Accelerated Transcranial Magnetic Stimulation for Post-Traumatic Stress Disorder

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:

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

Exclusion criteria

Participants meeting ANY of the following criteria will be excluded:

TMS Contraindications:

• 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
• History of seizure disorder (excluding single childhood febrile seizure)
• First-degree family member with epilepsy
• History of significant head trauma with loss of consciousness >10 minutes
• History of stroke, brain tumor, or other neurological disorder
• Neurosurgical procedures involving brain tissue

MRI Contraindications:

• Implanted medical devices incompatible with MRI
• Claustrophobia preventing MRI scan completion
• Body size preventing MRI scanner entry

Psychiatric Exclusions:

• Lifetime history of psychotic disorder (schizophrenia, schizoaffective disorder, delusional disorder)
• Lifetime history of bipolar I disorder
• Current (within past month) moderate or severe substance use disorder per DSM-5 criteria
• Current active suicidal ideation with intent or plan (Columbia Suicide Severity Rating Scale score ≥4)
• Psychiatric hospitalization within past 3 months

Medical Exclusions:

• Unstable medical condition that, in the investigator's judgment, would interfere with study participation or pose safety risk
• Pregnancy or breastfeeding (females of childbearing potential must have negative urine pregnancy test at screening)
• Prior TMS treatment within past 3 months
• Current participation in another interventional research study
• Initiation of psychotherapy specifically for PTSD within past 3 months (stable ongoing therapy is permitted)