Mechanisms of Recovery

In MS, several mechanisms have the potential to cause tissue injury and, as a consequence, several mechanisms of recovery can also be advocated. Although our ability to monitor recovery using MR is still limited, it is certain that such a goal would represent a major achievement in our understanding of the disease and the assessment of treatment efficacy. Table 3 summarizes some of the damaging/recovery aspects of MS in relation to MR techniques with the potential to provide estimates of tissue repair (if used in a longitudinal fashion and at appropriate time intervals). In case of severe and irreversible neuroaxonal damage, cortical reorganization might represent a major contributor in promoting functional recovery. Given the importance of the ''axonal hypotheisis'' in the pathophysiology of MS (6) and the fact that fMRI literature in MS is rapidly increasing, the rest of this paragraph reviews the major results obtained using MR technology in defining the role of cortical reorganization in limiting the functional consequences of MS-related tissue injury.

Functional cortical changes have been demonstrated in all MS phenotypes, using different fMRI paradigms. A study of the visual system (217), in patients who had recovered from a single episode of acute ON, demonstrated that such patients had an extensive activation of the visual network compared with healthy volunteers. An altered brain pattern of movement-associated cortical activations, characterized by an increased recruitment of the contralateral primary sensorimotor cortex (SMC) during the performance of simple tasks (102,103) and by the recruitment of additional "classical" and "higher-order" sensorimotor areas during the performance of more complex tasks (103) has been demonstrated in patients with CIS. An increased recruitment of several sensorimotor areas, mainly located in the cerebral hemisphere ipsilateral to the limb that performed the task has also been shown in patients with early MS and a previous episode of hemiparesis (218). In

Figure 15 Sagittal diffusion tensor magnetic resonance image of the cervical cord from a patient with relapsing-remitting multiple sclerosis: mean diffusivity map (A), fractional aniso-tropy map (B), and color-encoded map of directionality (dark gray color means a preferential fiber direction along the z-axis, gray color along the x-axis, light gray color along the y-axis). The loss of normal fiber directionality is visible (C).

Figure 15 Sagittal diffusion tensor magnetic resonance image of the cervical cord from a patient with relapsing-remitting multiple sclerosis: mean diffusivity map (A), fractional aniso-tropy map (B), and color-encoded map of directionality (dark gray color means a preferential fiber direction along the z-axis, gray color along the x-axis, light gray color along the y-axis). The loss of normal fiber directionality is visible (C).

patients with similar characteristics, but who presented with an ON, this increased recruitment involved sensorimotor areas which were mainly located in the contralateral cerebral hemisphere (219). In patients with established MS and a RR course, functional cortical changes have been shown during the performance of visual (220), motor (Fig. 16) (221-225), and cognitive (226-229) tasks. Movement-associated cortical changes, characterized by the activation of highly specialized cortical areas, have also been described in patients with SPMS (230) during the performance of a simple motor task. Finally, two fMRI studies of the motor system (225,231) of patients with PPMS suggested a lack of "classical" adaptive mechanisms as a potential additional factor contributing to the accumulation of disability. 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 SMC and the supplementary motor area (SMA) in case of a motor task. At a later stage, bilateral

Table 3 Main Damaging/Recovery Aspects of Multiple Sclerosis and Magnetic Resonance Imaging Techniques with the Potential to Provide Estimates of Tissue Repair

Tissue injury

Mechanisms of repair

MRI metrics

Acute cytokine release with intact myelination and preserved axons

Demyelination

Sublethal axonal injury

Irreversible tissue loss Irreversible neuro-axonal damage

Removal of inflammatory mediators

Remyelination Redistribution of Na+ channels on persistently demyelinated axons

Recovery of neuro-axonal function Reactive gliosis Cortical reorganization

Ceasement of Gd enhancement Disappearance of the Lac peak and increase of Cr on *H-MRS Generalized increase of all metabolites peaks on *H-MRS Increase of MTR Disappearance/reduction of T1

hypointensities Marked increase of MTR Reduction of Cho, ml, and lipid peaks on :H-MRS Reduction of MD with normal FA Increase of the NAA peak on

*H-MRS Decreased FA with normal MD Increased and widespread cortical recruitment

Abbreviations: Gd, gadolinium; 'H-MRS, proton magnetic resonance spectroscopy; Lac, lactate; MTR, magnetization transfer ratio; DW MRI, diffusion-weighted magnetic resonance imaging; Cho, choline; ml, myoinositol; NAA, N-acetylaspartate; MD, mean diffusivity; FA, fractional anisotropy.

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 recent study (232), which has provided a direct demonstration that MS patients, during the performance of a simple motor task, activate cortical regions that are part of a fronto-parietal circuit, the activation of which typically occurs in healthy subjects during object manipulation.

Functional and structural changes of the MS brain are strictly correlated (Fig. 17). Several moderate to strong correlations have been demonstrated between the activity of cortical and subcortical areas and the extent of brain T2-visible lesions (218,221,224,230,231), the severity of intrinsic lesion damage (219,224), the severity of NABT damage, measured using 1H-MRS (102,222), MT MRI or DW MRI (224,225,230), the involvement of specific white matter tracts, such as the pyramidal tract (233), the extent of GM damage (231,234) and, finally, the severity of cervical cord damage (225,235).

Although the actual role of cortical reorganization on the clinical manifestations of MS remains unclear, there are several pieces of evidence, in addition to the strong correlation found between functional and structural abnormalities, that suggest that cortical adaptive changes are likely to contribute in limiting the clinical consequences of MS-related structural damage. In detail, in a patient with an acute hemiparesis following a new, large demyelinating lesion located in the corticospinal tract, dynamic changes of the brain pattern of activation of the "classical" motor areas, ending in a full recovery of function, have been observed (223). The correlation found between the extent of functional cortical changes and NAA levels suggests that dynamic reorganization of the motor cortex can occur in response to axonal injury associated with MS activity. In patients complaining of fatigue, when

Figure 16 Relative cortical activations (color coded for t values) in nondisabled relapsing-remitting multiple sclerosis patients during a simple motor task with the right hand in comparison to healthy volunteers. (A) Contralateral primary sensorimotor cortex, ipsi- and contralateral supplementary motor areas and contralateral intraparietal sulcus. (B) Contralateral ascending bank of the sylvian fissure. (C) Ipsilateral cingulate motor area and ipsilateral supplementary motor area. (D) Contralateral cingulate motor area.

Figure 16 Relative cortical activations (color coded for t values) in nondisabled relapsing-remitting multiple sclerosis patients during a simple motor task with the right hand in comparison to healthy volunteers. (A) Contralateral primary sensorimotor cortex, ipsi- and contralateral supplementary motor areas and contralateral intraparietal sulcus. (B) Contralateral ascending bank of the sylvian fissure. (C) Ipsilateral cingulate motor area and ipsilateral supplementary motor area. (D) Contralateral cingulate motor area.

compared with matched nonfatigued MS patients (236), a reduced activation of a complex movement-associated cortical/subcortical network, including the cerebellum, the rolandic operculum, the thalamus, and the middle frontal gyrus has been found. In fatigued patients, a strong correlation between the reduction of thalamic activity and the clinical severity of fatigue was also found, suggesting that a less marked cortical recruitment might be associated to the appearance of clinical symp-tomathology in MS (Fig. 18). Finally, preliminary work has shown that the pattern of movement-associated cortical activations in MS is determined by both the extent of brain injury and disability, and that these changes are distinct (237).

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