Investigating the Neural Mechanisms of Repetitive Brain Stimulation With Invasive and Noninvasive Electrophysiology in Humans

Transcranial magnetic stimulation (TMS) is an effective treatment for depression, but clinical outcome is suboptimal, partially because investigators are missing biologically-grounded brain markers which show that TMS is modifying activity at the intended target in the brain. The goal of this proposal is to characterize the key markers of the brain's response to repeated doses of TMS with high resolution using invasive brain recordings in humans, and relate these brain markers to noninvasive recordings. These markers will improve the understanding of TMS and can be used to optimize and enhance clinical efficacy for depression and other psychiatric disorders.

Study Overview

• Status: Recruiting
• Conditions: Epilepsy; Major Depressive Disorder
• Intervention / Treatment: Device: Intracranial electrodes; Device: TMS

Detailed Description

Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for major depressive disorder, but remission rates are 20-40%, and ideal stimulation parameters are unknown. rTMS is thought to work by changing the synaptic strength of neurons. The ability of the brain to make these changes is referred to as plasticity. rTMS-induced changes are thought to build with successive treatment sessions, a process referred to as metaplasticity. While both plasticity and metaplasticity are well-established in single cell physiology, relevance to rTMS in humans remains unknown. To improve clinical efficacy, the investigators need to understand 1) the neural response to a single rTMS session (plasticity), 2) the neural response to repeated daily rTMS sessions (metaplasticity), and 3) whether computational models of plasticity based on single-cell physiology apply to human patients receiving rTMS for depression.

Goals of the study are to 1) establish a detailed mechanistic understanding of the brain changes during current rTMS treatment; 2) identify clinically meaningful electrophysiological biomarkers for rTMS treatment; 3) establish a computational model to help predict both brain and clinical changes.

• Study Type: Interventional
• Enrollment (Estimated): 49
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Jade Truong; Phone Number: (408) 840-3313; Email: kellerlab@stanford.edu

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Recruiting
      • Stanford University
      • Contact: Jade Truong; Email: kellerlab@stanford.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Men and women, ages 18 to 65
• Medication-refractory epilepsy requiring phase II monitoring
• Must have intellectual capacity to ensure adequate comprehension of the study and potential risks involved in order to provide informed consent
• No current or history of major neurological disorders other than epilepsy

Exclusion Criteria:

• Those with a contraindication for MRIs (e.g. implanted metal)
• Any unstable medical condition
• Neurological or uncontrolled medical disease
• Active substance abuse
• Currently pregnant or breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: TBS via direct electrical stimulation	Device: Intracranial electrodes; Intracranial electrodes will be used for the delivery of invasive brain stimulation.
Active Comparator: TBS via transcranial magnetic stimulation	Device: TMS; TMS will be used for the delivery of noninvasive brain stimulation both before and after implantation electrode surgery.
Sham Comparator: Sham TBS via direct electrical stimulation	Device: Intracranial electrodes; Intracranial electrodes will be used for the delivery of invasive brain stimulation.
Sham Comparator: Sham TBS via transcranial magnetic stimulation	Device: TMS; TMS will be used for the delivery of noninvasive brain stimulation both before and after implantation electrode surgery.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
TMS-iEEG change after one TBS session	Change in evoked response measured after a single TBS session for active and sham, by resting state iEEG (intracranial EEG) and/or sEEG (stereo EEG).	45 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ES-iEEG change after one TBS session	Change in evoked response measured after a single TBS session for active and sham, by resting state iEEG and/or sEEG.	45 minutes
ES-iEEG change between two sequential TBS sessions	Change in single-pulse evoked response, or cortico-cortical evoked potentials (CCEPs), measured between two sequential TBS sessions, by resting state iEEG and/or sEEG.	45 minutes
TMS-iEEG change between two sequential TBS sessions	Change in single-pulse evoked response, or cortico-cortical evoked potentials (CCEPs), measured between two sequential TBS sessions, by resting state iEEG and/or sEEG.	45 minutes

Collaborators and Investigators

• Sponsor: Stanford University
• Collaborators: National Institute of Mental Health (NIMH); Massachusetts General Hospital; University of Iowa

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2023
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: July 18, 2023
• First Submitted That Met QC Criteria: August 9, 2023
• First Posted (Actual): August 18, 2023

Study Record Updates

• Last Update Posted (Actual): March 12, 2026
• Last Update Submitted That Met QC Criteria: March 10, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Mood Disorders; Depressive Disorder; Depressive Disorder, Major; Epilepsy
• Other Study ID Numbers: 11354-1; 1R01MH132074 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No