# Mechanistic circuit markers of transcranial magnetic stimulation outcomes in pharmacoresistant depression

> **NIH NIH R01** · STANFORD UNIVERSITY · 2021 · $659,708

## Abstract

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PROJECT SUMMARY/ABSTRACT
Despite the wide scale adoption of repetitive transcranial magnetic stimulation (rTMS, hereafter simply TMS),
we still lack mechanistically-driven biomarkers designed to identify who is most likely to respond, and why.
rTMS is indicated for pharmacoresistant depression. It is imperative that we find more precise solutions for these
patients given that pharmacoresistant depression can be life threatening: suicide attempts are twice the rate of
non-resistant depression. Our objective is to use a prospective design to evaluate cognitive control network
connectivity as a predictive biomarker of the clinical effect of repetitive transcranial magnetic stimulation, and as
a response biomarker of change with TMS. We have a novel opportunity to address this objective through a
systematic evaluation of brain network biomarkers in 100 patients taking part in a Veterans Administration multi-
site clinical TMS program. By utilizing the umbrella Clinical rTMS Program, we can standardize delivered
parameters to ensure uniformity. Our primary biomarker is functional connectivity of the cognitive control
network of the human brain that is central to the regulation of thought and emotion. We will also assess
corresponding behavioral performance. Clinical outcomes are symptom severity, suicidality, and quality of life.
Biomarkers will be assessed at baseline, after 5 sessions of rTMS (“low dose”) to explore mechanisms of early
response, and upon completion of treatment after 30 sessions (“higher dose”). To power the study for an
anticipated conservative effect size of at least .25, we will recruit 100 patients participating in the VA Clinical
TMS Program. Using standardized stimulation parameters and harmonized neuroimaging procedures, our aims
are to 1) probe the putative mechanistic effect of rTMS on promoting cognitive control and to assess whether
connectivity of the cognitive control network changes in a dose-dependent manner, 2) to assess whether extent
of change in cognitive control network connectivity predicts corresponding change in behavioral performance
and, 3) to identify if baseline functional connectivity and behavior, along with early change in connectivity and
behavior, predict subsequent outcomes in symptom severity, suicidal ideation, and quality of life. Innovations
of our design include 1) adequate power to interrogate imaging markers, 2) standardization to minimize
variability, 3) implementation of a longitudinal design to quantify rTMS-related changes in imaging markers, 4)
integration of task-evoked and resting state imaging markers and, and 5) establishing the foundations for
expanding lessons learned to additional diagnoses and parameters.
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## Key facts

- **NIH application ID:** 10166947
- **Project number:** 5R01MH120126-03
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Leanne Williams
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $659,708
- **Award type:** 5
- **Project period:** 2019-09-10 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10166947

## Citation

> US National Institutes of Health, RePORTER application 10166947, Mechanistic circuit markers of transcranial magnetic stimulation outcomes in pharmacoresistant depression (5R01MH120126-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10166947. Licensed CC0.

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