Advances in neuroimaging, complementing histopathological insights, have established a multi-system involvement of cerebral networks beyond the traditional neuromuscular pathological view of amyotrophic lateral sclerosis (ALS). The development of effective disease-modifying therapy remains a priority and this will be facilitated by improved biomarkers of motor system integrity against which to assess the efficacy of candidate drugs. Functional MRI (FMRI) is an established measure of both cerebral activity and connectivity, but there is an increasing recognition of neuronal oscillations in facilitating long-distance communication across the cortical surface. Such dynamic synchronization vastly expands the connectivity foundations defined by traditional neuronal architecture. This review considers the unique pathogenic insights afforded by the capture of cerebral disease activity in ALS using FMRI and encephalography.