Various techniques, including optogenetics, chemogenetics, electrical stimulation, and lesions are used to probe brain function and dysfunction. However, the mechanistic consequences of such manipulations at the whole-brain scale remain poorly understood. This information is necessary for a proper interpretation of the functional consequences of local alterations. Combining mouse experimental datasets of focal interventions (thalamic lesion and chemogenetic silencing of cortical hubs), we demonstrate both local and global effects. Utilizing advanced whole-brain simulations of experimental data, we not only confirm the distributed nature of local manipulations but also offer mechanistic insights into these processes. Our simulations predict that the reconfiguration of hemodynamic functional connectivity is tightly coupled with the modulation of neurophysiological activity. This includes alterations in firing rates and spectral characteristics across specific brain networks, leading to structured changes in functional connectivity patterns. Crucially, the brain subnetworks most profoundly impacted are contingent upon the precise site of local intervention. Thus, these subnetworks serve as distinctive fingerprints, enabling pinpoint localization of the altered brain region. This knowledge holds the potential to inform clinical decision-making and address focal brain pathologies by developing circuit-level interventions and customized neuromodulation therapies.

Probing the Mechanisms of Global Brain Reconfiguration after Local Manipulations