Biophysical mechanisms of default mode network function and dysfunction

The default mode network (DMN) plays a fundamental role in internal cognitive function as well as dysfunction across numerous brain disorders. While human and rodent neuroimaging has revealed DMN suppression by salient external stimuli, the cellular mechanisms orchestrating this process remain unknown. Using whole-brain computational modeling informed by neuronal biophysics and retrograde tracer-derived directional mouse brain connectomics, we demonstrate that stimulation of the insula, involved in salience processing, suppresses DMN activity while within-DMN cingulate stimulation enhances it. Manipulating excitatory-inhibitory balance revealed how localized DMN disruptions propagate to cause distinct patterns of network dysfunction, with both reversals and paradoxical enhancements of normal suppression patterns. Brain-wide response analysis uncovered a functionally segregated frontal network and revealed a hierarchical organization with the DMN distinct from frontal regions. These findings provide a unified framework linking cellular mechanisms to large-scale network dynamics and demonstrate how region-specific disruptions might lead to the patterns of DMN dysfunction observed in brain disorders.