The Sad Cingulate

Yesterday, the New York Times magazine had an article on a new, extremely experimental treatment for depression: deep brain stimulation (DBS) in the ventral portion of the anterior cingulate cortex, in Brodmann's area 25. This procedure, which involves implanting electrodes deep into the brain, has been tested on 12 patients who failed to respond to multiple antidepressant medications and electroconvulsive therapy (8 of them responded to DBS). It works using the same sort of device used in deep brain stimulation for Parkinson's disease, which has been remarkably successful.

A preliminary report on the results was published last year in Neuron.

Deep Brain Stimulation for Treatment-Resistant Depression
Helen S. Mayberg, Andres M. Lozano, Valerie Voon, Heather E. McNeely, David Seminowicz, Clement Hamani, Jason M. Schwalb, and Sidney H. Kennedy
Neuron, Vol 45, 651-660, 03 March 2005

Treatment-resistant depression is a severely disabling disorder with no proven treatment options once multiple medications, psychotherapy, and electroconvulsive therapy have failed. Based on our preliminary observation that the subgenual cingulate region (Brodmann area 25) is metabolically overactive in treatment-resistant depression, we studied whether the application of chronic deep brain stimulation to modulate BA25 could reduce this elevated activity and produce clinical benefit in six patients with refractory depression. Chronic stimulation of white matter tracts adjacent to the subgenual cingulate gyrus was associated with a striking and sustained remission of depression in four of six patients. Antidepressant effects were associated with a marked reduction in local cerebral blood flow as well as changes in downstream limbic and cortical sites, measured using positron emission tomography. These results suggest that disrupting focal pathological activity in limbic-cortical circuits using electrical stimulation of the subgenual cingulate white matter can effectively reverse symptoms in otherwise treatment-resistant depression.

But why stimulate area 25 in depression? Previous neuroimaging studies by Mayberg and colleagues showed that this region is overactive in depression. This excessive activity is dampened in those who respond to SSRIs but remains elevated in those who don't respond to the meds:

Clinical improvement was uniquely associated with limbic and striatal decreases (subgenual cingulate, hippocampus, insula, and pallidum) and brain stem and dorsal cortical increases (prefrontal, parietal, anterior, and posterior cingulate). Failed response was associated with a persistent 1-week pattern and absence of either subgenual cingulate or prefrontal changes.

Mayberg HS, Brannan SK, Tekell JL, Silva JA, Mahurin RK, McGinnis S, Jerabek PA.
Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response.
Biol Psychiatry. 2000 Oct 15;48(8):830-43.

It's a dramatic next step to propose DBS to "turn off" area 25, but at least it's more grounded in the scientific literature than older forms of psychosurgery. Although by no means a trivial operation, DBS doesn't cause permanent damage in the manner of the old-school ablations.

However, statements like these make one a bit concerned about the ethics involved:

The expectations for the Toronto team's D.B.S. study were accordingly modest. When I later asked Mayberg's collaborator Dr. Andres Lozano, the neurosurgeon who performed the operations, what he had expected, he replied, "Nothing."

. . .

Mayberg, who speaks of a "paradigm shift," notes that she developed the trial to evaluate not a treatment but a hypothesis.

It would be really unethical to conduct a controlled treatment trial with a stimulator implanted in some other portion of the brain. The Neuron paper, however, did report on the use of "sham" stimulation (0.0 volts) in area 25 during a blinded, DBS discontinuation period (which seems a reasonable control, given the ethical considerations).

It's a good article (by David Dobbs), but as usual, someone in the popular press had to come up with a ridiculous title:

A Depression Switch?

If it were so simple!