White Matter Disruption in Pediatric Traumatic Brain Injury: Results from ENIGMA Pediatric msTBI

Abstract

Annually, approximately 3 million children around the world experience traumatic brain injuries (TBIs), of which up to 20% are characterized as moderate to severe (msTBI) and/or have abnormal imaging findings. Affected children are vulnerable to long-term cognitive and behavioral dysfunction, as injury can disrupt or alter ongoing brain maturation. Post-injury outcomes are highly variable, and there is only limited understanding of how inter-individual differences in outcomes arise. Small sample sizes have also complicated efforts to better understand factors influencing the impact of TBI on the developing brain. White matter (WM) disruption is a critical aspect of TBI neuropathology and diffusion MRI (dMRI) is particularly sensitive to microstructural abnormalities. Here we present the results of a coordinated analysis of dMRI data across ten cohorts from three countries. We had three primary aims: (1) to characterize the nature and extent of WM disruption across key post-injury intervals (acute/subacute - within 2 months, post-acute - 2-6 months, chronic - 6+ months); (2) evaluate the impact of age and sex on WM in the context of injury; and (3) to examine associations between WM and neurobehavioral outcomes. Based on data from 507 children and adolescents (244 with complicated mild to severe TBI and 263 control children), we report widespread WM disruption across all post-injury intervals. As expected, injury severity was a significant contributor to the pattern and extent of WM degradation, but explained less variance in dMRI measures with increasing time since injury, supporting other research indicating that other factors contribute increasingly to outcomes over time. The corpus callosum appears to be particularly vulnerable to injury, an effect that persists years post-TBI. We also report sex differences in the effect of TBI on the uncinate fasciculus (UNC), a structure with a key role in emotion regulation. Females with a TBI had significantly lower fractional anisotropy (FA) in the UNC than those with no TBI, and this phenomenon was further associated with more frequent parent-reported behavioral problems as measured by the Child Behavior Checklist (CBCL). These effects were not detected in males. With future harmonization of imaging and neurocognitive data, more complex modeling of factors influencing outcomes will be possible and help to identify clinically-meaningful patient subtypes.

Multimodal Analysis of Secondary Cerebellar Alterations after Pediatric Traumatic Brain Injury

“…In line with prior publications, 31 we divided msTBI participants into three post-injury windows: (i) acute/sub-acute (MRI within 7 weeks of injury), during which pathology such as intracerebral hemorrhage and edema dominate; (ii) post-acute (MRI 8 weeks -6 months after injury), where secondary injuries such as regional atrophy and microstructural alterations become apparent; and chronic (MRI more than 6 months after injury), when some recovery and/or atrophy continues, but the brain is considered to be more stable. As discussed in a prior paper, 31 the exact boundaries were based on published data and natural break points within our datasets. Within the msTBI group, 67 scans were conducted during the acute phase, 122 during the post-acute, and 224 during the chronic phase of injury.…”

“…Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) is a global consortium of researchers aimed at achieving greater statistical power through harmonized processing of legacy data. Combining 12 cohorts shared within the ENIGMA Pediatric Moderate/Severe TBI (msTBI) working group, 31,32 we measured regional cerebellar volume in a cohort of 598 children/adolescents, including those with mild complicated-severe TBI (msTBI; n = 314) or without TBI (non-TBI; n = 284) and examined its associations with white matter microstructure and executive functioning. We hypothesized that (1) cerebellar volume would be lower in participants with msTBI than the non-TBI group, that (2) these disruptions would be most prominent in patients furthest from the time of injury, and that (3) smaller cerebellar volume would be associated with poorer executive functioning.…”

“…5,37 DTI data were processed as per a prior analysis and full details may be found in our previous publication. 31 Briefly, data were processed through the ENIGMA-DTI pipeline (http://enigma.ini.usc.edu/protocols/dtiprotocols/), which is a modified tract-based spatial statistics (TBSS) approach 38 resulting in FA and other metrics averaged within a set of regions of interest (ROIs) from the Johns Hopkins University atlas. Of the 12 cohorts included here, 10 collected DTI data (parameters may be seen in Supplementary Table 4).…”

Altered Lateralization of the Cingulum in Deployment-Related Traumatic Brain Injury: An ENIGMA Military-Relevant Brain Injury Study

“…[23][24][25] It was built on the framework created by the ENIGMA consortium, which seeks to achieve greater statistical power through harmonized image processing and meta/mega-analysis. 26 The ENIGMA Diffusion Tensor Imaging (DTI) workflow 27 has been used to identify altered WM organization across a range of disorders, including moderate/severe TBI in pediatric patients, 28 post-traumatic stress disorder (PTSD), 29 major depression, 30 and other conditions. 31 We used the ENIGMA DTI workflow to analyze asymmetry of WM organization in military brain injury across sixteen cohorts.…”

A Preliminary DTI Tractography Study of Developmental Neuroplasticity 5–15 Years After Early Childhood Traumatic Brain Injury

“…There is limited research into the effects of early TBI on WM integrity several years post-injury; however, a large study of children and adolescents with moderate-to-severe TBI found disruptions to the integrity of various WM tracts at the acute/subacute, postacute, and chronic (6–26 months) post-injury periods ( 14 ). Specifically, significantly lower FA and higher MD was observed across tracts in those with TBI, relative to controls, at all three post-injury periods.…”