Longitudinal Neuroimaging in Pediatric Traumatic Brain Injury: Current State and Consideration of Factors That Influence Recovery

Abstract

Traumatic brain injury (TBI) is a leading cause of death and disability for children and adolescents in the U.S. and other developed and developing countries. Injury to the immature brain varies greatly from that of the mature, adult brain due to numerous developmental, pre-injury, and injury-related factors that work together to influence the trajectory of recovery during the course of typical brain development. Substantial damage to brain structure often underlies subsequent functional limitations that persist for years following pediatric TBI. Advances in neuroimaging have established an important role in the acute management of pediatric TBI, and magnetic resonance imaging (MRI) techniques have a particular relevance for the sequential assessment of long-term consequences from injuries sustained to the developing brain. The present paper will discuss the various factors that influence recovery and review the findings from the present neuroimaging literature to assess altered development and long-term outcome following pediatric TBI. Four MR-based neuroimaging modalities have been used to examine recovery from pediatric TBI longitudinally: (1) T 1 -weighted structural MRI is sensitive to morphological changes in gray matter volume and cortical thickness, (2) diffusion-weighted MRI is sensitive to changes in the microstructural integrity of white matter, (3) MR spectroscopy provides a sensitive assessment of metabolic and neurochemical alterations in the brain, and (4) functional MRI provides insight into the functional changes that occur as a result of structural damage and typical developmental processes. As reviewed in this paper, 13 cohorts have contributed to only 20 studies published to date using neuroimaging to examine longitudinal changes after TBI in pediatric patients. The results of these studies demonstrate considerable heterogeneity in post-injury outcome; however, the existing literature consistently shows that alterations in brain structure, function, and metabolism can persist for an extended period of time post-injury. With larger sample sizes and multi-site cooperation, future studies will be able to further examine potential moderators of outcome, such as the developmental, pre-injury, and injury-related factors discussed in the present review.

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

“…A Bonferroni correction is considered too conservative when there are correlations among the multiple dependent measures being tested (Nyholt, 2004;Li and Ji, 2005) . Therefore, we followed recent ENIGMA analyses (Dennis et al , 2019) and calculated the effective number of independent tests based on the observed correlation structure between the regional measures. The equation of Li and Ji (Li and Ji, 2005) yielded V eff = 10, giving a significance threshold of p <0.05/10=0.005.…”

“…Advanced magnetic resonance imaging (MRI) techniques have shown great promise in furthering our understanding of the injury and recovery processes that occur during dynamic periods of neurodevelopment (Dennis et al , 2018, Lindsey et al , 2019 . Research using diffusion MRI (dMRI) has revealed widespread disruption of brain microstructure in children and adolescents with moderate/severe TBI (msTBI) (Wozniak et al , 2007;Yuan et al , 2007;Levin et al , 2008;Caeyenberghs et al , 2009Caeyenberghs et al , , 2010Caeyenberghs et al , , 2012Oni et al , 2010;Wilde et al , 2010Wilde et al , , 2012Wu et al , 2010;McCauley et al , 2011;Treble et al , 2013a , b , 2017Johnson et al , 2015;Ewing-Cobbs et al , 2016;Faber et al , 2016;Genc et al , 2017;Königs et al , 2018, Lindsey et al , 2019Molteni et al , 2019;Watson et al , 2019) , which is less likely to be detected by conventional clinical neuroimaging. DMRI can model white matter (WM) tracts and assess tissue structure by mapping the diffusion of water molecules; it is particularly sensitive to traumatic axonal injury, a hallmark of msTBI (Ashwal et al , 2014, Dennis et al , 2017 .…”

“…Critically, outcomes after TBI are highly variable, and acute clinical measures of injury severity (e.g., Glasgow Coma Scale [GCS], post-traumatic amnesia, loss of consciousness) and conventional clinical neuroimaging only modestly account for inter-individual differences (Anderson et al , 2006;Lajiness-O'Neill et al , 2011, Lindsey et al , 2019Petranovich et al , 2020) . The prefrontal cortex is particularly vulnerable to TBI due to common injury mechanics and to the structure of the skull (Bigler, 2007) , potentially contributing to the high prevalence of emotional dysregulation, behavioral change, and executive dysfunction after TBI.…”

“…The ENIGMA Diffusion Tensor Imaging (DTI) workflow (Jahanshad et al , 2013) has revealed patterns of altered WM organization across a number of clinical populations (Kochunov et al , 2020) , including schizophrenia (Kelly et al , 2018) , post-traumatic stress disorder (Dennis et al , 2019) , and22q11.2 Deletion Syndrome (Villalón-Reina et al , 2019) . Here we applied these novel analytic methods to pediatric msTBI by analyzing data from over 500 participants across 10 cohorts.…”

Epigenetic Effects on Pediatric Traumatic Brain Injury Recovery (EETR): An Observational, Prospective, Longitudinal Concurrent Cohort Study Protocol

“…Children sustaining moderate to severe TBI often demonstrate neurobehavioral impairments that hamper their long-term functioning (2)(3)(4). Previous large-scale cohort studies in pediatric TBI have identified injury (e.g., severity, neuropathological, accidental vs. nonaccidental), developmental (e.g., age at injury, time since injury), child (e.g., premorbid functioning), and psychosocial (e.g., socioeconomic status, family functioning) factors as significant determinants of outcomes (5)(6)(7)(8)(9)(10)(11)(12). Current prediction models including these factors, however, explain only ∼35% of variance in outcomes (13).…”