In Milestone Finding, ‘Polypill’ Reduces Cardiovascular Mortality by 33 Percent in Patients Treated After a Heart Attack

Updated on Aug 26, 2022 | Featured, Research

Valentin Fuster, MD, PhD, at the European Society of Cardiology Congress in Barcelona, Spain

In a milestone in cardiovascular medicine, a  three-drug medication known as a “polypill” was found effective in preventing adverse events such as heart attacks or stroke in people who have previously had a heart attack, reducing cardiovascular mortality by 33 percent in this patient population. These are findings from the SECURE trial led by Valentin Fuster, MD, PhD, Director of Mount Sinai Heart and Physician-in-Chief of The Mount Sinai Hospital.

The study results were announced on Friday, August 26, at the European Society of Cardiology Congress (ESC 2022) in Barcelona, Spain, and published in The New England Journal of Medicine.

“The results of the SECURE study show that for the first time that the polypill, which contains aspirin, ramipril, and atorvastatin, achieves clinically relevant reductions in the recurrent cardiovascular events among people who have recovered from a previous heart attack because of better adherence to this simplified approach with a simple polypill, rather than taking them separately as conventional,” says Dr. Fuster, General Director of the Spanish National Center for Cardiovascular Research (CNIC), which developed the polypill.

Patients recovering from a heart attack—also known as myocardial infarction—are prescribed specific treatments to prevent subsequent cardiovascular events. Standard therapy includes three different drugs: an antiplatelet agent (like aspirin); ramipril or a similar drug to control blood pressure; and a lipid-reducing drug, such as a statin. However, fewer than 50 percent of patients consistently adhere to their medication regimen.

“Although most patients initially adhere to treatment after an acute event such as an infarction, adherence drops off after the first few months. Our goal was to have an impact right from the start, and most of the patients in the study began taking a simple polypill in the first week after having a heart attack,” Dr. Fuster explains.

“Adherence to treatment after an acute myocardial infarction is essential for effective secondary prevention,” says José María Castellano, MD, study first author and Scientific Director of Fundación de Investigación HM Hospitales.

The concept of a polypill for cardiovascular disease prevention was proposed in 2003 and widely debated among experts, with some arguing that it could reduce heart disease at a population level and others arguing that patients could wrongly consider it as a substitute for healthy lifestyles. In 2007, the potential value of applying the polypill strategy in high-risk patients was recognized by the WHO and the World Heart Federation, and Dr. Fuster authored a call to action in Nature Clinical Practice Cardiovascular Medicine,  “A polypill for secondary prevention: time to move from intellectual debate to action.”

Scientists at the CNIC, in partnership with FERRER laboratories, developed a polypill and have conducted a range of studies over the intervening years. CNIC scientists first demonstrated that prescription of the CNIC polypill significantly improved treatment adherence among patients recovering after a myocardial infarction, in the FOCUS study, published in the Journal of the American College of Cardiology (JACC).

The CNIC team launched the SECURE study, an international randomized clinical trial, to determine whether the improved treatment adherence with the polypill translated into a reduction in cardiovascular events. The polypill analyzed in the study, commercialized under the name Trinomia, contains aspirin (100 mg), the angiotensin-converting enzyme inhibitor ramipril (2.5, 5, or 10 mg), and atorvastatin (20 or 40 mg).

SECURE included 2,499 patients from seven European countries (Spain, Italy, Germany, the Czech Republic, France, Poland, and Hungary) recovering after a heart attack. Study participants were randomly assigned to receive standard therapy or the CNIC polypill. The average age of the participants was 76 years, and 31 percent were women. The study population included 77.9 percent with hypertension, 57.4 percent with diabetes, and 51.3 percent with a history of smoking tobacco.

Researchers analyzed the incidence of four major cardiovascular events: death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke, and need for emergency coronary revascularization (the restoration of blood flow through a blocked coronary artery). The study followed patients for an average of three years and produced conclusive results: patients taking the CNIC polypills had a 24 percent lower risk of these four events than patients taking the three separate drugs.

The standout finding of the study is the effect of the polypill on the key outcome of cardiovascular-related death, which showed a relative reduction of 33 percent, from 71 patients in the group receiving standard treatment to just 48 in the polypill group. Importantly, the study found that patients in the polypill group had a higher level of treatment adherence than those in the control group, thus confirming the findings of the earlier FOCUS study, and in part such good adherence appears to explain the benefits of the simple polypill.

“The SECURE study findings suggest that the polypill could become an integral element of strategies to prevent recurrent cardiovascular events in patients who have had a heart attack,” Dr. Fuster says. “By simplifying treatment and improving adherence, this approach has the potential to reduce the risk of recurrent cardiovascular disease and death on a global scale.”

Read the study in The New England Journal of Medicine

Jennifer Chan, PhD, Receives Robin Chemers Neustein Postdoctoral Fellowship Award for Innovative Research

Updated on Aug 31, 2022 | Featured, Research, School

Jenneifer Chan, PhD, and Ian Maze, PhD

Jennifer Chan, PhD, whose work is vastly expanding knowledge about pregnancy, brain health, and stress, is the recipient of the 2022 Robin Chemers Neustein Postdoctoral Fellowship Award, established in 2010 to encourage and support female research scientists at the Icahn School of Medicine at Mount Sinai.

Recipients are senior postdoctoral scientists who intend to complete their training within two years, have demonstrated high-impact accomplishments in biomedical sciences, and exhibit the potential for an independent scientific career. Dr. Chan is the 23rd recipient of the award, created through a generous gift from Robin Chemers Neustein, JD, MBA, a former member of Mount Sinai’s Boards of Trustees.

Dr. Chan works in the laboratory of neurobiologist Ian S. Maze, PhD, in the Nash Family Department of Neuroscience. Dr. Maze, who was appointed as a Howard Hughes Medical Institute (HHMI) Investigator in 2021, is a Professor of Neuroscience, and Pharmacological Sciences, and the founding director of the Center for Neural Epigenome Engineering at Icahn Mount Sinai, the nation’s first center devoted exclusively to neuroepigenomic engineering.

Dr. Maze’s lab is focused on delineating the molecular and biochemical mechanisms of neuroepigenetic plasticity—changes in the underlying biochemical mechanisms that control whether genes are turned on or off within a given cell-type in the brain. This plasticity is important for allowing brain cells to appropriately respond to changing environments, which is critical for proper neurodevelopment—and which can cause disease when there is inappropriate tuning of gene expression.

Jennifer Chan, PhD

For example, aberrations in these processes can produce devastating neurological and psychiatric disorders, such as epilepsy, Parkinson’s disease, Alzheimer’s disease, substance use disorders, and major depressive disorders. These aberrations can occur during brain development or throughout life due to such factors as environmental toxins, physical trauma, chronic stress, and exposure to drugs of abuse.

The Maze lab—through the integration of technologically innovative and sophisticated new methodologies in chemical biology, proteomics, protein biochemistry/engineering, and structural biology—is advancing the understanding of these processes and working toward the development of targeted neurotherapeutics to treat these conditions.

“Using the most advanced epigenomic, metabolomic, and gene editing approaches in my lab, Dr. Chan is revolutionizing our understanding as to how environmental stimuli, both adaptive and maladaptive, impact epigenetic regulation of gene expression in the maternal brain to alter neural circuitry and behavior,” says Dr. Maze. “Delineating the mechanisms through which the experience of pregnancy imparts long-lasting changes in molecular and physiological properties of the brain promises to greatly aid in our understanding of how such a profound lifetime experience—shared by so many—contributes to brain health. Dr. Chan is an exceptionally talented and innovative young scientist, and I am absolutely thrilled by such prestigious recognition of her paradigm-shifting work.”

Dr. Chan joined the lab in 2018. Her research interests focus on understanding how biological systems outside the nervous system interact with stress to impact the brain during windows of neuroplasticity—times of active brain organization that are particularly susceptible to environmental and physiological challenges. Specifically, her work examines periods of early brain development and female reproductive experiences in rodents, including the long-term impact of pregnancy and postpartum experiences on the brain, and how stress disrupts normal organizational processes during these important windows.

“The experience of being pregnant dramatically changes both the body and brain,” says Dr. Chan. “While studies in patient populations and animal models have shown that these changes can persist long after giving birth, we still don’t understand the molecular mechanisms that control these processes.”

In particular, Dr. Chan investigates the contribution of epigenetic mechanisms underlying these experiences by combining molecular, biochemical, genome editing, and behavioral approaches in her postdoctoral research.

“The fundamental understanding of what reproductive experience does to the brain long-term has not been well studied,” says Dr. Chan. “My work shows that stress during these periods has a significant effect on the maternal rodent brain. I hope that through my research we can learn more about how pregnancy and postpartum experiences contribute to brain health and also emphasize that overall we need to do a better job of reducing stress during these critical windows—such as encouraging parental leave and making sure people have the financial, social, and health-related resources needed to support themselves.”

Says Dr. Chan: “I am incredibly honored to be the recipient of this year’s Robin Chemers Neustein Postdoctoral Fellowship Award. The direction for this research project was sparked by personal interest, and I am extremely encouraged by Dr. Maze’s support and that the selection committee also believes in these important questions.”

Read more stories about research at Mount Sinai
Learn more about the Maze Lab

Epigenetic Disease in the HIV+ Brain: An Innovative Longitudinal Study Method

Updated on Aug 12, 2022 | Inside Mount Sinai Psychiatry, Psychiatry, Research

Schahram Akbarian, MD, PhD, is a recipient of the prestigious NIH Director’s Pioneer Award (DP1), a five-year award that supports creative scientists who are pursuing pioneering approaches to major scientific challenges.

Most clinical studies benefit from taking repeated measurements over weeks, months, years. Researchers studying epigenetic disease processes in the brain don’t have that luxury. “You harvest the brain, and you only get one time point,” says Schahram Akbarian, MD, PhD, Professor of Psychiatry and Neuroscience and Chief of the Division of Psychiatric Epigenomics at the Icahn School of Medicine at Mount Sinai. “In this field, most studies are cross-sectional.”

Now, Dr. Akbarian is developing a novel method — longitudinal epigenetic profiling — that allows him to study epigenetic changes in the brain over time. The innovative idea has earned him the National Institutes of Health (NIH) Director’s Pioneer Award (DP1), a five-year award that supports creative scientists who are pursuing pioneering approaches to major scientific challenges. The project, Single Chromatin Fiber Sequencing and Longitudinal Epigenomic Profiling in HIV+ Brain Cells Exposed to Narcotic and Stimulant, will use the new technique to explore dynamic changes in HIV-infected cells in the brain.

“In the last 10 or 15 years, research on the epigenetics of disease has taken off, thanks to modern sequencing technologies that allow us to study genome organization in a relatively cost-efficient way,” Dr. Akbarian says. “There’s a big need for more research on HIV in the brain, and I hope to morph this new idea into something specific and exciting for HIV research.”

HIV and the Brain
At the Akbarian Laboratory of Epigenetic Regulation of the Human Brain, much of the research has focused on psychiatric diseases such as schizophrenia and depression. Several years ago, Dr. Akbarian began to extend his research to HIV, in part because so many critical questions about the virus’ impact on the brain remain unanswered. More than 38 million people worldwide are living with HIV, and 1.5 million were newly infected in 2021, according to the World Health Organization. Some 75 percent of them have received antiretroviral therapy — yet for many, brain-related symptoms remain.

HIV can infect the microglia, the innate immune cells of the central nervous system, and can also cause inflammation. People with HIV can experience a range of symptoms, including headaches, forgetfulness, mood disorders, and behavioral changes. “People are still having neurological symptoms from HIV infection, even if they take antiretroviral drugs. The question is, why? What’s causing damage in the brain?” Dr. Akbarian says.

He hopes that his longitudinal epigenetic profiling method will begin to answer that question. The technique involves differentiating pluripotent human stem cells into microglia, then introducing those microglia into the brains of mice. Using epigenomic tagging of single chromatin fibers, he and his colleagues can explore dynamic changes of epigenomic dysregulation of the cells over time. “We can switch it on and off, then months later, isolate the immune cells and see how genome organization looked four months ago,” he says. “It’s a bit like a telescope that allows astronomers to look back in time in the universe. This “telescope” allows us to look back in time in the cell.”

In this study, he is focusing on HIV-infected cells that have also been exposed to opioids and stimulants. Drug abuse is a major risk factor for HIV, because drug use increases risky behaviors that can make a person more susceptible to infection. “A brain that’s exposed to drugs of abuse and to HIV is probably more unhealthy than brains from a person with HIV but no history of drug use,” Dr. Akbarian says. “We want to see if exposure to drugs of abuse makes the brains more vulnerable to infection with HIV, or to the neurological defects that HIV can trigger.”

A third goal of the project, he says, is to contribute to efforts to rid the body of HIV for good. HIV inserts itself into the genome, an ingenious trick that allows it to hide from the immune system and makes it devilishly complicated to treat. “The big question is, does HIV do this in the brain, and if so, how can we flush it out?” Dr. Akbarian says. “If we can rid the body of HIV in every cell, people can stop taking antiretroviral medication”— and effectively be cured of HIV.

Advancing Psychiatric Epigenetics Through Collaboration
The project is in its early stages, but if this longitudinal method proves effective, Dr. Akbarian hopes it could lead to new innovations for studying other diseases of the brain. Many psychiatric conditions, such as schizophrenia and depression, emerge in young adulthood. However, many researchers suspect the disease process begins much earlier, possibly even prenatally. “There’s lots of indirect evidence, but we can’t look back in time. If we study the brain of a person with schizophrenia, we have no idea what happened in their brain earlier in life,” he says. Someday, this novel longitudinal technique may uncover some important clues.

First, though, he’s applying the method to the intertwined problems of HIV and drug use. Though Dr. Akbarian’s name is on the Pioneer Award supporting the study, it’s a project he says he could not have done without support from his colleagues at Mount Sinai. “I’m a newcomer to the field of HIV. I wouldn’t be able to do this without the exceptionally collaborative atmosphere among my colleagues at Mount Sinai, including Benjamin Chen, MD, PhD, Talia Swartz, MD, PhD, and Susan Morgello, MD, who are doing experimental HIV research and were willing to help me learn,” he says. “It’s ironic that this award is in my name, because the success of this project depends so much on teamwork with these HIV researchers, as well as stem cell scientists including Samuele Marro, PhD.”

The collaborative culture at Mount Sinai makes this kind of innovation possible, he adds. “Mount Sinai has precisely the right mixture of top-notch basic neuroscience, top-notch clinical neuroscience, and a very active hospital setting,” he says. “Together they give very fertile soil to do productive research in the fields of neurology and psychiatry.”

 

Non-Hispanic Blacks Found Twice as Likely to Have Atherosclerosis as Hispanics in Study of Young Adults in Harlem

Updated on Jul 15, 2022 | Cardiology, Diversity and Inclusion, Featured, Research

A unique Mount Sinai study focused on a multiethnic, underserved community in Harlem found that young non-Hispanic Black adult participants were twice as likely to have atherosclerosis as young Hispanic adults.

The research, published in the Journal of the American College of Cardiology in July 2022, is part of the FAMILIA Project at Mount Sinai Heart, a pioneering trial created by Valentin Fuster, MD, PhD, Director of Mount Sinai Heart and Physician-in-Chief of The Mount Sinai Hospital.

The new study is one of the first to evaluate atherosclerosis—the plaque build-up in the arteries that can lead to a heart attack or stroke—in asymptomatic young populations. Its findings emphasize the importance of early screening and lifestyle interventions in high-risk minority groups to improve their cardiovascular (CV) health.

Valentin Fuster, MD, PhD, Director of Mount Sinai Heart and Physician-in-Chief of The Mount Sinai Hospital.

“What’s interesting about this study is that Black individuals appear to be more vulnerable to atherosclerosis early in life than people of Hispanic origin, even when adjusting for known cardiovascular and lifestyle risk factors such as smoking, unhealthy diet, lack of exercise, high blood pressure, and cholesterol,” Dr. Fuster says. “This can then put them at increased risk of cardiovascular disease, suggesting the existence of emerging or undiscovered cardiovascular risk factors in this population.”

The study is part of a multinational effort to intervene early in the lives of children, their caretakers, and teachers so they can form a lifetime of heart-healthy habits. These new results come after highly successful interventions involving more than 500 preschoolers, caretakers, and educators at 15 Head Start schools in the Harlem section of Manhattan, an urban area that is socioeconomically disadvantaged—a situation commonly linked to higher rates of obesity, heart disease, and other health issues.

The FAMILIA team focused on 436 adults, including preschoolers’ family members, caretakers, teachers, and school staff. Of that group, 147 participants were non-Hispanic Black and 289 were Hispanic, with an average age of 38; 80 percent were women. Non-Hispanic white, Asian, and Native American groups each formed a small proportion of participants (2.3 percent, 2.3 percent, and 0.3 percent respectively) and people in those groups were excluded from the analysis.

Each participant answered a comprehensive questionnaire at the start of the study, addressing their nutrition, physical activity, tobacco use, and alcohol consumption, and whether they had conditions such as heart disease, hypertension, diabetes, or a family history of health problems. They also had their weight recorded, and blood pressure and cholesterol checked.

Overall cardiovascular risk factors were prevalent for both ethnic groups at baseline. Thirty percent of non-Hispanic Black participants had hypertension, almost triple the rate of the Hispanic group, 11 percent. Conversely, non-Hispanic Black participants had lower rates of dyslipidemia—unhealthy levels of lipids/fat in the blood (18 percent) compared to the Hispanic group at 27 percent, and better eating habits, consuming more fruits and vegetables. Researchers used these data to calculate a predicted cardiovascular risk score for each group. They found the overall risk of having a cardiovascular event in 10 years was low for both Blacks and Hispanics—around four percent for both groups.

Participants also had 3D vascular ultrasounds to determine if they had atherosclerosis in their carotid (neck) and femoral (leg) arteries. These vascular ultrasounds pointed to a significant discrepancy between the groups. Overall, nine percent of participants had subclinical atherosclerosis (nearly one in ten participants showed at least one artery with plaque). Also, the rate of plaque build-up in the arteries was two times higher among non-Hispanic Blacks than Hispanics. The results were consistent even after adjusting for classic cardiovascular risk factors including age, sex, body mass index, hypertension, diabetes, and cholesterol; lifestyle factors including diet, physical activity, and tobacco use; and socioeconomic factors such as employment status.

The study noted some limitations and areas for further investigation. “The population included in the study was from a specific area, Harlem, with known intrinsic health disparities compared with other areas in New York City,” the study said. “This could, to some extent, limit our results’ generalizability.” In addition, “Given the heterogeneity among racial and ethnic groups, assessing associations between self-reported racial or ethnic identity and disease is complex and is vulnerable to confounding due to the effects of socioeconomic inequality, environmental disparity, unequal access to care, and other possible emerging or unknown CV risk factors.”

However, the study is one of the first to assess the presence of subclinical atherosclerosis by 3D vascular ultrasounds in an underrepresented younger population, the research team says, and it contributes to the understanding of higher rates of CV disease observed at an early age in disadvantaged communities.

“These findings may in part help to explain the observed differences in cardiovascular disease prevalence between racial and ethnic groups,” Dr. Fuster says. “Until underlying biological factors and other undiscovered cardiovascular risk factors are better understood and can be addressed by precision medicine, affordable noninvasive imaging techniques such as the portable 3D vascular ultrasounds used in this study, which are easily used and affordable, can be an important form of early detection in underserved communities, and provide valuable information about population disparities and increase the precision of health promotion and prevention programs.”

Dr. Fuster and his team will expand the FAMILIA program to schools across the five boroughs of New York City starting in September 2022. This project will also evaluate how family socioeconomic status and teachers’ characteristics may affect the implementation and efficacy of school-based health promotion programs.

The FAMILIA project was funded by a grant from the American Heart Association.

 

Learn more about Mount Sinai Heart

Computational Neuroscientist Opens Doors for New Ideas and Talent to Thrive

Jun 23, 2022 | Featured, Research

Computational Neuroscientist Opens Doors for New Ideas and Talent to Thrive

When Kanaka Rajan, PhD, an expert in neural networks, joined the Icahn School of Medicine at Mount Sinai in late 2018, it was the school’s way of investing in computational neuroscience. But since establishing her lab, she has achieved new heights not just in her area of study, but in paving roads for future diverse talents to enter what had been a rather homogenous field.

Dr. Rajan, an Assistant Professor of Neuroscience in The Friedman Brain Institute at Icahn Mount Sinai, was recently awarded the McKnight Scholar Award, a three-year honor that provides funding to early-career scientists, from the McKnight Foundation, a Minnesota-based organization that has supported work in arts and culture, neuroscience, and climate change.

“I am honored to be recognized by the McKnight Foundation this year. The announcement was such a pleasant surprise,” said Dr. Rajan. Awardees of such programs are not often pure theorists like herself, she said. But the less restricted nature of the funding will advance a new research direction her lab has taken on and will bring much needed exposure to a key problem in science: how does the brain work?

Growing the team

The Rajan lab builds recurrent neural networks—artificial networks of neural nodes or regions inspired by biological brains—toward two core goals. The first is to discover the pattern of cell activity and connectivity in the brain, especially in psychiatric disease models, using these networks. These include exploring how there might be unexpected similarities or differences across species.

One study in that vein was based on what Dr. Rajan calls “functional motifs”—brainwide neural maps that tracked motor dysfunction as a correlated passive coping mechanism, a trait associated with depression.

Larval zebrafish subjected to persistent stress were observed to shut down movement. By comparing computational models of the fish’s neural circuitry against what is known in similar studies in mice and humans, Dr. Rajan could extrapolate how multi-area brain communication and connectivity leads to behavior relevant to neuropsychiatric disease.

The second goal is studying the concept of generalized learning, in which skills learned for one task become applicable to other unrelated problems. This encompasses, among other things, how animals and people are able to multitask, and yet, unlike machines built with artificial intelligence, how people can fail to complete all or some of these tasks perfectly.

A recent breakthrough in generalized learning that Dr. Rajan is working on is getting recurrent neural networks to do “curriculum learning”—training them on designed syllabi of increasingly complex tasks.

The idea of curriculum learning is not new in psychology or cognitive neuroscience, in which animals learn through “shaping.” In a lab setting, animals can be shaped to perform a desired task through reinforcement, for example by rewarding successful completion of sequences of smaller tasks.

An illustrated look at Dr. Rajan’s work

Illustration credit: Jorge Cham

Using this method for recurrent neural networks was born partly out of recognition for how animals and children learn, and in part to address limitations of current training algorithms, Dr. Rajan said. She adds that her lab is among a handful to use curriculum learning in neuroscience, recognizing that understanding how people generalize requires understanding their full learning trajectory.

“It’s an exciting new chapter for this field and I’m hopeful the McKnight Scholar Award will help scale our efforts on this front,” Dr. Rajan said. Her team—comprising four postdoctoral researchers, some of whom are starting independent faculty positions later this year, and three graduate students—looks to add a few more members with the funding.

“This is a competitive field and city to hire scientists in,” she said. “Not only are we competing with other institutions; we’re also competing with industry, so it’s on us to make it an attractive proposition.”

But Dr. Rajan believes Mount Sinai offers something that other institutions or industry players might not: complete intellectual freedom.

“When I first arrived, I was told, ‘Welcome to the department. Let us know if you need anything,’ without any restrictions on my next steps,” Dr. Rajan recalled of her interactions with leadership in the Department of Neuroscience at Icahn Mount Sinai. “This was unlike previous institutions I had been at, where I had been gently nudged where I could or could not direct my research.”

Mapping new paths ahead

Just as Dr. Rajan felt she was given the opportunity to excel as a woman and person of color, she felt compelled to extend those opportunities to those who follow in her footsteps.

Dr. Rajan was allowed to tap her seed funding to start a pilot project in which she turned complex research papers into comic strips to get high school seniors and college students, especially those from disadvantaged communities, interested in joining the neuroscience field.

 

A peek at how Dr. Rajan makes complex research topics accessible to young students

Illustration credit: Jordan Collver

“There had been artificially high barriers to entry, like girls had been told they’re not good at math, or that AI and/or computational neuroscience are beyond their understanding,” Dr. Rajan said.

By turning complex ideas into jargon-free and engaging formats such as a comic strip, she hopes to help young students realize that they too can enter and flourish in such a technical field. A series of comic strips have been created and steps are underway to distribute them to schools in New York City and other cities.

“When I first started my lab, I had 116 applications to join my team. Guess how many were women?” Dr. Rajan asked. “Two. Computational neuroscience has a representation problem, and I want to fix what I can.” She continued, “I’ve taken small steps, but the ball rolled from Mount Sinai. Here, you see women really get to thrive.”

Helen Mayberg, MD: Seizing Unexpected Opportunities at Every Turn

Jun 8, 2022 | Featured, Research

Helen Mayberg, MD: Seizing Unexpected Opportunities at Every Turn

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.”

For her body of work integrating imaging techniques to reveal mechanisms of depression, Dr. Mayberg was elected to the National Academy of Sciences (NAS) in May.

Dr. Mayberg considers her career to have taken an unconventional arc. She first trained clinically in neurology at Columbia University, then did a research fellowship in nuclear medicine and functional imaging at Johns Hopkins University. Prior to joining Icahn School of Medicine at Mount Sinai, Dr. Mayberg held a series of cross-disciplinary appointments in neurology, psychiatry, radiology, neurosurgery, and neuroscience at various institutions, including Johns Hopkins, University of Texas, University of Toronto, and Emory University.

Dr. Mayberg was elected to the National Academy of Sciences along with Yasmin Hurd, PhD, Ward-Coleman Chair of Translational Neuroscience and Director of the Addiction Institute of Mount Sinai. Read more about Dr. Hurd’s achievements here.

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 closer look at Dr. Mayberg’s work

Dr. Eric Nestler

Eric Nestler, MD, PhD, Nash Family Professor of Neuroscience, Director of The Friedman Brain Institute, Dean for Academic Affairs of the Icahn School of Medicine at Mount Sinai, and Chief Scientific Officer for the Mount Sinai Health System, weighs in on what he found impressive about Dr. Mayberg’s research.

“Dr. Mayberg’s work is all translation since it’s all performed in humans,” said Dr. Nestler, “Even though her research has been tethered in basic neurobiology, thinking about how it intersects with patients is evident.”

Membership of the National Academy of Sciences—considered one of the highest honors for a scientist—comes through election by existing members only. Candidates’ entire bodies of work and contributions to the field are considered as part of the nomination process and their entries are voted on in April each year, with a maximum of 120 U.S. citizens and 30 non-citizens elected annually, according to NAS. There are currently approximately 2,400 U.S. members and 500 international members, of whom 190 have received Nobel prizes. Mount Sinai has six current faculty in the prestigious organization.

Dr. Mayberg had a longstanding track record in using brain imaging to study people with psychiatric disorders, but her breakthrough was using deep-brain stimulation to treat depression.

“What Helen did was extremely novel, especially because this was for a group of patients who had especially severe depression who did not respond to a wide range of existing treatments including electroconvulsive therapy, also known as ’shock’ therapy,” Dr. Nestler said.

The paper on using deep-brain stimulation for depression, published in Neuron in 2005, remains Dr. Mayberg’s most cited work. In her study, six patients with severe depression who had failed at least four different forms of treatment underwent the experimental stimulation procedure. All six saw improvement in clinical scores, with three achieving remission or near-remission that was sustained long term.

“It was a remarkable and brave study and she has since further developed its key findings and implications,” Dr. Nestler said.

Other notable publications from Dr. Mayberg included discovering areas of the brain that were involved in feelings of sadness, and how they exhibited dysfunction in returning to baseline state in people with depression. Dr. Mayberg considered that paper, published May 1999 in The American Journal of Psychiatry, one of her hardest to get published, but it ultimately led to her work with deep-brain stimulation.

“We recruited Dr. Mayberg because we had a great deal of confidence in her multidisciplinary approach,” Dr. Nestler said. “With the additional resources possible at Mount Sinai, she can take the program to the next level.”

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