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Cognitive dysfunction (affecting particularly attention and working memory) occurs early in patients with multiple sclerosis. Previous studies have focused on identifying potentially adaptive functional reorganization through recruitment of new brain regions that could limit expression of these deficits. However, lesion studies remind us that functional specializations in the brain make certain brain regions necessary for a given task. We therefore have asked whether altered functional interactions between regions normally recruited provide an alternative adaptive mechanism with multiple sclerosis pathology. We used a version of the n-back task to probe working memory in patients with early multiple sclerosis. We applied a functional connectivity analysis to test whether relationships between relative activations in different brain regions change in potentially adaptive ways with multiple sclerosis. We studied 21 patients with relapsing-remitting multiple sclerosis and 16 age- and sex-matched healthy controls with 3T functional MRI. The two groups performed equally well on the task. Task-related activations were found in similar regions for patients and controls. However, patients showed relatively reduced activation in the superior frontal and anterior cingulate gyri (P > 0.01). Patients also showed a variable, but generally substantially smaller increase in activation than healthy controls with greater task complexity, depending on the specific brain region assessed (P < 0.001). Functional connectivity analysis defined further differences not apparent from the univariate contrast of the task-associated activation patterns. Control subjects showed significantly greater correlations between right dorsolateral prefrontal and superior frontal/anterior cingulate activations (P < 0.05). Patients showed correlations between activations in the right and left prefrontal cortices, although this relationship was not significant in healthy controls (P < 0.05). We interpret these results as showing that, while cognitive processing in the task appears to be performed using similar brain regions in patients and controls, the patients have reduced functional reserve for cognition relevant to memory. Functional connectivity analysis suggests that altered inter-hemispheric interactions between dorsal and lateral prefrontal regions may provide an adaptive mechanism that could limit clinical expression of the disease distinct from recruitment of novel processing regions. Together, these results suggest that therapeutic enhancement of the coherence of interactions between brain regions normally recruited (functional enhancement), as well as recruitment of alternative areas or use of complementary cognitive strategies (both forms of adaptive functional change), may limit expression of cognitive impairments in multiple sclerosis.

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Axonal damage is a major factor contributing to permanent disability in patients with multiple sclerosis (MS); it has been extensively investigated in the brain using magnetic resonance spectroscopy (MRS). In this study, MRS was used to investigate the degree of neuronal damage in the cervical spinal cord in MS. Spectra were acquired from spinal cord and brain in 11 patients with MS (expanded disability status score Axonal damage is a well-recognized component of multiple sclerosis (MS) that has only rarely been quantitatively assessed using conventional histopathology, (1-3) but which has been extensively investigated using proton magnetic resonance spectroscopy (MRS) (for a review, see Ref. 4). MRS allows noninvasive quantitation of the metabolite N-acetyl-aspartate (NAA), which is found exclusively within neurons (5,6). MRS studies of the brain in MS have reported a reduction in NAA not just within discrete lesions (7,8), but also within the normal appearing white matter (NAWM) (9,10), indicating widespread axonal involvement. This diffuse axonal damage as measured by MRS is strongly correlated with disability (8,9,11), which is in contrast to conventional MRI measures, such as focal lesion volume, which only weakly correlate with clinical symptoms (12,13).The role of spinal cord damage in MS has been investigated to a lesser degree. Histological examination of spinal cord specimens has demonstrated both significant levels of cord atrophy and substantial axonal loss (3,14,15). However, there does not seem to be a strong relationship between these two measures, i.e., cord atrophy is not strongly correlated with total axonal number (3). This suggests that measures of spinal cord atrophy using MRI (16 -18) may substantially underestimate the true extent of axonal loss, and may not be the most sensitive marker of disease progression in the spinal cord. The additional measurement of axonal damage using MRS in the spinal cord may therefore provide a more complete picture of cord involvement in the individual MS patient.MRS of the spinal cord is more demanding than in the brain and has received little attention (19 -22). We have previously developed a robust protocol for MRS measurement in the spinal cord MRS (20). Here, we apply this method in a cohort of MS patients to explore the potential role of spinal cord MRS in assessing spinal cord damage; specifically, we hypothesize that the spinal cords of even moderately disabled MS patients will have significant levels of neuronal damage detectable as loss of NAA. PATIENTS AND METHODSA total of 11 patients with MS (five female, mean age 44 Ϯ 9 years, range 26 -55 years) were recruited from the local neurological service and compared with 11 healthy controls (four female, mean age 38 Ϯ 11 years, range 24 -59 years). Clinical assessment at the time of MR investigation comprised full history, neurological examination, medication, expanded disability status score (EDSS), timed walk over 10 m, and nine-hole peg test (see Table 1). The study was approved by the local ethical...