http://dana.org/news/features/detail.aspx?id=37186


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."

-----------------------

To change your mail settings or leave the C-PALSY list, go here:

http://listserv.icors.org/SCRIPTS/WA-ICORS.EXE?SUBED1=c-palsy