Synaptic Mechanisms of Continuous Theta Burst Stimulation in Depression

Study Summary

Many people with depression do not get better with standard treatments like medication. One promising alternative is transcranial magnetic stimulation (TMS), a non-invasive procedure that uses magnetic pulses to stimulate specific brain regions. A particular pattern of TMS called continuous theta-burst stimulation (cTBS) is thought to reduce overactive brain activity in depression, but the investigators do not yet fully understand how it works at the level of brain cells and connections. This study aims to determine the biological mechanism by which cTBS changes brain activity in people with depression. Specifically, the investigators are testing two competing ideas: (1) that cTBS works by weakening the connections between brain cells through a process called long-term depression (LTD), which is driven by a chemical messenger system called glutamate; or (2) that cTBS works by increasing the brain's natural "braking" system, driven by a different chemical messenger called GABA. To test these ideas, participants with depression will receive cTBS along with one of four FDA-approved medications, or placebo, that either boost or block these chemical messenger systems. The investigators will measure changes in brain activity using electroencephalography (EEG) recorded simultaneously with TMS. Specific patterns in the EEG signal, called TMS-evoked potentials (TEPs), act as a window into how different brain cell types are responding to stimulation. Each participant will complete four study visits, each testing a different drug-TMS combination in random order. One group of participants will test drugs targeting the glutamate system (d-cycloserine and memantine). A second group will test drugs targeting the GABA system (lorazepam and baclofen). All drugs are given as a single oral dose and are commonly used in clinical practice. Understanding exactly how cTBS works at a biological level could open the door to more effective, personalized TMS treatments.

Primary Outcome

Change in P30 TMS-evoked potential peak amplitude measured via simultaneous 64-channel EEG in response to single-pulse TMS delivered at the left dlPFC. P30 amplitude reflects AMPA receptor-mediated glutamatergic excitatory transmission and is the primary index of LTD-like synaptic depression induced by cTBS. Change is assessed between post-drug/pre-cTBS and post-cTBS timepoints, and relative to the sham+placebo condition.

Interventions

• DEVICE Transcranial Magnetic Stimulation Sham
• DRUG Memantine
• DRUG D-Cycloserine (DCS)
• DEVICE Continuous theta-burst stimulation (cTBS)
• DRUG Lorazepam (drug)