Distinctive structural and functional MRI footprint for cognitive dysfunction in pediatric MS?

Cognitive deficits (CD) affect a large proportion of adult patients with multiple sclerosis (MS), even at the early clinical stages of the disease. With the application of advanced MRI techniques, it has become possible to investigate structural and functional correlates of CD in adult MS. Structural MRI studies suggest that diffuse (microscopic) brain damage, rather than just focal (macroscopic) lesions, plays a crucial role in the emergence of CD in adult MS. In particular, cognitively impaired adults with MS show spatially distributed patterns of white matter (WM) and gray matter (GM) abnormalities when compared to cognitively preserved (CP) adults with MS. Complementary to structural findings, functional MRI (fMRI) studies conducted during cognitive tasks or resting-state conditions have shown that, after the exhaustion of functional adaptive mechanisms (observable in CP patients for a limited time), a derangement of cognitive-relevant networks, such as the default mode network (DMN), takes place in cognitively impaired adults with MS. Pediatric MS represents about 5%–10% of all MS cases. Although pediatric MS, compared to adult MS, is characterized by a slower accumulation of irreversible disability, CD are frequently encountered. As one might expect, the negative effect of CD on social and academic achievements is particularly worrisome at this stage of life. Therefore, there is an urgent need to clarify the pathophysiologic basis of CD in pediatric MS in order to provide reliable markers to predict CD evolution and monitor potential pharmacologic or rehabilitative interventions. Few, mostly structural, MRI studies have investigated the pathophysiologic substrates of CD in pediatric MS, showing that the most relevant structures might be the thalamus, the corpus callosum, and some frontal cortical areas. More comprehensive and integrated (structural and functional) MRI investigations have not been conducted. In this issue of Neurology®, Rocca et al. applied a multimodal approach to cognitively impaired and CP pediatric patients with MS in order to elucidate which pattern of structural and functional changes is linked to CD in pediatric MS. Using a 3T scanner, the authors looked simultaneously at the distribution of (1) focal and diffuse structural brain damage and (2) restingstate functional connectivity changes (characterized by a weakened or reinforced intrinsic connectivity) within the most cognitive-relevant network, the DMN. The brain structural analysis, in particular, explored focal T2 lesions distribution, through reconstruction of lesion-probability maps; regional WM and GM atrophy, through voxel-based morphometry; and regional microstructural WM damage, through tractbased spatial statistics. The results of these combined approaches clearly showed that cognitively impaired subjects, compared to CP ones, present—besides an expected greater involvement of the corpus callosum and the thalamus—a distributed pattern of structural damage characterized by the co-occurrence of focal (T2 lesions) and diffuse (WM and GM) tissue abnormalities within posterior paramedian brain regions. Interestingly, this pattern also colocalized with DMN functional connectivity changes that were mostly located in the posterior core region of the DMN, the precuneus. The final statistic model showed that cognitive impairment was best explained by diffuse damage to the corpus callosum and cingulate bundle in combination with altered DMN activity. Based on these results and other complementary post hoc analyses, the authors suggest that CD in pediatric MS might be strongly linked to the occurrence of structural-functional damage in midline posterior brain structures. They also argue that the impaired functional connectivity of the posterior parasagittal components of the DMN might be secondary to the colocalized structural damage. By contrast, CP patients showed enhanced connectivity within anterior components of the DMN, a (perhaps compensatory) phenomenon also observed in patients with early Alzheimer dementia. These results should be viewed in the context of those obtained in adult patients with MS for the following 2 reasons: very few structural and fMRI data are available as a reference in the pediatric MS