Synaptic Mechanisms of Intermittent Theta Burst Stimulation for Major Depressive Disorder

Major depressive disorder (MDD) affects an estimated 280 million people worldwide. Approximately one-third of patients do not respond adequately to first-line treatments, a population referred to as having treatment-resistant depression (TRD). Intermittent theta burst stimulation (iTBS) is an FDA-cleared form of repetitive transcranial magnetic stimulation (rTMS) for TRD, but roughly one-third of TRD patients do not respond and another one-third do not achieve full remission. Progress in improving iTBS outcomes is most likely to come from a better understanding of its underlying mechanism of action. iTBS is hypothesized to produce clinical effects through long-term potentiation (LTP), a process by which repeated stimulation strengthens synaptic connections between neurons. LTP depends critically on N-methyl-D-aspartate receptors (NMDARs). Evidence for this mechanism comes primarily from animal studies and from studies of the motor cortex in healthy human volunteers, where cortical excitability changes can be measured using motor-evoked potentials (MEPs) detected by electromyography. These studies have demonstrated that high-frequency rTMS produces LTP-like effects that are enhanced by NMDAR agonism and blocked by NMDAR antagonism. However, the relevance of motor cortex findings to the dorsolateral prefrontal cortex (dlPFC) - the clinical target for depression treatment - has not been directly tested. The motor cortex and dlPFC differ substantially in anatomy and interindividual variability. Depression itself is associated with reduced synaptic plasticity, as evidenced by neuropsychological, structural, and molecular findings including reduced expression of NMDAR subunits and synapse-related genes in postmortem prefrontal tissue. Whether LTP-like mechanisms established in the healthy motor cortex translate to the depressed dlPFC cannot be assumed. The principal investigator's laboratory has produced relevant foundational work. Prior studies demonstrated that the NMDAR partial agonist d-cycloserine (DCS) enhances rTMS-induced LTP-like plasticity in the healthy motor cortex, and that the NMDAR antagonist dextromethorphan (DXM) blocks these effects. A separate randomized clinical trial found that augmenting iTBS with DCS more than doubled remission rates in MDD relative to iTBS plus placebo. A motor cortex study further found that DCS normalized iTBS-induced plasticity in depressed patients, who otherwise showed blunted responses relative to healthy controls, suggesting a plasticity deficit in depression that NMDAR agonism can partially rescue. TMS-EEG now allows cortical excitability to be measured outside the motor cortex. TMS-evoked potentials (TEPs) are scalp-recorded electrical responses to individual TMS pulses, reflecting summated excitatory and inhibitory postsynaptic potentials from stimulated neuronal populations. Characteristic peaks are named by polarity and latency: positive peaks (P30, P60) are thought to reflect glutamatergic excitatory transmission, while negative peaks (N45, N100) reflect GABAergic inhibitory tone. The P30 peak is the primary outcome measure for this study based on its high correlation with MEP amplitude, its sensitivity to iTBS, and its established reduction by AMPA receptor blockade, consistent with the AMPA receptor upregulation that characterizes LTP. No prior study has combined receptor-modulating pharmacology with rTMS to directly test the synaptic mechanism of iTBS in the dlPFC. This is a two-phase study. Phase 1 is a within-subject crossover design in both healthy volunteers and participants with MDD, in which each participant completes 4 visits receiving different combinations of active or sham iTBS and oral study medication (placebo, DCS 100 mg, or DXM 150 mg) in randomized counterbalanced order, separated by at least one week. TMS-EEG is used to measure dlPFC excitability before drug administration, after drug administration but before iTBS, and immediately after iTBS. This phase tests whether NMDAR activity is necessary and sufficient for iTBS-induced plasticity in the dlPFC, and compares plasticity responses between healthy and depressed participants. Phase 2 is a parallel-group design restricted to MDD participants who completed Phase 1, in which participants receive 30 daily weekday iTBS sessions combined with once-daily administration of a single blinded study drug (placebo, DCS 100 mg, or DXM 150 mg). Weekly TMS-EEG assessments track longitudinal change in dlPFC excitability over the treatment course. Phase 2 is considered exploratory. DCS at 100 mg acts as a partial agonist at the glycine co-agonist site of the NMDA receptor, facilitating NMDAR-mediated synaptic transmission. It reaches near-peak plasma levels within 1-2 hours of oral administration. DXM at 150 mg produces brain concentrations consistent with NMDA receptor blockade in vitro and has been shown in prior studies to block the plasticity after-effects of iTBS, cTBS, tDCS, and other rTMS paradigms. All study medications are dispensed by the McLean Research Pharmacy in blinded, identical capsules. TMS is delivered using the Nexstim NBS-6 Research System and/or the MagVenture MagPro X100, both FDA-cleared devices with integrated EEG, EMG, and real-time neuronavigation. Individual structural MRI obtained prior to study visits is used for neuronavigation-guided dlPFC targeting and EEG source localization. Resting-state fMRI is collected to enable exploratory post-hoc comparisons of functional connectivity with TEP-measured plasticity.