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

BACKGROUND:

Multiple sclerosis (MS) is an immune mediated disease, targeting the central nervous system. Globally, the prevalence and incidence are increasing. It is a chronic condition, with no known definitive cure. Fatigue is among the most disabling MS symptoms, and is highly prevalent afflicting up to 78%-95% of patients. Fatigue in persons with MS (PwMS) is consistently associated with lower quality of life and severity of fatigue is generally associated with employment status, and may worsen over time.

PATHOPHYSIOLOGY:

The pathophysiological basis for fatigue in MS is poorly understood, with several possible contributors. However, trait fatigue in everyday life associates with task-related hyperactivation of the premotor cortex during a non-fatiguing grip force task. Patients who are able to increase premotor activity after performing a fatiguing motor task are less affected by fatigue during everyday life. Taken together, these findings support the hypothesis, that patients suffering from trait fatigue allocate their premotor "neural resources" less efficiently than patients without fatigue. This implies a mismatch in the physiological neuronal inhibition/excitation balance, and is evident as hyperactivity of the premotor cortex during "normal" motor activities, which in turn impedes an efficient upscaling of premotor activity.

CURRENT TREATMENTS:

Currently, the pharmacological treatment options for MS-related fatigue are limited and unsatisfactory. Neither of the 2 commonly used pharmaceutical agents, Amantadine nor Modafinil, show both a significant and a clinically relevant reduction in fatigue. Physical exercise has an overall positive, and clinically relevant, effect on MS-related fatigue, but physical therapy is not a feasible intervention for all PwMS. Evidence from TMS studies of the motor-cortex in fatigued PwMS, suggests that this effect may be mediated by changes in motor network excitability.

RTMS:

Repetitive Transcranial Magnetic Stimulation (rTMS) is a non-invasive method for inducing plastic focal changes in the brain. It has been investigated for multitudes of ailments, and is considered a generally safe intervention. rTMS has been repeatedly shown to have a direct and lasting neuromodulating effect on the motor cortex after stimulation of the premotor network. It is suggested that inhibitory rTMS targeting the dorsal premotor cortex can improve motor performance.

PREVIOUS TRIALS:

While rTMS is extensively investigated in other contexts, there exists few studies on MS-related fatigue. A single small study (n=33), focused on safety, targeting either motor cortex or prefrontal cortex with an H-coil, failed to show a significant effect of the intervention. Several studies have shown an effect on fatigue as a secondary outcome. However, the heterogeneity in interventional protocol and target prevents further analysis. As far as the investigators are aware, no studies have investigated alleviating fatigue by neuromodulation of the premotor network.

OBJECTIVES:

The investigators will conduct a double-blinded randomized controlled trial, investigating the effect of rTMS in fatigue in PwMS. The investigators will conduct clinical measurements for their primary outcome. Clinical outcomes will be supported by ultra-high field MRI and neurophysiological measurements, as well as supplementary clinical outcomes, in order to acquire a broad dataset for further illumination of mechanisms. For outcomes, see relevant section.

STUDY DESIGN:

The trial consists of a baseline period; an intervention period; and a follow-up period.

At the baseline visit (D0), all participants will undergo clinical testing; structural 7T MRI; 7T MR Spectroscopy (MRS) to acquire baseline neurometabolite concentrations; functional connectivity (rs-fMRI) and structural connectivity (DWI). Between D0 and the first intervention day, participants will wear a wrist-borne accelerometer and fill out a fatigue diary.

The intervention period consists of 5 sequential weekdays, Monday through Friday. On the first day of treatment (D1), neurophysiological measures of motor excitation/inhibition will be acquired before and immediately after the intervention, using single- and paired-pulse TMS, with electromyography (EMG) as a readout. On the fifth and last intervention day (D5), participants will undergo immediate follow-up 7T MRI with metabolic, functional- and structural connectivity measures.

The main follow-up is 6 days after the last rTMS session, day 11 counting from first intervention. Here they will undergo follow-up clinical testing, follow-up 7T MRI with metabolic, functional- and structural connectivity measures. Between D5 and the Follow-up, participants will again wear a wrist-borne accelerometer and fill out a fatigue diary. At first day after end of intervention, and at 4 weeks after end of intervention, participants will be invited to fill out electronic questionnaires of relevant patient-reported outcomes.

CRITERIA FOR DISCONTINUATION:

Patients are discontinued in the study in case of inability to perform a baseline MRI scan; occurrence of MS relapse; new occurrence of any condition that is a contraindication for rTMS; excessive lack of compliance to the experimental protocol as assessed by the experimenters. Additionally, all subjects reserve the right to, at any time, withdraw from the study for any reason.

QUALITY ASSURANCE:

This is a one-site study, and will be monitored by an internal monitoring process, akin to Good Clinical Practice guidelines. All procedures will be done according to a pre-defined protocol, ensuring a standard operating procedure for acquisition of all data.

Additionally. The MR- and EMG-data quality is inspected during and right after data acquisition, as is normal practice in the clinical routine and research.

Logbooks are kept for all sessions and all deviations from protocol will be noted. Data quality is further assessed through the subsequent offline data processing stage, through standardized processing pipelines.

All staff who perform MR and TMS have received comprehensive training in the respective methods, as well as safety training. All staff involved in the project will be familiar with the procedure and methods and trained the experimental procedure before conducting measurements.

DATA ANALYSIS PLAN:

Primary outcome: All patients who attend at least one rTMS session and have follow-up data available, will be included in the intention-to-treat analysis for the primary outcome, regardless of amount of rTMS sessions completed.

EMG and MRI data will be preprocessed by a blinded researcher according to standardized pipelines. For EMG data, all trials will be manually checked by a blinded researcher for muscle artefacts preceding the TMS pulse, and offending trials removed.

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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
• EDSS > 6.5
• Major psychiatric disorder, including current clinical depression.
• Intake of medication that primarily acts on CNS or neurotransmission, except SSRI or SNRI
• Pacemaker or other implanted electronic devices
• Any intracranial metal
• Any metallic implant incompatible with MR scanning
• Claustrophobia
• Either patient or their close relatives suffering from epilepsy
• Current Drug or alcohol abuse

In accordance with Danish data protection legislation, it is currently not allowed to publish individual participant data.

Data that underlie published results related to the primary and secondary outcome measures will, following anonymization, be made available upon reasonable request. However, data will be grouped in appropriate age categories with minimum 5 participants in each group.

The TMS stimulation machine (MagPro XP orange edition, MagVenture A/S, Farum, Denmark), in combination with an A/P-coil with a separate active and placebo (sham) side. The sham side is designed to deliver <5% of the magnetic field of the active side, with similar tactile and auditory input.

The coil is designed to be reversible, with no markings as to which side is which. There is an internal sensor that allows the device to determine which side is up. Masking is ensured by a pre-programmed code, unique to each participant, which is input in the device whereafter the device will indicate if the "wrong" side is being used for stimulation.