Longitudinal Gray Matter Trajectories in Pediatric Mild Traumatic Brain Injury

Objective: This prospective, longitudinal cohort study examined trajectories of brain gray matter macrostructure after pediatric mild traumatic brain injury (mTBI).

Methods: Children aged 8-16.99 years with mTBI or mild orthopedic injury (OI) were recruited from 5 pediatric emergency departments. Reliable change between pre-injury and 1-month post-injury symptom ratings was used to classify mTBI with or without persistent symptoms. Children completed post-acute (2-33 days) and/or chronic (3 or 6 months) post-injury T1-weighted MRI, from which macrostructural metrics were derived using automated segmentation. Linear mixed effects models were used, with multiple comparisons correction.

Results: Groups (N=623; 407 mTBI/216 OI; 59% male; age mean=12.03, SD=2.38 years) did not differ in total brain, white, or gray matter volumes, or regional subcortical gray matter volumes. However, time post-injury, age at injury, and biological sex moderated differences among symptom groups in cortical thickness of the angular gyrus, basal forebrain, calcarine cortex, gyrus rectus, medial and posterior orbital gyrus, and the subcallosal area, all corrected p<.05. Gray matter macrostructural metrics did not differ between groups post-acutely. However, cortical thinning emerged chronically following mTBI relative to OI in the angular gyrus in older children [d (95% confidence interval) = -0.61 (-1.15, -0.08)]; and in the basal forebrain [-0.47 (-0.94, -0.01)], subcallosal area [-0.55 (-1.01, -0.08)], and the posterior orbital gyrus [-0.55 (-1.02, -0.08)] in females. Cortical thinning was demonstrated for frontal and occipital regions 3 months post-injury in males with mTBI with persistent symptoms versus without persistent symptoms [-0.80 (-1.55, -0.05) to -0.83 (-1.56, -0.10)], and 6 months post-injury in females and younger children with mTBI with persistent symptoms relative to mTBI without persistent symptoms and OI [-1.42 (-2.29, -0.45) to -0.91 (-1.81, -0.01)].

Conclusions: These findings signal little diagnostic and prognostic utility of post-acute gray matter macrostructure in pediatric mTBI. However, mTBI altered the typical course of cortical gray matter thinning up to 6 months post-injury, even after symptoms typically abate in most children. Collapsing across symptom status obscured the neurobiological heterogeneity of discrete clinical outcomes after pediatric mTBI. Results illustrate the need to examine neurobiology in relation to clinical outcomes and within a neurodevelopmental framework.