Mental disorders are a leading cause of disability, morbidity, and mortality among civilian and military populations. Most available treatments have limited efficacy, particularly in disorders where symptoms vary over relatively short time scales. Targeted modulation of neural circuits, particularly through open-loop deep brain stimulation (DBS), showed initial promise but has failed in blinded clinical trials. We propose a new approach, based on targeting neural circuits linked to functional domains that cut across diagnoses. Through that framework, which includes measurement of patients using six psychophysical tasks, we seek to develop a closed-loop DBS system that corrects dysfunctional activity in brain circuits underlying those domains. We present convergent preliminary evidence from functional neuroimaging, invasive human electrophysiology, and human brain stimulation experiments suggesting that this approach is feasible. Using the Emotional Conflict Resolution (ECR) task as an example, we show that emotion-related networks can be identified and modulated in individual patients. Invasive and non-invasive methodologies both identify a network between prefrontal cortex, cingulate cortex, insula, and amygdala. Further, stimulation in cingulate and amygdala changes patients' performance in ways that are linked to the task's emotional content. We present preliminary statistical models that predict this change and allow us to track it at a single-trial level. As these diagnostic and modeling strategies are refined and embodied in an implantable device, they offer the prospect of a new approach to psychiatric treatment and its accompanying neuroscience.

Deep brain stimulation (DBS) is a circuit-oriented treatment for mental disorders. Unfortunately, even well-conducted psychiatric DBS clinical trials have yielded inconsistent symptom relief, in part because DBS’ mechanism(s) of action are unclear. One clue to those mechanisms may lie in the efficacy of ventral internal capsule/ventral striatum (VCVS) DBS in both major depression (MDD) and obsessive-compulsive disorder (OCD). MDD and OCD both involve deficits in cognitive control. Cognitive control depends on prefrontal cortex (PFC) regions that project into the VCVS. Here, we show that VCVS DBS’ effect is explained in part by enhancement of PFC-driven cognitive control. DBS improves human subjects’ performance on a cognitive control task and increases theta (5–8Hz) oscillations in both medial and lateral PFC. The theta increase predicts subjects’ clinical outcomes. Our results suggest a possible mechanistic approach to DBS therapy, based on tuning stimulation to optimize these neurophysiologic phenomena.

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