The goal of this clinical trial is to learn how transcranial magnetic stimulation (TMS) affects brain circuits involving the amygdala in adults with posttraumatic stress disorder (PTSD). The main questions it aims to answer are: * Can MRI-guided TMS engage the amygdala by stimulating an individualized brain target connected to the amygdala? * Does stimulation of this individualized target engage the amygdala differently than stimulation of control sites? * Does a 6-week course of active TMS, compared with sham TMS, change amygdala responses and physiological responses to fear? Researchers will compare active TMS with sham TMS to evaluate changes in the targeted brain circuit and fear-related responses. Participants will: * Receive active or sham TMS every weekday for 6 weeks * Undergo MRI scans with TMS before and after the 6-week intervention to measure brain responses to stimulation * Participate in fear learning and memory tasks while physiological responses are measured * Undergo additional MRI scans, clinical assessments, questionnaires, and cognitive testing * Complete remote follow-up assessments at 1, 6, and 12 months after the intervention
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
DOUBLE
Enrollment
60
The TMS intervention will involve two sets of intermittent theta-burst stimulation (iTBS) delivered every weekday for 6 weeks (30 sessions). Each iTBS set consists of 40 trains and 1,200 pulses, for a total of 2,400 pulses per treatment session. The two iTBS sets will be separated by approximately 5 minutes and delivered to the individualized amygdala-connected cortical target using MRI-guided neuronavigation.
The sham TMS intervention will follow the same treatment schedule and session structure as active TMS. Sham stimulation will be delivered using the shielded side of the TMS coil together with synchronized scalp electrical stimulation to mimic the sensation of active TMS without delivering the intended magnetic stimulation to the targeted brain region.
Average amygdala blood-oxygen-level-dependent (BOLD) signal change following single-pulse fMRI-guided TMS (TMS On vs. TMS Off) to the individualized amygdala-connected target.
This primary endpoint compares amygdala BOLD signal during TMS On and TMS Off conditions, averaging across participants, providing a direct assessment of average amygdala engagement during fMRI-guided TMS. The change in BOLD signal observed in this comparison is defined as the amygdala-evoked response. This endpoint addresses the lack of mechanistic knowledge regarding amygdala engagement in PTSD when using individualized resting-state fMRI connectivity to guide TMS targeting.
Time frame: Single visit (~2 hours)
Difference in average amygdala-evoked response from TMS stimulation to fMRI-guided sites versus TMS stimulation of control sites.
This secondary endpoint provides further mechanistic knowledge regarding amygdala engagement in PTSD when using individualized resting-state fMRI connectivity to guide TMS targeting by comparing the effectiveness of the fMRI-guided targeting to stimulation of a control site that is not expected to evoke a response in the amygdala.
Time frame: Single visit (~2 hours)
(1) Difference in amygdala-evoked response from pre-treatment to post-treatment between active rTMS and sham; (2) difference in psychophysiological measures of fear extinction retention between active repetitive TMS (rTMS) and sham.
This secondary endpoint evaluates whether repeated stimulation of an individualized amygdala-connected cortical target is associated with measurable changes in amygdala responsivity following treatment relative to a sham rTMS condition. Differential changes in the amygdala-evoked response between active and sham rTMS would provide evidence that the targeted cortico-amygdala circuit can be modulated with rTMS. Fear extinction retention measures will serve as a complementary physiological index of treatment-related changes in fear-processing circuits relative to sham.
Time frame: Up to 7 weeks
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