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Closed-Loop Neurostimulation for Biomarker-Driven, Personalized Treatment of Major Depressive Disorder

Published: July 7th, 2023



1Department of Neurological Surgery, University of California, San Francisco, 2Weill Institute for Neurosciences, University of California, San Francisco, 3Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, 4Department of Neurology, University of California, San Francisco

Deep brain stimulation triggered by a patient-specific neural biomarker of a high-symptom state may better control symptoms of major depressive disorder compared to continuous, open-loop stimulation. This protocol provides a workflow for identifying a patient-specific neural biomarker and controlling the delivery of therapeutic stimulation based on the identified biomarker.

Deep brain stimulation involves the administration of electrical stimulation to targeted brain regions for therapeutic benefit. In the context of major depressive disorder (MDD), most studies to date have administered continuous or open-loop stimulation with promising but mixed results. One factor contributing to these mixed results may stem from when the stimulation is applied. Stimulation administration specific to high-symptom states in a personalized and responsive manner may be more effective at reducing symptoms compared to continuous stimulation and may avoid diminished therapeutic effects related to habituation. Additionally, a lower total duration of stimulation per day is advantageous for reducing device energy consumption. This protocol describes an experimental workflow using a chronically implanted neurostimulation device to achieve closed-loop stimulation for individuals with treatment-refractory MDD. This paradigm hinges on determining a patient-specific neural biomarker that is related to states of high symptoms and programming the device detectors, such that stimulation is triggered by this read-out of symptom state. The described procedures include how to obtain neural recordings concurrent with patient symptom reports, how to use these data in a state-space model approach to differentiate low- and high-symptom states and corresponding neural features, and how to subsequently program and tune the device to deliver closed-loop stimulation therapy.

Major depressive disorder (MDD) is a neuropsychiatric disease characterized by network-level aberrant activity and connectivity1. The disease manifests a variety of symptoms that vary across individuals, fluctuate over time, and may stem from different neural circuits2,3. Approximately 30% of individuals with MDD are refractory to standard-of-care treatments4, highlighting a need for new approaches.

Deep brain stimulation (DBS) is a form of neuromodulation in which electrical current is delivered to targeted areas of the brain with the....

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This protocol has been reviewed and approved by the University of California, San Francisco Institutional Review Board.

1. Device setup for patient at-home recordings

  1. Work with a representative from the device company to set four configured channels for acquisition, two from each implanted lead.
    NOTE: Each channel records a bipolar recording. Configured channels may use adjacent (e.g., 1-2, 3-4) or interleaved (e.g., 1-3, 2-4) electrode contacts. When leads .......

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Data collected and presented here are from a single patient with four-channel leads implanted in the right orbitofrontal cortex (OFC) and the right subgenual cingulate (SGC) (Figure 1). A lead with 10 mm center-to-center pitch was used for the OFC in order to target both the medial and lateral aspects, while a lead with 3.5 mm pitch was used for the SGC in order to have more spatially concentrated coverage. Four bipolar recording channels were programmed using adjacent contacts: OFC1-OFC2, O.......

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Deep brain stimulation has become an established therapy for Parkinson's disease, essential tremor, dystonia, and epilepsy, and is actively being investigated in numerous other neuropsychiatric conditions26,27,28,29. The vast majority of DBS is delivered in open-loop mode, in which stimulation is delivered continuously. For symptoms which are paroxysmal in nature, continuous stimulation may.......

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This work was supported by the Ray and Dagmar Dolby Family Fund through the Department of Psychiatry at UCSF (KKS, ANK, NS, JF, VRR, KWS, EFC, ADK), by a National Institutes of Health award no. K23NS110962 (KWS), NARSAD Young Investigator grant from the Brain & Behavior Research Foundation (KWS), and 1907 Trailblazer Award (KWS).


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Name Company Catalog Number Comments
Depth Lead Neuropace DL-330-3.5 30 cm length, 3.5 mm contact spacing
Depth Lead Neuropace DL-330-10 30 cm length, 10 mm contact spacing
Depth Lead Neuropace DL-344-3.5 44 cm length, 3.5 mm contact spacing
Depth Lead Neuropace DL-344-10 44 cm length, 10 mm contact spacing
Hat with velcro Self-assembled NA Optional
Jupyter Notebook Project Jupyter NA
Magnet Neuropace M-01
Programmer Neuropace PGM-300 Clinician tablet
Python 3.10 Python NA
Remote Monitor Neuropace 5000 Patient laptop 
Responsive Neurostimulation System (RNS)  Neuropace RNS-320
Wand Neuropace W-02

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