Accelerated Transcranial Magnetic Stimulation for Post-Traumatic Stress Disorder

Feasibility and Preliminary Efficacy of Functional MRI-Guided Accelerated Transcranial Magnetic Stimulation for Post-Traumatic Stress Disorder: A Pilot Study

This study tests a new brain stimulation treatment for post-traumatic stress disorder (PTSD), a condition that affects millions after trauma, causing symptoms like flashbacks, avoidance, mood changes, and heightened alertness.

The investigators will enroll 15 adults (ages 18-65) with PTSD. First, participants get a brain scan (fMRI) to map their unique brain connections between areas involved in fear and control-the right amygdala (fear center) and right dorsolateral prefrontal cortex (control area). Using this personalized map, the investigators will apply accelerated transcranial magnetic stimulation (TMS), a safe, non-invasive method using magnetic pulses to adjust brain activity. Treatment lasts 5 days (10 short sessions daily, totaling 90,000 pulses) targeting the identified spot to strengthen control over fear responses.

The study checks if this approach is practical, safe (tracking side effects like headaches), and shows early signs of reducing PTSD symptoms (measured by questionnaires and interviews). Follow-up lasts 3 months, with repeat scans to see brain changes.

This study will see if personalized, fast-paced TMS targeting the disrupted fear-control brain circuit in PTSD can be feasible and safe, and preliminarily reduce symptoms by improving brain connectivity, potentially offering a quicker alternative to standard treatments.

This pilot study evaluates the feasibility, safety, and preliminary efficacy of functional magnetic resonance imaging (fMRI)-guided accelerated continuous theta burst stimulation (cTBS) targeting the right dorsolateral prefrontal cortex (rDLPFC) in adults with post-traumatic stress disorder (PTSD). PTSD is characterized by dysregulation in the fear circuitry, including amygdala hyperreactivity and impaired prefrontal regulation, leading to persistent symptoms despite standard treatments like trauma-focused psychotherapy or selective serotonin reuptake inhibitors, which achieve adequate response in only about 50% of patients.

The intervention leverages resting-state fMRI to identify individualized rDLPFC targets based on maximal positive functional connectivity to the right amygdala, addressing inter-individual variability in circuit topography (average 4.5 cm variation per recent literature). Imaging is acquired on a 1.5T scanner with T1-weighted structural (MPRAGE: TR=1645 ms, TE=3.8 ms, voxel=0.8 mm isotropic) and resting-state functional sequences (EPI: TR=2000 ms, TE=40 ms, voxel=3.75×3.75×4 mm, 900 volumes). Data processing via FSL includes motion correction, spatial smoothing (5 mm FWHM), bandpass filtering (0.01-0.1 Hz), and nuisance regression. The peak correlation voxel in the rDLPFC (Brodmann areas 8,9,10,46) serves as the target; fallback to MNI [40,28,44] if data quality fails.

Treatment employs an accelerated cTBS protocol over 5 consecutive days (50 sessions total: 10/day, 1,800 pulses/session, 90,000 pulses overall) using ANT Visor 2 neuronavigation for precise coil positioning. Each session delivers bursts of 3 pulses at 50 Hz, repeated at 5 Hz for 40 seconds (600 pulses/train), with 3 trains and 30-second inter-train intervals, at 65-80% resting motor threshold (determined via EMG over the first dorsal interosseous). Inter-session intervals are 50 minutes, with continuous monitoring for adverse events.

The single-arm, open-label design includes a screening/baseline phase (informed consent, medical history, safety screenings), baseline fMRI for targeting, treatment phase with daily safety checks, post-treatment assessments (within 48-72 hours), and follow-ups at 1 and 3 months. Total participant commitment is ~3.5 months. Pre- and post-treatment fMRI explores mechanistic changes in rDLPFC-amygdala connectivity (seed-to-seed Pearson correlation, Fisher z-transformed) and target shifts (Euclidean distance, component decomposition), correlating with clinical improvements.

This approach combines precision neuromodulation with accelerated delivery to reduce treatment burden (5 days vs. 4-6 weeks standard), building on meta-analyses showing moderate-to-large TMS effects in PTSD (SMD=1.02) and FDA-cleared neuroimaging-guided protocols like SAINT. The study aims to generate proof-of-concept data for larger randomized trials, focusing on circuit-specific modulation to enhance fear extinction and prefrontal control. Safety is prioritized with strict contraindication screening, real-time monitoring, and an independent safety monitor reviewing serious adverse events.

Inclusion Criteria

Participants must meet ALL of the following criteria:

1. Age 18-65 years (inclusive)
2. DSM-5 diagnosis of PTSD confirmed by Clinician-Administered PTSD Scale for DSM-5 (CAPS-5)
3. PCL-5 total score ≥33 (indicating at least moderate symptom severity)
4. PTSD symptom duration ≥3 months
5. If taking psychotropic medications, stable dose for ≥6 weeks prior to enrollment with no planned changes during study participation
6. Able to provide written informed consent
7. English-speaking (required for validated assessment measures)
8. Able to attend daily treatment sessions for 5 consecutive weekdays
9. Eligible for 1.5T MRI scanning (no contraindications)

Exclusion Criteria

Participants meeting ANY of the following criteria will be excluded:

TMS Contraindications:

1. Conductive, ferromagnetic, or other magnetic-sensitive metals implanted in the head or within 30 cm of the TMS coil (excluding the mouth), including:

   • Cochlear implants
   • Deep brain stimulators
   • Vagus nerve stimulators
   • Aneurysm clips or coils
   • Stents in the neck or brain
   • Electrodes
   • Any implanted electronic devices

2. History of seizure disorder (excluding single childhood febrile seizure)

3. First-degree family member with epilepsy

4. History of significant head trauma with loss of consciousness >10 minutes

5. History of stroke, brain tumor, or other neurological disorder

6. Neurosurgical procedures involving brain tissue

MRI Contraindications:

1. Implanted medical devices incompatible with MRI
2. Claustrophobia preventing MRI scan completion
3. Body size preventing MRI scanner entry

Psychiatric Exclusions:

1. Lifetime history of psychotic disorder (schizophrenia, schizoaffective disorder, delusional disorder)

2. Lifetime history of bipolar I disorder

3. Current (within past month) moderate or severe substance use disorder per DSM-5 criteria

4. Current active suicidal ideation with intent or plan (Columbia Suicide Severity Rating Scale score ≥4)

5. Psychiatric hospitalization within past 3 months

   Medical Exclusions:

6. Unstable medical condition that, in the investigator's judgment, would interfere with study participation or pose safety risk

7. Pregnancy or breastfeeding (females of childbearing potential must have negative urine pregnancy test at screening)

8. Prior TMS treatment within past 3 months

9. Current participation in another interventional research study

10. Initiation of psychotherapy specifically for PTSD within past 3 months (stable ongoing therapy is permitted)