Age-dependent differences in the impact of paediatric traumatic brain injury on executive functions: A prospective study using susceptibility-weighted imaging

Highlights

• Inhibitory control has been established sensitive to (long-term) consequences of TBI.

• SWI is associated with parent-reported EF behaviour of adolescents.

• Early childhood and adolescence may be vulnerable periods for TBI impact on EF.

Abstract

Childhood and adolescence represent sensitive developmental periods for brain networks implicated in a range of complex skills, including executive functions (EF; inhibitory control, working memory, and cognitive flexibility). As a consequence, these skills may be particularly vulnerable to injuries sustained during these sensitive developmental periods. The present study investigated 1) whether age at injury differentially affects EF 6 months and 2 years after TBI in children aged 5–15 years, and 2) whether the association between brain lesions and EF depend on age at injury. Children with TBI (n = 105) were categorized into four age-at-injury groups based on previous studies and proposed timing of cerebral maturational spurts: early childhood (5–6 years, n = 14), middle childhood (7–9 years, n = 24), late childhood (10–12 years, n = 52), and adolescence (13–15 years, n = 15). EF were assessed with performance-based tasks and a parent-report of everyday EF. TBI patients’ EF scores 6 months and 2 years post-injury were compared to those of typically developing (TD) controls (n = 42). Brain lesions were identified using susceptibility weighted imaging (SWI). Results indicated that inhibitory control performance 2 years post-injury was differentially affected by the impact of TBI depending on age at injury. Follow-up analyses did not reveal significant differences within the age groups, preventing drawing strong conclusions regarding the contribution of age at injury to EF outcome after TBI. Tentatively, large effect sizes suggest that vulnerability is most apparent in early childhood and adolescence. Everyday inhibitory control behaviour was worse for children with TBI than TD children across childhood and adolescence at the 2-year assessment. There was no evidence for impairment in working memory or cognitive flexibility after TBI at the group level. Given small group sizes, findings from analyses into correlations between EF and SWI lesions should be interpreted with caution. Extent, number and volume of brain lesions correlated with adolescent everyday EF behaviour 6 months post-injury. Taken together, the results emphasize the need for long-term follow-up after paediatric TBI during sensitive developmental periods given negative outcomes 2-year post injury. Inhibitory control seems to be particular vulnerable to the impact of TBI. Findings of associations between EF and SWI lesions need to be replicated with larger samples.

Introduction

Traumatic brain injury (TBI) is a common cause of childhood disability, affecting 691 per 100.000 children and adolescents per year across Western countries (Thurman, 2016). Paediatric TBI is associated with long-term cognitive impairments, with difficulties in the area of executive function (EF) being frequent and profound (Anderson and Catroppa, 2005, Babikian and Asarnow, 2009, Catroppa and Anderson, 2009, Mangeot et al., 2002, Sesma et al., 2008, van Heugten et al., 2006). EF are cognitive functions important for purposeful, goal-directed behaviour (Anderson, 2002, Diamond and Lee, 2011). They are essential for children's academic success and mental and physical health (Borella et al., 2010, Diamond, 2013, Gathercole et al., 2004). Their disruption can impact social participation and quality of life (Galvin et al., 2010, Levin et al., 2009, Levin et al., 1997, Rosema et al., 2012, Ylvisaker and Feeney, 2002). EF consist of three separable though interrelated constructs: inhibitory control, working memory and cognitive flexibility (Huizinga et al., 2006, Miyake et al., 2000). Inhibitory control refers to the ability to withhold dominant and pre-potent responses in contexts where they are not appropriate (Huizinga et al., 2006, Miyake et al., 2000). Working memory is a cognitive system which temporarily maintains and manipulates information (Baddeley and Hitch, 1974, Bayliss et al., 2005). Cognitive flexibility is the ability to shift attentional focus between tasks and mental sets (Anderson, 2002, Miyake et al., 2000). Although more severe TBI often leads to worse executive dysfunction (Anderson and Catroppa, 2005, Catroppa and Anderson, 2009, C, 1991, Anderson et al., 2009a, Woodward et al., 1999), outcomes vary widely and the relationship between injury severity and degree of EF impairment cannot yet be fully explained (Anderson and Catroppa, 2005, Catroppa and Anderson, 2009). Age at injury, as a proxy for brain and cognitive development, has received increasing attention in the literature as a potential influence on post-injury outcomes; however, research on its relationship to EF after paediatric TBI is still scarce.

Paediatric TBI occurs at a time of ongoing cognitive and neural development (Anderson and Catroppa, 2005, Anderson et al., 2005, Anderson et al., 2012, Anderson et al., 2011). The sensitive period model states that higher cognitive functions, such as EF, are particularly vulnerable when the insult occurs at times of rapid neural maturation of the function itself and its underlying networks (Anderson et al., 2011, Crowe et al., 2012, Dennis et al., 2014). For the three main EF components discussed above, development continues well into adolescence and early adulthood (Anderson, 2002, Casey et al., 2000, De Luca et al., 2003). Although each of the three EF components has a unique developmental trajectory, early and middle childhood (preschool up to approximately 9 years) has been identified as a key period for each (Anderson, 2002, Romine and Reynolds, 2005, Best et al., 2009, Jurado and Rosselli, 2007). During this stage, prior to the full maturation of EF, children have been argued to be particularly vulnerable. In support of this sensitive period model, a recent study found that children who sustained TBI in early (before 6 years) or middle childhood (7–9 years) demonstrated lower intellectual abilities than those with TBI in late childhood (10–12 years) (Crowe et al., 2012). Other studies have also reported age-dependent cognitive outcomes, including EF, in groups of children following paediatric brain injury (e.g. TBI, congenital injuries, stroke), highlighting increased vulnerability if children were injured at an age when EF were emerging (Anderson et al., 2009a, Anderson et al., 2010).

Despite protracted EF development throughout childhood and into adulthood (Anderson, 2002, Casey et al., 2000, De Luca et al., 2003), the impact of age at injury has rarely been investigated in patients beyond late childhood. Results of these studies seem to indicate that impact of TBI diminishes after early and middle childhood (Anderson, 2002, Crowe et al., 2012, Romine and Reynolds, 2005, Best et al., 2009, Jurado and Rosselli, 2007). However, the sensitive period model would predict that EF are at heightened risk for disruption during adolescence as well, since brain regions involved in these skills are undergoing rapid maturation (Giedd et al., 1999, Gogtay, 2004). In typically developing (TD) children, adolescence is identified as a sensitive period, characterised by rapid decrease in cerebral grey matter paralleled by increases in white matter, indicating synaptic pruning and myelination and resulting in functional maturation (Giedd et al., 1999, Gogtay, 2004). Immaturities in adolescent EF and underlying brain substrates are clearly apparent in, for example, enhanced risk-taking behaviour as a consequence of limited inhibitory control (Blakemore and Choudhury, 2006, Blakemore and Robbins, 2012, Sawyer et al., 2012). In the TBI literature, a recent study employed a global EF index, combining performance test scores and parent-ratings of EF, found that children with severe injuries during adolescence (13–15 years) had greater impairment than children injured during late childhood (10–12 years), and similar impairments to those injured in early or middle childhood (Krasny-Pacini et al., 2017). Adolescents showed almost no recovery over the two years post insult. Generalization of these results is difficult, however, due to small sample size and inability to determine specific EF profiles (Krasny-Pacini et al., 2017). Further investigation in larger studies is warranted, to better characterise the nature of EF impairment and its association with age at injury and injury severity.

Recent evidence suggests that EF components are supported by anatomically distributed brain networks (i.e. in frontal, temporal, parietal and subcortical regions) (Lewis et al., 2004, Monchi et al., 2006, Nowrangi et al., 2014, Power et al., 2007). A promising technique to establish a link between TBI related brain lesions and EF outcomes is susceptibility-weighted imaging (SWI). SWI makes use of a three-dimensional T2*-weighted gradient recalled echo sequence that is highly susceptible to the magnetic properties of extracellular and extravascular blood (Haacke et al., 2004, Tong et al., 2003). This technique is more sensitive than conventional imaging techniques in detecting focal as well as diffuse haemorrhagic pathology (Spitz et al., 2013, Beauchamp et al., 2011). Moreover, SWI is superior to other neuroimaging techniques such as computed tomography or conventional magnetic resonance imagining sequences in detecting micro-haemorrhages because it has increased sensitivity for revealing small traumatic axonal injuries, which may be more typical of mild TBI (Tong et al., 2003, Babikian et al., 2005, Beauchamp et al., 2011). Detecting the presence of SWI lesions can be done by visual examination, for example by radiologists, making it a useful clinical tool for diagnosis. The number and volume of lesions across the brain detected with ((sub)acute SWI analyses have been found to be predictive of general intellectual abilities from 6 months to 3 years post-injury as well as for a general neuropsychological functioning index including verbal and nonverbal memory, information processing, attention and language skills) 1–3 years post-injury (Babikian et al., 2005). The relationship between lesions detected with SWI and EF after paediatric TBI remains to be determined.

The present study extends previous research in two important ways. Firstly, given previous research has focused predominantly on severe TBI, we studied the impact of TBI across the entire spectrum of injury severity (i.e. mild, moderate, severe TBI), occurring from early childhood to adolescence. We hypothesized that, children sustaining TBI in key sensitive developmental periods including early and middle childhood and adolescence, would also demonstrate poorer EF at 6 months and 2 years post-injury. Secondly, we investigated the relations between EF outcomes after TBI and neuropathology as detected with SWI. To that end, we examined lesions in terms of extent (i.e. how many individual regions of the brain were affected, and thus how diffuse the lesions were), number and volume. We hypothesized that a greater extent, number and volume of SWI lesions would be associated with worse EF outcomes, and that the association would be stronger for children who were injured during early and middle childhood and adolescence (i.e. when the damage to the networks underlying EF occurred during a sensitive period of EF development) than for children injured during late childhood.