Potential Surgical Targets For Deep Brain Stimulation In Treatment-Resistant Depression

Jason S. Hauptman, MD; Antonio A. F. DeSalles, MD, PhD; Randall Espinoza, MD, MPH; Mark Sedrak, MD; Warren Ishida, MD

Disclosures

Neurosurg Focus. 2008;25(1):E3 

In This Article

Subgenual Cingulate Cortex: Area 25

The subgenual cingulate cortex, as discussed in the previous section, has critical projections to and from the ventral striatum, NAC shell, and limbic cortical loop (Fig. 3). The orbitofrontal, dorsomedial prefrontal, dorsolateral pre-frontal, and dorsal cingulate cortices have reciprocal connections to the subgenual cingulate cortex according to tracer studies. This area also has reciprocal connections with the centromedial amygdala, bed nucleus of the stria terminalis, hypothalamus, and serotonergic regions of the DRNs and periaqueductal gray; these reciprocal connections support the notion that the subgenual cingulate is involved in visceromotor and vegetative physiology.[31] These connections have been confirmed using diffusion tractography in humans.[24,60]

Figure 3.

Diffusion tensor and stereotactic images demonstrating localization of the subgenual cingulate cortex. Note the projections to and from the striatum, dorsal frontal cortices, and orbitofrontal cortices. Fractional anisotropy = 0.2; minimum fiber length 36 mm.

Early work by Mayberg et al.[39] has demonstrated the integral role played by the subgenual cingulate cortex in both normal and pathological shifts in mood. Increases in limbic and paralimbic blood flow (as measured using PET) occur in the subgenual cingulate cortex and anterior insula during sadness; there is a significant inverse correlation between blood flow in the subgenual cingulate cortex and right dorsolateral prefrontal cortex.[34,39] This inverse correlation has been confirmed by quantitative cytochrome oxidase histo-chemistry in rodent models.[61] A clinical response to antidepressants is associated with limbic and striatal (subgenual cingulate cortex, hippocampus, insula, and pallidum) decreases in metabolism and dorsal cortical (prefrontal, parietal, anterior, and posterior cingulate cortex) increases in metabolism.[13,38] Furthermore, abnormalities in the subgenual cingulate volume and cytoarchitecture have also been noted in patients with familial affective disorders.[5,19] High-frequency repetitive TMS of the dorsolateral prefrontal cortex has been correlated with SPECT-demonstrated changes in the ipsilateral subgenual cingulate cortex and striatum, further underscoring their anatomical and metabolic connectivity. These data suggest that functional inhibition of the subgenual cingulate cortex by using DBS mimics or enhances the metabolic effects of antidepressant therapy.

In 2005 Mayberg et al.[40] implanted DBS electrodes in the bilateral subgenual cingulate cortex in 6 patients with TRD. Blinded, sequential intraoperative stimulation at 130 Hz was applied to discover the thresholds for safe and effective stimulation. When stimulation was on, patients reported positive emotional phenomena, with psychomotor slowing and lightheadedness occurring on stimulation above the 7-V threshold. In the acute postoperative period patients experienced reproducible increases in activity and mood scores, changes that failed to occur during sham stimulation. Chronic stimulation at 130 Hz resulted in a significant response and remission of depression in 4 of the 6 patients at 6 months; in the 2 remaining patients, 1 experienced a significant reduction in depression over the first 4 months that fluctuated over time and remained submaximal, and the other patient had no response. Furthermore, the stimulation benefit seemed to continue for 3-4 weeks after stimulation was ended until depression recurred. Positron emission tomography studies performed in the responders corresponded to the antidepressant effects noted earlier by Mayberg et al.[38]—that is, a decrease in limbic and striatal cerebral blood flow and an increase in dorsal cortical regions. Postoperative neuropsychological testing showed improvement in many preoperatively deficient areas and no impairment in orbitofrontal functioning. In this small series, the subgenual cingulate cortex was a stimulation target with potentially high efficacy and low risks, although further work is necessary to identify anatomical or physiological risk factors for unresponsiveness to therapy.

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