Resting-state functional connectivity in children and adults with spinal muscular atrophy

Despite the use of disease-modifying therapies, many individuals with spinal muscular atrophy (SMA) have chronic motor impairments. Although neuromodulation therapies have been used successfully in other neurological disorders to optimize outcomes, the effects of early motor unit dysfunction on brain connectivity in SMA remain largely unknown. This study aimed to investigate differences in resting-state functional connectivity between individuals with SMA and peer controls. We conducted a multicenter cross-sectional case control study of children and adults with 5q SMA, and controls matched by age and sex. Blood oxygen level dependent (BOLD) fluctuations at rest were acquired on 3T magnetic resonance imaging (MRI) scanners. Seed-to-voxel functional connectivity analyses were performed using the connectivity toolbox (CONN), with site as a covariate. Twenty-five seeds of interest were selected a priori based on functional relevance and prior literature, using regions of interest defined by the Harvard-Oxford atlas. Connectivity between regions of interest identified on primary analysis, expressed as Fisher-transformed correlation coefficients, were then assessed for correlation with motor function, SMN2 copy number, and SMA type. Forty-two participants (21 with SMA and 21 peer controls) completed the study (mean age 17.4 years, range 7-40; 67% males). At the time of the study, 24% of individuals with SMA were independently ambulant. Compared to controls, individuals with SMA demonstrated lower functional connectivity within the cerebellum and within salience network regions, alongside higher functional connectivity between the precentral gyri and areas of the default mode network (corrected p<0.05). No association between the connectivity values and motor function, SMN2 copy number, or SMA type was observed when controlling for age at MRI and site. Differences in resting-state functional connectivity in individuals with SMA encompass various brain networks, extending beyond motor areas. Insights into the reorganization of brain networks in SMA may open new pathways for adjunctive therapies to optimize outcomes.