Repetitive Transcranial Magnetic Stimulation Paired with Augmented Reality to Alter Concussion Symptoms

The incidence of traumatic brain injury (TBI) is increasing in Canada, and it is expected to be one of the most common neurological conditions affecting Canadians by 2031. Up to 90% of TBIs are classified as mild (m)TBI, also known as concussion. A federal concussion report from 2019 indicated an annual prevalence of 200,000 mTBIs in Canada. Symptoms of mTBI, termed post-concussion symptoms (PCS), include dizziness, headache, alterations in mood, and cognitive impairment. PCS generally resolves on its own. However, some patients experience persistent PCS lasting beyond 3 months after the initial head injury.

Dizziness is the second most common symptom of mTBI after headache. It is estimated that up to 81% of mTBI patients will present with dizziness upon initial clinical examination, which may continue to persist beyond 1-year following the initial trauma in 25% of patients. Post-concussion dizziness (PCD) can present as postural instability, ongoing vertigo, balance impairments, nausea, and intolerance to head motion. These symptoms can drastically reduce quality of life and impact the ability to drive, work, and perform daily activities.

PCD is typically associated with vestibular impairment. Further, many patients complaining of dizziness following mTBI demonstrate physiologic abnormalities with the auditory and vestibular systems. Consequently, the most preferable treatment for PCD is a form of balance training called vestibular rehabilitation therapy (VRT). VRT consists of a set of exercises which promote adaptation, substitution, and habituation of the vestibular system. Adaptation, mediated by neuroplasticity, is the gradual remodelling of the nervous system as it "adapts" to the signals from the damaged vestibular system. Substitution is the process of learning strategies to compensate for poor vestibular function. Habituation is the gradual desensitization to certain movements through repeated exposure to those movements. These exercises are often individually prescribed based on personal areas of disability. Specific exercise types include gaze stability, habituation, substitution, and balance exercises. These target deficits in the vestibulo-ocular reflex (VOR), improve impaired motion sensitivity, facilitate central reprogramming, and improve balance. Traditional VRT, such as a balance task, is monotonous and often requires trained professionals to administer. VRT, in the form of interactive games, however, is engaging and has been shown to affect balance, dizziness, and mobility positively. A form of sensorimotor training consisting of an interactive game presented through augmented reality (AR) has not yet been explored. It may serve to reduce PCD by similar mechanisms as the aforementioned VRTs.

AR is typically presented through opaque glasses, which overlay virtual objects onto the user's environment. Users can then interact with both the virtual and physical environments simultaneously. Our AR intervention involves a game that promotes goal-directed movements of the head to accomplish tasks in various head orientations and postural positions. Through repeated exposure, this game aims to facilitate adaptation, substitution, and habituation of the vestibular system to reduce PCD.

A non-invasive neuromodulation technique called repetitive transcranial magnetic stimulation (rTMS) may improve AR vestibular training. One form of rTMS delivery called intermittent theta burst stimulation (iTBS) promotes synaptic plasticity by inducing long term potentiation (LTP)-like changes in neuronal excitability. Literature suggests that iTBS delivered to the primary motor cortex (M1) may improve learning in conjunction with motor training. rTMS may also improve dizziness. Ten sessions of rTMS reduce dizziness symptom severity and frequency by more than 50% in patients suffering from severe PCD. iTBS delivered to M1 improves balance in post-stroke patients. Systemic inflammation is an important physiological response to mTBI that may contribute to dizziness. Several studies have observed the anti-inflammatory effects of rTMS in clinical populations such as stroke and depression. Zhao et al. found that 20 sessions of rTMS on patients with refractory depression reduced elevated levels of TNF-⍺ and IL-1β to that of healthy controls. Levels of BDNF, which is important for brain growth, increased to that of healthy controls following the intervention. This effect on TNF-⍺, IL-1β, and BDNF was not observed in the clinical control group who did not receive rTMS. Cha et al. reported a similar reduction in inflammatory cytokines TNF-⍺, IL-1β, and IL-6 after 10 sessions of rTMS in post-stroke patients. Velioglu et al. found that 10 sessions of rTMS increased BDNF in patients with Alzheimer's disease. These effects also provide evidence towards a possible mechanism behind the effect of rTMS on other persistent PCS.

Patients with severe persistent PCD often require medical or surgical intervention. There is a clear need for non-invasive treatment options for these individuals. The primary objective of this study is to determine if the proposed technique is feasible and can be used to alter concussion symptoms in patients with PCD in a larger study. This study will also explore the effects of iTBS in combination with AR vestibular training on dizziness disability and postural stability in patients with PCD. Additionally, this research aims to determine if rTMS can modulate inflammation in persistent PCS.

• Balance Error Scoring System (BESS) [Срок оценки: At baseline (before the first intervention session) and post-intervention (following the final intervention session)]
• Activities-Specific Balance Confidence (ABC) Scale [Срок оценки: At baseline (before the first intervention session) and post-intervention (following the final intervention session)]
• Rivermead Post Concussion Symptoms Questionnaire (RPSQ-3 and RPSQ-13) [Срок оценки: At baseline (before the first intervention session) and post-intervention (following the final intervention session)]
• PROMIS-29 [Срок оценки: At baseline (before the first intervention session) and post-intervention (following the final intervention session)]
• Motor evoked potential (MEP) [Срок оценки: At baseline (before the first intervention session) and post-intervention (following the final intervention session)]
• Cytokines (IL-1ß, IL-6, TNF-⍺, IL-10) [Срок оценки: At baseline (before the first intervention session) and post-intervention (following the final intervention session)]
• C-reactive protein [Срок оценки: At baseline (before the first intervention session) and post-intervention (following the final intervention session)]
• Monocyte chemoattractant protein-1 [Срок оценки: At baseline (before the first intervention session) and post-intervention (following the final intervention session)]
• Brain-derived neurotrophic factor [Срок оценки: At baseline (before the first intervention session) and post-intervention (following the final intervention session)]