The contribution of the central nervous system to fatigue in patients suffering from MS

Fatigue is a frequently occurring symptom in MS patients. Several studies,
using a variety of measures of fatigue, report that approximately 70% of the
MS-patients suffer from fatigue (Krupp et al., 1988; van Engelen et al., 2004).
Moreover, fatigue is often considered one of the most disabling symptoms by
MS-patients; even 40 % of the patients report fatigue as the most serious
symptom (Murray, 1985). The underlying pathophysiology of MS-related fatigue is
still largely unknown and before directed therapeutic interventions can be
explored underlying mechanisms need to be identified and quantified. However,
whereas fatigue is generally thought difficult to define and to quantify, the
results of the proposed pilot study will yield a pragmatic starting point for
objective quantification of central aspects of fatigue, thereby providing a
measure to study symptom progression and a possible tool for the evaluation of
future drug therapies on fatigue in MS patients.
Mechanisms underlying motor fatigue can be separated into factors residing
within the muscle (peripheral fatigue) and factors within the central nervous
system (central fatigue). Several lines of evidence suggest that fatigue within
MS patients has a dominant central component (Sheean et al., 1997;Roelcke et
al., 1997;Colombo et al., 2000;Comi et al., 2001). In the proposed experiments
we intend to investigate both central and peripheral aspects of fatigue in
MS-patients using a combination of simultaneously applied techniques;
twitch-superimposition, electromyographic (EMG) and force recordings and
functional magnetic resonance imaging (fMRI). The twitch-superimposition
technique gives an indication of the efficiency of the central nervous system
driving the motoneurons. The EMG and force measurements quantify the outcome of
the central drive to the motoneurons. Functional MRI-data provide information
about the activation of the involved areas of the central nervous system during
fatigue. Hence, this combination of techniques gives a unique tool for the
study of the central and peripheral aspects of fatigue.

In the proposed experiments we intend to investigate both central and
peripheral aspects of fatigue in MS-patients using a combination of
simultaneously applied techniques; twitch-superimposition, electromyographic
(EMG) and force recordings and functional magnetic resonance imaging (fMRI).
The twitch-superimposition technique gives an indication of the efficiency of
the central nervous system driving the motoneurons. The EMG and force
measurements quantify the outcome of the central drive to the motoneurons.
Functional MRI-data provide information about the activation of the involved
areas of the central nervous system during fatigue. Hence, this combination of
techniques gives a unique tool for the study of the central and peripheral
aspects of fatigue.

Subject perform contractions with their index finger in a fMRI scanner.
At first short lasting contractions for the identification of the regions of
interest for the analysis of the brain data. Followed by long lasting fatiguing
contractions. During the contractions the muscle will be activated and we
compared the activity of the muscle (twitch superimposition) with the brains
activation.
The data obtained in healthy control subjects will be compared with data from
MS-patients (control subjects are age matched).

Subjects perform shortlasting contracties in the scanner followed by a
fatiguing 3-minute contraction.

The time investment is about 4 hours. No risks associated with the fMRI scanner
are known.