Prospective Study of Gray Matter Atrophy Following Pediatric Mild Traumatic Brain Injury

Abstract

Background and Objectives:The clinical and physiological time-course for recovery following pediatric mild traumatic brain injury (pmTBI) remains actively debated. The primary objective of the current study was to prospectively examine structural brain changes (cortical thickness and subcortical volumes) and age-at-injury effects.A prioristudy hypotheses predicted reduced cortical thickness and hippocampal volumes up to 4 months post-injury, which would be inversely associated with age-at-injury.Methods:Prospective cohort study design with consecutive recruitment. Study inclusion adapted from American Congress of Rehabilitation Medicine (upper threshold) and Zurich Concussion in Sport Group (minimal threshold) and diagnosed by Emergency Department and Urgent Care clinicians. Major neurological, psychiatric or developmental disorders were exclusionary. Clinical (Common Data Element) and structural (3 Tesla MRI) evaluations within 11 days (sub-acute visit [SA]) and at 4 months (early chronic visit [EC]) post-injury. Age and sex-matched healthy children (HC) to control for repeat testing/neurodevelopment. Clinical outcomes based on self-report and cognitive testing. Structural images quantified with FreeSurfer (version 7.1.1).Results:208 pmTBI (age=14.4±2.9; 40.4% female) and 176 HC (age=14.2±2.9; 42.0% female) included in final analyses (>80% retention). Reduced cortical thickness (right rostral middle frontal gyrus;d=−0.49) and hippocampal volumes (d=−0.24) observed for pmTBI, but not associated with age-at-injury. Hippocampal volume recovery was mediated by loss of consciousness/post-traumatic amnesia. Significantly greater post-concussive symptoms and cognitive deficits were observed at SA and EC visits, but were not associated with the structural abnormalities. Structural abnormalities slightly improved balanced classification accuracy above and beyond clinical gold standards (∆+3.9%), with a greater increase in specificity (∆+7.5%) relative to sensitivity (∆+0.3%).Discussion:Current findings indicate structural brain abnormalities may persist up to four months post-pmTBI, and are partially mediated by initial markers of injury severity. These results contribute to a growing body of evidence suggesting prolonged physiological recovery post-pmTBI. In contrast, there was no evidence for age-of-injury effects or for physiological correlates of persistent symptoms in our sample.

Longitudinal Gray Matter Trajectories in Pediatric Mild Traumatic Brain Injury

“…35 Persistent reduction of right rostral middle frontal cortical thickness and hippocampal volume were recently demonstrated postacutely and up to 4 months after pediatric mTBI relative to typical development in a larger sample (N = 384). 8 However, cortical thickness did not differ 6 months after pediatric mTBI relative to OI in another large (N = 330) cohort of children. 34 Discrepancies in findings likely reflect the use of different comparison groups, given the growing evidence that an OI comparison group provides a more conservative basis for comparisons in pediatric mTBI research than uninjured, typically developing children.…”

“…32 These results also indicate that collapsing across symptom status can obscure the neurobiological differences associated with discrete clinical outcomes in pediatric mTBI, consistent with diffusion imaging findings we previously reported in this sample 23 and with a recent independent study of pediatric mTBI relative to typical development. 8 Specifically, a less favorable clinical outcome (i.e., mTBI with persistent symptoms) was associated with cortical atrophy up to 6 months postinjury, although age at injury and biological sex moderated the differences in trajectories between the symptom groups.…”

“…41 Hormonal changes and differences could also contribute to the age-related and sex-related effects, 42 but more research is needed, especially considering that the moderating effects of age at injury have been consistently demonstrated. 8 However, the strong association of cortical macrostructure with age at injury and sex could also reflect accelerated developmental maturation of gray matter after mTBI rather than a specific neuropathology. Thus, cortical alterations after pediatric mTBI likely reflect a combination of focal and diffuse effects that must be considered within the context of typical brain development.…”

“…7 Thus, we investigated sex and age at injury as possible moderators of group differences in gray matter macrostructure. Based on past research, 5,8 minimal postacute (i.e., 1-2 weeks postinjury) differences in cortical thickness and subcortical volumes were expected between mTBI and mild OI groups while robust group differences were expected chronically (i.e., at 3 or 6 months postinjury). The largest differences in cortical thickness were expected in children with mTBI who demonstrated persistent symptoms (prolonged recovery) relative to children with mTBI without persistent symptoms (shorter recovery) or OI.…”

Gray Matter Matters in Mild Traumatic Brain Injury

“…What this research from Mayer and coworkers has emphasized is that researchers should not ignore what is also happening in the gray matter regions of the brain after mild TBI. 2…”