Is Transcranial Magnetic Stimulation a potential tool for cognitive therapy in Multiple Sclerosis?

Cognitive impairment, e.g. working memory impairment, is highly prevalent in
multiple sclerosis (MS) and causes severe impairment of daily living
activities. So far, just a few studies have been performed on cognitive
rehabilitation in MS, mostly applying mental training schemes or
pharmacological stimulation, and they showed only little improvement of
cognitive function. Repetitive transcranial magnetic stimulation (rTMS) may be
a suitable method to improve cognitive function in MS patients, as it is known
to induce neural plasticity as well as improvement in working memory function
in psychiatric patients. rTMS has been applied in MS patients to improve
spasticity. However, it has not yet been used to improve working memory
function. Within the scope of cognitive therapy and cognitive rehabilitation,
rTMS seems to be a promising method, but more research is now needed to
increase our understanding of the precise clinicocognitive effects of rTMS in
MS patients. The current study is planned to provide necessary insights for
future longitudinal studies using rTMS to treat cognitively impaired MS
patients.

The aim of the proposed pilot study is to explore the efficacy of rTMS in
inducing a (transient) localized increase in brain activity of MS patients
which is hypothesized to be beneficial for cognitive functioning. This is the
first step that needs to be taken to validate the technique for further studies
on compensatory brain mechanisms and cognitive rehabilitation in a future
longitudinal research setting.

This is a cross-sectional, double-blind, sham-controlled, pre-post intervention
study using different neuroimaging modalities, including conventional MRI and
advanced MRI techniques (task specific functional MRI (fMRI), resting state
fMRI, MR spectroscopy).
Neuropsychological testing will be used to differentiate between cognitively
preserved and cognitively impaired MS patients. The scans will be
post-processed and analyzed to obtain information on the differences in brain
activity between rTMS stimulation and no stimulation/sham condition.

Repetitive Transcranial Magnetic Stimulation (rTMS) will be used to temporarily
(30 minutes) stimulate the dorsolateral prefrontal cortex in patients and in
healthy controls.

Participants need to visit the outpatient clinic of the VUmc on three separate
occasions, specified as follows:
Day 1: Baseline visit
- Neuropsychological testing (60 min),
- MRI-session (structural and functional, approximately 60 min)
- rTMS to study motor cortex plasticity (10 min; positive control)
- Blood sample

Day 2: Intervention/ placebo intervention
- rTMS treatment (or sham condition) (30 min)
- MRI-session (50 min)

Day 3: Intervention/placebo intervention
- rTMS treatment (or sham condition) (30 min)
- MRI-session (50 min)

MRI:
Earplugs will be provided to reduce the noise of the scanner. The scan will be
made at 1.5T and is considered to have neglectable risks. Before every
examination the subjects will be screened for metal objects in their bodies,
risk of claustrophobia, or other MR dependent exclusion criteria. In between
the different scans that will be made, the researcher will ask the subject
after their condition. If necessary, the scan session can be stopped
immediately by the researcher or by the participant (emergency button). To our
knowledge, the MRI is not causing any damage as long as normal procedures are
followed.

rTMS:
With regard to the rTMS intervention, the published safety guidelines will be
followed sincerely. Since MS patients are more prone to epileptic activity
compared to the general population, additional safety precautions will be
taken, such as, exclusion of all subjects (both patient and control) with a
(first degree family) history of epilepsy, and/or use of tricyclic
antidepressants, neuropleptic agents, Fampridine, and other drugs that lower
the seizure threshold. Also, MS patients with extensive cortical pathology
(based on Calabrese et al., 2008 and the baseline MR scan) will be excluded
from participation to be conservative and on the safe side with regard to the
induction of epileptic activity by rTMS. Following these precautions, there are
hardly any risks for adverse events.

During the study, all participant do have the ability to withdraw from the
study without a reason and without consequences for further treatment in our
hospital.