Brain activity, corticospinal integrity and fatigue in MS patients

Fatigue is an important symptom in Multiple Sclerosis (MS). Despite its impact,
the underlying pathophysiology of MS related fatigue is still largely unknown.
Before directed therapeutic interventions can be explored underlying mechanisms
need to be identified and quantified.
Fatigue is generally thought difficult to define and to quantify, but motor
fatigue is an important aspect of fatigue that can be examined. Recently, we
developed a setup to measure central and peripheral aspects of fatigue with
functional magnetic resonance imaging (fMRI). Twitch-superimposition, EMG and
force measurements are used to quantify the voluntary drive to the muscles and
fMRI data provides information about the activation of involved brain areas.
Hence, this combination of techniques provides a unique tool to study central
and peripheral aspects of fatigue. In addition, it is known that corticospinal
tract integrity correlates with disease severity (Wilson 2003). In stroke
patients it is shown that force-related brain activity signal changes are
different in patients with more corticospinal system damage compared to healthy
controls (Ward 2007). It is interesting to investigate whether such a
relationship can be found in MS patients too. Corticospinal system damage can
be measured using transcranial magnetic stimulation (TMS).
Our pilot data clearly demonstrated that motor fatigue in MS patients was
accompanied by significantly lower brain activation in most of the
(contralateral) motor areas. However, in patients suffering from strong
feelings of fatigue, increased activation was observed in ipsilateral
sensorimotor areas. The reduction in activation probably reflects reduced
neuronal input to the motor areas whereas the additional activation points to
increased effort in fatigued patients.
In the proposed experiments we will use similar techniques to further address
fatigue-related changes in the central nervous system. In addition we hope to
entangle the relationship between brain activity and corticospinal integrity
using TMS.
Although it has been shown to be difficult to correlate TMS responses with
disability progression in MS (Kallmann 2006), we want to investigate the effect
of possible deterioration of MS on the relationship between brain activity,
force production, central activation and corticospinal tract integrity.
The experiments are important from both a fundamental and a clinical
perspective. Knowledge about the underlying cause of fatigue, factors mediating
fatigue and secondary effects of fatigue will increase the awareness of the
problems associated with fatigue and will provide caregivers with insight into
possible therapeutic interventions of fatigue related problems.

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. In addition we will use TMS
to investigate corticospinal tract integrity. This will be used to further
investigate the relationship between brain activity and MS. Hence, this
combination of techniques gives a unique tool for the study of the central and
peripheral aspects of fatigue.
After 3 years, patients will be measured again in a similar experiment again,
to investigate the effect of possible deterioration of MS on the relationship
between brain activity, force production, central activation and corticospinal
tract integrity.

Subject perform contractions with their index finger outside and in a MR
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
compare the activity of the muscle (twitch superimposition) with the brain
activation. During the session outside the scanner, TMS will be applied before
and after the fatiguing task.
The data obtained in healthy control subjects will be compared with data from
MS patients (control subjects are age matched).

The time investment is about 5 hours for patients and 4 hours for health
controls. No risks associated with the fMRI scanner, TMS or twitch
interpolation are known.