Individualized (fMRI-guided) TMS Intervention for Post-Traumatic Stress Disorder (PTSD)
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
Conditions
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
Enrollment (Estimated)
Phase
- Early Phase 1
Contacts and Locations
Study Contact
- Name: Almaris Figueroa Gonzalez
- Phone Number: 2157466751
- Email: almaris.figueroa-gonzalez@pennmedicine.upenn.edu
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Adult
- Older Adult
Accepts Healthy Volunteers
Description
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.
Study Plan
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 |
Intervention / Treatment |
|---|---|
|
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.
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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).
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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.
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What is the study measuring?
Primary Outcome Measures
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
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
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Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Desmond Oathes, PhD, University of Pennsylvania
Study record dates
Study Major Dates
Study Start (Estimated)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- 26-7454
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
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