NAcc Localization for DBS

The topographical location of the nucleus accumbens in relation to other brain structures on a horizontal plane 3 mm below the AC-PC plane (Schlaepfer et al., 2007).

As the previous post discussed, the nucleus accumbens (NAcc) is an experimental target for deep brain stimulation in severe forms of depression that have failed to respond to other treatments such as psychotherapy, antidepressants (and other drugs), and the ever-controversial electroconvulsive therapy, or ECT [see current edit wars at Wikipedia].

Position of deep brain stimulation electrodes

The location of the lowest contact of the stimulation electrode in a horizontal and coronal plane with projections of the left (green) and right (yellow) electrode path in the surgical planning stage. Stereotaxic coordinates are 1.5 mm rostral to the anterior edge of the anterior commissure, measured at the crossing point, 4 mm ventral and 7–8 mm lateral of the midline of the third ventricle. Burr holes were placed deep fronto laterally (Schlaepfer et al., 2007).

Theoretical motivations behind the procedure:

We believe that DBS to the ventral striatum, and in particular, the nucleus accumbens, will be a promising and efficacious treatment of severe depression. Our hypothesis is based on three lines of reasoning: (1) the ventral striatum is heavily implicated in both normal and abnormal reward processes, (2) the nucleus accumbens acts as a 'motivation gateway' between limbic systems involved in emotion and systems involved in motor control, and (3) the ventral striatum is uniquely located to modulate activity in other regions of the brain.

The case histories of the three patients included in the trial are predictably, well, depressing in their inability to obtain relief from any other form of treatment:

Patient 01 is a 66-year-old woman suffering from major depression since age 21. The current depression episode was her sixth, and lasted for 17 months. During the current episode, the patient failed seven antidepressant medication trials, and augmentation with five different neuroleptics also failed. The patient did not respond to both an adequate trial of psychotherapy and 13 treatments of bilateral ECT. At study entry the patient was severely depressed, with a Hamilton Depression scale (HDRS24) score of 38. At study entry she was treated with 90 mg duloxetine, 1 mg risperidone, 10 mg diazepam, 75 mg L-thyroxin, and 75 mg melperone.

Patient 02 is a 37-year-old unemployed university graduate (economics). The current episode was his second, and began 9 years ago. Seventeen different antidepressant medication treatments have failed, as did augmentation with five neuroleptics and lithium. The patient had four courses of unsuccessful ECT treatments with at least 10 treatment sessions (twice unilateral, twice bilateral), and psychotherapy was tried, again to no avail. At study entry he was treated with 50 mg quietapine and 75 mg amitryptiline.

Patient 03 is the 37-year-old monozygotic twin brother of patient 02; unipolar major depression had developed in both patients in almost exactly the same way at the same time, he had the same professional education and current state as his brother. His current episode began 11 years ago, and this patient has been unsuccessfully treated with at least eight antidepressant medications, and augmentation with at least three neuroleptics and with lithium failed. The patient had two ECT treatment courses (one unilateral and one bilateral), comprising 10 and 15 treatment sessions, respectively, with no success, and psychotherapy also failed. ... At study entry they were severely depressed (HDRS24 score of 31 and 32). At study entry he was treated with 50 mg quietapine, 150 mg amitryptiline, and 75 mg L-thyroxin.

The stimulator was turned on and off in a double-blind fashion, and...

Clinical ratings improved in all three patients when the stimulator was on, and worsened in all three patients when the stimulator was turned off. These effects were immediate and bi-directional (eg when the stimulator was turned off, depression ratings immediately worsened, and when the stimulator was turned on, depression ratings immediately improved).

The figure to the left shows that each patients' score on depression rating scales, MADRAS (Montgomery-Åsberg Depression Rating Scale) and HDRS24 (Hamilton Depression Rating Scale, 24-item version) -- shown in red and green lines, respectively -- fell when the stimulator was on (shown in purple line and indicated by gray shading).

Finally, PET imaging was performed before and after stimulation to examine which brain areas responded to the treatment. Predictably, after one week of stimulation, greater blood flow was observed in the NAcc. Metabolism also increased in dorsolateral and dorsomedial prefrontal cortex and in the amygdala [?? - which one might expect is overactive already in depression; see Drevets, 1999] but decreased in ventrolateral and ventromedial prefrontal cortex, caudate, and thalamus.

Caveats? Limitations?

These findings should be taken as very preliminary at the clinical level. We certainly do not suggest that DBS to the nucleus accumbens is a 'magic bullet' procedure that will cure depression.

References

Drevets WC. (1999). Prefrontal cortical-amygdalar metabolism in major depression. Ann NY Acad Sci. 877:614-37.

Schlaepfer TE, Cohen MX, Frick C, Kosel M, Brodesser D, Axmacher N, Joe AY, Kreft M, Lenartz D, Sturm V. Deep Brain Stimulation to Reward Circuitry Alleviates Anhedonia in Refractory Major Depression. Neuropsychopharmacology 2007 Apr 11; [Epub ahead of print]