Accelerated, Theta-burst Stimulation for the Treatment of Post-concussion Syndrome

Study Overview
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Brief Summary
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TMS has been safely and reliably delivered at the Harquail Centre for over 5 years, with a primary focus on conventional rTMS protocols for treatment-resistant depression. Recently, the investgator team has gained the capability to deliver sham-controlled intermittent theta-burst stimulation (iTBS) rTMS. Unlike conventional high frequency rTMS, which was used in the previous sham-controlled rTMS PCS pilot study, iTBS is a patterned form of stimulation that recapitulates endogenous activity patterns of neural circuits pairing gamma frequency (50Hz) burst pulses coupled in a theta frequency rhythm (5Hz).12 iTBS delivers 600 pulses in just over 3 minutes with similar or greater effects on neural plasticity compared to conventional rTMS (taking over 30-45 minutes) and similar tolerability and efficacy in trials of depression. Furthermore, novel accelerated iTBS protocols stimulating the left dorsolateral prefrontal cortex (dlPFC) over 8-10 treatments, 50 minutes apart over a 5 day interval has recently demonstrated robust efficacy in depression and received recent FDA approval. Thus, accelerated iTBS can be delivered in a single week of treatment compared to 6 weeks with conventional rTMS methods. Finally, the investigators recently acquired the technology to integrate MRI neuroimage-guided stimulation, which would allow to target specific brain regions/networks implicated in PCS at high spatial resolution. No studies to date have investigated image-guided accelerated iTBS rTMS for the treatment of PCS.

Official Title
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Image-guided, Accelerated, Theta-burst Stimulation for the Treatment of Post-concussion Syndrome

Conditions
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Post Concussion Syndrome

Intervention / Treatment
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* Device: Intermittent Theta-Burst Stimulation
* Device: Sham Intermittent Theta-Burst Stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented evidence of head trauma sufficiently severe to result in loss of consciousness, post-traumatic amnesia and/or acute altered mental status. At least three symptoms including headache, dizziness, fatigue, irritability, insomnia, memory difficulties, concentration difficulties, mood dysregulation. Onset of symptoms within 4 weeks following the head trauma. Age 18-60, inclusive. Persistence of PCS symptoms for at least 3 months but less than 12 months Able to provide informed consent and comply with the study protocol Patients will not be excluded solely on the basis of communication (i.e., non-English speaking) unless they have exclusion criteria that is the cause of the communication difficulties. Exclusion Criteria: Evidence of major structural neuroimaging abnormalities (e.g., intracranial hemorrhage, skull fracture or a large intracranial lesion) History of prior rTMS therapy, Contraindications to MRI (e.g., pacemaker, metallic implants etc.). Ferromagnetic, non-removable metallic implants from above the clavicle with the exception of dental work. Active personal injury litigation History of seizure disorder, not including febrile seizures in childhood Substance dependence within the last 6 months Pregnant Currently taking more than lorazepam 2 mg daily (or benzodiazepine equivalent) or any dose of an anticonvulsant (due to the potential to reduce rTMS efficacy) Currently taking an antiepileptic medication Mild and major comorbid medical conditions (as determined by investigators - e.g., neurological diseases, uncontrolled hypertension or diabetes, malignancy) A major comorbid psychiatric disorder (as determined by investigators - e.g., schizophrenia or bipolar disorder) and/or psychosis at the time of study enrollment

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br> | Device: Intermittent Theta-Burst Stimulation<br>* Accelerated course of left dlPFC iTBS, consisting of 600 pulses/session, 50 minutes intersession interval, 8 session/day for 5 days) at 90% resting MT<br>|
| Sham Comparator: Sham<br> | Device: Sham Intermittent Theta-Burst Stimulation<br>* Magventure Active/Placebo B70 coil specifically designed for randomized clinical trials with TMS. This system uses electrodes placed on the scalp to provide stimulation mimicking the active treatment condition<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rivermead Post Concussion Symptoms Questionnaire | RPQ, a validated measure of subjective global PCS symptoms. | Baseline, change from baseline to immediately before the first iTBS treatment | 
| Rivermead Post Concussion Symptoms Questionnaire | RPQ, a validated measure of subjective global PCS symptoms. | 5 days | 
| Rivermead Post Concussion Symptoms Questionnaire | RPQ, a validated measure of subjective global PCS symptoms. | 1 month post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Montgomery-Åsberg Depression Rating Scale | Montgomery-Åsberg Depression Rating Scale is a widely used clinician-rated measure of depressive severity | Baseline, post treatment day 5, and post treatment 1 month | 
| Repeatable Battery for the Assessment of Neuropsychological Status | RBANS is a brief, individually administered battery to measure cognitive decline or improvement | Baseline and post treatment 1 month | 
| The Behavior Rating Inventory of Executive Function | BRIEF-A is a standardized measure that captures views of an adult's executive functions or self-regulation in his or her everyday environment. | Baseline, post treatment day 5, and post treatment 1 month | 
| Headache Impact Test | HIT is a tool used to measure the impact headaches have on your ability to function on the job, at school, at home and in social situations. | Baseline and post treatment 1 month |