Synaptic Mechanisms of Continuous Theta Burst Stimulation in Depression

Major depressive disorder (MDD) affects an estimated 280 million people worldwide, and a substantial proportion do not respond adequately to first-line pharmacological treatments. Continuous theta-burst stimulation (cTBS) is a widely used form of repetitive transcranial magnetic stimulation (rTMS) that quiets targeted brain networks, and holds particular promise for patients who are not well-served by conventional excitatory TMS protocols due to safety or tolerability concerns. Despite its common clinical use, the synaptic mechanisms by which cTBS works remain poorly characterized, limiting systematic efforts to improve its efficacy.

Two mechanistic hypotheses have been proposed. The first is that cTBS induces LTD-like synaptic depression through NMDA receptor (NMDAR)-dependent mechanisms, analogous to the low-frequency stimulation protocols that produce AMPA receptor internalization and synapse weakening in animal models. Evidence for this comes from studies in the healthy motor cortex demonstrating that cTBS-induced corticomotor inhibition is blocked by NMDAR antagonists. The second hypothesis is that cTBS works through GABA receptor-mediated inhibition, either via GABA-A receptors reducing signal propagation through membrane hyperpolarization, or GABA-B receptors suppressing presynaptic neurotransmitter release. Whether GABAergic mechanisms contribute to cTBS effects has not been directly tested, and these hypotheses are not mutually exclusive.

Critically, all prior mechanistic evidence comes from the motor cortex in healthy volunteers. The dorsolateral prefrontal cortex (dlPFC), the clinical target for depression, differs substantially from motor cortex in anatomy, interindividual variability, and plasticity. Depression itself is associated with reduced synaptic plasticity, including reduced expression of NMDAR subunits and synapse-related genes in postmortem prefrontal tissue. Whether cTBS mechanism established in healthy motor cortex translates to the depressed dlPFC cannot be assumed, and has not been tested. Furthermore, whether cTBS-induced inhibition can be pharmacologically enhanced remains entirely unexplored.

This study uses a randomized, double-blind, placebo-controlled crossover design to directly test NMDAR- and GABA receptor-mediated contributions to cTBS-induced plasticity in the dlPFC of individuals with MDD. Participants are assigned to one of two parallel aims. Aim 1 tests glutamatergic mechanisms: participants complete four visits receiving cTBS paired with placebo, d-cycloserine (DCS), or memantine (MEM), with two placebo visits. Aim 2 tests GABAergic mechanisms: participants complete four visits receiving cTBS paired with placebo, lorazepam (LZP), or baclofen (BAC). All drugs are FDA-approved and administered as single oral doses timed to peak plasma concentration approximately two hours prior to cTBS.

TMS-EEG provides the primary measurement approach. TMS-evoked potentials (TEPs) are scalp-recorded electrical responses to individual TMS pulses that reflect summated excitatory and inhibitory postsynaptic activity from stimulated neuronal populations. Characteristic peaks are named by polarity and latency: P30 and P60 reflect glutamatergic excitatory transmission, N45 reflects GABA-A-mediated inhibitory tone, and N100 reflects GABA-B-mediated inhibitory tone. Up to 200 single TMS pulses are delivered per TEP session at the individualized dlPFC target. TEPs are acquired at several timepoints each visit. cTBS consists of 600 pulses delivered at 80% of resting motor threshold.