Pathophysiological Understanding and Treatment of PTSD: an rTMS Approach (PTSD)

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).

Stress Disorders, Post-Traumatic, Brain Injuries, Transcranial Magnetic Stimulation, Magnetic Resonance Spectroscopy, Biomarkers, Depression, Anxiety

Group 1: Treatment of the right dorsolateral prefrontal cortex Group 2: Treatment of the right dorsomedial prefrontal cortex

Patients will engage in a one-week placebo control lead-in (5 treatments) and then a four-week treatment protocol (20 treatments) to the right Dorsolateral Prefrontal Cortex (DLPFC). The right DLPFC will be located with MR brain scans and the BrainSight TMS neuronavigation software. The intensity of the rTMS will be 100-120% of resting motor threshold amplitude, 1500 pulses applied consistently with a frequency of 1 Hz.

Patients will engage in a one-week placebo control lead-in (5 treatments) and then a four-week treatment protocol (20 treatments) to the right Dorsomedial Prefrontal Cortex (DMPFC). The right DMPFC will be located with MR brain scans and the BrainSight TMS neuronavigation software. The intensity of the rTMS will be 100-120% of resting motor threshold amplitude, 1500 pulses applied consistently with a frequency of 1 Hz.

Transcranial magnetic stimulation (TMS) works by delivering a magnetic pulse to a focal brain region. TMS has a high degree of safety and has been studied as an intervention for many mental health and neurological conditions. Repetitive TMS (rTMS) delivers pulses at a set time interval in order to modulate neural activity in that region.

The sham TMS coil will make a similar sound to the real rTMS coil, but will not deliver a magnetic pulse. This is a no-treatment device.

Transcranial magnetic stimulation (TMS) works by delivering a magnetic pulse to a focal brain region. TMS has a high degree of safety and has been studied as an intervention for many mental health and neurological conditions. Repetitive TMS (rTMS) delivers pulses at a set time interval in order to modulate neural activity in that region.

Effect of 20-session rTMS Intervention to the DMPFC versus DLPFC on PCL Overall Score, Stratified by Verbal Memory Task Scores

To determine whether patients with PTSD_LVMS have a greater response to a 20-day low frequency rTMS treatment protocol of the right DMPFC compared to the DLPFC, and if patients with PTSD_NVMS respond better to a 20-day low frequency TMS treatment protocol of the right DLPFC compared to the DMPFC as measured by the clinician administered PTSD scale for DSM-5 (CAPS-5) in male and female participants (military personnel and civilians) at 4 weeks and 1 month post-treatment.

Change in PCL-5 score at pre-treatment appointment, compared with the score at 1 week, upon study completion, and 4 weeks post-rTMS treatment.

To determine if serum brain derived neurotrophic factor (BDNF), glutamate, glutathione, and MR spectroscopy imaging will predict rTMS response in individuals with PTSD compared to those that do not respond to rTMS treatment.

Change in serum BDNF, glutamate, and glutathione at the pre-treatment appointment compared with 1 week into treatment and upon study completion.

Effect of rTMS on Quality of Life After Brain Injury survey (QOLIBRI), headaches, anxiety and depression in individuals with PTSD

To determine if quality of life (QOLIBRI), including headaches, anxiety, and depression also improve with the rTMS treatment in individuals suffering with PTSD

Change in QOLIBRI score at the pre-treatment appointment compared with 1 week, upon study completion, and 4 weeks post treatment.

Inclusion Criteria: Adult participants represent a typically developing nervous system as a more reliable target for this stage of research. The presence of a PTSD diagnosis made by a physician will ensure participants are experiencing significant symptomatology and may benefit from treatment. The cutoff score on the PCL-5 will ensure that participants are experiencing similar levels of symptoms to each other. Need to have tried at least two types of treatment in the past Exclusion Criteria: Significant past medical history including seizures, stroke, severe traumatic brain injury, or central nervous system cancers may interfere with our evaluation of treatment outcome and will be criteria for exclusion. Metal in head/neck/eye is a contraindication to safety in the MRI scanner and TMS protocol. Women who are pregnant will not be included in the study due to potential risk of seizure during TMS. To determine if a patient is pregnant we will ask when their last menstrual cycle occurred. If there is a possibility of pregnancy, we will ask the participant to follow-up with their family doctor to confirm. We will then ask the participant to provide a written note from their treating practitioner stating they are not pregnant. Active suicidality Wellbutrin or benzodiazepine intake of more than 200mg/day, or more than 15 mg of Zopiclone per day as these medications lower seizure threshold Trauma experienced less than a year ago and/or trauma experienced only as a child Drug and/or alcohol abuse within the last 3 months (diagnosed by Canadian guidelines) Diagnosed schizophrenia, untreated bipolar disorder, or psychosis

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