Treatment of Post-concussion Syndrome With TMS: Using FNIRS as a Biomarker of Response

Summary

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Description

Annually, up to 280,000 people in Canada and 42 million worldwide experience a mild traumatic brain injury (mTBI). In patients with mTBI, symptoms experienced following injury usually resolve within 3 months. However, up to 25% of patients will experience persistent post-concussion symptoms (PPCS), ...

Annually, up to 280,000 people in Canada and 42 million worldwide experience a mild traumatic brain injury (mTBI). In patients with mTBI, symptoms experienced following injury usually resolve within 3 months. However, up to 25% of patients will experience persistent post-concussion symptoms (PPCS), which can continue up to 1 year following injury. Common symptoms include headaches, dizziness, fatigue, irritability, depression, anxiety, emotional lability, concentration or memory difficulties, insomnia, and reduced alcohol tolerance (ICD-10 post-concussion syndrome diagnostic criteria). To date, there is no "cure" for PPCS and current treatment entails trial and error with behavior management, environmental modifications and medications. Consequently, there is a significant need for new approaches to symptom management in order to help improve functional impairment and disease burden, associated with treating PPCS. Transcranial magnetic stimulation (TMS) has a high degree of safety and has been studied as an intervention for many mental health and neurological conditions, including major depression and migraines, and even showing initial promise for PPCS. The investigators propose to study this further in a randomized sham controlled trial of TMS for PPCS. RESEARCH QUESTIONS AND OBJECTIVES The overall aim is to study the application of rTMS treatment to the left dorsal lateral prefrontal cortex (DLPFC) in patients with PPCS to improve overall symptom burden and to explore biomarkers of response, specifically functional near infrared spectroscopy (fNIRS). Specifically the objectives are: Primary Objective: To determine whether patients with PPCS have significant improvement to a 20-day high frequency rTMS treatment protocol of the left DMPFC compared to patients with PPCS receiving a sham rTMS protocol as measured by the Rivermead post-concussion symptom questionnaire at 1, 3 and 6 months post-treatment. Secondary Objective: To determine what secondary outcomes such as quality of life, headaches, anxiety, and depression also improve with the TMS treatment in individuals suffering with PPCS. Quality of life will be measured via the Quality of Life after brain injury questionnaire (QOLIBRI), headache intensity will be measured via the Headache intensity Test - 6 (HIT-6), feelings of depression will be measured via the PHQ-9 and anxiety via the GADS-7 at 1, 3 and 6 months post treatment. Third objective: To explore whether fNIRS would be a useful biomarker of TMS-response in patients with PPCS. METHODS This study will be a double-blind, sham-controlled, concealed allocation, randomized, cross over clinical trial. Clinical Assessments: Demographic information will be collected two weeks prior to starting the study including age, sex, education, headache history, concussion history, past medical history, medication use, and family medical history. Baseline questionnaires will be completed including Headache Impact Test - 6 (HIT-6), Rivermead PPCS questionnaire, British Columbia post-concussion symptom inventory (BC-PSI), Montreal cognitive assessment (MoCA), quality of life after brain injury questionnaire (QOLIBRI), patient health questionnaire-9 (PHQ-9), generalized anxiety disorder scale-7 (GADS-7), Repeatable battery for the assessment of neurological status (RBANS), and the post traumatic stress disorder checklist for DSM-5 (PCL-5). Patients will keep a two-week baseline symptom diary before treatment, 2 weeks during treatment, 2 weeks following rTMS, and for 2 weeks at the 1, 3, and 6 month follow up assessments (total of 12 weeks). Patients will be reassessed at the completion of their rTMS treatment, and at 1, 3, and 6 months post-treatment. The questionnaires including: Rivermead PPCS questionnaire, HIT-6, BC-PSI, QOLIBRI, PHQ-9, GAD-7 and RBANS will be completed at all follow up visits. TMS Protocol: Patients will engage in a four-week treatment protocol (20 treatments). This was chosen as it is the midpoint between typical depression and migraine protocol durations. If available, patient MR brain scans will be loaded and processed using the Brainsight TMS neuronavigation software and stereotaxic data for localization of the TMS stimulation site will be determined through a co-registration method between the TMS coil position and the projected site on the MR brain scan. If not available, a standardized atlas brain with Montreal neurologic institute (MNI) coordinates will be used for navigation. The DLPFC will be located through MNI coordinates (-48, 26, 36) vs. (-41, 21, 38). The intensity of the rTMS will be 100-120% of resting motor threshold amplitude, with a frequency of 10 Hz, 10 trains of 60 pulses/train (total of 600 pulses) and inter-train interval of 45s. In the sham condition, a sham coil will be applied to the scalp after the resting motor threshold is determined. Patients will be able to hear the sound and feel the vibration of sham coil, but will not experience any effective stimulation. Previous sham studies have demonstrated efficacy of the blinding method. Imaging: Functional near infrared spectroscopy (fNIRS) scans will be recorded at baseline, immediately following rTMS, and at one month post-rTMS to investigate changes in brain physiology associated with rTMS treatment. fNIRS data will be recorded over the frontoparietal cortex at a sampling rate of 3.91 Hz, using the NIRScout fNIRS system (NIRx Medical Technologies, Berlin, Germany). Each recording will consist of a 5 min rest period, followed by a finger tapping exercise, and a graded working memory task. The fNIRS data will be processed and analyzed for task-evoked activation using an ordinary least squares method of general linear modeling, as implemented in the NIRS Brain AnalyzIR Toolbox. Statistical Analysis: Outcome parameters within each specific group (rTMS, sham, sex) will be analyzed by a one-way repeated measures analysis of variance (RM-ANOVA).

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