Many people with depression do not get better with standard treatments like medications or talk therapy. Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation treatment that uses magnetic pulses to stimulate areas of the brain involved in depression. One form of TMS called intermittent theta burst stimulation (iTBS) is FDA-cleared for depression and takes only 3 minutes to deliver. However, about one-third of patients do not respond to iTBS, and another one-third do not reach full remission. Improving iTBS requires a better understanding of how it works in the brain.

iTBS is thought to work by strengthening connections between brain cells, a process called synaptic plasticity. This process depends on a type of brain receptor called the NMDA receptor. Most of what researchers know about how iTBS affects these connections comes from studies of healthy people. It is not known whether iTBS works the same way in the prefrontal cortex - the brain region targeted during depression treatment - or in people who actually have depression.

This study has two phases.

In Phase 1, both healthy volunteers and people with depression will complete 4 research visits to test how iTBS changes brain activity in the prefrontal cortex and whether medications that increase or decrease NMDA receptor activity change those effects. Each visit involves active or sham (inactive) iTBS combined with one of three study medications: a placebo (inactive pill), d-cycloserine (a medication that increases NMDA receptor activity), or dextromethorphan (a medication that decreases NMDA receptor activity). Brain activity is measured before and after each TMS session using electroencephalography (EEG), a painless test that records electrical signals from the scalp through a cap placed on the head. All participants also complete a brain MRI before beginning study visits for targeting purposes.

In Phase 2, participants with depression will be offered a standard clinical course of 30 daily iTBS sessions (Monday through Friday over 6 weeks). Each session is combined with one blinded study medication (placebo, d-cycloserine, or dextromethorphan) taken daily. Brain activity measurements and standard depression and anxiety questionnaires are collected weekly throughout this phase to track how the brain changes over the course of treatment and whether those changes relate to improvements in symptoms.

Together, the two phases of this study aim to identify the brain mechanism by which iTBS works in people with depression. This knowledge could lead to more effective TMS treatments for people who have not responded to medications or other therapies.

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.

Inclusion Criteria:

• Can safely receive TMS and study drugs
• Stable medication regimen for one month prior to study participation, and for the duration of the study
• Not currently receiving TMS, ECT, or ketamine
• No active safety concerns related to suicidality

Exclusion Criteria:

• History of seizures or epilepsy
• History of intracranial pathology or lesions from any etiology
• History of traumatic brain injury including prolonged loss of consciousness more than 15 min
• Signs of increased intracranial pressure
• Any major neurological conditions (ex: recent stroke, tumor, neurodegenerative disorders, etc.)
• Major medical conditions that may cause a medical emergency in case of a provoked seizure (cardiac malformation, cardiac dysrhythmia, asthma, etc.)
• Severe migraines that may result in treatment intolerance.
• Inability to tolerate MRI.
• Pregnancy
• Known allergic reaction to d-cycloserine or dextromenthorphan

De-identified individual participant data will be shared through the National Institute of Mental Health Data Archive (NDA) in accordance with NIMH data sharing expectations. Data to be shared will include demographic information, clinical scale scores, and TMS-EEG outcome data. Data will be submitted to the NDA following standard de-identification procedures and will be made available to qualified researchers through the NDA data access request process.

Data will be submitted to the NDA within 1 year of primary study completion or upon publication of primary results, whichever comes first.

Data will be accessible to qualified researchers through the NIMH Data Archive data access request process.