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Amyotrophic lateral sclerosis (ALS) is a multisystem neurodegenerative disorder characterized by progressive degeneration of upper motor neurons and lower motor neurons, and frontotemporal regions resulting in impaired bulbar, limb, and cognitive function. Magnetic resonance imaging studies have reported cortical and subcortical brain involvement in the pathophysiology of ALS. The present study investigates the functional integrity of resting-state networks (RSNs) and their importance in ALS. Intra- and inter-network resting-state functional connectivity (Rs-FC) was examined using an independent component analysis approach in a large multi-center cohort. A total of 235 subjects (120 ALS patients; 115 healthy controls (HC) were recruited across North America through the Canadian ALS Neuroimaging Consortium (CALSNIC). Intra-network and inter-network Rs-FC was evaluated by the FSL-MELODIC and FSLNets software packages. As compared to HC, ALS patients displayed higher intra-network Rs-FC in the sensorimotor, default mode, right and left fronto-parietal, and orbitofrontal RSNs, and in previously undescribed networks including auditory, dorsal attention, basal ganglia, medial temporal, ventral streams, and cerebellum which negatively correlated with disease severity. Furthermore, ALS patients displayed higher inter-network Rs-FC between the orbitofrontal and basal ganglia RSNs which negatively correlated with cognitive impairment. In summary, in ALS there is an increase in intra- and inter-network functional connectivity of RSNs underpinning both motor and cognitive impairment. Moreover, the large multi-center CALSNIC dataset permitted the exploration of RSNs in unprecedented detail, revealing previously undescribed network involvement in ALS., Competing Interests: NO authors have competing interests

Competing Interests: Competing interests: Ari Breiner has served as site principal investigator for trials for amyotrophic lateral sclerosis funded by Mallinkrodt, Cytokinetics and the University of Calgary. He has also received research grant funding from CIDP/GBS Foundation International, Grifols and Muscular Dystropy Canada, and honoraria from CSL, Allergan, Pfizer and Akcea. Ari Breiner and Lorne Zinman have received honoraria from Mitsubishi Tanabe Pharma. Lorne Zinman has also received an honorarium from Biogen. No other competing interests were declared.