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

August 26, 2026 updated by: Desmond Oathes, University of Pennsylvania

Engaging the Amygdala With Brain Stimulation for PTSD

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

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Not yet recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

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

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
60

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

INCLUSION CRITERIA

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

  1. 18-65 years old
  2. Current diagnosis of PTSD based on Diagnostic and Statistical Manual of Mental Disorders-5 criteria, as assessed by the Clinician-Administered PTSD Scale-5.
  3. Patient Health Questionnaire (PHQ-9) score = or > than 10
  4. Comprehension of instructions in the English language.
  5. Capacity to provide informed consent and follow study procedures.
  6. 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:

  1. Implanted medical devices, metallic implants, or drug infusion pumps that are not MRI-safe (e.g., aneurysm clips, defibrillators, or cochlear implants)
  2. 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.
  3. Current substance use disorder.
  4. History of a psychotic or bipolar disorder, including manic or hypomanic episodes.
  5. 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.
  6. Inability to complete an MRI scan (e.g., claustrophobia, inability to remain still for extended periods).
  7. Inability to tolerate TMS administration
  8. Significant handicaps that would interfere with testing procedures
  9. Acute systemic infection, high fever
  10. Acute sleep deprivation or medication/substance intoxication or withdrawal (TMS seizure risk)
  11. Current use of cyclosporine, tacrolimus, or others that can cause leukoencephalopathy.
  12. Pregnancy
  13. Dialysis
  14. 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.
  15. 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.
  16. Transportation limits or physical limits to attending daily M-F treatment sessions.
  17. Per study physician discretion medications likely to interfere with blood flow or otherwise compromise functional imaging measures.
  18. 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:

  1. Refrain from substance use (including marijuana and illicit drugs) for the duration of the study (self-attestation alone)
  2. Abstain from alcohol for 24 hours before study visits (self-attestation alone)
  3. Maintain a consistent level of caffeine consumption throughout the study period and avoid any significant increases (self-attestation).
  4. Not initiate, discontinue, or adjust any psychiatric medications or therapy treatments during the study period.
  5. 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Active iTBS
Participants will receive active intermittent theta burst stimulation (iTBS) delivered to an individualized ventrolateral prefrontal cortex (vlPFC) target selected based on positive resting-state functional connectivity with the basolateral amygdala. Active iTBS will be administered every weekday for 6 weeks (30 sessions) and is intended to stimulate the targeted vlPFC-amygdala circuit.
Device: Active Transcranial Magnetic Stimulation (TMS)
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.
Placebo Comparator: Sham iTBS
Participants will receive sham iTBS at the same individualized amygdala-connected vlPFC target every weekday for 6 weeks (30 sessions).
Device: Sham Transcranial Magnetic Stimulation (TMS)
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.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
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.
Time Frame: Single visit (~2 hours)
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.
Single visit (~2 hours)

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Difference in average amygdala-evoked response from TMS stimulation to fMRI-guided sites versus TMS stimulation of control sites.
Time Frame: Single visit (~2 hours)
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.
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.
Time Frame: Up to 7 weeks
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.
Up to 7 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University of Pennsylvania

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Desmond Oathes, PhD, University of Pennsylvania

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
October 12, 2026

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
June 1, 2028

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
August 1, 2028

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
August 20, 2026

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 20, 2026

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
August 25, 2026

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
August 31, 2026

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 26, 2026

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
August 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 26-7454

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

Yes

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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