About this trial

The goal of this clinical trial is to learn if repetitive Transcranial Magnetic Stimulation (rTMS) of the left premotor cortex can lessen fatigue in patients with Multiple Sclerosis, and if this is a feasible intervention. It will also give further information on fatigue in Multiple Sclerosis. The main questions it aims to answer is:

* Does premotor rTMS decrease fatigue symptoms in patients with Multiple Sclerosis? * Is the change in fatigue reflected in an altered balance between brain excitation and inhibition in the targeted premotor cortex?

Researchers will compare real rTMS with sham rTMS (which does not stimulate with a magnetic field), to see if real rTMS works to alleviate fatigue.

Participants will:

* Receive real or sham rTMS for 30 minutes, 5 days in a row * Visit the clinic before and 6 days after for baseline and follow-up * Fill out on-line questionnaires 1 day and 4 weeks after the end of intervention * Undergo a total of 3 brain scans (Magnetic Resonance Imaging at ultra-high field), at baseline, end of intervention, and follow-up * Undergo lab neurophysiological measurements before and after the first intervention session * Keep a fatigue diary and wear an activity tracker in the period before and after the intervention

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

A confirmed diagnosis of relapse-remitting or secondary progressive multiple sclerosis, according to most recent McDonald's criteria (Thompson et al., 2018). This diagnosis must not be more recent than 3 months

Must have fatigue as a complaint, and an FSMC score corresponding to at least moderate fatigue (>53)

Stable MS medication for at least 3 months

Disqualifiers

Pregnancy, any subject with the potential to become pregnant must ensure against this (e.g. by taking oral contraceptives, or other high efficacy method)

MS Relapse or steroid treatment within 3 months prior to inclusion

Current treatment targeted towards fatigue, or previous if discontinued within 3 months prior to inclusion

History of neurologic disease or other significant medical conditions, aside from MS

Trial design

Design model

Parallel

Treatments tested in this trial

Real Repetitive Transcranial Magnetic Stimulation
Device
Five sessions of real paired-pulse rTMS at 0.72Hz (inter-pulse interval of 30ms and inter-pair interval of 1381ms), for a total of 1300 pulse-pairs (30 minutes), across 5 sequential days, Monday to Friday. The stimulation is applied with a MagPro XP Orange stimulator (MagVenture A/S, Farum, Denmark), through a B65-Cool-A/P-CO coil (Magventure A/S) with an active and placebo (sham) side. The active side is an actively cooled figure-of-eight coil with an outer diameter of 65mm. Intensity is 80% of resting motor threshold. It is kept the same across all 5 sessions. The target is the left PMd, at MNI coordinates (34, -2, 66), transformed into patient space. Optimal coil placement, with respects to induced e-field at the target coordinates, is simulated with SimNIBS, based on the participants own MR images. The coil positioning is guided and monitored continuously with a neuronavigation system (Localite, Bonn, Germany) and the aid of robotic arm (Axilum Robotics, Schiltigheim, France ).
Sham Repetitive Transcranial Magnetic Stimulation
Device
Five sessions of real paired-pulse rTMS at 0.72Hz (inter-pulse interval of 30ms and inter-pair interval of 1381ms), for a total of 1300 pulse-pairs (30 minutes), across 5 sequential days, Monday to Friday. The stimulation is applied with a MagPro XP Orange stimulator (MagVenture A/S, Farum, Denmark), through a B65-Cool-A/P-CO coil (Magventure A/S) with an active and placebo (sham) side. The sham side does not deliver a magnetic pulse to the participant. The target is the left PMd, at MNI coordinates (34, -2, 66), transformed into patient space. Optimal coil placement, with respects to induced e-field at the target coordinates, is simulated with SimNIBS, based on the participants own MR images. The coil positioning is guided and monitored continuously with a neuronavigation system (Localite, Bonn, Germany) and the aid of robotic arm (Axilum Robotics, Schiltigheim, France ).

Treatment groups

60 Participants

are divided into 2 treatment groups

Group A: Active Repetitive Transcranial Magnetic Stimulation (rTMS)Active comparator 1 intervention

Group B: Sham Repetitive Transcranial Magnetic StimulationSham comparator 1 intervention

Trial outcomes

Primary outcomes

1

Change from baseline in patient reported fatigue severity, measured by the Fatigue Scale for Motor and Cognitive Symptoms (FSMC) from baseline to +6 days

Difference in change in score in Fatigue Scale for Motor and Cognitive functions, between baseline and clinical follow-up, between real and sham group. It is a validated 20 item score, designed for fatigue in MS. It has motor and cognitive subscales. Range 20-100. Cut-off for mild, moderate and severe fatigue is 43, 53 and 63 respectively.

Time frame

Follow-up at 6 days post intervention. Compared to baseline

Secondary outcomes

1

Change from baseline in regional brain tissue concentration of glutamate/glutamine in the stimulated premotor cortex, measured by single-voxel Magnetic Resonance Spectroscopy

Difference in change in concentration in metabolites, measured using Ultra High Field MR Spectroscopy, between baseline and day 5 of the intervention and clinical follow-up. Between real and sham group. Glutamate and Glutamine are some of the major excitatory neurotransmitters. It is measured as an outcome to assess the inhibitory load in the premotor/motor system. At lower fields, they are often combined (to Glx) due to difficulties in separating them. At 7T this is typically not necessary.

Time frame

Day 5 of intervention and 6 days post end of intervention, compared to baseline

2

Change from baseline in Brain tissue concentration of GABA in the stimulated premotor cortex, measured by single-voxel Magnetic Resonance Spectroscopy

Difference in change in concentration in metabolites, measured using Ultra High Field MR Spectroscopy, between baseline and day 5 of the intervention and clinical follow-up. Between real and sham group. GABA is one of the major inhibitory neurotransmitters. It is measured as an outcome to assess the inhibitory load in the premotor/motor system.

Time frame

Day 5 of intervention and 6 days post end of intervention, compared to baseline

3

Change from baseline in patient reported fatigue severity, measured by the Fatigue Scale for Motor and Cognitive Symptoms (FSMC)

Difference in change in score in Fatigue Scale for Motor and Cognitive functions, between baseline and questionnaire follow-up, between real and sham group. Changes in fatigue score at other time points, than main follow-up, will be treated as a secondary outcome. It is a validated 20 item score, designed for fatigue in MS. It has motor and cognitive subscales. Range 20-100. Cut-off for mild, moderate and severe fatigue is 43, 53 and 63 respectively.

Time frame

Follow-up at 1 and 28 days post intervention. Compared to baseline.

4

Change from baseline in objective fatiguability, measured by the Fatiguability Index (FI)

Difference in change in fatiguability (state fatigue) measured as fatiguability index (FI). FI is calculated based on a sustained 30s maximum voluntary contraction, where FI is defined as the ratio between the actual area under the curve over the theoretical max if 100% had been sustained for the entire contraction. Range 0-1.

Time frame

Follow-up at 6 days post intervention. Compared to baseline.

Other outcomes

1

Change from baseline in patient reported physical fatigue severity, measured by the Fatigue Scale for Motor and Cognitive Symptoms (FSMC), physical subscore

Difference in change in score in Fatigue Scale for Motor and Cognitive functions, for the 2 physical and cognitive subscores, between baseline and questionnaire follow-up, between real and sham group. Changes in fatigue score subscores will be treated as secondary outcomes. It is a validated 20 item score, designed for fatigue in MS. It has 10 items each for motor and cognitive subscales. Range 10-50.

Time frame

Follow-up at 1, 6 and 28 days post intervention. Compared to baseline.

2

Change from baseline in patient reported cognitive fatigue severity, measured by the Fatigue Scale for Motor and Cognitive Symptoms (FSMC), cognitive subscore

Difference in change in score in Fatigue Scale for Motor and Cognitive functions, for the 2 physical and cognitive subscores, between baseline and questionnaire follow-up, between real and sham group. Changes in fatigue score subscores will be treated as secondary outcomes. It is a validated 20 item score, designed for fatigue in MS. It has 10 items each for motor and cognitive subscales. Range 10-50.

Time frame

Follow-up at 1, 6 and 28 days post intervention. Compared to baseline.

3

Per-session changes in patient reported fatigue using the Visual-Analogue Fatigue Scale (VAFS)

Difference in change in fatigue, by VAFS scale, before/after each intervention, across the 5 intervention sessions. Participants will self-assess fatigue by a VAS scale before and after each intervention. Asking before and after at each sessions allows differentiation between acute effects due to the intervention, and effects that consolidate between sessions.

Time frame

Time-series, 5 intervention days.

4

Change from baseline in patient-reported depression symptoms, measured with the Major Depression Inventory (MDI)

MDI depression score is a commonly used rating scale for depressive symptoms. Range 0-50. Cut-offs for mild-, moderate- and severe depression are 21, 26 and 31 respectively.

Time frame

Follow-up at 6 days post intervention. Compared to baseline.

Fatigue Alleviation Through Neuromodulating Therapy in Multiple Sclerosis

About this trial

Eligibility criteria

Qualifiers

Disqualifiers

Trial design

Treatments tested in this trial

Treatment groups

Trial outcomes

Primary outcomes

Secondary outcomes

Other outcomes

Sponsors and contacts