Non-invasive Brain Stimulation in Multiple Sclerosis Fatigue

Non-invasive Brain Stimulation for Altering Neuro-inflammatory Mediators of Central Fatigue in Multiple Sclerosis

The neurobiological basis of central fatigue in multiple sclerosis remained unclear so far. This study investigates reward-related brain mechanisms, inflammation, and their modulation by non-invasive brain stimulation using fMRI, proteomics, and clinical measures to improve future treatment of central fatigue in MS. In the study, persons suffering from relapsing-remitting MS (RRMS) with vs. without comorbid central fatigue will be included.

The study comprises five experimental visits conducted at Charité University Medicine on five consecutive days (i.e., V1 - V5) and two follow-up visits two (V6) and four (V7) weeks after V5. True or sham anodal transcranial Direct Current Stimulation (tDCS) is applied to the left dorsolateral prefrontal cortex (dlPFC) at the five visits V1 to V5. All primary and secondary outcomes are assessed at V1 and V5.

At V6 and V7, measures of central fatigue are additionally assessed via questionnaires which are send to and back from the patients via mail.

Participants of all groups will participate in all visits.

Study Overview

• Status: Recruiting
• Conditions: Multiple Sclerosis; Fatigue in Multiple Sclerosis
• Intervention / Treatment: Device: tDCS of dlPFC; Device: Sham Stimulation of dlPFC

• Study Type: Interventional
• Enrollment (Estimated): 84
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Janina Dr. Behrens, Dr. med.; Phone Number: +49 30 7560921; Email: janina.behrens@charite.de
• Study Contact Backup: Name: Martin Dr. Weygandt, PhD; Email: martin.weygandt@mdc-berlin.de

Study Locations

• Germany
  • State of Berlin
    • Berlin, State of Berlin, Germany, 10117
      • Recruiting
      • Charite Campus Mitte
      • Contact: Janina Dr. Behrens, MD; Phone Number: +49 30 7560921; Email: janina.behrens@charite.de
      • Sub-Investigator: Zoe J Mossmann, MD/PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Men and women

  • 18 - 70 years
  • Established MS diagnosis (relapsing-remitting MS; RRMS) prior to study inclusion
  • Maximal EDSS of 4
  • Maximal disease duration 10 years
  • Existing health insurance
  • Stable or no treatment with disease modifying treatment (DMT) in last six months prior to study onset
  • Persons with RRMS and FSMC score ≥ 22 will be included in group "RRMS with fatigue"
  • Persons with RRMS and FSMC score < 22 will be included in group "RRMS without fatigue"

Exclusion Criteria:

• • MRI contraindications

  • Known endocrine, immunologic, psychiatric, and neurologic disease (other than RRMS and Major Depressive Diosorder)
  • Current treatment with pharmaceuticals affecting monoaminergic functioning such as Levodopa, Amantadin, Fluoxetin, Paroxetin or antipsychotics
  • Relapse or treatment with steroids in last four weeks window prior to study onset
  • DMT other than B-cell depleting monoclonal antibodies or fumarates
  • Sleep disorder as assessed with Pittsburgh Sleep Quality Index

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: tDCS Stimulation of dlPFC; Medical device: tDCS Stimulation over left dorsolateral prefrontal cortex (DLPFC) for 20 min daily over 5 consecutive days	Device: tDCS of dlPFC; Transcranial direct current stimulation over left dorsolateral prefrontal cortex (DLPFC) for 20 min daily over 5 consecutive days at 1200 uA
Sham Comparator: Sham Stimulation of dlPFC; Medical device: Placebo Sham stimulation over left dorsolateral prefrontal cortex (dlPFC) for 20 min daily over 5 consecutive days	Device: Sham Stimulation of dlPFC; Sham Stimulation of the dlPFC via tDCS device for 20 minutes on 5 consecutive days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Central fatigue	Assessed with cognitive subscale of with Fatigue Scale for Motor and Cognitive Functions (FSMC): Minimum 20 points, maximum 100 points, higher values denoting worse outcome	At enrolment and 4 days, two weeks and four weeks after enrolment
Neurobehavioral markers of effort discounting	Measured in a functional MRI (fMRI) task	At enrolment and 4 days after enrolment
Neurobehavioral markers of habit formation	Measured in an fMRI task	At enrolment and 4 days after enrolment
White matter integrity MRI measure	Computed as voxel-wise quotients of T1-weighted and T2-weigted anatomical MRI brain scan parameters	At enrolment and 4 days after enrolment
Brain age marker	Inferred via machine learning from anatomical T1-weighted brain scan	At enrolment and 4 days after enrolment
Whole-brain grey matter fraction	Inferred from anatomical T1-weighted brain MRI scans	At enrolment and 4 days after enrolment
Whole-brain volume of focal brain lesions	Inferred from anatomical T2-weighted brain MRI scans	At enrolment and 4 days after enrolment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in concentration of inflammatory markers	124 blood-derived inflammatory cytokine and chemokine markers determined via an inflammatory panel	At enrolment and 4 days after enrolment
Change in cognitive performance	Brief International Cognitive Assessment for MS (BICAMS)	At enrolment and 4 days after enrolment
Complementary fatigue markers	Fatigue Severity Scale (FSS), Minimum value 7, Maximum value 63, higher score denoting a worse outcome.	At enrolment, and 4 days, two and four weeks after enrolment
Severity of depressive symptoms	Beck Depression Inventory (BDI-II), Minimum value 0, Maximum value 63, higher values denoting worse outcome	At enrolment and 4 days after enrolment
Sleep quality	Pittsburgh Sleep Quality Index (PSQI), Minimum Score 0, Maximum Score 21, higher score denoting worse outcome	At enrolment and 4 days after enrolment
Severity of anxiety symptoms	Measured on the State-Trait Anxiety index-I (STAI-I), minimum score 20, maximum score 80, higher score denoting worse outcome	At enrolment and 4 days after enrolment
Change in Fatigue severity	Visual analogue scale of fatigue (VAS-F), minimum value 1, maximum value 10, higher score denoting worse outcome	At enrolment, and 1,2,3,4 days, two and four weeks after enrolment

Collaborators and Investigators

• Sponsor: Charite University, Berlin, Germany
• Investigators: Principal Investigator: Chotima Dr. Böttcher, PhD, Max-Delbrück-Centrum Berlin

Study record dates

Study Major Dates

• Study Start (Estimated): March 2, 2026
• Primary Completion (Estimated): March 1, 2028
• Study Completion (Estimated): June 1, 2028

Study Registration Dates

• First Submitted: February 12, 2026
• First Submitted That Met QC Criteria: February 23, 2026
• First Posted (Actual): February 27, 2026

Study Record Updates

• Last Update Posted (Actual): February 27, 2026
• Last Update Submitted That Met QC Criteria: February 23, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Multiple Sclerosis; Fatigue; Transcranial direct current stimulation
• Additional Relevant MeSH Terms: Nervous System Diseases; Autoimmune Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Multiple Sclerosis; Fatigue
• Other Study ID Numbers: FAMS-DFG; EA4/044/25 (Other Grant/Funding Number: Charite University Ethics Comission)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie the results of reported articles (text, tables, figures, supplemental data) will be shared after deidentification.
• IPD Sharing Time Frame: Beginning three years after project end
• IPD Sharing Access Criteria: Researchers who provide a methodologically sound proposal.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No