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DBS in Major Depression
Mechanistic Understanding
Depression is a common disorder affecting as many as 30 million Americans. Moreover, from 20% to 50% of depressed patients eventually fail standard pharmacotherapy. Recent advances in treatment, including DBS, have yielded insights into the pathophysiology of this disorder.
Depression is now viewed as a disorder arising from abnormal communications among systems of limbiccortical pathways. Various methods, including neuroimaging, lesion studies, clinical trials, neuronal recordings, and postmortem autopsies have contributed to our understanding of the neural networks underpinning mood disorders. Anatomical structures across the brain are implicated, including the amygdala, ventromedial prefrontal cortex, orbitofrontal cortex, subgenual and pregenual anterior cingulate cortex, posterior cingulate cortex, ventral striatum, pallidum, medial thalamus, hypothalamus, and brainstem. Deep brain stimulation has itself provided a remarkable opportunity to study cortical areas implicated in depression. One recent study of single neuron recordings in the subgenual cingulate cortex (SCC) showed that certain populations of neurons are specific for emotional category. The authors defined 5 emotional categories (disturbing, sad, neutral, happy, and exhilarating) to represent different combinations of high or low valence and arousal. While some neurons responded only to valence or to arousal levels, others responded to 1 specific emotional category. Moreover, a majority of sampled neurons responded selectively to negative emotions, suggesting that SCC targeting in depression may inhibit this negatively prone bias. Another study, this time in the ventromedial prefrontal cortex, found coherent activation in low β-band (15–20 Hz) frequencies just prior to patients' passing a negative affective judgment in ambiguous (neutral valence) cases. The authors concluded that coherent β-band activation reflects ventromedial prefrontal cortex communication to downstream targets, suggesting that abnormal ventromedial prefrontal cortex β coherence could play a role in the negative affective bias or indecisiveness experienced by depressed patents. Further study will be required to know if modulation of β activity, as in PD, is a therapeutic mechanism of DBS in this region. Another study of frontal activity showed that increases in frontal θ coherence were positively correlated with better clinical response to SCC DBS at 6 months. As illustrated by this example, a better understanding of circuit abnormalities could aid in developing control signals for SCC stimulation and in providing mechanistic insights.
The field of optogenetics is also contributing to our understanding of depression neurocircuitry through the use of animal models of depression. One study employed an optogenetic 100-Hz burst stimulation on the medial prefrontal cortex in a mouse model of depression, resulting in a reversal of symptoms. Optogenetics has also been used to explore the role of dopaminergic signaling in depression. Using optogenetic probes, phasic activation of ventral tegmental area neurons projecting to the nucleus accumbens promoted a depression-like phenotype in mice, whereas stimulation of medial prefrontal cortex–projecting cells was associated with resilience to the depressed phenotype. Further efforts will be required to harness this knowledge of the relevant circuitry to improve treatment options.
Current Practice
All current targets of stimulation for the treatment of depression are still under investigation. The SCC, and specifically Brodmann area 25 (Cg25) within the SCC, has emerged as one of the leading targets for stimulation, and several series have demonstrated promising results. Unfortunately, all data from this target are currently from open-label trials, and there are reports of mixed outcomes. A Phase III multicenter, randomized, sham-controlled trial is underway, with a goal of enrolling 200 patients. This trial should help clarify outstanding questions of efficacy and patient selection. Other targets under investigation include the ventral striatum/nucleus accumbens, inferior thalamic peduncle, and habenula.
Areas of Evolving Practice
As discussed in a recent review, there is a lack of specific biomarkers for depression. Furthermore, because the clinical presentation of depression is broad and the anatomy of involved structures is diverse, it is likely that multiple different neuropathological abnormalities can manifest as depression. Further research is needed to define concrete predictors of response for different targets of stimulation in depression.
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