Multiple sclerosis (MS) is a chronic demyelinating disease estimated to affect 2.8 million people globally. Recent human studies indicate that MS is not merely a consequence of demyelination, but it also involves an intricate neuronal component, which remains poorly understood. Here, we employed the experimental autoimmune encephalomyelitis (EAE) mouse model of MS to study the neuronal response during autoimmune neuroinflammation, with a particular focus on the prodromal phase, which precedes axonal demyelination. We implemented Targeted Recombination in Active Populations (TRAP) and a comprehensive brain-wide quantification approach to generate neuronal activity maps at the peak of disease and at a pre-symptomatic stage (day 6). Our data revealed that EAE mice experience an overall reduction in the number of active neurons when compared to healthy controls, with 210 brain regions showing a significant decrease at the peak of disease. Many of the affected brain regions belong to the visual and somatosensory pathways, both of which show abnormal functional connectivity in humans with MS. Interestingly, of those 210 regions, 15 are less active already at the prodromal phase, and the cortical changes are specific to layer V. Our findings identify an early pattern in the MS brain, prior to immune cell infiltration and demyelination, wherein specific neuronal networks show reduced activity. Better understanding of the neuronal changes across different stages of EAE may help elucidating disease progression and identify longitudinal patterns to factor in diagnostic tools for the human disease.