Pathophysiological Understanding and Treatment of PTSD: an rTMS Approach

Overview

In Canada, the prevalence of PTSD is approximately 12%, similar to Canadian military personnel. Current treatments for PTSD are limited in efficacy and durability - indicating a dire need for novel interventions in this population. Transcranial magnetic stimulation (TMS) has a high degree of safety and has been studied as an intervention for many mental health and neurological conditions; even showing initial promise for PTSD. We propose to study this further in a randomized sham controlled trial of TMS for PTSD.

In Canada, the prevalence of PTSD is approximately 12%, similar to Canadian military personnel. However, a 2002 study of members of Canadian Armed Forces found there was a striking positive correlation between the number of missions taken by the regular/reserve force and increase risk of developing PTSD, suggesting a dire need for further treatment options. Transcranial magnetic stimulation (TMS), a neuromodulation technique applied to the brain, has been studied as a treatment that has the potential to improve symptoms in a variety of neurological/mental health conditions. TMS is a safe and non-invasive technique that applies an electrical current to the brain to induce neuronal depolarization, changing regional brain function with the goal of improving neurological/psychiatric symptoms. Although multiple studies using TMS have suggested it as an efficacious treatment option for PTSD, clear knowledge gaps exist that prevent it from becoming evidence-based clinical care. A recent meta-analysis on TMS and PTSD found that no study has examined the difference between genders, and recommended that further studies with larger sample sizes, equal male and female participants, and more stringent study designs were required. Our study is novel and seeks to bridge the gap from research to clinical care by completing a study investigating repetitive TMS (rTMS) treatment for PTSD that recruits a large sample size, uses a randomized controlled clinical trial with a sham lead-in, and follows a stringent TMS protocol with equal sex participants. Not all individuals with PTSD respond to TMS treatment, and no study to date has explored what biomarkers may predict TMS responders in the PTSD population. Previous studies propose glutamate, BDNF and glutamatergic changes on MR spectroscopy may be altered in other mental health illnesses, which suggests they may be useful biomarkers of TMS response in PTSD. Therefore, this study will be the first of its kind to develop predictive biomarkers of response by sampling serum BDNF, glutamate, and glutamatergic changes in MR spectroscopy pre- and post rTMS treatment, in patients with PTSD that respond to TMS compared to those that do not. Recent studies have shown single-pulse TMS is beneficial for some individuals with chronic PTSD, and emerging evidence suggests there are specific phenotypes within PTSD that may require different TMS protocols. A recent study by Etkin et al. explored whether there were multiple phenotypes within chronic PTSD that would explain treatment responses. They found individuals with PTSD that scored significantly lower on verbal memory tasks (LVMS) (list repetition) had significantly impaired functional connectivity in the brain's ventral attention network (VAN) compared to patients with PTSD that had normal scores (NVMS). This suggests there may be a subgroup of patients with PTSD that would respond better to TMS in the right dorsal medial prefrontal cortex (DMPFC) (corresponding to the VAN) than to the right dorsal lateral prefrontal cortex (DLPFC).