# Determining whether TMS changes the brain through brain synaptic plasticity

> **NIH NIH P20** · BUTLER HOSPITAL (PROVIDENCE, RI) · 2022 · $178,765

## Abstract

Transcranial Magnetic Stimulation (TMS) has transformed the approach to neuropsychiatric illness 
although many limitations remain. Without a mechanistic understanding of how TMS produces lasting 
therapeutic changes in the brain, advances will be serendipitous and TMS will only reach a fraction of its 
potential. There are unlimited combinations of parameters possible in TMS including stimulation intensity, 
frequency, pulse width, time on and off, patterns, and anatomic location. Moreover, the way each of these 
parameters affect the brain will change based on brain location, regional cell types, circuits and activity 
patterns specific to each disorder, and brain state will all determine outcome. It is therefore essential to 
establish the basic mechanism of TMS effects, so that the explosion of clinically-orientated, 
hypothesis-driven research will have a mechanistic rationale. 
Building on the extensive animal work in synaptic plasticity, I will bridge the basic neurobiological 
mechanisms of learning and cognition learned in my dissertation with the translational work of TMS I have 
learned during residency to address the major gap in TMS research: how does it produce lasting 
therapeutic changes in the brain? A mechanistic approach to this question remains essentially untested. I 
hypothesize that excitatory TMS (including high-frequency repetitive (r)TMS and intermittent theta-burst 
stimulation (TBS)) induces long-term potentiation (LTP), and inhibitory TMS (including low-frequency 
rTMS and continuous TBS) induces long-term depression (LTD). Both of these processes depend on 
neuronal and NMDA receptor activity, and both are under the influence of inhibitory gamma-aminobutryric 
acid (GABA) innervation. 
I propose a series of experiments in healthy human subjects combining pharmacologic manipulation of 
the LTP and LTD cascades with TMS treatment protocols to the motor cortex. Electrophysiologic 
approaches assessing motor evoked potentials (MEPs) with electromyography (EMG) will allow further 
elucidation of the contribution of glutamatergic versus GABAergic inputs, and will directly impact 
stimulation strategies. A mechanistic understanding of TMS-induced changes to the brain could unleash 
its full therapeutic potential, and thereby, transform the treatment of brain disorders.

## Key facts

- **NIH application ID:** 10545460
- **Project number:** 5P20GM130452-04
- **Recipient organization:** BUTLER HOSPITAL (PROVIDENCE, RI)
- **Principal Investigator:** Joshua C Brown
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $178,765
- **Award type:** 5
- **Project period:** 2022-02-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10545460

## Citation

> US National Institutes of Health, RePORTER application 10545460, Determining whether TMS changes the brain through brain synaptic plasticity (5P20GM130452-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10545460. Licensed CC0.

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