Abstract Text: Background: Concussions can impair service member (SM) readiness in the near term and, for some, carry debilitating long-term consequences. Concussions are heterogenous clinical diagnoses because they are based on neurological dysfunction in the absence of neuroimaging evidence of brain structural damage. Yet, animal studies show neurological symptoms arise from damage to brain microcircuits, too small to be seen in clinical imaging. These microcircuits are made up of different cells, some of which are highly susceptible to the effects of injury (i.e., parvalbumin-expressing interneurons), and others that take up the burden of those cells that are lost or damaged after injury (i.e., somatostatin-expressing interneurons). It would be extremely valuable to know if, and to what degree, these circuits are damaged, and if so, which interneurons are lost and whether they have recovered or regenerated. We explored these patterns using data retrieved from the Federal Interagency Traumatic Brain Injury Research (FITBIR) portal that were collected as part of the NCAA-DOD CARE Consortium 1.0 Study from NCAA student-athletes at ARC sites.
Methods: From FITBIR we retrieved Post Concussion Symptom Scale (PCSS) scores that had been collected from concussed athletes 24-48 hours post-injury (T0; 50 athletes, 16% female) and high-resolution brain structural imaging data that were collected at T0, 24 hours after asymptomatic medical clearance (T1; 40 athletes), after unrestricted return-to-play (T2; 33 athletes), and 6 months post-injury (T3; 34 athletes). Brain structural imaging data were also retrieved for age- and gender-matched non-concussed NCAA student-athletes, who served as controls, at T0 (132 athletes, 20%female), T1 (125 athletes), T2 (123 athletes), and T3 (95 athletes). Individual cortical surfaces were reconstructed (Freesurfer 7.1.0) and mean cortical thickness (CT) and surface area (CSA) were calculated for each of 200 cortical areas. Areal features were regressed on sex, age, and sport in the controls to generate ‘abnormal’ morphometric maps (w-maps) for each participant. Interneuron populations were distinguished by preferential expression of somatostatin (SST) and parvalbumin (PAVLB) and enrichment with genes coding for GABAA receptor subunits (GABRG1) using the Allen Human Brain Atlas. A multivariate analysis tested whether w-maps were associated with symptoms and permutation testing was used to identify significant latent variables (LVs) as relationships between PCSS scores and individual ‘brain scores’ (the product of areal features and ‘brain saliences’). Pearson correlations defined associations between brain saliences and gene enrichment. Physiological brain recovery was assessed by comparing individual and group-level changes in w-maps from T0.
Results: Participants with low CT in areas with high GABRG1 enrichment (r=-.24, p<.001) and greater CSA in areas with high SST enrichment (r=.25, p<.001) experienced greater symptom burden (permutation-p=.035). Compared to T0, CT increased at T1 and T2 (t<-4.9|, p<.001) and CSA decreased at T2 (t=4.56, p<.001). On average, increases in CT at T1 and T2 occurred in areas that had contributed the most to initial PCSS scores at T0 (r<-.228, p<.001). At T3, CT decreased and CSA increased compared to T0 (t>|7.01|, p<.001). On average, decreases in CT at T3 occurred in areas that had contributed the most to initial symptom burden at T0 (r=.299, p<.001). Brain scores did not change from T0 (t<|1.43|, p>.15)
Conclusion: Post-concussion symptom burden was associated with greater atrophy (lower CT) and cortical folding (greater CSA) in participants who sustained a concussion compared to controls. Areas driving these effects were characterized by SST-expressing interneurons and GABAergic receptors. Increased CT and reduced CSA at follow-up, with the resolution of symptoms and return to competition, suggestive of physiological recovery. Collectively, these patterns suggest that athletes with less grey matter in areas typically associated with injury-resilient interneurons experienced the greatest symptom burden 24-48 hours after injury. However, concussed athletes exhibited a regression—greater atrophy and cortical folding—6 months later. The inclusion of sport-matched controls means that this regression is not likely caused by ‘sub-concussive’ (asymptomatic) impacts. Thus, it is plausible that these patterns represent latent, pre-injury patterns of abnormal cortical morphology and a risk factor for worse neurological sequelae after concussion, opening the possibility for a brief (5-7 minute) brain scan to serve as a screening tool of SM risk and resilience.