Post-Traumatic Stress Symptoms after Pediatric Injury: Relation to Pre-Frontal Limbic Circuitry

Abstract

Pre-frontal limbic circuitry is vulnerable to effects of stress and injury. We examined microstructure of pre-frontal limbic circuitry after traumatic brain injury (TBI) or extracranial injury (EI) and its relation to post-traumatic stress symptoms (PTSS). Participants aged 8 to 15 years who sustained mild to severe TBI (n = 53) or EI (n = 26) in motor vehicle incidents were compared with healthy children (n = 38) in a prospective longitudinal study. At the seven-week follow-up, diffusion tensor imaging was obtained in all groups; injured children completed PTSS ratings using a validated scale. Using probabilistic diffusion tensor tractography, pathways were seeded from bilateral amygdalae and hippocampi to estimate the trajectory of white matter connecting them to each other and to targeted pre-frontal cortical (PFC) regions. Microstructure was estimated using fractional anisotropy (FA) in white matter and mean diffusivity (MD) in gray matter. Prefrontal limbic microstructure was similar across groups, except for reduced FA in the right hippocampus to orbital PFC pathway in the injured versus healthy group. We examined microstructure of components of pre-frontal limbic circuitry with concurrently obtained PTSS cluster scores in the injured children. Neither microstructure nor PTSS scores differed significantly in the TBI and EI groups. Across PTSS factors, specific symptom clusters were related positively to higher FA and MD. Higher hyperarousal, avoidance, and re-experiencing symptoms were associated with higher FA in amygdala to pre-frontal and hippocampus to amygdala pathways. Higher hippocampal MD had a central role in hyperarousal and emotional numbing symptoms. Age moderated the relation of white and gray matter microstructure with hyperarousal scores. Our findings are consistent with models of traumatic stress that implicate disrupted top-down PFC and hippocampal moderation of overreactive subcortical threat arousal systems. Alterations in limbic pre-frontal circuitry and PTSS place children with either brain or body injuries at elevated risk for both current and future psychological health problems.

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

“…This disparity could also point to long-term impacts of injury that are not restricted to TBI. Hospitalization, psychological trauma from the injury event, and biological responses associated with secondary injury (such as inflammation) could all contribute to alterations in brain structure and function even when the brain itself is not directly injured (McDonald et al , 2016;Sheeler, 2016;Yang et al , 2016;Nicholson et al , 2018;Ewing-Cobbs et al , 2019) .…”

Post-acute white matter microstructure predicts post-acute and chronic post-concussive symptom severity following mild traumatic brain injury in children

“…However, findings have varied widely across studies. For example, both higher and lower fractional anisotropy (FA) have been reported in post-acute pediatric mild TBI (Babcock et al., 2015; Beek et al., 2015; Chu et al., 2010; Ewing-Cobbs et al., 2019; Mac Donald et al., 2019; Mayer et al., 2018; Murdaugh et al., 2018; Mustafi et al., 2018; Schmidt et al., 2018; Wilde et al., 2008), although a recent meta-analysis of mild TBI in children and adults suggested that FA is generally increased post-acutely but reduced in chronic injury phases (Eierud et al., 2014). Generally, mean diffusivity (MD) is reduced in children with mild TBI up to 6 months post-injury relative to controls (Babcock et al., 2015; Chu et al., 2010; Wilde et al., 2008), although differences have not been reported in all studies of chronic time periods (Bartnik-Olson et al., 2014; Königs et al., 2018).…”

“…Generally, mean diffusivity (MD) is reduced in children with mild TBI up to 6 months post-injury relative to controls (Babcock et al., 2015; Chu et al., 2010; Wilde et al., 2008), although differences have not been reported in all studies of chronic time periods (Bartnik-Olson et al., 2014; Königs et al., 2018). Alterations of white matter microstructure have been reported in many regions, including the corpus callosum, cortico-spinal tract, thalamic radiations, superior longitudinal fasciculus, and frontal white matter (Babcock et al., 2015; Beek et al., 2015; Chu et al., 2010; Ewing-Cobbs et al., 2019; Königs et al., 2018; Mac Donald et al., 2019; Mayer et al., 2018; Murdaugh et al., 2018; Mustafi et al., 2018; Schmidt et al., 2018; Wilde et al., 2008). These subcortical white matter tracts have shown the greatest strain and parenchymal deformation in association with mild TBI (Okamoto et al., 2019; Wu et al., 2004).…”

“…DTI studies of pediatric mild TBI have generally relied on small sample sizes that have been highly heterogeneous with regards to participant and injury characteristics (Dodd et al., 2014). Age ranges of participants have varied widely between studies (Babcock et al., 2015; Chu et al., 2010; Ewing-Cobbs et al., 2019; Mayer et al., 2010; Mustafi et al., 2018; Wilde et al., 2018b, 2008; Wozniak et al., 2007). Given that childhood is a period of dynamic maturation, further investigation of a broad age range in a single, larger sample is warranted to help determine whether mild TBI affects expected age-related trajectories of white matter development.…”

“…Some studies have included non-concussed athletes or athletes who participate in noncontact sports (Mustafi et al., 2018; Spader et al., 2018). Less commonly, children with mild TBI have been compared to children with mild extracranial or orthopedic injuries (OI; Babcock et al., 2015; Ewing-Cobbs et al., 2019). The inclusion of typically developing children is problematic for several reasons (Mathias et al., 2013; Wilde et al., 2018a).…”