Restoring a Delicate Balance: Dr. Hilary Blumberg Seeks Ways to Therapeutically Address Subtle Brain Changes that Imaging Has Revealed in Mood Disorders

Posted: January 27, 2020
Restoring a Delicate Balance: Dr. Hilary Blumberg Seeks Ways to Therapeutically Address Subtle Brain Changes that Imaging Has Revealed in Mood Disorders

“I love the science of it!” says Dr. Hilary Blumberg, a research pioneer who has used advanced imaging to figure out how the brain subtly changes in bipolar disorder, major depression, and other mood disorders.

“But what really drives me,” she stresses, “is bringing this work to the point where it is helping people—helping to relieve their suffering, improving their prognosis, and decreasing early mortality due to suicide. That’s what guides me first every morning. I have a feeling of not being able to go fast enough, because so many people are suffering and people are losing their lives every day. I feel an urgency in this work.”

Dr. Blumberg, a psychiatrist and clinical researcher, has been on the faculty of the Yale School of Medicine for more than 21 years, for the last 15 years serving as director of the Mood Disorders Research Program. She has been driven to reveal the inner workings of human emotions since she was 16 years old. That was when, as a precocious Hunter College High School student growing up in New York City, she was given her first chance to do research—at Cornell-New York Hospital (now Weill Cornell Medicine).

Dr. Blumberg was editor of a recent special issue of the Journal of Affective Disorders devoted to new research on suicide. In her introductory essay she noted that while it is “a preventable cause of death,” suicide occurs somewhere in the world every 40 seconds, resulting in 800,000 deaths annually. Recently it has been estimated that people suffering from mood disorders have a lifetime risk of suicide 20 times greater than average (in the U.S., the average is 1.4 suicides per 10,000 people). As many as one person in two diagnosed with bipolar disorder makes a suicide attempt during their lifetime.


There is no shortage of urgent causes in medicine. Dr. Blumberg relates that during her medical training at New York Hospital, she found herself reflecting on the “terrible things I was seeing as an intern at the Memorial-Sloan Kettering Cancer Center. It was devastating—you could see people losing their lives prematurely, every day.” But then, as she gazed out of her apartment window, her eyes focused on the Payne Whitney Clinic, the psychiatric hospital across the street. “I thought: the young people with psychiatric disorders in that facility actually may have a higher rate of mortality—and those illnesses could potentially be preventable. That realization fueled my motivation to focus on trying to help relieve the suffering of mental illness and prevent suicide.”

She did her medical residency in psychiatry and became “really immersed in the clinical side—the art of taking care of patients.” At the same time, “in the back of my mind, I had so many questions about the biology”—how changes in the brain are related to behaviors and symptoms seen in mental illness.

During her post-training fellowship, also at New York Hospital, Dr. Blumberg learned how to use a positron emission tomography (PET) scanner to look at the brain in people diagnosed with bipolar disorder. A research paper that emerged, published in 1999, helped establish her reputation. It was the first time brain scanning research showed decreases in functioning in the right prefrontal cortex in individuals who were experiencing manic symptoms of bipolar I disorder.

What exactly is going on inside the brain while individuals experience various symptoms of psychiatric illnesses? While doctors diagnose mental illnesses on the basis of behavioral symptoms—visible “on the outside”—the causes have remained stubbornly obscure. Research seeks to get to the level of mechanisms—changes in the biology of the brain across different subsets of patients, and between affected and unaffected individuals.

Findings in adults with bipolar disorder have focused attention on parts of the brain which regulate emotions. These include areas that span from emotional processing regions below the cortex, such as the amygdala, to the frontal regions of the cortex, the seat of higher thinking that provides executive control over emotions and impulses.


It is remarkable how much the brain changes even after the end of adolescence. This is evident, for example, in imaging studies of the brain’s grey and white matter. As Dr. Blumberg explains, “The grey matter is where the cell bodies are.” She refers to the billions of neurons that populate the brain and comprise its complex circuits. “You can think of grey matter structures as ‘nodes’ in the circuitry.” Gray matter, especially in prefrontal cortex, continues to change and mature through early adulthood. “It remains plastic during adulthood, but it is especially plastic during childhood and adolescence, so these are important times to minimize risk factors and build resilience,” she says.

White matter is the brain’s wiring, and specifically the insulation around the wiring, made of the whitish-yellow fatty substance called myelin. Bundles of white matter carry the connections between brain cells and between different brain regions. “Since white matter

continues to change, into a person’s mid-adult decades, this suggests there are important windows in this period, as well, to prevent the progression of adverse brain changes that increase risk of mood disorders and suicide.”

Differences in the brain between people who have bipolar disorder and those who do not, as well as between those in each group who have suicidal thoughts or make a suicide attempt and those who do not “are quite subtle,” Dr. Blumberg points out. “We are not talking about differences that can be detected by holding up two scans using current technology to tell who does and who does not have bipolar disorder. These are subtle differences that are in brain areas that show plasticity. We are learning ways to help reverse some of these changes. New therapeutic strategies are being intensively researched, and new brain imaging technologies will be coming that will help guide us in developing them.”


Dr. Blumberg has devoted considerable effort in recent years to the study of adolescents with bipolar disorder. “Since symptoms are often first recognized during adolescence, it could be an age period that holds clues about the development of the illness,” she says, “and its study could provide targets for early interventions to prevent the progression of symptoms.”

She achieved important firsts in the field, showing brain differences in adolescents with bipolar disorder, and particularly in the emotion centers below the cortex. Her findings in the amygdala in adolescents are especially important. She explains that “the deeper you go in the brain, the more primitive the structures and their functions.” She’s referring to the limbic centers that include the amygdala, which are central in emotional processing. These tend to mature earlier than frontal “executive” regions of the brain.

Over the past decade, Dr. Blumberg and her team have delved into the circuitry that contributes to the risk for suicide in individuals with mood disorders. In a paper appearing in the American Journal of Psychiatry in 2017, for example, her team used various imaging types to study adolescents and young adults with bipolar disorder—and found differences in the structure and the functioning of prefrontal regions that were more pronounced in those who had made suicide attempts.

Most recently, her group has provided preliminary evidence that there are similar brain differences in adolescents and young adults with major depression and bipolar disorder who have attempted suicide. In another longitudinal study, Dr. Blumberg and her group provided preliminary evidence that prefrontal differences may be a predictor of future suicide. This is important, since “right now no one knows in advance which individuals will attempt suicide.” Thus, the focus in Dr. Blumberg’s current research is on the longitudinal approach—following people over time.

Among her many current projects, Dr. Blumberg is the U.S. lead investigator of a new international consortium that is looking for brain biomarkers of suicidal ideation in adolescents and young adults. Her team is focusing on individuals followed over the years, as they mature, and also in the periods before and after pharmacological and talk therapies. She is also attentive to the problems of older adults with mood disorders. “This is an area that has received less study but is critical,” she points out, “since it is the group at highest risk for suicide.


At Yale, Dr. Blumberg and colleagues are recruiting individuals for clinical trials testing a non-drug therapy, called BE-SMART, which stands for Brain Emotion Circuitry-Targeted Self-Monitoring and Regulation Therapy. Its goal is to help people who have mood disorders or who are at risk for them to better regulate their emotions. It targets prefrontal brain circuitry that regulates emotions, reflecting what Dr. Blumberg and colleagues have learned from brain imaging. It seeks to unlock the potential value in teaching people healthy strategies for modifying their behavioral responses to emotions as well as regularizing sleep and other daily activities.

“If someone’s got a mood disorder, they could be really sensitive to disruptions in the timing and amount of their sleep and other activity patterns, which in turn disrupt the alignment of other bodily rhythms,” Dr. Blumberg explains. “I’ve long had the dream that you could strengthen the brain to reduce acute symptoms and potentially prevent progression and improve prognosis while reducing suicide, by teaching healthy habits and ways for individuals to better self-regulate.”

Preliminary findings, she says, show that over 12 weeks of the intervention, with the majority of sessions provided by therapists via computer or smartphone videoconferencing apps, “emotional control and mood symptoms are improving, as reflected in improved functioning of prefrontal circuitry observed with functional MRI.”

The current BE-SMART program in bipolar disorder involves young people aged 16 to 24, as well as some younger participants at risk for bipolar disorder. Dr. Blumberg hopes to test it in other age groups and disorders. She is also incorporating wearable devices and smartphone technology to learn more about real-time changes in study participants. She plans to eventually incorporate feedback during therapy for patients and therapists, to optimize results.

Dr. Blumberg emphasized that there are many paths to mood disorders and many potential ways to address them therapeutically. “Drug therapies, new targeted biological non-pharmacological treatments, talk therapies to improve ‘top-down’ emotion regulation, and behavioral therapies that enhance healthy habits, each has potential to provide benefits,” she says.

“And there are many new therapies on the horizon. The future is very hopeful —I believe we will continue to make progress on reducing the suffering and the risk of suicide in mental illnesses.”

Written By Peter Tarr

Click here to read the Brain & Behavior Magazine's December 2019 issue

Hilary P. Blumberg, M.D.

Director, Mood Disorders Research Program

John and Hope Furth Professor of Psychiatric Neuroscience and Professor of Psychiatry, of Radiology and Biomedical Imaging, and in the Child Study Center

Yale University School of Medicine

Scientific Council Member

Dr. Blumberg Talks About BBRF

“I absolutely believe that BBRF has been instrumental in my career. The Young Investigator award [in 2002] was so important for me to be able to do the multi-modal imaging work in bipolar disorder. Then I got an Independent Investigator award [in 2006] which enabled me to look at individuals at risk and pursue that work. Since then, many of my trainees have been awarded BBRF grants. So you start with my early award and see all these branches, opening into different aspects of my work over my career and that of people I’ve helped train. And as people in my lab get opportunities from awards of their own, the whole ‘tree’ just exponentially grows. It means a great deal to me to sit with my trainees and know that there are Young Investigator awards still out there to be won—this gives me tremendous hope that they’re going to be able to successfully launch their own programs, which is really crucial to the future of brain research.”