The pericontused cortex can support function early after TBI but it remains functionally isolated from normal...

Traumatically injured brain functional connectivity (FC) is altered in a region-dependent manner with some regions functionally disconnected while others are hyperconnected after experimental TBI. Remote, homotopic cortical regions become hyperexcitable after injury, and we hypothesize that this results in increased trans-hemispheric cortical inhibition, preventing reorganization of the primary injured hemisphere. Previously we have shown that temporary silencing the contralesional cortex at 1wk normalizes affected forelimb behavioral use, but not at 4wks. To investigate the potential mechanism for this and to determine whether this occurs due to restoration of afferent pathway FC, and/or reorganization of brain circuits, we probed forelimb circuit function with sensorimotor task-evoked-fMRI, resting state fMRI seed-based analysis, and exploratory structural equation modelling (SEM) of directed causal connections due to forelimb task at 1 and 4wks post-injury after temporary, contralateral silencing with intraparenchymal injection of muscimol versus vehicle, as well as from sham rats. As predicted, silencing at 1wk and 4wks post-injury decimated the contralesional cortical forelimb map evoked by stimulation of the opposite, unaffected forelimb compared to vehicle-injected injured rats indicating the success of the intervention. Surprisingly however, this also resulted in activation of the pericontused cortex ipsilateral to the stimulated forelimb at 1wk, yet this same region could not be activated by directly stimulating the opposite, injury-affected forelimb. Underpinning this were significant increases in interhemispheric FC at the level of the cortex but decreases within subcortical regions. Causal SEM analysis confirmed increased corticothalamic connectivity and suggested changes from and to bilateral thalamus are important for the effect. At 4wks post-injury only cortical increases in FC were found in response to silencing indicating a less flexible brain, and ipsilesional cortex evoked activity was mostly absent. The absence of a reinstatement of ipsilesional evoked activity through normal pathways by temporary neuromodulation despite prior data showing behavioral improvements under the same conditions, indicates that while the pericontused cortex does retain function initially after injury, it is too functionally disconnected to be controlled by normal afferent input. More significant alterations in cross-brain FC during neuromodulation at 1wk compared to 4wk post-injury, suggest that more distributed brain activity accounts for prior behavior improvements in sensorimotor function, and that hemispheric imbalance in function is causally involved in early loss of sensorimotor function in this TBI model.