How does deep brain stimulation work?

s p t s D eep brain stimulation (DBS) presents the promise of effective treatment for central nervous system disorders that are resistant to other available treatments. Deep brain stimulation has been reported to be effective in Parkinson’s disease, essential tremor, pain syndromes, and medication resistant obsessivecompulsive disorder (OCD). Deep brain stimulation has also been reported to exert a remarkably large antidepressant effect in openlabel, single blind lead-in, and long-term follow-up studies, even in patients in whom aggressive medication strategies and electroconvulsive therapy have failed (1). This is notable, given the expected low placebo response in such refractory patients. However, expectancy of benefit from invasive procedures such as DBS can be high, and the results of a sham-controlled randomized trial have yet to be published, although a large-scale trial is presently underway. Amidst the excitement about this exciting treatment that permits the translation of knowledge with regard to pathological circuits into a focal therapeutic circuit modulation, there looms a vexing and as yet unanswered question: How does it work? If indeed DBS for depression is more effective than other available treatments and is able to achieve remission when all else has failed, then answering this question of mechanism is of great importance to advancing understanding of the causes of severe neuropsychiatric disorders and could shed light on their effective treatment and, hopefully, ultimately their cure. Historical explanatory models for the mechanism of action of DBS for depression as a virtual lesion have since been replaced with a more nuanced understanding of the impact of patterned electrical stimulation on neurocircuit functioning. For example, computational modeling of the impact of electric fields on subcompartments of neurons suggests that, dependent upon neuronal orientation relative to the field and intensity of stimulation, soma might be hyperpolarized whereas axons might be depolarized, resulting in a decoupling of cell body and axonal effects (2). This might in part explain observations of local inhibition coupled with increased axonal firing in response to DBS. Mechanisms of action of DBS can be approached from multiple levels of analysis (molecular, cellular, and circuit), each of which can be expected to be important to a comprehensive understanding of how DBS exerts its clinical effects. At the cellular level, attention has been mostly focused on neuronal effects (local neurons, afferent inputs, and fibers of passage), but recent reports suggest that glia might also play a role. At the circuit level, consideration has been paid mostly to the topography of effects on connected brain regions within distributed mood regulatory networks, as revealed via diffusion tensor tractography (3). Recent work in Parkinson’s disease DBS mechanisms has emphasized not just the spatial topography of circuit effects but also the temporal components of circuit