Responsive Neurostimulation for Treatment Resistant Depression

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PROJECT SUMMARY This UH3 application seeks to address the major public health burden of treatment-resistant major depression (trMDD) by developing a novel form of Deep Brain Stimulation (DBS). This approach is unique among recent approaches toward DBS optimization in that it incorporates individualized stimulation target location selection and a closed-loop stimulation strategy where a personalized circuit activity biomarker of the pathologic state is identified and used to trigger therapeutic stimulation only when needed. This approach is based on our conceptual model that MDD is a dynamic process in which symptoms arise when dysfunctional activity emerges in one or more brain mood-related networks. The networks affected differ among individuals leading to symptom heterogeneity. Our approach has the potential to maximize efficacy by personalizing stimulus location targeting while minimizing the stimulation needed to maintain a therapeutic effect, thereby minimizing side-effects and neural adaptation and preserving device longevity. We propose a 3-stage feasibility, safety, and initial efficacy study based on our pilot work to test this approach in 12 patients with severe trMDD. Stage 1 will involve surgical implantation of 10 intracranial EEG (iEEG) electrodes for a 10- day period of intensive inpatient monitoring for personalized site selection and biomarker discovery. Stage 2 involves implantation of a chronic DBS device (NeuroPace RNS® System) with electrodes placed in sensing and stimulation targets identified in stage 1. A biomarker-based MDD state detection algorithm is then developed and integrated into closed-loop therapy. Stage 3 consists of a randomized, double-blind, sham- controlled and active-controlled (intermittent stimulation triggered by a sham biomarker) cross-over study of the resulting individualized closed-loop DBS therapy. This research will help pave the way for approval of the NeuroPace RNS System for trMDD and, if successful, will demonstrate for the first time that personalized closed-loop DBS is a promising therapy for trMDD, justifying a larger subsequent trial. It would also demonstrate proof-of-concept for biomarker development and therapeutic target selection that could critically advance our understanding of the circuit dysfunction underlying MDD and the development of personalized closed-loop DBS for MDD and other neuropsychiatric conditions.