Evidence for adaptive functional changes in the cerebral cortex with axonal injury from multiple sclerosis

Abstract

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.

Classifying minimally disabled multiple sclerosis patients from resting state functional connectivity

“…Along with the decreased connectivities, these might reflect functional reorganisation to cope with pathological damage, in keeping with results from several imaging studies in MS (Reddy et al, 2000a;Morgen et al, 2004;Mainero et al, 2004;Morgen et al, 2007;Trapp et al, 1998;Hawellek et al, 2011). Compensatory activation is often considered as a process arising at early stages, which tends to be lost with disease progression (Bonavita et al, 2011;Roosendaal et al, 2010).…”

“…Several fMRI studies have highlighted brain circuit plasticity and its potentially adaptive role in recovery or compensation in response to brain lesions (Reddy et al, 2000b), for motor (e.g. finger tapping) (Lee et al, 2000;Reddy et al, 2000a;Morgen et al, 2004) as well as cognitive tasks (e.g. working memory and attention tasks) (Mainero et al, 2004;Morgen et al, 2007).…”

Clinical correlations of brain lesion distribution in multiple sclerosis

“…Aside from this influence of LL, cortical adaptive changes may also limit correlations between localized lesion probability and symptoms. Adaptive changes have been shown to contribute to functional recovery after axonal injury (32)(33)(34). These changes after axonal loss can involve local synaptic reorganization, reorganization at more distant sites, or recruitment of parallel existing pathways (33), hampering relations between the location of an original lesion and its remaining symptoms after the development of adaptation.…”

“…Adaptive changes have been shown to contribute to functional recovery after axonal injury (32)(33)(34). These changes after axonal loss can involve local synaptic reorganization, reorganization at more distant sites, or recruitment of parallel existing pathways (33), hampering relations between the location of an original lesion and its remaining symptoms after the development of adaptation. Importantly, diffuse pathology in the NAWM, which may also contribute to disability (35,36) is not included in total lesional disease burden (12).…”

Imaging of multiple sclerosis: Role in neurotherapeutics

“…Reductions in NAA and increased signal from lipids are also found in PP MS in a manner that is consistent with findings of widespread neuronal dysfunction in RR MS. 116 Regional reductions in NAA correlate with cognitive dysfunction, 117 and the extent of adaptive cortical reorganization for motor movements shown by functional imaging has been correlated with altered NAA/Cr ratios in the centrum semiovale. 118 Reductions in NAA are associated with total T2 BOD, the extent of global tissue loss or atrophy, and the extent of tissue damage reflected by cerebral T1-hypointense lesion load. Whereas these are interrelated measures of tissue damage, the specificity of NAA for axonal dysfunction and axonal loss makes MRS the more intellectually appealing of these measures.…”