Electroconvulsive Therapy Seems to Stem Excess Connectivity

by Tom Valeo

April 23, 2012

After 70 years, researchers may have figured out how electroconvulsive therapy (ECT) works. With this knowledge, they may be closer to finding a replacement therapy that relieves depression without producing memory problems.

A team at the University of Aberdeen in Scotland has found that ECT quells excessive connectivity with the dorsolateral prefrontal cortex (dlPFC) located behind the top left side of the forehead. To detect this difference the researchers performed functional magnetic resonance imaging (fMRI) on 9 people with severe depression, measuring blood flow in 27,000 voxels (tiny cubes of brain tissue). Presumably, when blood flow increases in two areas simultaneously, those areas are connected.

The patients then received ECT, and were scanned again. Using an intensive mathematical comparison of the two scans, researchers found the biggest change by far involved connections to and from the dlPFC.

“I was skeptical we’d find anything at all, or rather, I expected we’d find lots of changes, since ECT is a treatment that affects many brain regions,” said Ian Reid, a professor at University of Aberdeen and lead author of the study, which appeared in the March 19 issue of the Proceedings of the National Academy of Science (PNAS). “We thought it would be difficult to make any sense out of what we would see, so we were very surprised to find that the impact of ECT was very specific in terms of the reduction of connectivity it produced.”

Reid and his colleagues had reason to suspect the dlPFC would be involved because of the recent findings of Yvette Sheline, a professor at Washington University School of Medicine in St. Louis. In 2010 Sheline and her colleagues performed brain scans on 18 depressed patients and detected a pattern of hyperconnectivity between three widely scattered brain networks: the “affective network,” which regulates emotional responses; the “cognitive control network,” which enables the reasoning ability and judgment characteristic of human thought; and the “default mode network,” which increases its activity when the mind is wandering and the brain is not engaged in a specific cognitive task.

Sheline dubbed these three areas the “dorsal nexus.” In the healthy brain, the three areas play nicely together. In people with depression, however, patterns of hyperconnectivity develop, and cause certain brain areas become over-active, which may contribute to the rumination, emotional intensity, and concentration difficulties characteristic of the disorder.

“We have found that the networks responsible for introspection and emotional reactivity can get overly connected,” Sheline said. “For example, instead of doing a math problem you contemplate over and over again the mistakes you’ve made on past math problems, and dwell on that. Having overly connected networks that 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.”

Andrew Leuchter at UCLA’s Semel Institute for Neuroscience and Human Behavior has produced similar evidence. He and his colleagues analyzed brain networks using quantitative EEG, which uses sensors attached to the scalp to pick up electrical activity in the brain. By measuring the energy and the synchronization of the signals they detected a pattern of diffuse hyperconnectivity in people with depression, in the same regions identified by Sheline and the Scottish researchers.

“Areas of the brain—particularly the prefrontal cortex—were excessively synchronized,” Leuchter said. “A series of articles have suggested that the rhythmic oscillations of brain electrical activity may play a crucial regulatory role in brain function.”

Leuchter  agrees with Sheline and the Scottish researchers that the connections among brain areas seem to play a broad role in mental health.

“We know that normal intellectual function, normal mood regulation, and normal cognitive processing all depend on our ability to recruit brain areas to work in synchrony,” he said. “If the ability to regulate connectivity is disrupted we may see host of consequences ranging from deficient mood regulation, aberrant thinking, hallucinations, cognitive deficits—the list goes on and on.”

Provoking seizures to improve health

The idea of provoking a seizure in hopes of restoring normal mental function was applied first to schizophrenia, not depression. On January 2, 1934, Laszlo Meduna, a 38-year-old Hungarian psychiatrist, injected a solution containing 20 percent camphor into 6 severely schizophrenic patients at the Royal Hungarian State Psychiatric Institute in Budapest. They failed to develop seizures, so the next day he doubled the dose and tried again. Three of the patients developed seizures, and two actually improved, which supported Meduna’s hypothesis that seizures would somehow suppress the symptoms of schizophrenia. In 1935 he published a paper modestly titled, “An attempt to influence the course of schizophrenia by biologic means.”

Ugo Cerletti, a physician in Rome, picked up the idea. While watching pigs knocked unconscious by electroshock before slaughter he got the idea of using electroshock to induce seizures in patients with schizophrenia. After all, people with epilepsy appeared to be immune to schizophrenia, Cerletti said, so causing seizures in schizophrenics should help to alleviate their symptoms.

Cerletti first used ECT on a person with schizophrenia in April 1938, in collaboration with another physician, Lucio Bini. They claimed the patient’s symptoms disappeared, and the two men were nominated several times for a Nobel Prize.

The grand mal seizures induced by ECT has made the treatment appear barbaric to many. “One Flew Over the Cuckoo’s Nest”—both the 1962 novel by Ken Kesey and the 1975 movie starring Jack Nicholson –effectively equated ECT to torture. Yet, the treatment does alleviate depression in the vast majority of cases it is indicated for, so ECT has continued to be used, even increasing in frequency since the 1980s. A preliminary draft of the Surgeon General’s Report on Mental Health, released in 1999, caused an uproar by characterizing ECT as “a safe and effective treatment for depression,” and recommended it for “select groups of patients with severe depression, particularly those with associated active suicidal ideation, psychosis, or catatonia.” The use of anesthesia and muscle relaxants also minimized the grimacing and violent spasms of the grand mal seizure induced by ECT.

However, the memory problems caused by ECT, which includeboth the loss of existing memories and difficulty forming new memories, remain a serious drawback that has resisted all efforts at remedy. Harold Sackeim, a professor with the College of Physicians and Surgeons of Columbia University, has spent his career investigating ways to reduce the memory problems while maintaining the benefits of seizure therapy. He has tried placing electrodes on one side of the head only, delivering electricity to small areas of the prefrontal cortex, and using magnetic instead of electrical stimulation, but nothing seems to be as effective at treating depression as traditional ECT.

That’s why Sackeim, although intrigued by the explanation of ECT’s effectiveness provided by the Scottish researchers, remains skeptical that it would lead to an alternative treatment any time soon.

“Ultimately the goal would be to mimic the effects of ECT with a treatment that is more convenient, and that carries less risk, and the hope is that such a treatment will emerge when we understand the mechanism of action, but we’re very far from that,” Sackeim said. “The reality is, no treatment we have today comes anywhere near the efficacy of ECT.”