Synaptic Mechanisms of Continuous Theta Burst Stimulation in Depression

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 we 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, we 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. We 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.

Eligibility

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
* Moderate to severe Major Depressive Disorder as indicated by the Patient Health Questionnaire or Quick Inventory of Depressive Symptomatology

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, baclofen, memantine, or lorazepam

Conditions2

Interventions4

Locations1 site

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