Abstract
The molecular mechanisms underlying the diverse psychiatric and neuropathological sequalae documented in subsets of athletes with concussion have not been identified. We have previously reported elevated quinolinic acid (QuinA), a neurotoxic kynurenine pathway metabolite, acutely following concussion in football players with prior concussion. Similarly, work from our group and others has shown that increased functional connectivity strength, assessed using resting state fMRI, occurs following concussion and is associated with worse concussion-related symptoms and outcome. Moreover, other work has shown that repetitive concussion may have cumulative effects on functional connectivity and is a risk factor for adverse outcomes. Understanding the molecular mechanisms underlying these cumulative effects may ultimately be important for therapeutic interventions or the development of prognostic biomarkers. Thus, in this work, we tested the hypothesis that the relationship between QuinA in serum and functional connectivity following concussion would depend on the presence of a prior concussion. Concussed football players with prior concussion (N = 21) and without prior concussion (N = 16) completed a MRI session and provided a blood sample at approximately 1 days, 8 days, 15 days, and 45 days post-injury. Matched, uninjured football players with (N = 18) and without prior concussion (N = 24) completed similar visits. The association between QuinA and global connectivity strength differed based on group (F(3, 127) = 3.46, p = 0.019); post-hoc analyses showed a positive association between QuinA and connectivity strength in concussed athletes with prior concussion (B = 16.05, SE = 5.06, p = 0.002, 95%CI[6.06, 26.03]), but no relationship in concussed athletes without prior concussion or controls. Region-specific analyses showed that this association was strongest in bilateral orbitofrontal cortices, insulae, and basal ganglia. Finally, exploratory analyses found elevated global connectivity strength in concussed athletes with prior concussion who reported depressive symptoms at the 1-day visit compared to those who did not report depressive symptoms (t(15) = 2.37, mean difference = 13.50, SE = 5.69, p = 0.032, 95%CI[1.36, 25.63], Cohen's d = 1.15.). The results highlight a potential role of kynurenine pathway (KP) metabolites in altered functional connectivity following concussion and raise the possibility that repeated concussion has a "priming" effect on KP metabolism.