The Good and Bad News About Deep Brain Stimulation for Treatment-Resistant Depression
Deep brain stimulation is a treatment in which electrodes are implanted in the brain to treat movement or affective disorders. At the 2014 meeting of the International College of Neuropsychopharmacology, Thomas Schlaepfer reviewed the current status of studies of deep brain stimulation for depression. The bad news is that two double-blind randomized controlled studies are no longer recruiting patients because interim analysis failed to show a benefit to the deep brain stimulation over a sham stimulation. The studies targeted two of the most promising parts of the brain for deep brain stimulation—the subgenual anterior cingulate (important for motivation) and the anterior limb of the internal capsule (which contains nerve fibers going to and from the cerebral cortex), so their failure is a disappointment. However, Helen Mayberg, one of the lead researchers studying the subgenual anterior cingulate, will continue to study this target for deep brain stimulation.
The better news is that Schlaepfer repositioned the electrodes to target a site in the medial forebrain bundle nearer to the ventral tegmental area. After this shift he observed rapid onset of antidepressant response (within two days) in seven of the first eight patients studied, and these responses persisted over many months of follow up. This response was achieved at 2.8 microamps, a lower stimulation current than was used in other studies of deep brain stimulation.
Editor’s Note: Since patients started to feel better when they were still on the operating table, this may offer an opportunity to more rapidly assess effectiveness, do a double-blind study, and see if the findings can be replicated as another mode of achieving rapid-acting and long-lasting antidepressant effects in treatment-resistant patients. Intravenous ketamine has rapid-onset antidepressant effects, but its effects are short-lived.
A New Target for Deep Brain Stimulation (DBS) for Refractory Depression
Deep brain stimulation (DBS) is a treatment for illnesses such as Parkinson’s, chronic pain, and depression. In DBS, electrodes inserted in the brain produce electrical impulses. Different anatomical parts of the brain have been targeted successfully using DBS. These include the subgenual anterior cingulate (Area 25), the nucleus accumbens, and the habenula. Now researcher Thomas E. Schlaepfer has found that inserting the n. accumbens electrode deeper and closer to the ventral tegmental area or the VTA (which contains dopamine cell bodies) produces more rapid onset of antidepressant effects (in a matter of days) in a high percentage of patients (7 out of 8 according to one of Schlaepfer’s reports). Stimulation of the nucleus accumbens in the typical location resulted in 50% improvement in 5 out of 10 patients after one year of follow-up.
Schlaepfer believes that changing the position of the electrode places it in the medial forebrain bundle (MFB), which contains fibers going from the VTA to the nucleus accumbens. Interestingly, when animals are given the opportunity to self-stimulate this area (by pressing a lever that activates an electrode placed in the area), they will, indicating it is rewarding or pleasurable. The same animals will avoid self-stimulating certain other fiber tract sites in the brain.
Schlaepfer’s research was presented at the 2013 meeting of the Society of Biological Psychiatry, and the abstract is available in the Convention Supplement to the journal Biological Psychiatry, Volume 73, Number 9S.
Deep Brain Stimulation
In the 1990s, the pioneering studies of Helen Mayberg and colleagues showed that stimulation of an area in the ventral part of the prefrontal cortex called the subgenual anterior cingulate gyrus (or Brodmann area 25, the part of the brain under the anterior corpus collosum) is associated with improvement in depression that resisted almost all other treatments. At the 65th Annual Scientific Convention of the Society of Biological Psychiatry this year, a number of research groups reported following up on Mayberg’s studies. The latest positive data on stimulation of Brodmann area 25 for treatment-resistant depression mirror new findings from other research groups who have stimulated the dopaminergic reward area of brain called the nucleus accumbens or ventral striatum with successful results.
In one of the first systematic studies intended to identify the best frequency and pulse width duration parameters for this type of intracranial stimulation in patients with treatment-resistant depression, researcher Swati Chavda of the University of Calgary reported that patients with depression improved when they were stimulated at 130 Hz (cycles/sec.) with a pulse width of 90 micro-seconds. In this double-blind study, depression neither improved nor worsened under other conditions, such as when the stimulation was turned off, when a low frequency (20 Hz) was used, or when much higher frequencies (185 Hz) with a pulse width of 420 micro-seconds were used.
Editor’s note: These data indicate that the positive effects of deep brain stimulation on clinical depression may depend on the frequencies used, with more intermediate stimulation parameters better than very high or very low ones. More clinical exploration is required in order to define optimal stimulation parameters for different brain regions. For the moment, this type of deep brain stimulation remains highly experimental, but is being pursued by a number of investigative groups in the US and Europe.
Brain Stimulation for Treatment-Resistant Depression
There are many methods of stimulating the brain directly, ranging from the very invasive to the non-invasive. Below we discuss deep brain stimulation, frontal lobe and vagal nerve stimulation, repeated transcranial magnetic stimulation, electroconvulstive therapy (in particular the new right unilateral ultra-brief pulse method), and low level magnetic fields.
- Repetitive transcranial magnetic stimulation (rTMS) is a technique for noninvasive stimulation of the adult brain. Stimulation is produced by generating a brief, high-intensity magnetic field by passing a brief electric current through a magnetic coil. Compared with the growing number of clinical trial with rTMS, there are surprisingly few animal studies on its basic mechanisms of action, constraining the ability to perform hypothesis-driven clinical studies.
This is an Open Access image distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. From: Arias-Carrión International Archives of Medicine 2008 1:2 doi:10.1186/1755-7682-1-2
Deep Brain Stimulation
At the American Psyciatric Association meeting in San Francisco in May 2009, Giacobbe et al. reported on the results of deep brain stimulation of an anterior-ventral part of the prefrontal cortex called the subgenual cingulate cortex in patients with refractory major depressive disorder. In deep brain stimulation, electrodes are inserted directly into the brain. Twenty-one patients received this treatment in an open study at sites in Canada at McGill University, the University of British Columbia, and the University of Toronto. This multi-center trial replicated results reported by Mayberg et al. (2005) with stimulation of what is also called Broadman’s area 25, or the part of the prefrontal cortex just under the anterior part of the corpus callosum (which carries fiber tracts between the left and right sides of the brain).
Read more
