Multiple SclerosisPhase 1NCT07562074
Transcranial Magnetic Stimulation for Depression in Multiple Sclerosis
A Phase 1 study testing Repetitive Transcranial Magnetic Stimulation (rTMS) in people with Multiple Sclerosis and Depression - Major Depressive Disorder, run by University of Calgary at 1 site in Canada.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Multiple Sclerosis, Depression - Major Depressive Disorder, Fatigue
- What is being tested?
- Repetitive Transcranial Magnetic Stimulation (rTMS)
- Type of treatment
- Medical device
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 20 participants
- Where
- 1 siteCanada
- Study dates
- 15 Jun 2026to 30 Dec 2027
- Phase
- Phase 1
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 18-65 years of age, inclusive.
- Males, females, and non-binary.
- 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.
- Expanded Disability Status Scale score <7.
- Fatigue Severity Scale ≥ 4.
- Moderate to severe major depressive disorder as defined by a Hamilton Depression Rating Scale-17 item score ≥18.
Show all 12Show fewer
- Did not benefit adequately from ≥ 1 antidepressant or course of psychotherapy.
- Stable immunotherapy for at least 3 months and medications for at least 4 weeks.
- Have no contraindications to TMS or magnetic resonance imaging.
- 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.
- Are able to adhere to the treatment schedule
- Pass the TMS adult safety screening (TASS) questionnaire
Who cannot join
- 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.
- 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.
- History of seizures.
- 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).
- Previous surgeries opening the skull leaving skull defects capable of allowing the insertion of a cylinder with a radius ≥ 5mm.
- Any diagnosis of a psychiatric diagnosis determined to be primary.
Show all 14Show fewer
- Are at a significant risk of harm to themselves or others.
- Have a substance or alcohol use disorder within the last three months.
- 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.
- Are currently pregnant, breast feeding, or plan to become pregnant over the duration of the study.
- Active suicidal ideation as defined by a score of 4 ≥ on item 10 of MADRS
- Have failed a course of ECT in the current episode. Previous ECT treatment outside of the current episode does not influence inclusion.
- 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
- Have concomitant major unstable medical illness
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Canada1 site
Foothills Medical Centre
Calgary, Alberta, T2N 2T9
Anna Bourgeois, 4039887901, anna.bourgeois@ucalgary.ca
About this study
Official title: A Pilot Study: Dorsolateral Prefrontal Cortex Transcranial Magnetic Stimulation Target Engagement and Safety in Primary Progressive and Relapsing-remitting Multiple Sclerosis
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.
Read more
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.
Read the detailed description
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.
- Being tested
- Repetitive Transcranial Magnetic Stimulation (rTMS)
- Keywords
- Multiple Sclerosis, TMS, rTMS, Depression, Brain Stimulation
- Medical subject headings
- Multiple Sclerosis, Fatigue, Depression
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Repetitive Transcranial Magnetic Stimulation (rTMS)Device
Treatment of iTBS for 5 consecutive days. iTBS will involve 600 pulses per session delivered as triplets of 50Hz repeated at 5Hz at 80% resting motor threshold (rMT).
| Study group | Role | What they receive |
|---|---|---|
| Stimulation to the Left Dorsolateral Prefrontal Cortex (DLPFC) | Experimental | Participants will receive intermittent theta burst stimulation (iTBS) targeting the left dorsolateral prefrontal cortex (Magstim D70 AFC Air Film coil). Prior to treatment, participants will undergo magnetic resonance imaging and individualized electric field modeling to ensure that the stimulation target and its downstream projections do not overlap with demyelinating lesions.
iTBS will be delivered at 80% of resting motor threshold, consisting of 600 pulses per session administered as triplets at 50 Hz repeated at 5 Hz. Treatments will be delivered five times per day, with a one-hour inter-session interval, over five consecutive weekdays. Clinical, cognitive, and neurophysiological outcome measures will be assessed at baseline, post-treatment, and at -week follow-up to evaluate safety, feasibility, and preliminary clinical effects. Receives: Device: Repetitive Transcranial Magnetic Stimulation (rTMS) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Presence of demyelinating lesions within the TMS-induced electric field and downstream projections (Safety)
Overlap between individualized TMS electric field modeling and demyelinating lesions identified on MRI, including cortical target and tractography-defined downstream pathways.
Measured: Baseline (prior to intervention)
Clinical Global Impression-Severity and -Improvement scales (CGI-S, CGI-I)
The CGI provides an overall clinician-determined summary measure that takes into account all available information, including a knowledge of the patient's history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the patient's ability to function.
Measured: Baseline, Day 5 (post-treatment), and 4-week follow-up
Montgomery-Åsberg Depression Rating Scale (MADRS)
The Montgomery-Asberg Rating Scale (MADRS) is a 10-item clinician-rated assessment for depression in adults (18+). The MADRS focusses more upon functional impairment and somatic symptoms than other assessments which might focus more upon depressive cognitive attitudes (Montgomery and Asberg, 1979).
Measured: Baseline, Day 5 (post-treatment), and 4-week follow-up
17-item Hamilton Rating Scale for Depression (HAM-D-17)
The 17-item Hamilton Rating Scale for Depression (HAM-D-17) is a widely used clinician-rated tool to assess the severity of depressive symptoms, focusing on mood, guilt, suicide, insomnia, work/activity, retardation, agitation, anxiety, somatic symptoms, and weight loss.
Measured: Baseline, Day 5 (post-treatment), and 4-week follow-up
Columbia-Suicide Severity Rating Scale (C-SSRS).
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a questionnaire used for suicide assessment
Measured: Baseline, Day 5 (post-treatment), and 4-week follow-up
Secondary outcomes (9)
TMS Safety and Tolerability
Tolerability of intermittent theta burst stimulation (iTBS) will be assessed using a standardized TMS Safety and Tolerability Questionnaire administered before and after each treatment day. Measures will include participant-reported discomfort, pain, headache, scalp irritation, and other stimulation-related side effects, as well as the need for stimulation intensity adjustments or treatment discontinuation due to intolerance.
Measured: Daily during the 5-day treatment period and at post-treatment assessment (Day 5)
Fitness watch data
Participants will be provided with a fitness watch that will synch with a research app to collect sleep, actigraphy, and heart rate variability data. Continuous data transfer from the fitness watch will occur over the course of the treatment and follow-up periods for sleep and heart rate. Participants will aim to wear watches all the time and record when they take them off.
Measured: Watches will be given at the baseline session and be worn until the last follow-up session. (4 weeks after the intervention).
The Quick Inventory of Depressive Symptomatology - Self-Report (QIDS-SR)
A brief, 16-item self-assessment tool used to measure the severity of depressive symptoms over the past week, covering key areas like sleep, mood, appetite, energy, and concentration.
Measured: Time Frame: Baseline, Day 5 (post-treatment), 4-week follow-up
Generalized Anxiety Disorder 7-item scale (GAD-7)
A screening tool for generalized anxiety.
Measured: Time Frame: Baseline, Day 5 (post-treatment), 4-week follow-up
Scale for Suicidal Ideation (SSI)
Scale for Suicidal Ideation (SSI) is a widely used 19-item clinical rating scale (often semi-structured) that assesses the intensity of a person's suicidal thoughts, attitudes, and behaviors over the past week, measuring active desire, specific plans, and passive ideation
Measured: Time Frame: Baseline, Day 5 (post-treatment), 4-week follow-up
World Health Organization Quality of Life Questionnaire (WHOQOL)
The World Health Organization Quality of Life Questionnaire (WHOQOL) is a set of instruments for assessing an individual's subjective perception of their life, considering their culture, goals, and values, and covering domains like physical health, psychological well-being, independence, social relationships, and environment
Measured: Time Frame: Baseline, Day 5 (post-treatment), 4-week follow-up
Pain/Discomfort: Visual Analog Scale (VAS)
The Visual Analog Scale (VAS) for pain/discomfort is a simple, self-reported tool using a straight line (usually 10cm/100mm) with "no pain" at one end and "worst imaginable pain" at the other, where patients mark their current feeling; it measures subjective intensity for tracking symptoms, guiding treatment, and assessing overall progress by quantifying subjective experience on a continuous scale.
Measured: Time Frame: Baseline, Day 5 (post-treatment), 4-week follow-up
Insomnia Severity Index (ISI)
Designed as a brief screening tool for insomnia, the seven-item questionnaire asks respondents to rate the nature and symptoms of their sleep problems using a Likert-type scale.
Measured: Time Frame: Baseline, post-intervention, 4-week follow-up
Brief Fatigue Inventory (BFI)
The Brief Fatigue Inventory (BFI) is used to rapidly assess the severity and impact of fatigue.
Measured: Time Frame: Baseline, Day 5 (post-treatment), 4-week follow-up
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 May 2026
- Study start15 Jun 2026 (estimated)
- Primary completion30 Jun 2027 (estimated)
- Study completion30 Dec 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Multiple SclerosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 20 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Calgary
- Sponsor type
- University, hospital or other
- Collaborators
- Hotchkiss Brain Institute, University of Calgary
- Responsible party
- Principal investigator, Adrianna Giuffre, University of Calgary
- Investigators
- Adrianna Giuffre, PhD., Principal investigator, Cumming School of Medicine, University of Calgary
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07562074
- Sponsor's protocol ID
- REB25-0285
- Status last verified
- Apr 2026
- First submitted
- 6 Jan 2026
- Last updated
- 1 May 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: 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.
Publications
Ahmadpanah M, Amini S, Mazdeh M, Haghighi M, Soltanian A, Jahangard L, Keshavarzi A, Brand S. Effectiveness of Repetitive Transcranial Magnetic Stimulation (rTMS) Add-On Therapy to a Standard Treatment in Individuals with Multiple Sclerosis and Concomitant Symptoms of Depression-Results from a Randomized Clinical Trial and Pilot Study. J Clin Med. 2023 Mar 27;12(7):2525. doi: 10.3390/jcm12072525.
PubMed 37048608Siegert RJ, Abernethy DA. Depression in multiple sclerosis: a review. J Neurol Neurosurg Psychiatry. 2005 Apr;76(4):469-75. doi: 10.1136/jnnp.2004.054635.
PubMed 15774430Rossi S, Antal A, Bestmann S, Bikson M, Brewer C, Brockmoller J, Carpenter LL, Cincotta M, Chen R, Daskalakis JD, Di Lazzaro V, Fox MD, George MS, Gilbert D, Kimiskidis VK, Koch G, Ilmoniemi RJ, Lefaucheur JP, Leocani L, Lisanby SH, Miniussi C, Padberg F, Pascual-Leone A, Paulus W, Peterchev AV, Quartarone A, Rotenberg A, Rothwell J, Rossini PM, Santarnecchi E, Shafi MM, Siebner HR, Ugawa Y, Wassermann EM, Zangen A, Ziemann U, Hallett M; basis of this article began with a Consensus Statement from the IFCN Workshop on "Present, Future of TMS: Safety, Ethical Guidelines", Siena, October 17-20, 2018, updating through April 2020. Safety and recommendations for TMS use in healthy subjects and patient populations, with updates on training, ethical and regulatory issues: Expert Guidelines. Clin Neurophysiol. 2021 Jan;132(1):269-306. doi: 10.1016/j.clinph.2020.10.003. Epub 2020 Oct 24.
PubMed 33243615Uygur-Kucukseymen E, Pacheco-Barrios K, Yuksel B, Gonzalez-Mego P, Soysal A, Fregni F. Non-invasive brain stimulation on clinical symptoms in multiple sclerosis patients: A systematic review and meta-analysis. Mult Scler Relat Disord. 2023 Oct;78:104927. doi: 10.1016/j.msard.2023.104927. Epub 2023 Aug 4.
PubMed 37595371
Study at a glance
From the registry record, last updated by the sponsor on 1 May 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Pilot Study: Dorsolateral Prefrontal Cortex Transcranial Magnetic Stimulation Target Engagement and Safety in Primary Progressive and Relapsing-remitting Multiple Sclerosis
- ClinicalTrials.gov ID
- NCT07562074
- Acronym / sponsor ID
- REB25-0285
- Keywords
- Multiple Sclerosis, TMS, rTMS, Depression, Brain Stimulation
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 20 participants (estimated)
- Lead sponsor
- University of CalgaryUniversity, hospital or other
- Collaborators
- Hotchkiss Brain Institute, University of Calgary
- Study start
- 15 Jun 2026 (estimated)
- Primary completion
- 30 Jun 2027 (estimated)
- Study completion
- 30 Dec 2027 (estimated)
- First posted
- 1 May 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Stimulation to the Left Dorsolateral Prefrontal Cortex (DLPFC) | Experimental | Device: Repetitive Transcranial Magnetic Stimulation (rTMS)Participants will receive intermittent theta burst stimulation (iTBS) targeting the left dorsolateral prefrontal cortex (Magstim D70 AFC Air Film coil). Prior to treatment, participants will undergo magnetic resonance imaging and individualized electric field modeling to ensure that the stimulation target and its downstream projections do not overlap with demyelinating lesions. iTBS will be delivered at 80% of resting motor threshold, consisting of 600 pulses per session administered as triplets at 50 Hz repeated at 5 Hz. Treatments will be delivered five times per day, with a one-hour inter-session interval, over five consecutive weekdays. Clinical, cognitive, and neurophysiological outcome measures will be assessed at baseline, post-treatment, and at -week follow-up to evaluate safety, feasibility, and preliminary clinical effects. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- 18-65 years of age, inclusive.
- Males, females, and non-binary.
- 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.
- Expanded Disability Status Scale score <7.
- Fatigue Severity Scale ≥ 4.
Key exclusion criteria (14 listed)
- 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.
- 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.
- History of seizures.
- 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).
- Previous surgeries opening the skull leaving skull defects capable of allowing the insertion of a cylinder with a radius ≥ 5mm.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Repetitive Transcranial Magnetic Stimulation (rTMS)Treatment of iTBS for 5 consecutive days. iTBS will involve 600 pulses per session delivered as triplets of 50Hz repeated at 5Hz at 80% resting motor threshold (rMT). | Device | Stimulation to the Left Dorsolateral Prefrontal Cortex (DLPFC) |
Primary outcome
Presence of demyelinating lesions within the TMS-induced electric field and downstream projections (Safety)
Time frame: Baseline (prior to intervention)
Overlap between individualized TMS electric field modeling and demyelinating lesions identified on MRI, including cortical target and tractography-defined downstream pathways.
Clinical Global Impression-Severity and -Improvement scales (CGI-S, CGI-I)
Time frame: Baseline, Day 5 (post-treatment), and 4-week follow-up
The CGI provides an overall clinician-determined summary measure that takes into account all available information, including a knowledge of the patient's history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the patient's ability to function.
Montgomery-Åsberg Depression Rating Scale (MADRS)
Time frame: Baseline, Day 5 (post-treatment), and 4-week follow-up
The Montgomery-Asberg Rating Scale (MADRS) is a 10-item clinician-rated assessment for depression in adults (18+). The MADRS focusses more upon functional impairment and somatic symptoms than other assessments which might focus more upon depressive cognitive attitudes (Montgomery and Asberg, 1979).
17-item Hamilton Rating Scale for Depression (HAM-D-17)
Time frame: Baseline, Day 5 (post-treatment), and 4-week follow-up
The 17-item Hamilton Rating Scale for Depression (HAM-D-17) is a widely used clinician-rated tool to assess the severity of depressive symptoms, focusing on mood, guilt, suicide, insomnia, work/activity, retardation, agitation, anxiety, somatic symptoms, and weight loss.
Columbia-Suicide Severity Rating Scale (C-SSRS).
Time frame: Baseline, Day 5 (post-treatment), and 4-week follow-up
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a questionnaire used for suicide assessment
9 secondary outcomes
TMS Safety and Tolerability
Time frame: Daily during the 5-day treatment period and at post-treatment assessment (Day 5)
Fitness watch data
Time frame: Watches will be given at the baseline session and be worn until the last follow-up session. (4 weeks after the intervention).
The Quick Inventory of Depressive Symptomatology - Self-Report (QIDS-SR)
Time frame: Time Frame: Baseline, Day 5 (post-treatment), 4-week follow-up
Generalized Anxiety Disorder 7-item scale (GAD-7)
Time frame: Time Frame: Baseline, Day 5 (post-treatment), 4-week follow-up
Scale for Suicidal Ideation (SSI)
Time frame: Time Frame: Baseline, Day 5 (post-treatment), 4-week follow-up
World Health Organization Quality of Life Questionnaire (WHOQOL)
Time frame: Time Frame: Baseline, Day 5 (post-treatment), 4-week follow-up
Pain/Discomfort: Visual Analog Scale (VAS)
Time frame: Time Frame: Baseline, Day 5 (post-treatment), 4-week follow-up
Insomnia Severity Index (ISI)
Time frame: Time Frame: Baseline, post-intervention, 4-week follow-up
Brief Fatigue Inventory (BFI)
Time frame: Time Frame: Baseline, Day 5 (post-treatment), 4-week follow-up
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 May 2026.
- Background: PubMed 37048608Ahmadpanah M, Amini S, Mazdeh M, Haghighi M, Soltanian A, Jahangard L, Keshavarzi A, Brand S. Effectiveness of Repetitive Transcranial Magnetic Stimulation (rTMS) Add-On Therapy to a Standard Treatment in Individuals with Multiple Sclerosis and Concomitant Symptoms of Depression-Results from a Randomized Clinical Trial and Pilot Study. J Clin Med. 2023 Mar 27;12(7):2525. doi: 10.3390/jcm12072525.
- Background: PubMed 15774430Siegert RJ, Abernethy DA. Depression in multiple sclerosis: a review. J Neurol Neurosurg Psychiatry. 2005 Apr;76(4):469-75. doi: 10.1136/jnnp.2004.054635.
- Background: PubMed 33243615Rossi S, Antal A, Bestmann S, Bikson M, Brewer C, Brockmoller J, Carpenter LL, Cincotta M, Chen R, Daskalakis JD, Di Lazzaro V, Fox MD, George MS, Gilbert D, Kimiskidis VK, Koch G, Ilmoniemi RJ, Lefaucheur JP, Leocani L, Lisanby SH, Miniussi C, Padberg F, Pascual-Leone A, Paulus W, Peterchev AV, Quartarone A, Rotenberg A, Rothwell J, Rossini PM, Santarnecchi E, Shafi MM, Siebner HR, Ugawa Y, Wassermann EM, Zangen A, Ziemann U, Hallett M; basis of this article began with a Consensus Statement from the IFCN Workshop on "Present, Future of TMS: Safety, Ethical Guidelines", Siena, October 17-20, 2018, updating through April 2020. Safety and recommendations for TMS use in healthy subjects and patient populations, with updates on training, ethical and regulatory issues: Expert Guidelines. Clin Neurophysiol. 2021 Jan;132(1):269-306. doi: 10.1016/j.clinph.2020.10.003. Epub 2020 Oct 24.
- Background: PubMed 37595371Uygur-Kucukseymen E, Pacheco-Barrios K, Yuksel B, Gonzalez-Mego P, Soysal A, Fregni F. Non-invasive brain stimulation on clinical symptoms in multiple sclerosis patients: A systematic review and meta-analysis. Mult Scler Relat Disord. 2023 Oct;78:104927. doi: 10.1016/j.msard.2023.104927. Epub 2023 Aug 4.
- Individual participant dataSharing planned: No. 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.
Related trials for Multiple Sclerosis
RecruitingPhase 3
Efficacy and Safety of Remibrutinib After Switching From Ocrelizumab in Participants Living With Relapsing Multiple Sclerosis.
Relapsing Multiple Sclerosis
Active, not recruitingObservational study
A Study to Evaluate Long-Term Safety of Vumerity and Tecfidera in Participants With Multiple Sclerosis (MS)
Multiple Sclerosis
RecruitingObservational study
Study of Skin Tumors in Tuberous Sclerosis
Tuberous Sclerosis
Recruiting
The Effects of Synchronous and Asynchronous Pilates Training Based on Telerehabilitation on Core Stabilization, Balance, Cognitive Functions, and Quality of Life in Individuals With Multiple Sclerosis: A Single-Blind Randomized Controlled Trial
Multiple Sclerosis
RecruitingObservational study
Care in Multiple Sclerosis (MS)
Multiple Sclerosis
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Adrianna Giuffre, PhD. principal investigator
Cumming School of Medicine, University of Calgary
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Repetitive Transcranial Magnetic Stimulation (rTMS) in people with Multiple Sclerosis and Depression - Major Depressive Disorder, run by University of Calgary at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 1 May 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Anna L Bourgeois, MSc. (4039887901, anna.bourgeois@ucalgary.ca), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Presence of demyelinating lesions within the TMS-induced electric field and downstream projections (Safety) (time frame: Baseline (prior to intervention)). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT07562074, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 May 2026.