Stage 1 Clinical Trial: eTMS for PTSD

This study was funded by the State of Ohio Department of Behavioral Health.

Results from this study are available via clinicaltrials.gov

Results from the MRI study are in review:

Pyle K, Hildreth M, Phillips B, Gilpin AMK, Mysiw WJ, Pandey S, Suresh L, Clark C, Sherwood MS (in review). Alterations of Resting Arterial Spin Labeling Perfusion in Veterans and First Responders with Post-Traumatic Stress Disorder Following an Open-Label eTMS Treatment Protocol. Neuroscience and Behavioral Physiology.

This study was presented at Psychology Grand Rounds, Wright State University and Premier Health. This presentation can be found here. 

This study was presented at the 17th World Congress of the International Neuromodulation Society. The full presentation can be found here and the poster can be found here.

Introduction

Military veterans and first responders experience higher rates of post-traumatic stress disorder (PTSD) than the general population. Despite the availability of evidence-based psychotherapies and pharmacological treatments, a substantial proportion of individuals continue to experience persistent symptoms, including hyperarousal, intrusive recollections, avoidance, and negative alterations in cognition and mood. Treatment-resistant PTSD remains a significant clinical challenge, highlighting the need for novel therapeutic approaches that target underlying neurobiological mechanisms. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising noninvasive neuromodulation intervention for many psychiatric disorders. However, most clinical protocols rely on standardized scalp-based targeting methods, which may not account for individual variability in brain organization and network dysfunction. PTSD has been increasingly conceptualized as a disorder of dysregulated large-scale brain networks, including alterations in connectivity between prefrontal, limbic, and salience systems, providing a rationale for targeted neuromodulation strategies. EEG-informed or frequency- guided rTMS (eTMS) may enhance treatment efficacy by aligning stimulation with patient-specific neural dynamics4,5. Although early studies have demonstrated the feasibility and potential efficacy of TMS in PTSD, there remains a need to evaluate personalized targeting approaches in clinically relevant populations. In the present open-label clinical trial, we evaluated the effects of EEG-targeted rTMS in a sample of veterans and first responders with PTSD. We hypothesized that eTMS would reduce PTSD symptom severity over the course of treatment. By focusing on a high-risk, trauma-exposed population and incorporating precision neuromodulation, this study aims to contribute to the growing literature on personalized interventions for PTSD.

Methods

All participants were prescreened via telephone for potential eligibity prior to completing a pre-treatment eligibity assessment. At the eligibility assessment, voluntary informed consent was first collected followed by the collection of several assessments using standardized and non-standardized instruments, medical screening and an initial EEG. After eligibility was determined, participants then scheduled 20 eTMS treatments. The first 16 participants received 1 treatment per visit (1x) completing 20 treatment visits within a maximum of 35 days. The last 14 participants received 2 treatments per visit (2x) completing 10 treatment visits in no more than 21 days. The frequency of rTMS was computed for each individual using a single frequency computed from the alpha band of their pre-treatment EEG derived via an automated proprietary algorithm. Each eTMS treatment lasted 13min providing 30-6s trains of stimulation with an inter-train interval of 20s. eTMS was provided to Fz at an intensity of 80% motor threshold which was determined at the first treatment visit. Participants in the 2x group had at least 30min of rest between treatments. All participants completed 18 or more treatments. After all treatment visits, select assessments were repeated during a separate follow-up visit. The follow-up visit was completed within the 35-day (1x) or 21-day (2x) treatment window. Figure 1 provides a visual of the experimental design. Prior to treatment, participants could enroll in a separate MRI study which acquired MRI pre- and post-treatment. Neuroimaging was performed on a 3-Tesla MRI using a 32-channel phased array headcoil and several sequences including 3D psuedo-continuous arterial spin labeling (pcASL) to quantify cerebral perfusion.

Results

The intent-to-treat group consisted of 30 participants (mean age 42.7 years +/- 9.5). The demographics are:

Overall, stimulation was tolerated well by all participants. A total of 31 adverse events (AEs) were reported, with 2 being severe and 3 moderate. 17 AEs were determined to be not related to treatment, 5 suspected and 9 definitely related to treatment. 14 of the 30 participants in the ITT group reported at least 1 AE. Headache was the most common reported AE with 19 occurrances (10 of which were determined to be not related to treatment).

The per-protocol (PP) group consisted of 27 individuals whom completed at least 80% of the treatments. This included 13 participants from the 1x group and 14 from the 2x group. A 2x2 (time by group) linear mixed-effects model was fitted using the lme4 package in R with a random intercept to account for within-subject repeated measures. The two groups did not significantly vary in their response to treatment. A post-hoc pairwise comparison of time was conducted using estimated marginal means revealed a significant decrease in PCL-5 scores following treatment, with an average reduction of 30.393 points.

16 participants underwent the separate MRI study where resting perfusion (CBF) was assessed from 3D pcASL pre- and post-treatment. Increased resting perfusion was found in several regions including the amygdala and hippocampus following treatment.

Increased perfusion in the amygdala and hippocampus were found to significantly correlate with decreased PTSD symptomology, suggesting those participants with a greater reduction in PTSD symptom severity were found to have a larger change in perfusion.

Discussion

The PTSD Checklist for the DSM-5 (PCL-5) was used to assess PTSD symptom severity and provide a probability for the prevalence of PTSD. Individuals with a PCL-5 total score of 31 or higher, and also meeting the PCL-5 rubric were eligible for the study. We performed 20 treatments of electroencephalogram transcranial magnetic stimulation (eTMS), each consisting of 30-6s trains with 20s inter-train intervals. TMS was provided at 80% motor threshold to Fz. 30 participants in our ITT group completed a total of 597 eTMS treatments, 16 receiving 1 treatment per day and 14 receiving 2 treatments per day. 31 total adverse events were reported, with 14 of the 30 participants reporting at least 1 adverse event (6 in the 1x group and 8 in the 2x group). 9 of the adverse events were determined to be definitely related to treatment and 5 were suspected to be related to treatment. Headache was the most frequent adverse event with 19 occurrances (10 not related to treatment). 27 participants formed the per protocol group all completing 20 treatments (13 in the 1x group, 14 in the 2x group). 

Changes in PTSD symptom severity did not significantly vary between the 1x and 2x groups suggesting an accelerated application of eTMS can provide similar results to a single treatment per day. Combining groups, PTSD symptom severity was found to significantly decrease following treatment. PCL-5 totals scores decreased by over 30 points on average, with 24 of the 27 participants demonstrating a clinically significant decrease of over 10 points.

16 participants completed the separate MRI study where resting perfusion was found to increase from pre- to post-treatment in several areas of the brain including the amygdala and hippocampus which are core to emotion regulation and fear responses. Amygdala and hippocampus perfusion was also found to be significantly lower pre-treatment than that observed in an uncontrolled healthy group. This increased perfusion was found to significantly correlate to the changes in PTSD symptom severity.

In conclusion, eTMS was well tolerated and produced a clinically significant reduction in PTSD symptom severity. Neuroimaging found significant increases in resting perfusion including the amygdala and hippocampus, with larger changes observed in participants with larger decreases in PTSD symptom severity. This suggests dysregulation of the amygdala and hippocampus at rest may contribute to PTSD symptomology and eTMS may decrease the dysregulation leading to symptom improvement.