Canada has one of the highest rates of multiple sclerosis (MS). MS patients experience disabling motor, visual, and sensory symptoms, and a high risk of comorbid major depressive disorder (MDD) and severe fatigue. The lifetime prevalence of MDD in MS patients is about 50%, and nearly 90% experience severe fatigue, both of which are not responsive to typical treatments. Repetitive transcranial magnetic stimulation (rTMS) is a first line, Health Canada approved non-invasive neurostimulation treatment for MDD. rTMS induces electrical activity in the cortex using magnetic fields generated outside of the head to drive neuronal firing in the target site. However, MS is typically an exclusion criterion due to safety concerns.

The goal of this clinical trial is to learn if repeated transcranial magnetic stimulation (rTMS) can be used to treat depression symptoms in adults with multiple sclerosis (MS). rTMS is a non-invasive form of brain stimulation that uses magnetic pulses to stimulate specific parts of the brain.

The main questions it aims to answer are:

Is rTMS safe, tolerable, and feasible to deliver as a treatment for depression and fatigue symptoms in individuals with MS? Does rTMS show preliminary effectiveness in improving depression and fatigue symptoms in this population?

Researchers will determine whether rTMS treatment improves mood, fatigue, and cognition across time points (baseline, after treatment, and 4-week follow-up).

Participants will: Complete screening, questionnaires, clinical assessments, cognitive tests, a brain MRI to help tailor the TMS treatment, and receive daily TMS sessions for 5 consecutive days, including: Pre-TMS brain mapping, five rTMS treatments (3 minutes) per day, separated by one hour. A safety and tolerability questionnaire will be administered daily. Complete post-treatment assessments (questionnaires, cognitive tests, psychiatric evaluation). Complete a 4-week follow-up visit, in person or virtually. Wear a fitness tracking watch during the study so researchers can collect activity data remotely.

About 20 people will take part in this study through the University of Calgary.

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.

Inclusion Criteria:

1. 18-65 years of age, inclusive.
2. Males, females, and non-binary.
3. Clinical diagnosis of relapsing-remitting or primary-progressive multiple sclerosis according to the revised McDonald criteria and as determined by the study neurologist and medical records.
4. Expanded Disability Status Scale score <7.
5. Fatigue Severity Scale ≥ 4.
6. Moderate to severe major depressive disorder as defined by a Hamilton Depression Rating Scale-17 item score ≥18.
7. Did not benefit adequately from ≥ 1 antidepressant or course of psychotherapy.
8. Stable immunotherapy for at least 3 months and medications for at least 4 weeks.
9. Have no contraindications to TMS or magnetic resonance imaging.
10. Ability to provide written consent obtained from study subject or subject's legal representative and ability for study subject to comply with the requirements of the study.
11. Are able to adhere to the treatment schedule
12. Pass the TMS adult safety screening (TASS) questionnaire

Exclusion Criteria:

1. Presence of any disease, medical condition, or physical condition that, in the opinion of the study investigator, study psychiatrist, or study neurologist, may compromise interfere, limit, affect, or reduce the study subject's ability to complete the study.
2. Presence of any disease, medical condition, or physical condition that, in the opinion of the study investigator, study psychiatrist, or study neurologist, may adversely impact the safety of the study subject or the integrity of the data.
3. History of seizures.
4. Any cranial metal implants (excluding ≤ 1mm thick epicranial titanium skull plates and dental fillings) or medical devices (i.e. cardiac pacemaker, deep brain stimulator, medication infusion pump, cochlear implant).
5. Previous surgeries opening the skull leaving skull defects capable of allowing the insertion of a cylinder with a radius ≥ 5mm.
6. Any diagnosis of a psychiatric diagnosis determined to be primary.
7. Are at a significant risk of harm to themselves or others.
8. Have a substance or alcohol use disorder within the last three months.
9. If participating in psychotherapy, must have been in stable treatment for at least three months prior to entry into the study, with no anticipation of change in the frequency of therapeutic sessions, or the therapeutic focus over the duration of the study.
10. Are currently pregnant, breast feeding, or plan to become pregnant over the duration of the study.
11. Active suicidal ideation as defined by a score of 4 ≥ on item 10 of MADRS
12. Have failed a course of ECT in the current episode. Previous ECT treatment outside of the current episode does not influence inclusion.
13. Have any significant neurological disorder or insult including, but not limited to: any condition likely to be associated with increased intracranial pressure, space occupying brain lesion, any history of epilepsy, cerebral aneurysm, Parkinson's disease, Huntington's chorea, significant head trauma with loss of consciousness for greater than or equal to 5 minutes
14. Have concomitant major unstable medical illness

Individual participant data will not be shared due to the small sample size and the heightened risk of participant re-identification. Additionally, the dataset contains sensitive personal health information related to mental health, and participant consent does not permit broader data sharing.