Influence of Focal Activity on Macroscale Brain Dynamics in Health and Disease

Macroscopic recordings of brain activity (e.g. fMRI, EEG) are a sensitive biomarker of the neural networks supporting neurocognitive function. However, it remains largely unclear what mechanisms mediate changes in macroscale networks after focal brain injuries like stroke, seizure, and TBI. Recently, optical neuroimaging in animal models has emerged as a powerful tool to begin addressing these questions. Using widefield imaging of cortical calcium dynamics in mice, this dissertation investigates the mechanisms by which focal disruptions in activity alter brain-wide functional dynamics. In two chapters, I demonstrate 1) that focal sensory stimulation elicits state-dependent, global slow waves propagating from primary somatosensory cortex (S1). Using a focal ischemic stroke model, I show that bilateral activation of somatosensory cortices is required for initiating global SWs, while spontaneous SWs are generated independent of S1. 2) That regional disruption of cortical excitability induces widespread changes across cortical networks, using chemogenetic manipulation of parvalbumin interneurons to model focal epileptiform activity in S1. We further show that local imbalances in excitability propagate differentially through intra- and interhemispheric connections, and can induce plasticity in large-scale networks. These studies begin to define the mechanisms of macro-scale network disruption after focal injuries, adding to our understanding of how local cortical circuits modulate global brain networks

Homotopic contralesional excitation suppresses spontaneous circuit repair and global network reconnections following ischemic stroke

Understanding circuit-level manipulations that affect the brain\u27s capacity for plasticity will inform the design of targeted interventions that enhance recovery after stroke. Following stroke, increased contralesional activity (e.g. use of the unaffected limb) can negatively influence recovery, but it is unknown which specific neural connections exert this influence, and to what extent increased contralesional activity affects systems- and molecular-level biomarkers of recovery. Here, we combine optogenetic photostimulation with optical intrinsic signal imaging to examine how contralesional excitatory activity affects cortical remodeling after stroke in mice. Following photothrombosis of left primary somatosensory forepaw (S1FP) cortex, mice either recovered spontaneously or received chronic optogenetic excitation of right S1FP over the course of 4 weeks. Contralesional excitation suppressed perilesional S1FP remapping and was associated with abnormal patterns of stimulus-evoked activity in the unaffected limb. This maneuver also prevented the restoration of resting-state functional connectivity (RSFC) within the S1FP network, RSFC in several networks functionally distinct from somatomotor regions, and resulted in persistent limb-use asymmetry. In stimulated mice, perilesional tissue exhibited transcriptional changes in several genes relevant for recovery. Our results suggest that contralesional excitation impedes local and global circuit reconnection through suppression of cortical activity and several neuroplasticity-related genes after stroke, and highlight the importance of site selection for targeted therapeutic interventions after focal ischemia