SEATTLE—It is easy to see depression as a disorder of deficit —patients are slow, their mood is low, “everything about them is as though the brain is underactive,” said Helen S. Mayberg, MD, in her opening remarks in a lecture here at the AAN annual meeting.
But the professor of psychiatry and neurology at Emory University School of Medicine said she was more apt to accept the description by William James — that depression “is an active state of the brain,” one of “psychic pain.” The disorder is not one of the brain being offline, she said, but instead it is in an “aberrant active state.”
This view has fueled Dr. Mayberg's pioneering study of deep brain stimulation (DBS) for treating intractable depression.
DEFINING A DEPRESSION NETWORK
Dr. Mayberg noted that research in the mid-1980s suggested that lesions in specific brain areas were associated with a greater risk for post-stroke depression. Shortly thereafter, using FDG-PET imaging, Dr. Mayberg began a long series of experiments to define which cerebral areas and circuits were altered in depressed patients.
Her work led to defining a “paralimbic network” involving the bilateral frontal cortex, cingular cortex, and the anteromedial temporal cortex. “It wasn't one place in the brain — it was a set of places,” she said.
When patients recovered from depression, she observed a return to normal cerebral activity in the frontal cortex, and suppression of metabolism in an area within the subcallosal cingulated in Brodmann area 25.
Suppression of area 25 activity was induced whether clinical recovery resulted from psychoactive drugs, placebo, or electroconvulsive therapy; if the patient was clinically unresponsive, the area remained overactive. When she induced a transient, intense negative mood in healthy people by asking them to recall a personal memory, area 25 became overactive, and the frontal cortex was underactive.
“So the very simple question became, if you can talk it down, drug it down, and shock it down, maybe you can actually regulate activity in this region and thereby affect all of its connections directly,” Dr. Mayberg said.
In collaboration with neurosurgeon Andres Lozano, MD, at the University of Toronto, Dr. Mayberg conducted a small trial of bilateral DBS in six patients with intractable depression. “It was just like doing a Parkinson disease DBS study, but the target was different,” she explained, with the electrodes placed in the white matter, directly adjacent to the subcallosal cingulate gray matter.
In a 2005 paper in the journal Neuron, Drs. Mayberg and Lozano reported that four patients experienced a dramatic relief of symptoms; Hamilton depression scores improved 30-to 40-percent in the early stages of testing, with progressive improvement thereafter, ultimately approaching remission.
The accompanying neuroimaging confirmed that stimulation reduced the overactive area 25. “We confirmed our hypothesis that downregulation of area 25 and the regions connected to it would lead to a release of frontal cortex and a normalization of functioning,” she said.
They extended the study to 20 patients, still open-label, who were followed for one year on continuous stimulation. Dramatic changes were seen by one month. Most gratifyingly, she said, “If you got better, you stayed better with continued stimulation. You didn't lose the effect of the dose.” And once the right stimulation parameters were achieved, they remained effective. “It was almost ‘set it and forget it’ once you achieved the effect,” she said.
Unlike the effects of oral medications, there were no late-developing side effects, and neuropsychological testing showed no effects on frontal functioning. “Most remarkably, many of these chronically disabled patients are going back to work, resuming their lives,” Dr. Mayberg said. “This really goes against the odds of anyone who is sick for that length of time.”
Patients undergoing the procedure report effects even within the operating room. Dr. Mayberg quoted one who said: “This vortex, this sinking feeling, this hole, this psychic pain, absolutely dissipated immediately, and it was a relief and an absence of negative — it was not an elevation.”
Patients “suddenly had a sense of ‘intense calm’, ‘quiet’, ‘a relief’, ‘a resolution of dread.’” Once that happens, she said, the patients feel more energetic and more attentive to their surroundings. “They notice other people in the operating room, and describe color changes — things are brighter, and more details are visible,” she explained.
It wasn't like something had been added, Dr. Mayberg said —instead, something had been taken away. The procedure allowed the patient to realize “that now he was in a position to work on his own recovery.”
“It's turning out that this phenomenon in the operating room may be predictive of long-term outcome,” Dr. Mayberg said. It's still possible to recover if a patient doesn't experience it, she added, “but if you do, you get well and stay well. We have to know what that is. What is that immediate effect? What is area 25 talking to?”
Answering these questions is a principal focus of Dr. Mayberg's ongoing work, and early results suggest that connections to the amygdala are important. She also wants to understand the neuroplastic changes brought about by the procedure.
“There is something about initiating deep brain stimulation acutely that sets the stage for later plasticity, and this is a very important way to think about the nonresponders and the mechanism,” she said. She hopes this work will begin to shed light on why, among such a select and homogenous group of patients, a substantial fraction are unresponsive.
“Obviously, placebo-controlled trials are critical” for moving forward, she said, noting that she has described phase I safety data only. She added that commercial interests have moved “prematurely” to larger clinical trials. “It's obvious there are other targets to consider,” she said. “We should remain agnostic about what the best targets are.”
THE FUTURE OF NEUROSCIENCE
“What is exciting about Dr. Mayberg's work is that it brings together issues that are timely and hot in basic neuroscience with advances in functional neurosurgery and neuroimaging, and brings them into the therapeutic purview of what we've thought of as behavioral disorders,” said John Griffin, MD, professor of neurology at Johns Hopkins University in Baltimore. “This work is the exemplar of what really is the future of all the neurosciences.”
The history of neuropsychiatry, he said, has something in common with plate tectonics. “There was one big neuropsychiatric continent in the 1900s, and then a rift valley developed,” dividing disorders with detectable brain pathology, such as Parkinson disease and Alzheimer disease, from those without it. The former became the province of neurologists, and the latter, largely comprising the behavioral disorders, fell to the psychiatrists.
“But those distinctions make no sense in modern neuroscience,” with increasing understanding of synaptic and neurotransmitter defects, as well as whole-brain network disorders such as depression appears to be. “A coming back together of these fields is inevitable,” he said.
Caution is warranted about moving too fast on DBS for depression, however. “The pressure to do definitive things of this sort is coming from patients. The problem is not to sell the procedure, but to not to use it prematurely. There is also an enormous potential for hype,” which both industry and the press are at risk for exacerbating. “But Dr. Mayberg has been exemplary in avoiding that,” he said.•