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

Nucleus Accumbens and Ventral Striatum

The reward circuitry of the ventral striatum and NAC has been associated with drug addiction and depression for many years (Fig. 2).[30,42,45,66] Changes in dopaminergic receptor densities in this region have been associated with inescapable stress and learned helplessness.[33] In mouse models, genetic predisposition may inhibit the metabolism and release of dopamine in the NAC under stressful conditions, providing a susceptibility to learned helplessness and thus depression.[70] In models of hypercortisolism-induced depression, high levels of cortisol have been associated with dopamine attenuation in the NAC.[49] Furthermore, empirical data obtained during TMS have suggested that increased mesolimbic dopamine within the NAC (as well as other structures) may contribute to successful neuromodulation for depression.[26,72] The NAC is also involved in processing affective stimuli and has a potential role in depression, according to functional MR imaging studies.[42]

Figure 2.

Diffusion tensor and stereotactic images showing localization of the ventral striatum/NAC. Note the projections to and from the ventral tegmentum, brainstem, orbitofrontal cortex, insula, cingulate cortex, and mesolimbic structures. Fractional anisotropy = 0.2; minimum fiber length 36 mm.

From a neuroanatomical perspective, the NAC and ventral striatum receive projections mainly from the anterior cingulate cortex, agranular insular cortex, and orbitofrontal cortex. Whereas the core of the NAC receives input from all of these areas, the shell receives input mainly from the subgenual and pregenual cingulate cortices.[31] The NAC and ventral striatum then project to the dorsomedial nucleus of the thalamus by way of the ventral tegmental area, ventral pallidum, and substantia nigra—which in turn projects back to the prefrontal cortex, orbitofrontal cortex, anterior cingulate cortex, amygdala, and hypothalamus; this forms the limbic loop of the basal ganglia.[31,59] The association of the NAC with areas intimately involved in depression makes it a practical candidate for neuromodulation.

In 2004 Aouizerate et al.[1] reported their first case of DBS in the ventral caudate in a patient suffering from intractable obsessive-compulsive disorder and concomitant major depression (the depression did respond to medical therapy). The patient underwent bilateral electrode implantation so that the deepest contacts were located in the NAC, and the superficial contacts in the ventromedial caudate. The tip of the right electrode was located 3 mm below the AC-PC line, 36.5 mm anterior to the PC, and 8.9 mm lateral to the AC-PC line; the left electrode was located 31.4 mm anterior to the PC line and 7.6 mm lateral and 1.7 mm below the AC-PC line. Stimulation of the bilateral NAC and ventral caudate at 130 Hz resulted in significant relief from depression and anxiety, until a remission at 6 months. Global function improved and neuropsychological scores were unaffected. Unfortunately, the psychiatric comorbidity in this patient and medication-responsive nature of the depression limit extrapolation of these data to patients with TRD only.

In a recently published report, Schlaepfer et al.[59] have described bilateral implantation in the shell and core of the NAC in 3 patients with TRD. The coordinates used were as follows: 1.5 mm rostral to the AC and 4 mm ventral and 7-8 mm lateral to the midline of the third ventricle. When all of the patients received continuous stimulation at 145 Hz, they showed continual improvement in scores for anhedonia and depression (without any negative side effects) and worse scores when the stimulator was turned off. Furthermore, PET studies performed before and during stimulation demonstrated a significant increase in the metabolism of the bilateral ventral striatum, bilateral dorsolateral and dorsomedial prefrontal cortices, cingulate cortex, and bilateral amygdala after 1 week of therapy. Metabolism of the ventral and ventrolateral medial prefrontal cortex, shown in previous studies to be hyperactive in depression, was decreased.[7] Complete remission of depression was not achieved, but the clinical follow-up was 23 weeks in 1 patient and 5-7 weeks in the other 2. Regardless, neuromodulation of the ventral caudate and/or NAC appears to be safe and efficacious.

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