# Responsive Neurostimulation for Treatment Resistant Depression

> **NIH NIH UH3** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $1,759,693

## Abstract

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.

## Key facts

- **NIH application ID:** 10513243
- **Project number:** 1UH3NS123310-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** ANDREW D KRYSTAL
- **Activity code:** UH3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $1,759,693
- **Award type:** 1
- **Project period:** 2023-06-15 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10513243

## Citation

> US National Institutes of Health, RePORTER application 10513243, Responsive Neurostimulation for Treatment Resistant Depression (1UH3NS123310-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10513243. Licensed CC0.

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