Psychiatric symptoms caused by multiple concussions may be due to the kynurenine pathway and structural changes in the brain in collegiate-aged athletes

By Ella Webster. This article was initially published in the 12/19/24 edition of our Concussion Update newsletter; please consider subscribing.

In a study published in Brain, Behavior, and Immunity, Timothy B. Meier et al. investigated the link between concussion history, changes in limbic brain structure (the emotional processing system), and psychiatric symptoms, focusing on the kynurenine pathway (KP) as a potential mechanism. The KP is a metabolic pathway connected to inflammation, the immune system, and neurological conditions.

While prior studies have identified correlations between a higher incidence of concussions and mood disorders, this study suggests that inflammation-induced activation of the KP may underlie the association between cumulative concussions, psychiatric symptoms, and brain structure changes. The authors believe that the changes in the KP could explain these connections, noting that this pathway is associated with the development of mood disorders.

The study suggests that inflammation from repeated concussions activates the KP, diverting tryptophan (an essential amino acid) metabolism away from kynurenic acid (a neuroprotective metabolite) and toward Quinolinic Acid (QuinA), which is a potentially neurotoxic byproduct. These findings highlight the KP’s role in concussion-related psychiatric outcomes, particularly in female athletes. The study describes the association between changes in the KP pathway, reduction in hippocampal volume and white matter changes in the brain, and psychiatric outcomes.

The researchers analyzed 212 healthy collegiate athletes (male and female), collecting data on concussion history, psychiatric symptoms, serum biomarkers, and MRI scans. They found that a history of concussions was linked to greater depression, anxiety, and anhedonia symptoms (inability to experience joy or pleasure) in females and increased depression symptoms in males. More concussions were associated with MRI results revealing structural changes in the hippocampus (primarily associated with memory and learning), including hippocampal volume reduction and white matter microstructure changes, which were associated with “more severe anxiety and depression symptoms.”

These structural brain changes were also associated with blood serum level indicators of changes in the kynurenine pathway and with psychiatric symptoms in both sexes. In the KP, females with more concussions showed elevated levels of QuinA in the blood, while males exhibited reduced tryptophan levels. Elevated QuinA was associated with worse anxiety symptoms in females, while hippocampal volume reduction and white matter microstructure changes correlated with psychiatric symptoms. In males, lower tryptophan levels and smaller hippocampal volumes were associated with “more severe anxiety and depression symptoms.” 

While the initial findings of this study are promising, the study emphasizes the need for further research to confirm the KP’s involvement and explore sex-specific effects in concussion recovery.