Compensatory mechanisms amidst demyelinating disorders: insights into cognitive preservation

Abstract

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.

Keywords: cognitive performance; compensatory mechanisms; demyelinating disorders; network connectivity; structure-function coupling.

Graphical Abstract

Figure 1

Compensatory mechanisms amidst demyelinating disorders, leading to cognitive preservation. Despite the progressive white matter microstructural changes experienced by children with demyelinating disorders, such as MS and MOGAD, many of these children do not differ from typically developing children on cognitive outcomes, such as saccade reaction times and direction errors on pro- and anti-saccade tasks. This cognitive preservation is hypothesized to be due to an adaptive functional reorganisation in response to white matter changes, such as an increased recruitment of parallel pathways as a compensatory mechanism. Examining how network neural function adapts and compensates for structural compromise is important for not only understanding the neural basis of typical cognition, but also for understanding how network disturbances may be associated with cognitive impairments.

Figure 2

Similar behavioural group performance on (A) the pro- and anti-saccade tasks between (B) typically developing children and children with demyelinating disorders on saccade reaction times and (C) saccade direction errors. During the pro- and anti-saccade task (A), trials began with a central instructional cue on a black background for 1000 ms; a green fixation cue indicated a pro-saccade trial, and a red fixation cue indicated an anti-saccade trial. After a 200 ms gap period, a white peripheral stimulus appeared 10° to the left or right of the central instructional cue for 1000 ms. Participants were instructed to look towards the white peripheral stimulus during pro-saccade trials, and away from the stimulus in the opposite direction during anti-saccade trials. Both trial conditions and stimulus locations were pseudo-randomly interleaved. Saccade reaction time was defined as the time from stimulus appearance to the first saccade away from fixation that exceeded 30°/s. Two-sample t-tests examined group differences on pro- and anti-saccade reaction times and direction errors for 28 typically developing children, 18 children with MS and 14 children with MOGAD. Within groups (B), participants had longer saccade reaction times and (C) greater direction errors on the anti- versus pro-saccade task (P < 0.05); however, there were no behavioural group differences on either task (P > 0.05). Note. Standard errors are shown; * = P < 0.05; MOGAD, children diagnosed with myelin oligodendrocyte glycoprotein-associated disorders; MS, children diagnosed with multiple sclerosis.

Figure 3

Default mode and ECN network connections with compromised structural connectivity for children with demyelinating disorders compared to typically developing children. Values generated using t-test in network-based statistics, for 26 typically developing children, 18 children with MS and 14 children with MOGAD, with value <3 denoted as non-significant. Wider connections depict more significant differences between groups. This figure demonstrates that children with demyelinating disorders had significant DMN and ECN myelin and axon compromise relative to typically developing children. Furthermore, children diagnosed with MS displayed greater structural compromise than children diagnosed with MOGAD. Note. PCC, posterior cingulate cortex; mPFC, medial prefrontal cortex; MTL, medial temporal lobe; AG, angular gyrus; DLPFC, dorsolateral prefrontal cortex; ACC, anterior cingulate cortex; PPC, posterior parietal cortex; TDC, typically developing children; MOGAD, children diagnosed with myelin oligodendrocyte glycoprotein-associated disorders; MS, children diagnosed with multiple sclerosis; LH, left hemisphere; RH, right hemisphere.

Figure 4

Default mode and ECN network connections with compromised pro- and anti-saccade functional connectivity for children with demyelinating disorders compared to typically developing children. Values generated using t-test in network-based statistics, for 26 typically developing children, 17 children with MS and 13 children with MOGAD, with value <3 denoted as non-significant. The connectivity matrices presented in this figure depict group differences in mean node connectivity strength of pairwise associations for each measure, with brighter connectivity colours indicating a larger group difference in mean metric values. There were no significant differences between patient groups in network neural synchrony. PCC, posterior cingulate cortex; mPFC, medial prefrontal cortex; MTL, medial temporal lobe; AG, angular gyrus; DLPFC, dorsolateral prefrontal cortex; ACC, anterior cingulate cortex; PPC, posterior parietal cortex; TDC, typically developing children; MOGAD, children diagnosed with myelin oligodendrocyte glycoprotein-associated disorders; MS, children diagnosed with multiple sclerosis; LH, left hemisphere; RH, right hemisphere.

Figure 5

Adaptive functional reorganisation in response to white matter changes resulting in cognitive preservation for children with demyelinating disorders. Results from our PLS path modelling for 26 typically developing children, 17 children with MS and 13 children with MOGAD (A) indicates that children with demyelinating disorders had greater myelin and axon compromise of the DMN and ECN networks relative to typically developing children. In turn, increased structural compromise directly predicted longer pro- and anti-saccade reaction times and greater pro- and anti-saccade direction errors. However, in our model both children with demyelinating disorders and increased myelin and axon compromise of the DMN and ECN separately predicted greater pro- and anti-saccade DMN and ECN functional connectivity, which highlights potential adaptive functional reorganisation of these networks in response to structural compromise. In turn, increased DMN and ECN functional connectivity predicted faster saccade reaction times and fewer pro- and anti-saccade direction errors. To examine the influence of disease disability on DMN and ECN structure-function connectivity and saccade performance, separate PLS path models were conducted for children with demyelinating disorders. For both children diagnosed with MS (B) and MOGAD (C), we found that increased disease disability, highlighted by EDSS, age at diagnosis and number of optic neuritis episodes, predicted greater myelin and axon compromise of the DMN and ECN. In turn, increased structural compromise directly predicted longer pro- and anti-saccade reaction times and greater pro- and anti-saccade direction errors. Increased disease disability and increased myelin and axon compromise of the DMN and ECN both directly predicted decreased pro- and anti-saccade DMN and ECN neural synchrony. In turn, decreased DMN and ECN functional connectivity predicted longer pro- and anti-saccade reaction times and greater pro- and anti-saccade direction errors. MOGAD, children diagnosed with myelin oligodendrocyte glycoprotein-associated disorders; MS, children diagnosed with multiple sclerosis; ON, optic neuritis; EDSS, expanded disability status scale; * = P < 0.05.