,” he said. “They told me they would do everything they could to powerfully launch my career as a physician-scientist because that’s where I would thrive the most.”
To that end, during his first year of residency, he split his time as an intern seeing patients (including in the ICU and ER during the height of COVID-19), and the other half initiating experiments on how regret-related processes in the brain are altered in depression.
“I began working on this experiment the first day I moved to New York,” he said. “My training directors saw the clear path forward, entrusted my vision and drive, and supported me in every way. We’re working to publish these discoveries right now.” Within the first six months of residency, Dr. Sweis was awarded third place for best research by a psychiatry resident in New York City by the American Psychiatric Association.
Finally, Dr. Sweis chose The Mount Sinai Hospital because of the faculty he wanted to work with, including Eric Nestler, MD, PhD, Scott Russo, PhD, and Denise Cai, PhD. Dr. Sweis launched his first set of experiments in Dr. Nestler’s and Dr. Russo’s labs studying how regret may be processed differently in rodents that develop depressive-like symptoms following exposure to stress (stress-susceptible individuals) versus animals that are more stress-resilient.
“Dr. Nestler and his colleagues provided a home for me to continue my research from UMN in an independent manner,” he said. “The opportunity for collaboration was obvious: I took a well-validated model of depression their labs and others developed, and combined it with my expertise in neuroeconomics, which was quite new to their labs.”
Now that he completed his first set of experiments and has hit the ground running, Dr. Sweis is expanding his research horizon and learning from other expert faculty including Dr. Cai, a leader in the field of memory research. Dr. Cai’s lab leverages cutting-edge technology that she and others developed to image the living brain in ways never before possible in order to ask deeper questions about how experiences are dynamically processed and stored.
The microscope and raw footage of a rodent’s brain. Image credit: Daniel Aharoni, PhD, and Denise Cai, PhD.
Her group developed a miniature microscope the size of a penny that can be implanted into a rodent’s brain. The microscope can record videos of individual neurons that together look like stars in the night sky, where each flickering light represents a biological event. This electrical cellular activity is engineered to be converted into a visual signal that can be captured with a camera. Hidden in this display are coordinated “constellation-like” patterns that together represent aspects of a memory distributed across a network of neurons.
“This type of work is truly incredible,” said Dr. Sweis. “Information represented this way in the brain—in networks—would have previously otherwise gone unseen without this technology. Identifying new ways in which these complex processes break down is only the beginning toward developing a richer understanding of psychiatric illnesses.” Dr. Sweis and Dr. Cai together recently published a review article on the current state of this research and where these new technologies are taking the field.
Career plans
A fundamental issue in brain research is that animal work and human work can be very disconnected, but Dr. Sweis plans to keep a foot in both worlds. He sees his translational research ultimately extending back into clinical patient populations, where he has aligned interests with another mentor: Helen Mayberg, MD, director of the Nash Family Center for Advanced Circuit Therapeutics. As a neurologist who works in neurosurgery to advance next-generation treatments for psychiatric disorders through deep brain stimulation, she emulates the type of neuroengineering approach to psychiatry Dr. Sweis is aiming to grow further into with his research and clinical background. While certain techniques and questions can only be investigated in mice, he hopes some of the insights he gains by studying animal behavior in complex ways can bring a different spin or new elements to questions being asked on the human side (such as Dr. Mayberg’s research).
For example, deep brain stimulation doesn’t work for every depressed patient. “Why is that? Is the implanted device slightly missing the intended target? Or does this person have a fundamentally distinct sub-type of depression in which treatments would be better tailored toward a different pathway in the brain?” said Dr. Sweis. “One of the primary goals of my translational research is to be able to differentiate sub-types of a psychiatric disease by refining the way in which we understand how behaviors come about in the first place—and to be better at describing those processes.”
Scientists trained as physicians, like Dr. Sweis, are in a unique position to understand and enhance the links between preclinical research and clinical applications in humans to advance patient treatments. “During my residency interview, my program directors told me that the toolkit of a psychiatrist lies in the interview,” he said. “It’s a surgical interview—much like a scalpel is to a surgeon, so is the art of interviewing a patient to a psychiatrist.”
He hopes that his research in neuroeconomics will equip psychiatrists with a new language to dissect the multifaceted drivers of behavior and sharpen the precision of a surgical interview such that it can tap into the different circuits at play. This is one of the goals of the emerging field of computational psychiatry, and he knows his training as a clinician is making all the difference as he moves toward that goal.
“By learning how to practice psychiatry and working directly with patients, I can begin to identify what needs to change the most in this field and where to best direct my efforts as a neuroscientist,” he said.