Targeted Accelerated TMS for Post-Traumatic Stress Disorder

Overview

Post-traumatic stress disorder (PTSD) is a highly prevalent and debilitating condition among veterans and active-duty military personnel, with rates as high as 30% in certain combat-exposed populations. Conventional treatments such as prolonged exposure therapy and pharmacotherapy have limited efficacy and high dropout rates, highlighting the need for novel, rapidly effective interventions. Transcranial magnetic stimulation (TMS) has been well established for treatment-resistant depression (TRD). Traditional TMS, which involves 6 to 7 weeks of daily, weekday scalp-targeted treatment, shows open-label response and remission rates of 58.1% and 30%, respectively. However, such protocols may be impractical for military personnel with limited medical leave. A new form of accelerated TMS (aTMS) that involves 10 imaging-guided treatments per day for 5 consecutive days has demonstrated substantial antidepressant benefits within days and response rates of 69% at 1-month follow-up. This protocol has not been tested for PTSD, in part because there was no causally informed brain circuit target. In this study, the investigators will test aTMS for PTSD using a novel PTSD circuit that the investigators have derived.

Detailed description

In a recent study in Nature Neuroscience, the investigators analyzed three independent datasets to derive a brain circuit causally linked to PTSD in military veterans. Investigators found that brain lesions that reduce the probability of developing PTSD (n=193) were connected to the same brain circuit based on the functional connectivity profiles of individual patients with PTSD using fMRI (n=180). Finally, investigators demonstrated that scalp-targeted TMS to our circuit rapidly improved PTSD symptoms (n=20).

Separately, the investigators partnered with a private clinic to administer open-label, circuit-targeted aTMS to patients with PTSD (n=8). Investigators found that the treatment was safe and tolerable. Response and remission rates were 75% and 63%, respectively. Of note, these response and remission rates assess outcomes up to 4 weeks after the treatment ends. This approach captures individual variability in response trajectory and aligns with our own data from aTMS treatment of TRD.

The strength of these findings has inspired us to launch a pilot randomized controlled aTMS trial in which the investigators prospectively target our PTSD circuit using each patient's neuroimaging data in combination with the accelerated TMS treatment protocol.

Interventions

• Procedure Transcranial Magnetic Stimulation
  Transcranial magnetic stimulation (TMS) is a focal, non-invasive form of brain stimulation that has FDA clearance for depression. In this study, a form of TMS called accelerated intermittent theta burst stimulation (aiTBS) will be administered under the supervision of a physician with TMS expertise.

Primary outcome measures

• PTSD Checklist with Criterion A for DSM-5 (PCL-5) [Time frame: Before treatment to 1-month post treatment]

Secondary outcome measures (1)

• PTSD Checklist with Criterion A for DSM-5 (PCL-5) [Time frame: Before treatment to 1-month post treatment]

Eligibility criteria

Inclusion criteria

• Age 18-65
• DSM-5 diagnosis of PTSD per PTSD Checklist for DSM-5 (CAPS-5)
• At least moderate symptoms of PTSD per PCL-5 (≥21)
• English proficiency sufficient to understand risks/benefits
• No new medications or medication increases before, during, or after aTMS
• Primary clinician (e.g. psychiatrist, therapist, psychologist, APRN, PA, etc.) responsible for psychiatric care before, during, and after the trial
• Agreement to lifestyle considerations:
• Abstain from becoming pregnant from screening to one-month after treatment (the MRI visit)
• Continue usual intake patterns of caffeine- or xanthine-containing products (e.g. coffee, tea, soft drinks, chocolate) throughout treatment
• No changes to routine intake of alcohol, tobacco, and recreational drugs if patients are using them at baseline for at least 24 hours before the start of each MRI and TMS session

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

United States · 1 center

• Brigham and Women's Hospital — Boston

Publications

• Carpenter LL, Janicak PG, Aaronson ST, Boyadjis T, Brock DG, Cook IA, Dunner DL, Lanocha K, Solvason HB, Demitrack MA. Transcranial magnetic stimulation (TMS) for major depression: a multisite, naturalistic, observational study of acute treatment outcomes in clinical practice. Depress Anxiety. 2012 Jul;29(7):587-96. doi: 10.1002/da.21969. Epub 2012 Jun 11. PMID 22689344
• Hoge CW, Castro CA, Messer SC, McGurk D, Cotting DI, Koffman RL. Combat duty in Iraq and Afghanistan, mental health problems, and barriers to care. N Engl J Med. 2004 Jul 1;351(1):13-22. doi: 10.1056/NEJMoa040603. PMID 15229303
• Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry. 1995 Dec;52(12):1048-60. doi: 10.1001/archpsyc.1995.03950240066012. PMID 7492257
• Siddiqi SH, Philip NS, Palm ST, Carreon DM, Arulpragasam AR, Barredo J, Bouchard H, Ferguson MA, Grafman JH, Morey RA, Fox MD. A potential target for noninvasive neuromodulation of PTSD symptoms derived from focal brain lesions in veterans. Nat Neurosci. 2024 Nov;27(11):2231-2239. doi: 10.1038/s41593-024-01772-7. Epub 2024 Sep 24. PMID 39317797
• Cole EJ, Stimpson KH, Bentzley BS, Gulser M, Cherian K, Tischler C, Nejad R, Pankow H, Choi E, Aaron H, Espil FM, Pannu J, Xiao X, Duvio D, Solvason HB, Hawkins J, Guerra A, Jo B, Raj KS, Phillips AL, Barmak F, Bishop JH, Coetzee JP, DeBattista C, Keller J, Schatzberg AF, Sudheimer KD, Williams NR. Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression. Am J Ps PMID 32252538
• Cole EJ, Phillips AL, Bentzley BS, Stimpson KH, Nejad R, Barmak F, Veerapal C, Khan N, Cherian K, Felber E, Brown R, Choi E, King S, Pankow H, Bishop JH, Azeez A, Coetzee J, Rapier R, Odenwald N, Carreon D, Hawkins J, Chang M, Keller J, Raj K, DeBattista C, Jo B, Espil FM, Schatzberg AF, Sudheimer KD, Williams NR. Stanford Neuromodulation Therapy (SNT): A Double-Blind Randomized Controlled Trial. PMID 34711062

Identifiers

NCT: NCT07245641 · 2025P002359

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗