Axonal injury occurs even in the earliest stages of multiple sclerosis. Magnetic resonance spectroscopic imaging (MRSI) measurements of brain N:-acetylaspartate (NAA), a marker of axonal integrity, show that this axonal injury can occur even in the absence of clinically evident functional impairments. To test whether cortical adaptive responses contribute to the maintenance of normal motor function in patients with multiple sclerosis, we performed MRSI and functional MRI (fMRI) examinations of nine multiple sclerosis patients who had unimpaired hand function. We found that activation of the ipsilateral sensorimotor cortex with simple hand movements was increased by a mean of fivefold relative to normal controls (n = 8) and that the extent of this increase was strongly correlated (sigma = -0.93, P = 0.001) with decreases in brain NAA. These results suggest that compensatory cortical adaptive responses may help to account for the limited relationship between conventional MRI measures of lesion burden and clinical measures of disability, and that therapies directed towards promoting cortical reorganization in response to brain injury could enhance recovery from relapses of multiple sclerosis.

Previous work has demonstrated potentially adaptive cortical plasticity that increases with brain injury in patients with multiple sclerosis. However, animal studies showing use-dependent changes in motor cortex organization suggest that functional changes also may occur in response to disability. We therefore wished to test whether brain injury and disability lead to distinguishable patterns of activation with hand movement in patients with multiple sclerosis. By employing a passive as well as an active movement task, we also wished to test whether these changes were independent of voluntary recruitment and thus more likely to reflect true functional reorganization. Fourteen patients [Extended Disability Status Score (EDSS) 0-7.5] with relapsing-remitting multiple sclerosis were selected on the basis of pathology load and hand functional impairment for three study groups: group 1, low diffuse central brain injury (DCBI) as assessed from relative N-acetylaspartate concentration (a marker of axonal integrity) and normal hand function (n = 6); group 2, greater DCBI and normal hand function (n = 4); and group 3, greater DCBI and impaired hand function (n = 4). Functional MRI (fMRI) was used to map brain activation with a four-finger and both one-finger passive and active flexion-extension movement tasks for the three groups. Considering all the patients, we found increased activity in ipsilateral premotor and ipsilateral motor cortex (IMC) and in the ipsilateral inferior parietal lobule with increasing global disability (as assessed from the EDSS score). These changes appear to define true functional reorganization, as fMRI activations in IMC (r = 0.87, P < 0.001) and in the contralateral motor cortex (r = 0.67, P < 0.007) were highly correlated between active and passive single finger movements. We attempted to disambiguate any distinct effects of disability and brain injury by direct contrasts between patients differing predominantly in one or the other. To make these contrasts as powerful as possible, we used impairment of finger tapping as a measure of disability specific to the hand tested. A direct contrast of patients matched for DCBI, but differing in hand disability (group 3 - group 2) showed greater bilateral primary and secondary somatosensory cortex activation with greater disability alone. A contrast matched for hand disability, but differing in DCBI (group 2 - group 1) showed a different pattern of changes with relative ipsilateral premotor cortex and bilateral supplementary motor area activity. We conclude that the pattern of brain activity with finger movements changes both with increasing DCBI and with hand disability in patients with multiple sclerosis, and that these changes are distinct. Those related directly to disability may reflect responses to altered patterns of use. As injury- and disability-related activation changes are found even with passive finger movements, they may reflect true brain reorganization.

Although multiple sclerosis (MS) is an inflammatory demyelinating disease, there can be substantial axonal injury and loss. We therefore hypothesized that adaptive cortical changes may contribute to limiting functional impairment, particularly in the early stages of the disease. To test our hypothesis, we used functional magnetic resonance imaging (MRI) to characterize the localization and volumes of activation in the motor cortex during simple flexion‐extension finger movements. There were differences in the patterns of cortical activation with movement between the 12 MS patients and the 12 normal controls. All patients showed greater relative supplementary motor area activation than did the normal controls. The relative hemispheric lateralization of sensorimotor cortex (SMC) activation decreased in direct proportion to the total cerebral T2‐weighted MRI hyperintense lesion load. This appeared to be due primarily to increases in ipsilateral SMC activation with increasing lesion load in white matter of the hemisphere contralateral to the limb moved. The center of activation in the contralateral SMC was shifted a mean of 8.8 mm posterior in patients relative to controls, providing additional evidence for cortical adaptive responses to injury. The magnitude of this posterior shift in the SMC activation increased with greater T2 lesion loads. These observations demonstrate that cortical recruitment for simple finger movements can change both quantitatively and qualitatively in the SMCs of MS patients, suggesting that cortical reorganization or “unmasking” of latent pathways can contribute to functional recovery. These adaptive changes are another factor potentially limiting the strength of the relationship between MRI measures of pathology and clinical measures of disability. Ann Neurol 2000;47:606–613