Multi-tract multi-symptom relationships in pediatric concussions

Abstract

The heterogeneity of white matter damage and symptoms in concussions has been identified as a major obstacle to therapeutic innovation. In contrast, the vast majority of diffusion MRI studies on concussion have traditionally employed group-comparison approaches. Such studies do not consider heterogeneity of damage and symptoms in concussion. To parse concussion heterogeneity, the present study combines diffusion MRI (dMRI) and multivariate statistics to investigate multi-tract multi-symptom relationships. Using dMRI data from a sample of 306 children ages 9 and 10 with a history of concussion from the Adolescent Brain Cognitive Development Study (ABCD study), we built connectomes weighted by classical and emerging diffusion measures. These measures were combined into two informative indices, the first capturing a mixture of patterns suggestive of microstructural complexity, the second representing almost exclusively axonal density. We deployed pattern-learning algorithms to jointly decompose these connectivity features and 19 behavioural measures that capture well-known symptoms of concussions. We found idiosyncratic symptom-specific multi-tract connectivity features, which would not be captured in traditional univariate analyses. Multivariable connectome-symptom correspondences were stronger than all single-tract/single-symptom associations. Multi-tract connectivity features were also expressed equally across different sociodemographic strata and their expression was not accounted for by injury-related variables. In a replication dataset, the expression of multi-tract connectivity features predicted adverse psychiatric outcomes after accounting for other psychopathology-related variables. By defining cross-demographic multi-tract multi-symptom relationships to parse concussion heterogeneity, the present study can pave the way for the development of improved stratification strategies that may contribute to the success of future clinical trials and the improvement of concussion management.