Targeted electrode-based modulation of neural circuits for depression

During the last 20 years of neuroscience research, we have witnessed a fundamental shift in the conceptualization of psychiatric disorders, with the dominant psychological and neurochemical theories of the past now complemented by a growing emphasis on developmental, genetic, molecular, and brain circuit models.Facilitating this evolving paradigm shift has been the growing contribution of functional neuroimaging, which provides a versatile platform to characterize brain circuit dysfunction underlying specific syndromes as well as changes associated with their successful treatment.Discussed here are converging imaging findings that established a rationale for testing a targeted neuromodulation strategy, deep brain stimulation, for treatment-resistant major depression.Depression affects at least 10% of the world population and is a leading cause of worldwide disability (1).Major depressive disorder (MDD) is clinically defined as a multidimensional syndrome, involving disruption of mood, cognition, sensorimotor functions, and homeostatic/drive functions (including those that control sleep, appetite, and libido).While depression can be treated in many cases with either medication or an evidence-based psychotherapy, remission rates in controlled trials using currently available treatments rarely exceed 30%, and relapse is the rule rather than the exception (2).For many patients, combinations of multiple medications and electroconvulsive therapy (ECT) are required.For those who remain severely depressed despite these aggressive approaches, new strategies are needed (3).This Review describes the development and testing of a new interventional strategy, deep brain stimulation (DBS), directed at this group of patients who are otherwise resistant to treatment.Critical to the development of DBS as a new treatment for intractable MDD has been the evolving understanding of the brain circuits that mediate normal and abnormal mood states and the systematic characterization of changes in these circuits that accompany successful and unsuccessful response to various treatments, measured using functional imaging (reviewed in refs.4-8).Based on brain circuit models of depression derived primarily from PET scan measures of glucose metabolism and blood flow, the first region of the brain to be targeted with DBS in patients with treatment-resistant depression (TRD) was the subcallosal cingulate (SCC), the ventral-most segment of the cingulate gyrus (Figure 1).As detailed in the following sections, this region of the brain was considered a critical node within a putative mood regulatory circuit, as it showed the most consistent changes in metabolism and blood flow with clinical recovery, using various well-established antidepressant interventions (9).As such, it was hypothesized that direct stimulation of the SCC and adjacent

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