Even in abbreviated form, a career synopsis of Scientific Council Member Helen Mayberg, M.D., presents a remarkable set of achievements.

Formally trained as a neurologist in the 1980s, by 1997 Dr. Mayberg had made use of brain imaging technologies to formulate what she termed “a working model of depression” that continues to be highly influential. The concept of depression that she advanced moved signifi cantly beyond the model linked with antidepressant medications that tens of millions take daily. These medicines have long been assumed to address chemical imbalances involving message-carrying neurotransmitters and the molecules that transport them from cell to cell.

While not rejecting a role for these factors, Dr. Mayberg has championed an alternative, distinctly neurological view of depression, stressing circuits and networks in the brain that interact with one another in ways that change from moment to moment. Depression, she has suggested, arises when certain parts of the brain are out of synch.

Mayberg is most famous for her role in developing an experimental treatment for people with debilitating major depression who have not been helped by any available therapy. Called DBS, or deep-brain stimulation, it has worked spectacularly for some patients in small clinical trials, its impact described by those helped as a “lifting of the veil” and a “return to connectedness.”

While continuing to learn from and improve DBS, Dr. Mayberg is deeply engaged with a range of research projects at her new post as Director of the Center for Advanced Circuit Therapeutics at the Icahn School of Medicine at Mount Sinai, where she is a professor in four departments. In this highly interdisciplinary environment, her most recent work on depression is devoted to learning how to predict which depressed patients will benefi t from which forms of therapy, and just as important, who is not likely to benefit.

Talking in depth to Dr. Mayberg, one realizes that there is a consistent theme underlying all of her accomplishments. “Everything I’ve done reflects my training as a neurologist,” she says, meaning that she is a doctor who is also a scientist. From the beginning, she says, “the needs of patients have driven the kind of scientific questions I try to answer.” She is strongly motivated by a feeling that “the status quo” for patients is not adequate.

The scientist in Mayberg rules out working from intuitions or hunches. The brain is an organ of the body that in certain ways doesn’t work properly in depression and other mental illnesses. “The brain has regions that are connected to one another in pathways. Circuits, or subsystems, convey information for behaviors, actions, and thoughts in a very organized way,” she says. These networks have only begun to come into focus during the course of her career.

Mayberg the scientist is interested in evidence. When Sigmund Freud and other ancestors of modern neuroscience and psychiatry formed their ideas about mental illness, they had almost nothing to look at, beyond outward behaviors of their patients. “They couldn’t see depression” in the organ in which it is rooted, Mayberg reminds us.

Indeed, no one could claim to have seen depression until the era of neuroimaging, which took off when Mayberg was in training. In fact, Mayberg identifi es with other intellectual precursors–the doctors and surgeons of the last century who performed exploratory operations and postmortems on people with brain injuries. They learned facts about brain function by correlating an injury in a particular brain area with the way that injury affected behavior and/or bodily functions.

Though deeply fascinated by the problem of how the brain works, Mayberg stresses that as a doctor who treats suffering patients, her quest is not merely intellectual or academic. “All the science is driven by clinical need. People want answers. They have sick family members,” she says. She became interested in the problem of depression when, as a neurologist, she began to ask why people with Parkinson’s disease are often depressed. It was generally assumed that the depression was “just a psychological reaction” to having this serious illness. But with the help of brain imaging she was able to suggest something dramatically different: that the physical degeneration of the brain that attends the disease impacts areas of the brain where dopamine, a neurotransmitter central in Parkinson’s pathology, has an impact on mood.

Having access to PET (positron emission tomography) scanning technology during her research fellowship training, which was fairly new at the time, Mayberg performed experiments that provided an example for future work. She used the scans to map glucose metabolism as well as dopamine, serotonin, and opioid receptors and their distribution in the brain, overlaying the chemistry on what then was a rudimentary understanding of brain areas and their functions.

“If you could map these things out in a living brain, you could then look at dynamic and not just static abnormalities,” she explains. The inspiration was that old yet fruitful approach of matching injuries in the brain to changes in the functioning of patients. Except now, one could watch these systems change their state over time. It was like the difference between having a still picture and movies.

This work “began to lay out the puzzle of where are the common places in the brain that, when damaged, cause someone to experience depression,” she says. In its earliest phases, this approach, with brain scans playing a key role, was denigrated by some as “blob-ology.” Mayberg and others were “trying to take the illuminated areas on the scans–bright or dim blobs– and imagine them within the structure in the brain where they live,” as she describes the approach. She had the clear idea of relating changing patterns of activity within known brain regions to the way those regions functioned.

Over the years she used data from patients to form theories about depression. “No complex behavior–no simple behavior, for that matter–is the exclusive domain of any one cell or region in the brain,” Mayberg says. The evidence from the scans led her to propose that depressed behavior, which affects many systems in the brain, might result when key brain regions that normally work together fail to synchronize properly.

This tended to corroborate the theory she fi rst advanced in 1997, in which she suggested that depression was the result of a failure of two fundamental brain networks to coordinate properly–the limbic system, which is the seat of the emotions, and higher cortical areas associated with thought. This fi rst sketch has proved remarkably robust as constantly improving imaging technologies have shed much more light on pathways and circuits of brain areas associated with these two basic brain functions.

It’s very important to Mayberg to make clear that this was not something she arrived at because it made sense in theory. She has arrived at all of her major insights by working backward from biological evidence. In the electronics industry this is called reverse-engineering. She muses that the tools available “are becoming more and more sophisticated, which allows us to push the envelope in probing both how the the brain is organized and how it breaks down in disease.” She looks forward to seeing how other scientists tackle these various complex problems including the secrets of consciousness. “For me, my hands are full studying depression.”

In repeated efforts to determine why certain depressed patients respond to a given treatment and others don’t, there were “straightforward experiments” she could readily perform that were very likely to shed light. “Our antidepressant treatments are evidence-based. Sometimes the effect in an individual patient is great, sometimes small, and sometimes there is no effect. We know that some people do recover. Our idea is to understand how any patient goes from sick to well.”

If the state of the individual’s brain can be observed in scans and through other measures to change over time while the treatment is being given, then valuable data is generated. Do this in many patients, with different reactions to different treatments, and a nuanced picture begins to emerge.

“Why can I give people that I think suffer from the same problem the same treatments–and some get better and others don’t? There must be an effect of treatment on the brain, irrespective of whether someone gets better or not. Something is happening in the brain. Can the [live-imaging] map show me?” she says. There are many variables to consider, which is why it is important to try to match comparable patients–to try to compare apples with apples. Yet, depression may begin differently in different patients. If this is true, then it is possible they might respond differently to treatments, even if they report similar symptoms.

These and many other variables have been carefully considered, even agonized over, by Mayberg and her colleagues. They have the aim, already partly fulfi lled, of developing what doctors call “treatment algorithms” for depression. Also called “decision- trees,” these are widely used in other areas of medicine. Treatments given to people reporting trouble with their heart or who are found to have a cancerous tumor are based on a wealth of empirical evidence gathered in the clinic about how comparable patients have responded to available treatments.

The idea is to make a science of making treatment decisions –instead of following a hunch. That thought is the essence of Mayberg’s motivation as a doctor-researcher. She wants to take emotion and guessing out of the equation–because evidence- based facts, if they are available, are more liable to help the patient. It’s a way of removing the trial-and-error factor in psychiatric treatment.

“It is envisioned that in the future a psychiatrist making a decision to treat a patient with major depression will choose a pharmacological, psychotherapeutic, or somatic [bodily] intervention on the basis of objective measures of brain function in the context of known risk factors including genetics, co-morbid conditions, psychosocial issues, and past history,” Mayberg wrote in the pages of Biological Psychiatry a decade ago. Last spring, she and colleagues reported in the American Journal of Psychiatry that, on average, previously unmedicated patients with major depression who received medication experienced a similar reduction in symptoms over 12 weeks as did comparable patients who were assigned to receive cognitive behavioral therapy, a form of talk therapy. But that was not the key fi nding. By comparing individual outcomes with the brain scans of each participant taken before treatment began, the team identifi ed patterns of brain activity that would help them predict who would respond well to each treatment approach, and for which patients each treatment was likely to fail.

“In my career it has always been a matter of: What is depression? How does it live in the brain? How does it change? What is its variability? All these questions feed into the big question: How does the brain go wrong and how do we fi x it?” Hard evidence is leading at last to decision-trees for treatment that are likely to prevent or curtail an incalculable amount of human suffering–a kind of suffering that has been part of the human experience since the origin of our species.

— Written By Peter Tarr, Ph.D.

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