Early Brainwave Biomarkers for Personalized Neuromodulation in Treatment-resistant Depression

• Personalized iTBS (Device): Intermittent theta burst stimulation delivered to the left dorsolateral prefrontal cortex using individualized pulse count (600, 1200, or 1800 pulses) and intensity (90% or 120% rMT) determined by EL-TEP screening.
• Non-Personalized iTBS (Device): Intermittent theta burst stimulation delivered to the left dorsolateral prefrontal cortex at fixed parameters: 1800 pulses, 120% resting motor threshold.
• Sham iTBS (Device): Inactive sham stimulation using a shielded coil with electrical scalp stimulation to mimic sensory experience of active iTBS.

Primary outcomes

• Percent Change in Early Local TMS-Evoked Potential (EL-TEP) Amplitude [Baseline, end of 10 iTBS sessions within a single testing day (10 hours)]: EL-TEP amplitude is the peak-to-trough amplitude of the early (20-60 ms) EEG response recorded over the left dorsolateral prefrontal cortex following single TMS pulses. Percent change is calculated from pre-iTBS to post-iTBS for each stimulation condition.

Secondary outcomes

• Acute EL-TEP Suppression Following Each Screened iTBS Condition [Baseline, end of each iTBS session during the screening phase (3 screening days, up to approximately 3 weeks)]: Percent change in EL-TEP amplitude from before to after each of the six screened iTBS parameter combinations during the screening phase.
• Trajectory of EL-TEP Change Across Multiple Sessions Within a Testing Day [Baseline, before and after sessions 1, 2, 3, and 10 within a single testing day (10 hours)]: EL-TEP amplitude measured before and after sessions 1, 2, 3, and 10 on each testing day to characterize cumulative effects.
• Change in Montgomery-Åsberg Depression Rating Scale (MADRS) Score [Baseline, end of each testing day (up to approximately 7 weeks)]: Clinician-administered scale assessing depressive symptom severity. Score range: 0-60 (higher scores indicate greater severity).
• Change in Quick Inventory of Depressive Symptomatology (QIDS) Score [Baseline, end of each testing day (up to approximately 7 weeks)]: Self-report measure of depressive symptom severity. Score range: 0-27 (higher scores indicate greater severity).
• Change in Generalized Anxiety Disorder 7-Item Scale (GAD-7) Score [Baseline, end of each testing day (up to approximately 7 weeks)]: Self-report measure of anxiety symptom severity. Score range: 0-21 (higher scores indicate greater severity).
• Change in N-Back Task Performance [Baseline, end of each testing day (up to approximately 7 weeks)]: Working memory performance assessed using the N-back task. Outcome is accuracy and reaction time.
• Change in Multi-Source Interference Task (MSIT) Performance [Baseline, end of each testing day (up to approximately 7 weeks)]: Executive function assessed using the MSIT. Outcome is accuracy and reaction time.
• Change in Affective Processing Task Performance [Baseline, end of each testing day (up to approximately 7 weeks)]: Emotional face recognition task performance. Outcome is accuracy.

Sex: All, ages: 18 Years to 65 Years

Inclusion Criteria:

* Aged 18-65 years
* Clinical diagnosis of Major Depressive Disorder (MDD), confirmed by structured clinical interview
* Current moderate-to-severe depressive episode (MADRS score ≥ 20)
* Moderate-to-severe treatment resistance, assessed using the Maudsley Staging Method
* Able to comprehend English sufficiently to complete study procedures and assessments
* Able to maintain stable antidepressant regimen or remain medication-free for at least 4 weeks prior to and during the study

Exclusion Criteria:

* Primary psychiatric diagnosis other than MDD
* Contraindications to MRI (e.g., implanted metal)
* Conditions or medications that may increase risk associated with TMS
* Prior exposure to repetitive TMS (rTMS)
* Non-response to electroconvulsive therapy (ECT)
* History of psychosurgery for depression
* High suicidal risk as assessed by the Columbia Suicide Severity Rating Scale (C-SSRS)

• Corey J Keller, MD, PhD, Principal investigator, Stanford University

NIH grants: R61MH140799