Individualized (fMRI-guided) TMS Intervention for Post-Traumatic Stress Disorder (PTSD)

This double-blind, randomized, sham-controlled clinical trial will investigate engagement and modulation of amygdala-related brain circuitry using individualized resting-state functional magnetic resonance imaging (fMRI)-guided transcranial magnetic stimulation (TMS) in adults with posttraumatic stress disorder (PTSD).

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 an individualized cortical stimulation target within the ventrolateral prefrontal cortex (vlPFC) that is positively connected with the basolateral amygdala.

Before the 6-week intervention, participants will undergo a TMS/fMRI session to evaluate whether stimulation of the individualized target engages the amygdala. Single-pulse TMS will be delivered to three sites: the individualized amygdala-connected target, an individualized cortical control target with minimal functional connectivity to the amygdala, and a vertex control site. Amygdala blood oxygen level-dependent (BOLD) responses during TMS will be measured to assess target engagement and determine whether amygdala responses differ across stimulation sites.

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

Psychophysiological assessments will be conducted before, during, and after the intervention to evaluate fear learning, extinction, and extinction retention. During these tasks, physiological responses to fear-related stimuli will be measured. Following the 6-week intervention, participants will undergo a second TMS/fMRI session using the same stimulation targets and procedures as the pre-intervention session. Changes in amygdala responses from pre- to post-intervention will be compared between the active and sham groups to evaluate modulation of the targeted brain circuit.

Clinical assessments, questionnaires, and cognitive testing will also be conducted throughout the study. Participants will complete remote follow-up assessments at 1, 6, and 12 months after their last TMS intervention session. After the 1-month follow-up, participants assigned to sham will be unblinded and may be offered an optional open-label active TMS intervention if they continue to have clinically significant PTSD symptoms and meet study eligibility criteria.

Inclusion criteria

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

• 18-65 years old
• Current diagnosis of PTSD based on Diagnostic and Statistical Manual of Mental Disorders-5 criteria, as assessed by the Clinician-Administered PTSD Scale-5.
• Patient Health Questionnaire (PHQ-9) score = or > than 10
• 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 substance use disorder.
• History of a psychotic or bipolar disorder, including manic or hypomanic episodes.
• Prior failed response to full rTMS or Electroconvulsive Therapy (ECT)/Magnetic Seizure Therapy (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.
• 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.)

DURING STUDY REQUIREMENTS

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.