Transcranial Magnetic Stimulation for Depression in Multiple Sclerosis

Background \& Rationale: Multiple sclerosis (MS) is a chronic disease of the central nervous system characterized by demyelination that produces a wide range of neurological impairments. These circuit-level disruptions can result in functional consequences to individual neural systems, such as motor or sensory systems. However, they can also be distributed and produce syndromic neuropsychiatric presentations. Major depressive disorder (MDD) is particularly impairing and prevalent in individuals with MS, with a lifetime prevalence of about 50%. Similarly, nearly 90% of MS patients experience severe fatigue. Existing treatment strategies for MS importantly target the immune system to address the underlying disease processes, depression and fatigue symptoms can be present in absence of radiographic evidence of active disease and reflect broader circuit-level dysfunction. Unfortunately, they are often neglected and do not respond to conventional therapies. This highlights the critical need for alternative treatment options to treat neuropsychiatric symptoms in MS patients. In particular, non-invasive brain stimulation techniques offer circuit-level interventions and have shown great promise in several neuropsychiatric conditions. Repetitive transcranial magnetic stimulation (rTMS) is a first-line non-invasive neurostimulation treatment for MDD in Canada. rTMS involves the induction of magnetic fields and their reciprocal electrical currents in the brain to drive adaptation in specific neural circuits. However, exogenously inducing currents in the brain can cause a seizure, and historically, any neurological condition has been an exclusion criteria from the clinical trial evidence base for rTMS. This was true of the pivotal trials for regulatory approval and remains true today. Yet, more recent rTMS expert consensus statements and safety guidelines are explicit that rTMS can be safely delivered in individuals with neurological comorbidities if the structural lesion is not within the region of stimulation. In this study, it will be investigated whether intermittent theta burst stimulation (iTBS), a type of high-frequency rTMS, engages demyelinating lesions in individuals with relapsing-remitting and primary progressive MS (RR-MS \&PP-MS). The feasibility and effectiveness of iTBS in improving depression and fatigue symptoms in individuals with RR-MS and PP-MS will be investigated. This study is an open-label pilot trial consisting of 20 participants (10 RR-MS and 10 PP-MS) with comorbid depression. Research Question \& Objectives: Conduct an open-label pilot study to determine the safety and effectiveness of iTBS as a treatment for depression and fatigue symptoms in individuals with RR-MS \& PP-MS. The primary goal of this study is to evaluate the feasibility, safety, and preliminary clinical effects of a 5-day course of iTBS for depression in individuals with multiple sclerosis. This pilot trial is primarily intended to assess tolerability, safety, and procedural feasibility, and to provide preliminary evidence of potential clinical improvement that can inform the design and power calculations of future randomized controlled efficacy trials. Any changes in clinical scores across time points (baseline, post-treatment, and 4-week follow-up) will be interpreted as exploratory indicators of possible treatment-related trends, rather than definitive measures of efficacy. Methods: 20 participants with MS will be recruited (10 RR-MS and 10 PP-MS) with at least moderate to severe comorbid depressive symptoms. They must have failed at least one prior antidepressant treatment or psychotherapy. Eligible participants will undergo magnetic resonance imaging (MRI) of the brain, this will include high-resolution anatomical imaging to identify demyelinating lesions and high-resolution tractography to map the projections throughout the brain that originate from the TMS stimulation site within the left dorsolateral prefrontal cortex (DLPFC). Electrical field modelling will be performed using SimNIBS to identify the individual specific anatomical engagement by TMS in the DLPFC target region and whether presence of demyelinating lesions overlap with TMS-induced EF within the targeted circuitry. Individuals who do not have evidence of lesions at the target site will then be eligible for the TMS protocol to evaluate neurophysiological metrics of cortical excitability. They will then go on to receive an open-label course of iTBS targeting the left DLPFC using the Beam F3 method. This will involve five daily treatments of iTBS treatments for five consecutive days. iTBS will involve 600 pulses per session delivered as triplets of 50Hz repeated at 5Hz at 80% resting motor threshold (rMT) targeting the left DLPFC. The primary outcome will be reduction in depressive symptoms as per the Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary outcomes include fatigue (Modified Fatigue Impact Scale), self-reported mood symptoms, cognitive task performance, as well as measures of sleep, actigraphy, and heart rate variability using a fitness watch.