Individualized fMRI-guided TMS for Depression

This double-blind, randomized, sham-controlled clinical trial will investigate engagement and modulation of brain circuitry involving the subgenual anterior cingulate cortex (sgACC) using individualized resting-state functional magnetic resonance imaging (fMRI)-guided transcranial magnetic stimulation (TMS) in adults with depression.

Following screening, participants will undergo a baseline MRI session that includes structural, diffusion, and resting-state imaging. Resting-state functional connectivity will be used to identify individualized cortical stimulation targets that are positively and negatively connected with the sgACC. Participants will also complete baseline clinical assessments, questionnaires, and cognitive testing.

Before the 6-week intervention, participants will undergo a TMS/fMRI session to measure sgACC responses to stimulation. Single-pulse TMS will be delivered to three sites: an individualized target positively connected with the sgACC, an individualized target negatively connected with the sgACC, and a vertex control site. TMS/fMRI data will also be collected before and after brief intermittent theta burst stimulation (iTBS) to the positively and negatively connected targets. These procedures will be used to evaluate whether sgACC responses before treatment are associated with subsequent improvement in depressive symptoms.

Participants will then be randomized in a 1:1 ratio to receive active or sham iTBS delivered to the individualized positively connected sgACC target every weekday for 6 weeks (30 sessions). Sham procedures will be designed to resemble active stimulation without delivering the intended therapeutic magnetic stimulation to the targeted brain circuit.

The TMS/fMRI procedures will be repeated after approximately 3 weeks of treatment and again following the 6-week intervention. Changes in TMS-evoked sgACC responses over the course of treatment will be evaluated in relation to changes in depressive symptoms and compared between the active and sham groups to assess modulation of the targeted brain circuit.

Clinical assessments and questionnaires will be conducted throughout the study to evaluate depressive symptoms and related clinical outcomes. The Montgomery-Åsberg Depression Rating Scale (MADRS) will serve as the primary measure of depression severity, and the Patient Health Questionnaire-9 (PHQ-9) will serve as a secondary measure. Participants will also complete the NIH Toolbox Cognition Battery before and after the 6-week intervention to assess cognitive functioning and explore relationships between cognitive performance, clinical outcomes, and neuroimaging measures.

Participants will complete remote follow-up assessments at 1, 6, and 12 months after completion of the blinded intervention. After the 1-month follow-up, participants assigned to sham who continue to have clinically significant depressive symptoms and meet study eligibility criteria may be offered an optional open-label active TMS intervention. Data from the open-label phase will be analyzed separately from the randomized sham-controlled phase.

Inclusion criteria

In order to participate in this study, potential participants must meet all of the following eligibility criteria:

• 18-65 years old
• DSM-5 diagnosis of major depressive (at least 90%) or persistent depressive disorder (no more than 10%) as per SCID clinical interview.
• PHQ-9 score = or > than 10 (to maintain minimal severity of symptoms in the MDD sample)
• Comprehension of instructions in the English language.
• Capacity to provide informed consent and follow study procedures.
• Availability for the duration of the study.

Exclusion criteria

Any individual who meets any of the following criteria at the time of enrollment will be excluded from participation:

• Implanted medical devices, metallic implants, or drug infusion pumps that are not MRI-safe (e.g., aneurysm clips, defibrillators, or cochlear implants)
• History of significant medical events (e.g., stroke, seizures, brain scarring) or neurological/neurodevelopmental conditions (e.g., epilepsy) that are contraindications for TMS and MRI or may adversely affect brain function and data interpretation.
• Current psychosis, mania, or substance use disorder
• Prior failed response to full rTMS or ECT/MST trial. Any successful prior treatments are acceptable and support a prognosis that a new rTMS treatment would be worth attempting.
• Inability to complete an MRI scan (e.g., claustrophobia, inability to remain still for extended periods).
• Inability to tolerate TMS administration
• Significant handicaps that would interfere with testing procedures
• Acute systemic infection, high fever
• Acute sleep deprivation or medication/substance intoxication or withdrawal (TMS seizure risk)
• Current use of cyclosporine, tacrolimus, or others that can cause leukoencephalopathy.
• Pregnancy
• Dialysis
• Suicide attempt in past 6 months (safety precaution); similarly, if ideation is particularly pronounced, Drs. Oathes and Sheline will decide with the patient whether the benefit of participating in a sham controlled (all patients given the option to receive active treatment eventually) study outweighs the risks. If the patient has a mental health provider and acquiesces, consultation with the provider will also be instrumental in this decision.
• Current use of Bupropion (Wellbutrin) above 300 mg, benzodiazepines, lithium, monoamine oxidase inhibitors (MAOIs), and/or high doses of stimulant medication is exclusionary. Note: Exclusionary dosages or medications may be reduced or discontinued under the supervision of a medical provider. For detailed information please refer to section 5.3.1.
• Transportation limits or physical limits to attending daily M-F treatment sessions.
• Per study physician discretion medications likely to interfere with blood flow or otherwise compromise functional imaging measures.
• Any other factor that in the investigators' judgment may affect patient safety or compliance (e.g. distance greater than 100 miles from procedure site; unlikely to be able to schedule daily treatment sessions, etc.)

Study Participation Expectations

During this study, participants will be asked to:

• Refrain from substance use (including marijuana and illicit drugs) for the duration of the study (self-attestation alone)
• Abstain from alcohol for 24 hours before study visits (self-attestation alone)
• Maintain a consistent level of caffeine consumption throughout the study period and avoid any significant increases (self-attestation).
• Not initiate, discontinue, or adjust any psychiatric medications or therapy treatments during the study period.
• Inform the study team of any new medical treatments or prescribed medications (e.g., antibiotics) to allow for safety review and determination of continued eligibility for the study.

Participants who do not follow these considerations will be evaluated on a case-by-case basis. Principal Investigator will determine if study withdrawal is appropriate.