Authors :
Presenting Author: Samantha Bottom-Tanzer, MD/PhD Candidate – Tufts University
Sofia Corella, MD/PhD Student – Case Western Reserve University; Moritz Armbruster, PhD – Tufts University; Farzad Noubary, PhD – Northeastern University; Matthew Shtrahman, PhD – University of San Diego; Jochen Meyer, PhD – Baylor College of Medicine; Timothy Murphy, PhD – University of British Columbia; Shane Heiney, PhD – University of Iowa; Michael Higley, MD/PhD – Yale University; Jessica Cardin, PhD – Yale University; Chris Dulla, PhD – Tufts University
Rationale:
Traumatic brain injury (TBI) is the leading cause of death in young people and can cause cognitive and motor dysfunction, post-traumatic epilepsy (PTE), and disruptions in network connectivity. In human TBI patients and in rodent TBI models, connectivity is decreased after injury. Epilepsy patients have altered connectivity between cortical networks that is exacerbated by disease duration. Recovery of connectivity after TBI is associated with improved cognition and memory, suggesting an important link between connectivity and functional outcome. Whether changes in functional connectivity after TBI contribute to later epilepsy is unknown but could provide important insights into potential biomarkers and PTE mechanisms.
Methods:
We chose to examine widespread alterations in network connectivity following TBI by leveraging basic science imaging and electrical recording modalities in a mouse model. We used simultaneous widefield mesoscale GCaMP7c calcium imaging and electrocorticography (ECoG) in mice injured via controlled cortical impact (CCI). Combining this injury model with widefield cortical imaging permits us unprecedented access to characterize network connectivity changes throughout the entire cortex over time. Adult CD1 mice underwent CCI or sham injury and implantation of a cortical widow, ECoG, and headbar. Imaging and ECoG recording were performed beginning 3 days post-injury while animals were head-fixed and allowed to run freely on a wheel.
Results:
Excitingly, our data show that CCI disrupts coherent cortical activity most profoundly immediately after injury. Connectivity is partially regained over three weeks post-injury. This increase in functional connectivity appears to be primarily driven by a return of connectivity in the injured hemisphere. CCI-injured animals also display increased functional connectivity contralateral to the injury compared to shams. Examining discrete periods of movement and stillness revealed on ECoG that cortical theta power is state dependent, with theta power increasing with movement in CCIs and shams. Following TBI, theta power was further depressed during stillness but returned to sham levels over 21 days indicating that CCI affected still or resting state but not moving or high arousal state. In sham injured mice, functional connectivity was highest at rest and decreased with movement, however this state-dependent differential was lost in CCI mice. Functional connectivity during resting state, but not during movement, was significantly altered in injured mice suggesting a state-specific injury effect on ECoG activity and functional connectivity.
Conclusions:
These findings show that connectivity is decreased after TBI and gradually returns over 21 days. In the contralateral cortex, functional connectivity is increased above sham levels suggesting a possible compensatory response to injury. When broken down by state, cortical activity during resting state is perturbed by injury. Together, these findings demonstrate cortex-wide dynamic changes in functional connectivity and resting state networks, changes that may be used to understand epileptogenesis after TBI.
Funding:
DOD CDMRP Epilepsy Research Program Idea Development Award