Functional MRI

Although the resolution of acute inflammation, remyeli-nation, redistribution of voltage-gated sodium-channels in persistently demyelinated axons, and recovery from sub-lethal axonal injury are all factors likely to limit the clinical impact of damaging MS pathology (Waxman and Ritchie, 1993; De Stefano et al., 1995b), other mechanisms have been recently recognized as potential contributors to the recovery or to the maintenance of function in the presence of irreversible MS-related axonal damage. Brain plasticity is a well-known feature of the human brain that is likely to have several pathological substrates, including an increased axonal expression of sodium channels (Waxman, 1998), synaptic changes, increased recruitment of parallel existing pathways or "latent" connections, and reorganization of distant sites. All these changes might have a major adaptive role in limiting the functional consequences of axonal loss. The signal changes seen during fMRI studies depend on the blood oxygenation level-dependent mechanism, which in turn involves changes of the transverse magnetization relaxation time—either T2* in a gradient echo sequence, or T2 in spin echo sequence. These changes are attributable to differences in deoxyhemoglobin subsequent to variations of neuronal activity (Ogawa et al., 1993). The application of fMRI to the study of the motor, visual, and cognitive systems in patients with MS has provided new insights into the mechanisms contributing to the progressive clinical worsening of these patients.

Functional cortical changes have been demonstrated in all MS phenotypes, using different fMRI paradigms. A study of the visual system (Werring et al., 2000) in patients who had recovered from a single episode of acute optic neuritis demonstrated that such patients had an extensive activation of the visual network (including the claustrum, lateral temporal, and posterior parietal cortices and thalamus in addition to the primary visual cortex) compared to healthy volunteers. An altered brain pattern of movement-associated cortical activations, characterized by an increased recruitment of the contralateral primary sensorimotor cortex during the performance of simple tasks (Rocca et al., 2003a;

Filippi et al. , 2004a) (Fig. 3) and by the recruitment of additional "classical" and "higher-order" sensorimotor areas during the performance of more complex tasks (Filippi et al., 2004a), has been demonstrated in patients with CIS. An increased recruitment of several sensorimotor areas, mainly located in the cerebral hemisphere ipsilateral to the limb which performed the task has also been demonstrated in patients with early MS and a previous episode of hemi-paresis (Pantano et al., 2002a). Interestingly, in patients with similar characteristics, but who presented with an optic neuritis, this increased recruitment involved sensorimotor areas which were mainly located in the contralateral cerebral hemisphere (Pantano et al., 2002b). In patients with established MS and an RR course, functional cortical changes have been shown during the performance of visual (Rombouts et al., 1998), motor (Lee et al., 2000b; Reddy et al., 2000a, 2000b; Filippi et al., 2002a; Rocca et al., 2002a), and cognitive (Staffen et al., 2002; Hillary et al., 2003; Parry et al., 2003) tasks. Movement-associated cortical changes, characterized by the activation of highly specialized cortical areas, have also been described in patients with SP-MS (Rocca et al., 2003b) during the performance of a simple motor task (Fig. 4). Two fMRI studies of the motor system (Filippi et al., 2002b; Rocca et al., 2002b) of patients with PP-MS suggested a lack of "classical" adaptive mechanisms as a potential additional factor contributing to the accumulation of disability in this unusual phenotype of the disease.

The results of all these studies suggest that there might be a "natural history" of the functional reorganization of the cerebral cortex in MS patients, which might be characterized, at the beginning of the disease, by an increased recruitment of those areas "normally" devoted to the performance of a given task, such as the primary sensorimotor cortex and the supplementary motor area in case of a motor task. At a later stage, bilateral activation of these regions is first seen, followed by a widespread recruitment of additional areas, which are usually recruited in normal people to perform novel/complex tasks. This notion has been supported by the results of a study (Filippi et al., 2004b) that has provided a direct demonstration that, during the performance of a simple motor task, patients with MS activate some regions that are part of a frontoparietal circuit, whose activation occurs typically in healthy subjects during object manipulation (Filippi et al., 2004b).

Such functional cortical changes are likely to be adaptive (or maladaptive) phenomena more than to be a mere reflection of a different task performance between patients and controls. If performance factor was, in fact, not controlled in preliminary fMRI studies (Lee et al., 2000b; Reddy et al., 2000a, 2000b), more recent studies have taken into account this confounder either by studying patients with no overt clinical involvement of the investigated system (Filippi et al., 2002a, 2002b; Rocca et al., 2002a, 2003a, 2003b, 2003c) or by assessing the performance of passive tasks

Figure 3 Brain patterns of cortical activations on a rendered brain in right-handed healthy subjects (A and C) and patients at presentation with clinically isolated syndromes suggestive (CIS) of multiple sclerosis (B and D) during the performance of a simple motor task with their clinically-unimpaired and fully normal functioning upper left hands. In patients with CIS, an increased activation of the right primary sensorimotor cortex is visible (B and D).

Figure 3 Brain patterns of cortical activations on a rendered brain in right-handed healthy subjects (A and C) and patients at presentation with clinically isolated syndromes suggestive (CIS) of multiple sclerosis (B and D) during the performance of a simple motor task with their clinically-unimpaired and fully normal functioning upper left hands. In patients with CIS, an increased activation of the right primary sensorimotor cortex is visible (B and D).

(Reddy et al., 2002). The following are the main findings supporting the adaptive role of functional cortical changes in MS:

1. The activity of some cortical areas may be influenced by the extent and the severity of T2-visible lesion damage. Several studies have found a strong correlation between the increased cortical activation of several areas with increasing T2-lesion load in patients with relapsing MS (Lee et al. , 2000b; Pantano et al., 2002b; Rocca et al., 2002a, 2002b), as well as in those with SP-MS (Rocca et al., 2003b) (Fig. 4) and PP-MS (Rocca et al., 2002b). Some studies also found increased sensorimotor cortex recruitment with increasing lesion damage of the corticospinal tracts, measured on ^-weighted images (Pantano et al., 2002b), or with whole brain intrinsic lesion damage, measured on MTR and MD maps (Rocca et al., 2002a).

2. The severity of normal-appearing brain tissue damage, measured using MRS (Reddy et al., 2000a; Rocca et al., 2003a), MT MRI, or DW MRI (Filippi et al., 2002b; Rocca et al. , 2002a, 2003b), is another important factor that modulates movement-associated cortical reorganization, as shown by studies of patients with various disease phenotypes and different levels of disability (Reddy et al., 2000a), patients at presentation with CIS suggestive of MS (Rocca et al., 2003a), patients with RR-MS and no clinical disability (Rocca et al., 2002a), and patients with PP-MS and SP-MS with different degrees of clinical involvement (Filippi et al., 2002b; Rocca et al., 2003b).

3. Subtle gray matter damage, not detected when using cMRI, may play a role in modulating cortical excitability, as demonstrated in patients with SP-MS (Rocca et al., 2003b) and in patients with clinically definite MS and

Figure 4 Brain patterns of cortical activations on an axial rendered brain (A) from right-handed patients with secondary progressive multiple sclerosis (MS) during the performance of a simple motor task with their clinically unimpaired and fully normal functioning upper right hands. The activity of the contralateral middle frontal gyrus (MFG) was significantly correlated (r = 0.87, P < 0.001) with brain dual-echo lesion load (B).

Figure 4 Brain patterns of cortical activations on an axial rendered brain (A) from right-handed patients with secondary progressive multiple sclerosis (MS) during the performance of a simple motor task with their clinically unimpaired and fully normal functioning upper right hands. The activity of the contralateral middle frontal gyrus (MFG) was significantly correlated (r = 0.87, P < 0.001) with brain dual-echo lesion load (B).

nonspecific (less than three lesions) cMRI findings (Rocca et al., 2003c).

4. The demonstration of strong correlations between cortical activations and cervical cord damage, quantified using MT MRI, in patients with PP-MS (Rocca et al., 2002b), patients with a previous episode of acute myelitis of probable demyelinating origin (Rocca et al., 2003d) (Fig. 5), and patients with Devic's neuromyelitis optica (Rocca et al. , 2004) suggests that not only brain, but also spinal cord pathology can induce cortical changes with the potential to limit the functional impact of the disease.

Although the actual role of cortical reorganization on the clinical manifestations of MS remains unclear, the demonstration that patients with MS may have a normal level of performance despite the presence of diffuse tissue damage suggests that cortical adaptive changes are likely to contribute in limiting the clinical consequences of MS-related structural damage (Filippi and Rocca, 2003). The most compelling evidence that cortical reorganization may have a role in recovery from axonal damage derives from the study by Reddy et al. (2000b), who, with serial MRS and fMRI examinations, evaluated a patient after the onset of an acute

Figure 5 Brain patterns of cortical activations on an axial rendered brain (A) from right-handed patients with a previous isolated acute myelitis during the performance of a simple motor task with their clinically unimpaired and fully normal functioning upper right hands. The activity of the ipsilateral middle frontal gyrus (MFG) was significantly correlated (r = -0.80, P < 0.001) with average cervical cord magnetization transfer ratio (MTR) (B).

Figure 5 Brain patterns of cortical activations on an axial rendered brain (A) from right-handed patients with a previous isolated acute myelitis during the performance of a simple motor task with their clinically unimpaired and fully normal functioning upper right hands. The activity of the ipsilateral middle frontal gyrus (MFG) was significantly correlated (r = -0.80, P < 0.001) with average cervical cord magnetization transfer ratio (MTR) (B).

hemiparesis and a new, large demyelinating lesion located in the corticospinal tract. In this patient, clinical recovery preceded complete normalization of NAA and was accompanied by increased recruitment of ipsilateral primary sensorimotor cortex and supplementary motor area. In line with these findings, in a group of patients who complained of fatigue when compared to matched nonfatigued patients with MS, there was a reduced activation of a complex movement-associated cortical/subcortical network, including the cerebellum, the rolandic operculum, the thalamus, and the middle frontal gyrus (Filippi et al., 2002a). In these patients, a strong correlation between the reduction of thalamic activity and the clinical severity of fatigue was found, indicating that a less marked cortical recruitment might be associated with the appearance of clinical symptomatology in MS.

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