Different Trajectories of Functional Connectivity Captured with Gamma-Event Coupling and Broadband Measures of EEG in the Rat Fluid Percussion Injury Model.

Abstract

Functional connectivity (FC) after TBI is affected by an altered excitatory-inhibitory balance due to neuronal dysfunction, and the mechanistic changes observed could be reflected differently by contrasting methods. Local gamma event coupling FC (GEC-FC) is believed to represent multiunit fluctuations due to inhibitory dysfunction, and we hypothesized that FC derived from widespread, broadband amplitude signal (BBA-FC) would be different, reflecting broader mechanisms of functional disconnection. We tested this during sleep and active periods defined by high delta and theta EEG activity, respectively, at 1,7 and 28d after rat fluid-percussion-injury (FPI) or sham injury (n=6/group) using 10 indwelling, bilateral cortical and hippocampal electrodes. We also measured seizure and high-frequency oscillatory activity (HFOs) as markers of electrophysiological burden. BBA-FC analysis showed early hyperconnectivity constrained to ipsilateral sensory-cortex-to-CA1-hippocampus that transformed to mainly ipsilateral FC deficits by 28d compared to shams. These changes were conserved over active epochs, except at 28d when there were no differences to shams. In comparison, GEC-FC analysis showed large regions of hyperconnectivity early after injury within similar ipsilateral and intrahemispheric networks. GEC-FC weakened with time, but hyperconnectivity persisted at 28d compared to sham. Edge- and global connectivity measures revealed injury-related differences across time in GEC-FC as compared to BBA-FC, demonstrating greater sensitivity to FC changes post-injury. There was no significant association between sleep fragmentation, HFOs, or seizures with FC changes. The within-animal, spatial-temporal differences in BBA-FC and GEC-FC after injury may represent different mechanisms driving FC changes as a result of primary disconnection and interneuron loss. Significance statementThe present study adds to the understanding of functional connectivity changes in preclinical models of traumatic brain injury. In previously reported literature, there is heterogeneity in the directionality of connectivity changes after injury, resulting from factors such as severity of injury, frequency band studied, and methodology used to calculate FC. This study aims to further clarify differential mechanisms that result in altered network topography after injury, by using Broadband Amplitude-Derived FC and Gamma Event Coupling-Derived FC in EEG. We found post-injury changes that differ in complexity and directionality between measures at and across timepoints. In conjunction with known results and future studies identifying different neural drivers underlying these changes, measures derived from this study could provide useful means from which to minimally-invasively study temporally-evolving pathology after TBI.