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

Lateral Habenula

The lateral habenula has been proposed as a putative target for DBS; however, no human trials appear in the literature (Fig. 6).[58] Depression is associated with an increase in the activation of the lateral habenular nucleus, downregulation of monoaminergic (norepinephrine, serotonin, and dopamine) systems, and stimulation of the hypothalamic-pituitary axis.[58] From an anatomical standpoint, the habenular nuclear complex projects to the DRNs and locus ceruleus (both with projections to the medial prefrontal cortex).[16,58] In depressed rats, metabolic activity and regional cerebral blood flow in the lateral habenula are increased.[8,58] Global metabolic rates are decreased in the forebrain, and regional metabolic rates are decreased in the dorsal medial prefrontal cortex and anterior ventral nucleus of the thalamus. The administration of monoamine oxidase inhibitor antidepressants prevents the hypermetabolism found in the lateral habenula.[8,58]

Figure 6.

Diffusion tensor and stereotactic images demonstrating localization of the lateral habenula. Note the projections to and from the dorsal frontal cortices, orbitofrontal cortex, insula and mesolimbic areas, and ventral tegmentum/brainstem. Fractional anisotropy = 0.2; minimum fiber length 36 mm.

Habenular lesions attenuate the rise of serotonin in the DRNs under stressful conditions (leading to decreased serotonin in the DRNs projection areas via negative feedback), a process that could otherwise lead to depression.[58] When the lateral habenula is inhibited by electrical stimulation in rats, norepinephrine in the hippocampus/prefrontal cortex increases, as does serotonin in the striatal circuits (independent of DRNs control).[16,58] High-frequency stimulation attenuates the rise of serotonin in the DRNs, which would lead to higher serotonin levels in projection areas.[16,58] In a study by Yang et al.,[71] depressed rats were lesioned in the lateral habenula, which resulted in decreased behavioral measures of depression (less immobility time during forced swimming) as well as lower levels of serotonin in the DRN by microdialysis. Thus, functional inhibition of this area using high-frequency DBS may have therapeutic benefit.

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