Biophysical mechanisms of default mode network function and dysfunction

Abstract The default mode network (DMN) plays a fundamental role in internally focused cognition, and its disruption is implicated in numerous brain disorders. While neuroimaging has revealed DMN suppression by salient 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 node of the salience network suppresses DMN activity, whereas cingulate cortex stimulation produces antagonistic effects, enhancing retrosplenial cortex activity. Prelimbic cortex stimulation showed intermediate patterns, partially replicating insula-mediated suppression while failing to suppress cingulate regions, suggesting its role as a functional bridge between networks. Systematic brain-wide analysis confirmed the insula’s unique pattern of simulated DMN suppression. Comprehensive parameter space exploration demonstrated that DMN emergence as a functionally segregated network is robust across wide ranges of excitatory-inhibitory balance regimes and cholinergic modulation. However, outside these boundaries, DMN integrity breaks down through three distinct failure modes: loss of responsiveness, reversal of suppression to enhancement, and network fragmentation. The retrosplenial cortex emerged as a particularly vulnerable regulatory hub whose excitatory-inhibitory disruption reversed normal suppression patterns across the DMN, while prelimbic cortex demonstrated remarkable robustness. Brain-wide analysis also identified a functionally segregated frontal network displaying antagonistic dynamics with the DMN. Our findings provide mechanistic insights into DMN robustness and vulnerability, establishing a framework that links cellular excitatory-inhibitory balance to large-scale network dynamics. This model could explain how region-specific disruptions can produce the heterogeneous patterns of DMN dysfunction observed across brain disorders. Significance Statement To respond to important external events, the brain must suppress internal thought processes implicating the default mode network. This suppression fails in psychiatric conditions, that also involve imbalances between excitatory and inhibitory neurons. However, the connection between cellular imbalances and default-mode-network dysfunction has remained unclear. We used brain-wide computer simulations incorporating neuronal properties to understand how imbalance at the cellular scale disrupts network function. Our simulations reveal the precise excitatory-inhibitory balance needed for normal suppression. Additionally, we identified distinct failure modes and discovered that certain brain hubs are more vulnerable than others to disruption. Our findings reveal how cellular alterations scale up to cause network-level dysfunction, potentially guiding treatments targeting specific brain regions in individual patients. Competing Interest Statement The authors have declared no competing interest. Footnotes We conducted more than 17,000 new simulations comprising comprehensive parameter space exploration across multiple dimensions: local excitatory and inhibitory synaptic conductance, inter-regional coupling architecture, and cholinergic neuromodulation. The comprehensive parameter exploration has yielded important new mechanistic insights that substantially advance our understanding: 1.Identified parameter regimes for DMN integrity: We systematically mapped the specific excitatory-inhibitory balance regimes and cholinergic modulation levels necessary for maintaining DMN organization and insula-mediated suppression, revealing precise boundaries outside which these fundamental properties break down. 2.Confirmed robustness of DMN emergence: Despite these vulnerabilities in specific response properties, DMN emergence as a functionally segregated network proved remarkably robust across wide parameter ranges, establishing DMN organization as a fundamental principle. 3.Discovered three distinct breakdown modes: Our exploration revealed that DMN organization fails through three mechanistically distinct mode: localized loss of responsiveness, localized reversal from suppression to enhancement, and distributed reversal to enhancement across regions. 4.Established regional vulnerability hierarchy: Retrosplenial cortex emerged as a particularly vulnerable regulatory hub whose E/I disruption reverses normal suppression patterns, while prelimbic cortex showed remarkable robustness across parameter perturbations, revealing differential regional susceptibility potentially relevant to disorder heterogeneity. Systematic regional comparison: We performed comprehensive simulations comparing insula stimulation effects against all brain regions, confirming the insula's unique capacity for distributed DMN suppression and distinguishing it from sensory and motor cortices. Appropriate scientific framing: We extensively revised the manuscript throughout to clearly present findings as model predictions rather than empirical observations, added detailed discussion of model limitations, and included explicit testable predictions for experimental validation in each Discussion section. Enhanced translational context: We added substantive discussion of cross-species homology limitations, particularly for frontal cortex, with direct implications for interpreting findings in the context of psychiatric disorders. Streamlined presentation: We substantially shortened and reorganized the Introduction and Discussion to eliminate repetition and focus on key insights.