Compensatory mechanisms amidst demyelinating disorders: insights into cognitive preservation

Demyelination disrupts the transmission of electrical signals in the brain and affects neurodevelopment in children with disorders such as multiple sclerosis and myelin oligodendrocyte glycoprotein-associated disorders. Although cognitive impairments are prevalent in these conditions, some children maintain cognitive function despite substantial structural injury. These findings raise an important question: in addition to the degenerative process, do compensatory neural mechanisms exist to mitigate the effects of myelin loss? We propose that a multi-dimensional approach integrating multiple neuroimaging modalities, including diffusion tensor imaging, magnetoencephalography and eye-tracking, is key to investigating this question. We examine the structural and functional connectivity of the default mode and executive control networks due to their significant roles in supporting higher-order cognitive processes. As cognitive proxies, we examine saccade reaction times and direction errors during an interleaved pro- (eye movement towards a target) and anti-saccade (eye movement away from a target) task. 28 typically developing children, 18 children with multiple sclerosis and 14 children with myelin oligodendrocyte glycoprotein-associated disorders between 5 and 18.9 years old were scanned at the Hospital for Sick Children. Tractography of diffusion MRI data examined structural connectivity. Intracellular and extracellular microstructural parameters were extracted using a white matter tract integrity model to provide specific inferences on myelin and axon structure. Magnetoencephalography scanning was conducted to examine functional connectivity. Within groups, participants had longer saccade reaction times and greater direction errors on the anti- versus pro-saccade task; there were no group differences on either task. Despite similar behavioural performance, children with demyelinating disorders had significant structural compromise and lower bilateral high gamma, higher left-hemisphere theta and higher right-hemisphere alpha synchrony relative to typically developing children. Children diagnosed with multiple sclerosis had greater structural compromise relative to children with myelin oligodendrocyte glycoprotein-associated disorders; there were no group differences in neural synchrony. For both patient groups, increased disease disability predicted greater structural compromise, which predicted longer saccade reaction times and greater direction errors on both tasks. Structural compromise also predicted increased functional connectivity, highlighting potential adaptive functional reorganisation in response to structural compromise. In turn, increased functional connectivity predicted faster saccade reaction times and fewer direction errors. These findings suggest that increased functional connectivity, indicated by increased alpha and theta synchrony, may be necessary to compensate for structural compromise and preserve cognitive abilities. Further understanding these compensatory neural mechanisms could pave the way for the development of targeted therapeutic interventions aimed at enhancing these mechanisms, ultimately improving cognitive outcomes for affected individuals.