"Cortical Stimulation" for Depression

The last decade saw a number of new experimental treatments for depression based around the idea of using electricity to alter brain function - deep brain stimulation (DBS), vagus nerve stimulation (VNS), and transcranial magnetic stimulation (TMS).

The mechanics of these technologies differ, but they're all being promoted as options for "treatment-resistant depression" - depression which hasn't responded to more conventional approaches. They're also alike in that their usefulness is uncertain - either because there have been no randomized-controlled trials (DBS), or because the results of randomized trials are mixed at best (TMS,VNS).

Now there's a new kid on the neurostimulatory block: epidural prefrontal cortical stimulation (EpCS). This involves implanting electrodes beneath the skull, but above the meninges, the "skin" surrounding the brain. So it's unlike deep brain stimulation (DBS), in which the electrodes are placed inside the brain itself.

Late last year, Nahas et al reported on EpCS in a paper, Bilateral Epidural Prefrontal Cortical Stimulation for Treatment-Resistant Depression. They took 5 severely depressed patients, with either major depression or bipolar disorder, who'd all tried many treatments and experienced no benefit:

The mean age was 44.2 years. Four were women, and three were diagnosed with recurrent major depressive disorder; two others had bipolar affective disorder I, depressed type. All were unemployed, and three were receiving disability. The average length of depressive illness was 25.6 years. The average length of the current depressive episode was 3 years, 7 months ... participants had received an average of 9.8 unsuccessful clinical treatments during the current major depressive episode ... They enrolled in the study taking on average 6 psychotropic drugs.

Electrodes were implanted bilaterally over the "anterior and midlateral frontal cortex". This is as sensible a place to stimulate as any, although we really don't know what these parts of the brain do, or how they relate to depression. Nor do we know what "60 Hz, 2–4 V, 30 min on/ 2.5 hours off from 8 AM to 10 PM." stimulation does to these areas.

2 weeks after surgery the electricity was turned on, and the stimulation was then optimized over 2-3 weeks. Did it work? Out of the 5 patients, one didn't get any better, two felt somewhat better, and two were greatly improved at the end of the study 7 months post-op. And there were no major side effects or cognitive changes; one patient got a bacterial infection, but it was treatable. Hurrah!

But hang on. There was no control group, so the improvement could have been due to the placebo effect or, more likely, the passage of time. The guy with the single best response, Subject 2, was as depressed as ever during the first 4 months, but then improved dramatically by month 7. It may not be a coincidence that this subject was bipolar. Bipolar people who are depressed eventually stop being depressed - that's kind of the point.

Indeed, all of the others who improved did so between 2 weeks and 4 months after the stimulation was started, not straight away. So it's not like flicking a switch and turning off the depression... but on the other hand it's exactly that if you listen to what the patients say during the operation itself.

They reported feeling happier and less anxious as soon as the current was turned on (they weren't told when this was, so this is unlikely to have been a placebo effect). Some said things like

“I feel attentive,” “feel better and I can talk now,” “I can think clearer.” A patient noted during anterior frontal pole stimulation feeling as if a “weight [was] lifting off my shoulder,” “I feel calm”; another stated, “and although I am worried, I feel
dissociated from it. I can think back at my worry.”

Subject 2, the guy who got much better a long time after the operation, was the only patient who didn't enjoy any nice effects during the operation itself, which only adds to my suspicions that he would have got better anyway.

What does all this mean? It's hard to say. The results are very similar to those seen with DBS for depression - patients report suddenly feeling happier as soon as the current is turned on during the operation (the only placebo-controlled aspect of the trials), but afterwards the improvement seems gradual, taking weeks or months.

There's two main ways of interpreting this. The optimistic view is that stimulating the right bits of the brain instantly treats depression, and the apparent "time lag" in improvement after the operation is a product of the fact that when someone's been depressed for so long, as these patients have, it takes time for them to readjust to normal life even once they start feeling much better.

The pessimistic view is that stimulating the brain doesn't treat depression, it just causes a "high" which doesn't last very long, and the subsequent slow, gradual improvement would have happened anyway.

This is why we need randomized controlled trials. Nahas et al note that there has been one randomized controlled trial of EpCS for depression, comparing active EpCS to placebo EpCS with the electrodes switched off. It hasn't been published yet, but a preliminary analysis found no difference between the two conditions - it didn't work. And that trial was more than twice as big as this one (12 patients vs. 5). But, they point out, in that trial only the left side of the brain was stimulated, whereas they stimulated both sides.

Overall, just like DBS, EpCS could be either a great leap forward or a waste of time, money and neurosurgery. Hopefully, by the end of this decade, we'll know. Watch this space.

Links: Dr Shock covered this paper when it came out.

Nahas, Z., Anderson, B., Borckardt, J., Arana, A., George, M., Reeves, S., & Takacs, I. (2010). Bilateral Epidural Prefrontal Cortical Stimulation for Treatment-Resistant Depression Biological Psychiatry, 67 (2), 101-109 DOI: 10.1016/j.biopsych.2009.08.021