Electroconvulsive therapy (ECT) has been found effective for treating refractory, severe depression. But what is the brain mechanism at work? In a March 19 online edition of the Proceedings of the National Academy of Sciences (PNAS), a team of Scottish investigators proposed that the therapy provides long-lasting relief by altering hyperconnectivity between the left dorsolateral prefrontal cortex (dlPFC) and other brain regions.
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Using mathematical analysis of fMRI data from nine depressed patients before and after ECT, the researchers determined that functional connectivity — a measure of information flow between brain regions — decreased in and around the dlPFC after treatment. Further analysis revealed that ECT significantly reduced functional connectivity between the dlPFC and the anterior cingulate, the medial prefrontal cortex, and other areas implicated in major depression. The decrease in functional connectivity was accompanied by a significant decrease in depressive symptoms, with scores on the Montgomery Asberg Depression Rating Scale dropping from a mean score of 36.4, indicating severe depression, to 10.7, which is at the low end of mild depression.
“When we set out to do this I was skeptical,” said lead author Ian Reid, PhD, professor of mental health and clinical lead for psychiatry at the University of Aberdeen, and chair of the Royal College of Psychiatry's Special Committee on ECT. “We thought it would be difficult to make any sense out of what we would see because ECT affects many brain regions, so we were very surprised to find that the impact of ECT was very highly restricted in terms of reduction of connectivity, and very anatomically specific.”
Harold A. Sackeim, PhD, professor of psychiatry and radiology in the College of Physicians and Surgeons of Columbia University, who was not involved with the study, expressed skepticism about the findings, however.
“Virtually every new method of investigating the brain that's applied to ECT produces some consistent findings, but the question is always, how relevant is it to the therapeutic process?” said Dr. Sackeim, a founding editor of the journal Brain Stimulation, and former chief of the department of biological psychiatry at the New York State Psychiatric Institute. “This paper basically says two things: we have this effect on the brain, and people got better. It implies a linkage between the two, but there's no evidence in this paper, based on only nine patients, that there is any relationship to the clinical outcome.”
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Dr. Reid emphasized that the effect he and his colleagues found emerged very distinctly from an intensive analysis of fMRI measures of blood-oxygen increases in 27,000 voxels.
“We didn't choose the dorsolateral prefrontal cortex as an area of interest,” he said. “I expected to see a blizzard of changes across the cortex, but an undirected analysis of the activity of every voxel with every other voxel in the brain pointed directly to an area of the brain that's clearly implicated in depression. The strength of the study was that there was no predetermination of the area we were interested in.”
Dr. Sackeim, who has pioneered other ways to deliver ECT that produce the same therapeutic benefits without the accompanying memory problems, also suspects that the role of the left dorsolateral prefrontal cortex that emerged from the statistical analysis may be the result of the bilateral ECT that the nine patients received.
“Delivering ECT on the right side of the head only reduces or even eliminates almost all physiologic effects in the left hemisphere, so the centrality of the change on the left side is probably an artifact of their method,” he said. “ECT produces dramatic decreases in blood flow, glucose metabolism and other functional activity in the brain, so claiming that a change in one area is responsible for the therapeutic effect is difficult. I'm not surprised by the findings. They certainly indicate an effect on prefrontal function, but it may well be a function of the marked reduction in functional activity in those regions.”
The role found for the dlPFC, however, corresponds with recent findings reported by Yvette Sheline, MD, director of the Center for Depression, Stress and Neuroimaging, and professor of psychiatry, radiology, and neurology at Washington University School of Medicine.
She was the lead author of a 2010 paper in the PNAS that reported increased connectivity in depressed patients across three brain networks, including one encompassing the dlPFC, intersecting in an area dubbed the dorsal nexus.
The dorsal nexus includes the default mode network, the cognitive control network (which includes the dlPFC), and the affective network, so increased connectivity could potentially contribute to the major symptoms of depression, according to Dr. Sheline. The findings of the Scottish researchers lend credence to that possibility.
“We have found increased connectivity across networks responsible for introspection, emotional reactivity, and remembering the past,” she said. “This new study is saying that overly connected networks may be one of the ways in which depression takes hold and prevents the person from getting out of the mental rut they're in. It's a small study — only nine people — but carefully done by good group, and it's an important study because it provides a plausible mechanism about how ECT works.”
Dr. Sheline and her colleagues plan on investigating how cognitive behavioral therapy affects hyperconnectivity across networks.
Another team of researchers using quantitative EEG, which measures synchronization of brain waves, has also detected hyperconnectivity in depressed patients, according to study results reported in the February 2012 issue of PLoS One.
“We found a pattern of diffuse hyperconnectivity in depressed patients,” said lead author Andrew F. Leuchter, MD, professor in the department of psychiatry and biobehavioral science and director of the Laboratory of Brain, Behavior, and Pharmacology, and senior research scientist at the Semel Institute for Neuroscience and Human Behavior at the University of California, Los Angeles. “Areas of the brain — particularly the prefrontal cortex — were excessively synchronized in terms of connections with other brain regions.”
The “hub nodes” most often involved in the increased connectivity were located in the frontopolar and dlPFC — a finding that coincides with the work of Dr. Sheline and other researchers, the authors point out.
Dr. Leuchter believes his EEG data coincides with the fMRI data produced by the Scottish researchers. “In fact, the BOLD signal you pick up with fMRI may be regulated by electrical oscillations of the brain,” he said. “Brain oscillatory activity and fMRI may be two sides of same coin.”
That's why he believes the recent findings may have far-reaching implications not just for major depression, but for an array of disorders.
“The brain is a massively distributed network, and oscillatory activity represents the glue that holds cognitive and emotional processes together,” he said. “That's what allows us to have an integrated sense of the world around us. We know normal intellectual function, normal mood regulation, and normal cognitive processing all depend on our ability to recruit brain areas to work in synchrony, and to suppress certain areas so that others can become activated. If the ability to regulate connectivity is disrupted we can see a host of manifestations ranging from deficient mood regulation, aberrant thinking, hallucinations, cognitive — the list goes on and on.”
• Perrin JS, Merzb S, Schwarzbauer C, et al. Electroconvulsive therapy reduces frontal cortical connectivity in severe depressive disorder. Proc Natl Acad Sci 2012; E-pub 2012 March 19.
• Sheline YI, Price JL, Yan Z, Mintun MA. Resting-state functional MRI in depression unmasks increased connectivity between networks via the dorsal nexus. Proc Natl Acad Sci
• Leuchter AF, Cook IA, Horvath S, et al. Resting-state quantitative electroencephalography reveals increased neurophysiologic connectivity in depression. PLoS One