Journal of the Neurological Sciences 244 (2006) 1 – 2
www.elsevier.com/locate/jns
Editorial
Toward a better understanding of cerebral plasticity in multiple sclerosis
It is now well-established that spontaneous clinical
recovery may occur after central nervous system (CNS)
injury associated to different neurological conditions. Over
the past decade, a large effort has been devoted to achieve a
better understanding of the mechanisms responsible for such
a recovery with the ultimate goal of developing new and
more effective treatment strategies. In this context, neuro-
physiologic and neuroimaging studies have provided
convincing evidence that the adult human cerebral cortex
is capable of significant functional plasticity, which may be
due to different substrates, such as an increased axonal
expression of sodium channels, synaptic changes, increased
recruitment of parallel existing pathways or blatentQ
connections, and reorganization of distant sites.
Functional magnetic resonance imaging (fMRI) is a safe
and non-invasive method which is currently used for
investigating brain plasticity in healthy and diseased
subjects. In multiple sclerosis (MS), fMRI is progressively
improving our understanding of the mechanisms responsi-
ble for the recovery of function and, conversely, for those
associated to the accumulation of irreversible disability [1].
In this context, fMRI-based studies are suggesting that the
lack or paucity of the correlation between structural MRI
metrics and the clinical manifestations of the disease [2]
could be explained, at least partially, by the variable
effectiveness of inter-patient reparative and recovery
mechanisms.
At present, most of the fMRI studies performed in MS
have interrogated the motor system [1]. This is likely the
consequence of several facts, including that motor symp-
toms and signs are frequently encountered in MS patients
and that motor paradigms are easy to be standardized and
provide reproducible results. More recently, cognitive
impairment, which is another frequent and clinically
relevant manifestation of MS, has become an additional
major area where fMRI has been applied extensively for
achieving a more complete picture of disease pathophysi-
ology [3–14]. Against this background, the elegant study of
Rachbauer et al., published in this issue of The Journal of
the Neurological Sciences, represents an additional step
toward a better understanding of the role of brain plasticity
in this disease [15].
0022-510X/$ - see front matter D 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jns.2005.12.001
In this study, the authors obtained a visual version of the
paced auditory serial addition test (PASAT), which is a
clinical tool used worldwide to test cognitive performance in
MS patients, to investigate the fMRI patterns of brain
activations from patients at presentation with clinically
isolated syndromes (CIS) suggestive of MS, patients with
definite MS and healthy controls. The study design is
similar to that of Staffen et al. [3], but an important novelty
has been introduced, i.e., a rigorous control to correct for
patients’ task performance during the fMRI acquisitions.
Indeed, a critical issue in the interpretation of fMRI studies
in MS is that the observed changes might be influenced by
different task performances between patients and controls.
While this problem can be easily overcome when using
motor paradigms (for instance, by selecting patients with no
overt clinical symptomatology or by studying passive
movements), the use of cognitive paradigms requires an
accurate quantification of subjects’ performance in order to
interpret the observed patterns of activations correctly. The
lack of such a rigorous control could contribute to explain
some of the discrepancies between the present study [15]
and a previous one [3].
Rachbauer et al. found an altered recruitment of several
brain areas in both groups of patients when compared with
healthy individuals [15]. The demonstration of an abnormal
pattern of activations in CIS patients during the paced visual
serial addition test (PVSAT) agrees with previous results
obtained when assessing movement-associated changes
[16,17]. This strengthens the notion that cortical reorgani-
zation is an early phenomenon in the course of MS. These
findings are also in line with those obtained from subjects at
risk of developing Alzheimer’s disease [18], and suggest the
potential of fMRI for detecting an abnormal pattern of
cortical activations, probably reflecting subclinical involve-
ment, early in the course of various CNS conditions.
Compared with controls, both patients’ groups had bless
focussedQ patterns of brain activations and tended to recruit
several areas in the frontal, parietal and occipital lobes,
which have different roles in cognitive processing. The
finding that, when contrasted to healthy individuals, MS
patients show an increased recruitment of a widespread
brain cognitive network is consistent with the results
2 Editorial
obtained using motor paradigms [1]. However, recent data
suggest that the movement-associated patterns of increased
brain recruitment change with disease evolution [19].
Clearly, the cognitive network has a different organization
and hierarchy than the motor one but, at present, when
considering together the results of the available fMRI
studies performed to investigate cognition in MS [3–14],
such a temporal profile does not seem to emerge. Therefore,
the results of Rachbauer et al. [15] are also important in this
respect and call for further investigations to confirm whether
motor and cognitive brain networks do behave differently in
response to the progressive accumulation of tissue injury
associated with MS progression.
The patients studied had a normal performance at the
PVSAT and PASAT [15]. This suggests that the observed
functional changes are likely to have a compensatory role in
limiting the cognitive outcome of MS-related tissue damage.
Unfortunately, the relation between fMRI changes and MR-
metrics of tissue injury has not been investigated by
Rachbauer et al. [15]. Albeit previous fMRI studies have
demonstrated that cortical reorganization in MS is associ-
ated to the amount and severity of brain and cervical cord
pathology (including T2-visible lesion load, diffuse normal-
appearing white matter damage and gray matter involve-
ment) [1], different aspects of MS pathology are likely to
contribute differently to the genesis of specific functional
systems’ impairment. As a consequence, quantifying the
severity of overall brain atrophy and gray matter damage in
MS patients with cognitive impairment and correlate them
to the fMRI findings might provide useful additional insight
into the pathogenesis of the disease.
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Maria A. Rocca
Massimo Filippi4
Neuroimaging Research Unit, Department of Neurology,
Scientific Institute and University Ospedale San Raffaele,
via Olgettina 60, 20132 Milan, Italy
E-mail address: filippi.massimo@hsr.it.
4Corresponding author. Tel.: +39 02 26433032;
fax: +39 02 26433054.
5 December 2005