Depression has long been considered a serious mental disorder caused by extreme stress or a chemical imbalance that is treated by psychotherapy or medication. That is, until Helen Mayberg, MD, Professor of Neurology, Neurosurgery, Psychiatry, and Neuroscience, and founding Director of the Nash Family Center for Advanced Circuit Therapeutics at Mount Sinai, took a different approach.

“I am a neurologist, and neurologists map signs and symptoms to specific locations in the brain,” she said. She had always seen depression as a circuit disorder and the availability of brain imaging early in her training provided a method and strategy to study a psychiatric disorder as a neurological one. “That was a novel, if not heretical, idea at the time,” Dr. Mayberg said. “Now, it’s commonplace.”

Over the last 35 years, she had used neuroimaging techniques to study abnormal brain circuits in depressed patients, explaining not just mood, motivation, cognitive, and motor feature characteristics of depression, but also providing a systematic strategy to understand how different treatments work and how to match a patient with an optimal treatment.

Forging partnerships, breaking frontiers

A milestone in her collaborative work came about when Dr. Mayberg discovered the critical role of Brodmann area 25 of the brain, a region of the prefrontal cortex, in negative mood in healthy individuals as well as how it was targeted when antidepressant treatments were successful for depression. The area is known to play a role in mood, appetite, and sleep, but its role in depression was unknown.

Following work on Brodmann area 25, Dr. Mayberg found that deep-brain stimulation—implanted electrodes that deliver electrical stimulation to precise brain locations to treat Parkinson’s disease and epilepsy—was a potential treatment for patients with treatment-resistant depression. Mapping studies she did in the 1990s led to her testing the new treatment in 2003, in which a majority of treated patients showed long-term recovery.

Every move to a new institution has been a scientific adventure with opportunity to work in a new environment with new colleagues, Dr. Mayberg said, but a constant has always been unexpected, exciting, and important new insights. “Creative disruption seems to best describe my trajectory,” she said.

Dr. Mayberg considers transdisciplinary collaboration as the philosophical anchor of her work, one that forms the overarching mission of the Nash Family Center for Advanced Circuit Therapeutics, which she founded in 2018. “The opportunity to fully realize this vision was the condition of my move to New York,” she said.

The Center brings neurology, psychiatry, neurosurgery, imaging, physiology, engineering, and behavioral health under the same roof. Researchers are working on circuit disorders, including Parkinson’s disease, depression, and obsessive-compulsive disorder, which can be treated with deep-brain stimulation, albeit in different brain targets.

“We all knew we needed to work together so that a discovery or new method developed for one disease could inform the others,” Dr. Mayberg said, “so we’re not reinventing the wheel each time.”

Continuing progress through collaborations

Technology innovations in the last several years have further advanced the deep-brain stimulation field, providing new opportunities for Dr. Mayberg and the investigators at the Center. With the capability to read electrophysiological signals in real-time via the stimulating electrodes, researchers at the Center are working on improving delivery of deep-brain stimulation, understanding what kind of patients are most appropriate and why the treatment works.

The Center is also interested in answering more basic questions, such as whether deep-brain stimulation repairs brain circuits or promotes brain plasticity. These studies are complemented by parallel work in animal models at The Friedman Brain Institute. “I consider my research ‘bedside to bench.’ I have always taken advantage of the work of basic neuroscientists, even if their methods cannot be fully applied to human patients,” Dr. Mayberg said.

“My work has had the same basic thread over the course of 35 years: what is the neurology of depression and how do we optimally treat it; not just generally, but in individual patients,” Dr. Mayberg said. “Mount Sinai is the ultimate place for this work, with a committed set of clinicians, scientists, and engineers who share this transdisciplinary vision.”

A couple of decades ago, most people familiar with cannabis called it marijuana—and had probably never heard of cannabidiol (also known as CBD), one of its components.

Today, many people have heard about CBD and its potential therapeutic uses thanks to the work of Yasmin Hurd, PhD, Ward-Coleman Chair of Translational Neuroscience and Director of the Addiction Institute of Mount Sinai, who pioneered research into the compound, cannabis more generally, and their various interactions with substance-use disorders.

“I believe I had been asking questions that no one was asking at the time,” said Dr. Hurd. Her work helped her get elected to the National Academy of Sciences (NAS) in May. She is also a member of the National Academy of Medicine.

Dr. Hurd’s research focuses on the neurobiology of drug addiction and various psychiatric disorders, spanning both basic science research and translational work in humans. Having evidence in both non-clinical and clinical settings has helped the research be applicable in guiding treatment and health policy, she said.

The Potential of a Limitless Environment

More than a decade ago, in the field of medicine, marijuana was still seen as having limited evidence for being a treatment for any condition and many thought that it was a benign drug without long-term impact on the brain. “My research into the developmental effects of cannabis as well as potential therapeutic aspects of cannabidiol made people take another look at cannabis and have shaped the questions people are asking today,” she said.

Being able to ask the questions that no one was asking requires the combination of the researcher’s driving instinct and institutional support. “I think Mount Sinai helped me to not only ask, but to answer those questions,” Dr. Hurd said.

“Physicians had always focused on treating the adult patient in front of them, but the thinking about what had brought them there in the first place was unaddressed,” she said. As she studied adults with substance-use disorders, she found many had drug exposures early in life, and sought to understand whether those early exposures were linked to psychiatric illnesses later on as adults.

Dr. Hurd recalled that when she joined Mount Sinai in 2006, she pitched ideas about advancing her preclinical work into humans to Dennis Charney, MD, Anne and Joel Ehrenkranz Dean of Icahn Mount Sinai and President for Academic Affairs of the Mount Sinai Health System. She had begun to study how cannabidiol worked in animal models but had not yet investigated it in live human beings. “Dean Charney said, ‘You could absolutely do that here,’ and just knowing that was possible enabled me to run clinical trials.”

“Early in my career, I never thought that my research would evolve the way it has,” Dr. Hurd said. “Instead of being theoretical about translation, I actually got to study it in humans.”

“The whole thing about being in an environment where there are no limitations placed on you is that it becomes dependent on your drive, on the questions you want to ask,” Dr. Hurd said. “I remember going away from that meeting feeling happy, thinking, ‘Whoa, there are no limits. What do I really want to do now?’”

Even today, that is a question Dr. Hurd asks herself. A constant in her research is for her work to always reveal something relevant to the human condition. As she advanced her work in addiction, she has come to understand that addiction is more a disorder of epigenetics, in contrast to a disease of genetic inheritance.

“Our next phase, especially in medication development, is to see if we can leverage the knowledge about epigenetic dysregulation to develop targeted interventions to reverse addiction,” Dr. Hurd said.

Addressing the Future of Addiction Research

Epigenetic changes are reversible, and this gives rise to hope that addiction ultimately can be, too. “When I started in this field, there was the pervasive stigma of the common phrase ‘Once an addict, always an addict,’” she said. “After studying this for such a long time, I know it’s not true. The effects may be long-lasting, but they are not locked for perpetuity.”

The road ahead will be challenging. Some challenges are merely logistical, such as space issues for animal and clinical research. Others are more systemic. “Those problems I face today remain the same I had at the start of my career,” Dr. Hurd said. “Getting grant money is still challenging, especially for high-risk projects. Stigma still surrounds addiction, even within science.”

Addressing the stigma will help with securing funding. They’re linked, Dr. Hurd said. “But with good support, I believe I’ll get there.”