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Ask Dr. Helen Mayberg about her work on deep brain stimulation (DBS), a potential new therapy for people with treatment-resistant depression, and the research that formed the foundation of the method, and she immediately thanks NARSAD: The Mental Health Research Association.

“NARSAD has given me support throughout my career,” says Dr. Mayberg, 50, professor of psychiatry and neurology at Emory University School of Medicine, in Atlanta, and, since last year, a member of NARSAD’s Scientific Council. “But the organization’s awarding me of the Distinguished Investigator honor in 2002 gave me the critical funding and peer-reviewed endorsement to initiate in 2003 the first pilot studies of DBS in patients with treatment-resistant depression.”

Results from that small study of six patients, performed at the Toronto Western Hospital in Canada, show that four of the subjects responded significantly to DBS. “These were people who had failed multiple treatments — including psychotherapy, more than four different classes of medications and, in most cases, electroconvulsive therapy (ECT) — and were medically disabled by their depression,” Dr. Mayberg says. “Now they were working again, re-engaging with family and friends, and enjoying pursuits that gave them pleasure and satisfaction.”

The findings were published in Neuron on March 3, 2005, and reported in an extensive article in the New York Times Magazine on April 2, 2006. The Toronto team has now implanted 16 patients and continues to recruit additional subjects. Dr. Mayberg will be starting a new DBS research study at Emory in the fall. Clinical trials of DBS also are being developed to further assess the treatment’s safety and efficacy.

DBS for treatment-resistant depression involves implanting electrodes near the brain’s center, in a region called Area 25, and then submitting the tissue to chronic low voltage to modulate its activity. Dr. Mayberg believes Area 25, a part of the anterior cingulate cortex, is severely dysregulated in patients with treatment-resistant depression and changes their mood, sleep, appetite and motivation. The cingulate is part of the brain’s limbic region, a group of structures that also includes the amygdala, hippocampus, septum and basal ganglia, which work together to regulate emotion, memory and certain aspects of movement.

Before choosing Area 25 as a target, though, Dr. Mayberg perform-ed years of neuroimaging studies in different groups of depressed patients to characterize what the depression circuit “looks” like in the brain and how to affect it. Today, her collective findings have led to a new view of how to think about depression. Prior to neuroimaging, the prevailing notion of depression was that it was due to a chemical imbalance in the brain, correctable with medications. Where those medications were acting in the brain was less important than which chemicals were involved. Using imaging, Dr. Mayberg’s research looks at neurochemistry and different treatments in the context of specific brain regions and circuits.

NARSAD, Dr. Mayberg says, provided support at critical junctures in her professional life. Now, Dr. Mayberg is a world-renowned ex-pert in depression: She has been a principal investigator on more than 20 research projects and an invited speaker at scientific conferences and lectures. She is a member of the National Institute of Neurological Disorders Advisory Council and has served on the editorial boards of Neuroimage, Human Brain Mapping and Bio-logical Psychiatry. She has won numerous awards and is a member of many scientific societies. Dr. Mayberg also has mentored graduate and postdoctoral students, including several NARSAD Young Investigators.

But early in Dr. Mayberg’s career, it was neurology, not psychiatry that led her to pursue research about depression. After medical school at the University of Southern California, where she obtained her M.D. in 1981, she specialized in neurology. Dr. Mayberg did her residency training at Columbia University’s Neurological Institute in New York City from 1982 through 1985, and then completed a research fellowship at Johns Hopkins University’s PET facility from 1985 to 1987.

At Columbia, Dr. Mayberg observed how some neurological patients, such as stroke victims and people with Parkinson’s disease, also were depressed.* At the time, she wondered whether a similar brain problem might be contributing to depression in both conditions. She decided to pursue this question by working with Johns Hopkins’ Robert Robinson, M.D., one of a few scientists then using computerized tomography (CT) scans of the brain to study the relationship between neurological and psychiatric conditions. In 1984, Dr. Robinson had found stroke patients with frontal lobe damage were more likely to be depressed.

Following up on the finding, in 1985, Mayberg, Robinson and colleagues performed a positron emission tomography (PET) imaging study of stroke patients to differentiate patients with and without depression. They found a pattern in depressed stroke patients affecting the cingulate, temporal and frontal cortex, suggesting involvement of brain regions responsible for communication between the emotional and thinking regions of the brain. The temporal and frontal cortices are involved in cognitive processes.

Similar scan changes were seen in other studies of depressed Parkinson’s and Huntington’s disease patients. The cingulate (emotional)-frontal (thinking) pattern in depressed patients with different neurological disorders was an important early observation, Dr. Mayberg says. But were these areas also playing a part in patients with primary depression?

To address that question, Dr. Mayberg and colleagues began to study depressed patients without neurological disorders. A similar pattern of abnormalities again was identified.

In 1991, Dr. Mayberg moved to the University of Texas Health Science Center in San Antonio, which had a new state-of-the-art PET facility. There, she continued her research about depression’s brain circuitry, and, in 1991, received a NARSAD Young Investigator grant and, in 1995, a NARSAD Independent Investigator grant.

“Although imaging today has become an important research tool to understand psychiatric disease mechanisms, in the mid-80s and early 90s, it was a novel and relatively untested approach,” Dr. Mayberg explains. “NARSAD provided early funding for several of our imaging studies, facilitating my transition from a postdoctoral fellow to an assistant and later associate professor. These studies also provided the foundation for the later development of our depression model and ultimately, our DBS study.”

At San Antonio, she and others performed new studies testing why certain SSRI antidepressants work in some people but not in others by comparing PET scan changes in patients receiving either Prozac (an SSRI) or placebo. Those patients who responded to active treatment after six weeks had increased activity in cortical (thinking) regions and decreased activity in the limbic (emotional) regions. Interestingly, she also saw the same finding for patients who had responded to placebo.

Simultaneously, she did a PET study on healthy women as they were asked to read an account of a personal sad experience. Dr. Mayberg found that as the women re-experienced the poignant feelings evoked by memory of the event, activity increased in the limbic region and decreased in the frontal cortex. When the women returned to a neutral mood, limbic region activity lessened, while the cortical region amplified.

These results led Dr. Mayberg to theorize that depression resulted from an imbalance between the emotional (limbic) brain and the thinking (cortical) brain. If the limbic brain was overactive relative to the cortical brain, the person would become depressed.

In 1999, Dr. Mayberg moved to the University of Toronto as the Sandra Rotman Chair in Neuro-sychiatry. Having been intrigued by earlier findings that a placebo similar to a medication could change brain activity of depressed patients, Dr. Mayberg and collaborators decided to study cognitive behavioral therapy’s (CBT) impact on the brain. In the study, patients underwent a one-hour, weekly session of CBT for 15 weeks. Their brains were imaged before and after the treatment. Dr. Mayberg expected to see in pa-tients who responded to treatmeny increased activity of the cortical regions and then suppression of the limbic regions, as seen with placebo and medication. But she found CBT produced a unique pattern of change, namely decreases in the frontal cortex, and involvement in brain areas not previously seen with medication.

Although surprised by the results, Dr. Mayberg quickly realized she had to revise her circuitry model and the effects on the circuit from different treatments. Instead of the idea that all treatments act on a final common brain system, the data showed different treatments act in complementary but differ-ent targets within the circuit. “My current view is that different patterns of brain activity, or different states of the network, are present in different groups of depressed patients,” Dr. Mayberg says. “The implication of this is that depressed patients with different brain circuitry might benefit from differ-
ent treatments.”

Recently, Dr. Mayberg used PET to categorize depressed patients according to those who would respond to CBT, those who respond to drugs and those who do not respond to drugs. She found that each group of patients has unique brain activity, a finding that implies that each pattern may serve as a marker to predict treatment outcome, Dr. Mayberg says. People who do not respond to drugs, for example, show increased limbic region activity and a poor connectivity to the dormant cortical regions.

In 2003, Dr. Mayberg moved to Emory. She maintains her affiliation with the University of Toronto on the DBS study and continues research to test brain imaging markers that predict the most effective treatment for depressed patients. “Does everyone with de-pression need medication or do they need more aggressive treatment?” Dr. Mayberg asks. “As we use biomarkers for making treatment decisions for other medical illnesses, such as heart disease, we need to identify biomarkers that guide us to the optimal treatment of the psychiatric patient.”

People with the most severe depression often suffer through many years of futile treatments, she explains. “Perhaps, we can identify brain patterns that might predict sooner the likelihood of such a malignant course of illness and steer us earlier to pursue more aggressive treatments, such as ECT, vagus nerve stimulation or, in the future, DBS,” she says.

As she gains notoriety for her work, Dr. Mayberg often gets asked how she knew where to put the electrodes in the DBS study of treatment-resistant depression. “Our imaging studies provided critical direction,” she says. “Findings over the last 15 years led us to what we felt was the most logical target, namely Area 25.” Addition-al studies, including replication by other researchers, will help to further test and refine the hypothesis.

But questions remain, such as why did some patients not respond to DBS and how is DBS working? Dr. Mayberg and other scientists are working on resolving these issues. They are also looking at the relationship between genetic and brain biomarkers in different groups of patients with depression. “With the help of NARSAD supporting a new crop of scientists, and continued resources from the federal government and private industry,” Dr. Mayberg says, “I believe we will soon be able to significantly improve the quality of life of people living with depression.”

*An extensive description of Dr. Mayberg’s research can be found in “Mapping the Blues,” by Mark Witten in The Walrus, April/May 2004, from which material in this article has been adapted.

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