Article Text

other Versions

Download PDFPDF
Research paper
rTMS affects working memory performance, brain activation and functional connectivity in patients with multiple sclerosis
  1. H E Hulst1,
  2. T Goldschmidt1,
  3. M A Nitsche2,3,
  4. S J de Wit4,
  5. O A van den Heuvel1,4,
  6. F Barkhof5,
  7. W Paulus6,7,
  8. Y D van der Werf1,
  9. J J G Geurts1
  1. 1Department of Anatomy and Neurosciences, Section of Clinical Neuroscience, VUmc MS Center Amsterdam, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, The Netherlands
  2. 2Leibniz Research Centre for Working Environment and Human Factors, Dortmund, Germany
  3. 3Department Neurology, University Medical Hospital Bergmannsheil, Bochum, Germany
  4. 4Department of Psychiatry, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, The Netherlands
  5. 5Department of Radiology and Nuclear Medicine, VUmc MS Center Amsterdam, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, The Netherlands
  6. 6Department of Clinical Neurophysiology, University of Göttingen, Gottingen, Germany
  7. 7Institutes of Neurology and Healthcare Engineering, UCL, London, United Kingdom
  1. Correspondence to HE Hulst, VU University Medical Center, Department of Anatomy and Neurosciences, De Boelelaan 1108, 13E01 (O2 gebouw), Amsterdam 1081 BT, The Netherlands; he.hulst{at}


Objective To investigate the effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) of the right dorsolateral prefrontal cortex (DLPFC) on working memory performance, while measuring task-related brain activation and task-related brain connectivity in patients with multiple sclerosis (MS).

Methods 17 patients with MS and 11 healthy controls (HCs) underwent 3 experimental sessions (baseline, real-rTMS, sham-rTMS), all including an N-back task (3 task loads: N1, N2, N3; control condition: N0) inside the MR scanner. Prior to imaging, real-rTMS (10 Hz) was applied to the right DLPFC. The stimulation site was defined based on individually assessed N-back task activation at baseline and located using neuronavigation. Changes in whole brain functional activation and functional connectivity with the right DLPFC were calculated.

Results N-back task accuracy (N2 and N3) improved after real-rTMS (and not after sham-rTMS) compared with baseline (p=0.029 and p=0.015, respectively), only in patients. At baseline, patients with MS, compared with HCs, showed higher task-related frontal activation (left DLPFC, N2>N0), which disappeared after real-rTMS. Task-related (N1>N0) functional connectivity between the right DLPFC and the right caudate nucleus and bilateral (para)cingulate gyrus increased in patients after real-rTMS when compared with sham stimulation.

Conclusions In patients with MS, N-back accuracy improved while frontal hyperactivation (seen at baseline relative to HCs) disappeared after real-rTMS. Together with the changes in functional connectivity after real-rTMS in patients, these findings may represent an rTMS-induced change in network efficiency in patients with MS, shifting patients’ brain function towards the healthy situation. This implicates a potentially relevant role for rTMS in cognitive rehabilitation in MS.

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.


  • HEH and TG contributed equally.

  • Contributors HEH, TG, MAN, YDvdW, OAvdH, JJGG provided substantial contributions to the conception or design of the work, or the acquisition, analysis or interpretation of data. All authors were involved in drafting the work or revising it critically for important intellectual content and final approval of the version published. JJGG and HEH were involved in agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

  • Funding Dr. Werner Jackstädt-Stiftung, Dutch MS research foundation (MS 12-799 & 09-538d).

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval Ethics Review Board of the VU University Medical Center.

  • Provenance and peer review Not commissioned; externally peer reviewed.

Linked Articles