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.

A patient was followed after the new onset of hemiparesis from relapse of MS with serial MR spectroscopy and functional MRI. The association of clinical improvement with recovery of N-acetylaspartate, a marker of neuronal integrity, and progressive reduction of abnormally large functional MRI cortical activation with movement demonstrates that dynamic reorganization of the motor cortex accompanies remission of MS.

We performed a short-term, double-blind, placebo-controlled, crossover trial of sodium dichloroacetate (DCA) therapy in 11 patients affected by various primary mitochondrial disorders. Independent measures of oxidative metabolism (venous blood metabolites, exercise testing, phosphorus magnetic resonance [MR] spectroscopy of muscle, and proton MR spectroscopy of brain) were used in order to monitor metabolic responses to the drug. One week of DCA treatment produced significant decreases (p < 0.05) in blood lactate, pyruvate, and alanine at rest and after bicycle exercise. Proton MR spectra collected from a supraventricular volume of interest in brain of seven of 11 patients also showed significant changes. Brain lactate/creatine ratio decreased by 42% during DCA treatment (p < 0.05). Brain choline/creatine ratio (which is low in patients with myelinopathies) increased by 18% (p < 0.01) after therapy. N-Acetylaspartate/creatine ratio (an index of neuronal damage or loss) increased by 8% after treatment (p < 0.05). Proton MR spectra collected in two of 11 patients from a volume of interest including the basal ganglia showed similar results (decrease of 36.6% in lactate/creatine; increases of 16% in choline/creatine and 4.5% in N-acetylaspartate/creatine). Phosphorus MR spectroscopy of muscle and self-assessed clinical disability were unchanged. Our study indicates that short-term DCA treatment not only lowers blood lactate but also improves indices of both brain oxidative metabolism and neuronal and glial density or function.

Localized brain proton MR spectra were acquired from patients with different mitochondrial encephalomyopathies (myoclonus epilepsy with ragged-red fibers [MERRF], Kearns-Sayre syndrome [KSS], and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes [MELAS]). The regional brain metabolic abnormalities in patients with these syndromes showed different features consistent with the distinct phenotypes. In MERRF, only one of four patients showed an increase in the lactate/creatine resonance intensity ratio (an index of impairment of oxidative metabolism) in spectra from central (supraventricular) or occipital brain volumes, and this was small. There were significant decreases in N-acetylaspartate/creatine (a measure of neuronal loss or dysfunction) in central cerebral volumes of demented patients and, more prominently, in occipital volumes. In the one patient in whom it was studied, the cerebellum also showed a decreased N-acetylaspartate/creatine. Spectra from two patients with KSS both showed large (four- to sevenfold) increases in lactate/creatine and large decreases in N-acetylaspartate/creatine in central brain volumes. Yet another pattern of regional metabolic abnormality was present in the MELAS syndrome, where proton spectroscopic imaging demonstrated focal localization of abnormally increased lactate/creatine and decreased N-acetylaspartate/creatine to the regions of the stroke-like lesions on conventional MR images. Serial studies emphasized that the regional metabolic abnormalities in MELAS are highly variable as the stroke-like lesions appear and evolve.