Further recommendations of the International Paediatric Brain Injury Society (IPBIS) for the post-acute rehabilitation of children with acquired brain injury.

BACKGROUND: Paediatric acquired brain injury is a life-long condition which impacts on all facets of the individual's lived experience. The existing evidence base continues to expand and new fields of enquiry are established as clinicians and researchers uncover the extent of these impacts. PRIMARY OBJECTIVE: To add to recommendations described in the International Paediatric Brain Injury Society's 2016 paper on post-acute care for children with acquired brain injury and highlight new areas of enquiry. REVIEW OF INFORMATION: Recommendations were made based on the opinions of a group of experienced international clinicians and researchers who are current or past members of the board of directors of the International Paediatric Brain Injury Society. The importance of each recommendation was agreed upon by means of group consensus. OUTCOMES: This update gives new consideration to areas of study including injuries which occur in pre-school children, young people in the military, medical referral, young offenders and the use of technology in rehabilitation.

Autologous bone marrow mononuclear cells to treat severe traumatic brain injury in children.

Autologous bone marrow mononuclear cells (BMMNCs) infused after severe traumatic brain injury have shown promise for treating the injury. We evaluated their impact in children, particularly their hypothesized ability to preserve the blood-brain barrier and diminish neuroinflammation, leading to structural central nervous system preservation with improved outcomes. We performed a randomized, double-blind, placebo-sham-controlled Bayesian dose-escalation clinical trial at 2 children's hospitals in Houston, TX and Phoenix, AZ, USA (NCT01851083). Patients 5-17 years of age with severe traumatic brain injury (Glasgow Coma Scale ≤ 8) were randomized to BMMNC or placebo (3:2). Bone marrow harvest, cell isolation, and infusion were completed by 48 hours post-injury. Bayesian continuous reassessment method was used with cohorts of size 3 in the BMMNC group to choose the safest between 2 doses. Primary endpoints were quantitative brain volumes using magnetic resonance imaging and microstructural integrity of the corpus callosum (CC; diffusivity and edema measurements) at 6 months and 12 months. Long-term functional outcomes and ventilator days, intracranial pressure monitoring days, intensive care unit days, and therapeutic intensity measures were compared between groups. Forty-seven patients were randomized, with 37 completing 1-year follow-up (23 BMMNC, 14 placebo). BMMNC treatment was associated with an almost 3-day (23%) reduction in ventilator days, 1-day (16%) reduction in intracranial pressure monitoring, and 3-day (14%) reduction in intensive care unit (ICU) days. White matter volume at 1 year in the BMMNC group was significantly preserved compared to placebo (decrease of 19891 vs 40491, respectively; mean difference of -20600, 95% CI: -35868 to -5332; P = 0.01), and the number of CC streamlines was reduced more in placebo than BMMNC, supporting evidence of preserved CC connectivity in the treated groups (-431 streamlines placebo vs. -37 streamlines BMMNC; mean difference of -394, 95% CI: -803 to 15; P = 0.055), but this did not reach statistical significance due to high variability. We conclude that autologous BMMNC infusion in children within 48 hours after severe traumatic brain injury is safe and feasible. Our data show that BMMNC infusion led to 1) shorter intensive care duration and decreased ICU intensity; 2) white matter structural preservation; and 3) enhanced CC connectivity and improved microstructural metrics.

Novel Oppositional Defiant Disorder or Conduct Disorder 24 Months After Traumatic Brain Injury in Children and Adolescents.

OBJECTIVE: The authors sought to identify predictive factors of new-onset or novel oppositional defiant disorder or conduct disorder assessed 24 months after traumatic brain injury (TBI). METHODS: Children ages 5 to 14 years who had experienced TBI were recruited from consecutive hospital admissions. Soon after injury, participants were assessed for preinjury characteristics, including psychiatric disorders, socioeconomic status (SES), psychosocial adversity, and family function, and the presence and location of lesions were documented by MRI. Psychiatric outcomes, including novel oppositional defiant disorder or conduct disorder, were assessed 24 months after injury. RESULTS: Of the children without preinjury oppositional defiant disorder, conduct disorder, or disruptive behavior disorder not otherwise specified who were recruited in this study, 165 were included in this sample; 95 of these children returned for the 24-month assessment. Multiple imputation was used to address attrition. The prevalence of novel oppositional defiant disorder or conduct disorder was 23.7 out of 165 (14%). In univariable analyses, novel oppositional defiant disorder or conduct disorder was significantly associated with psychosocial adversity (p=0.049) and frontal white matter lesions (p=0.016) and was marginally but not significantly associated with SES. In the final multipredictor model, frontal white matter lesions were significantly associated with novel oppositional defiant disorder or conduct disorder (p=0.021), and psychosocial adversity score was marginally but not significantly associated with the outcome. The odds ratio of novel oppositional defiant disorder or conduct disorder among the children with versus those without novel depressive disorder was significantly higher for girls than boys (p=0.025), and the odds ratio of novel oppositional defiant disorder or conduct disorder among the children with versus those without novel attention-deficit hyperactivity disorder (ADHD) was significantly higher for boys than girls (p=0.006). CONCLUSION: Approximately 14% of children with TBI developed oppositional defiant disorder or conduct disorder. The risk for novel oppositional defiant disorder or conduct disorder can be understood from a biopsychosocial perspective. Sex differences were evident for comorbid novel depressive disorder and comorbid novel ADHD.

Multimodal Analysis of Secondary Cerebellar Alterations After Pediatric Traumatic Brain Injury.

Importance: Traumatic brain injury (TBI) is known to cause widespread neural disruption in the cerebrum. However, less is known about the association of TBI with cerebellar structure and how such changes may alter executive functioning. Objective: To investigate alterations in subregional cerebellum volume and cerebral white matter microstructure after pediatric TBI and examine subsequent changes in executive function. Design, Setting, and Participants: This retrospective cohort study combined 12 data sets (collected between 2006 and 2020) from 9 sites in the Enhancing Neuroimaging Genetics Through Meta-Analysis Consortium Pediatric TBI working group in a mega-analysis of cerebellar structure. Participants with TBI or healthy controls (some with orthopedic injury) were recruited from trauma centers, clinics, and institutional trauma registries, some of which were followed longitudinally over a period of 0.7 to 1.9 years. Healthy controls were recruited from the surrounding community. Data analysis occurred from October to December 2022. Exposure: Accidental mild complicated-severe TBI (msTBI) for those in the TBI group. Some controls received a diagnosis of orthopedic injury. Main Outcomes and Measures: Volume of 18 cerebellar lobules and vermal regions were estimated from 3-dimensional T1-weighted magnetic resonance imaging (MRI) scans. White matter organization in 28 regions of interest was assessed with diffusion tensor MRI. Executive function was measured by parent-reported scores from the Behavior Rating Inventory of Executive Functioning. Results: A total of 598 children and adolescents (mean [SD] age, 14.05 [3.06] years; range, 5.45-19.70 years; 386 male participants [64.5%]; 212 female participants [35.5%]) were included in the study, with 314 participants in the msTBI group, and 284 participants in the non-TBI group (133 healthy individuals and 151 orthopedically injured individuals). Significantly smaller total cerebellum volume (d = -0.37; 95% CI, -0.52 to -0.22; P < .001) and subregional cerebellum volumes (eg, corpus medullare; d = -0.43; 95% CI, -0.58 to -0.28; P < .001) were observed in the msTBI group. These alterations were primarily seen in participants in the chronic phase (ie, >6 months postinjury) of injury (total cerebellar volume, d = -0.55; 95% CI, -0.75 to -0.35; P < .001). Smaller cerebellum volumes were associated with higher scores on the Behavior Rating Inventory of Executive Functioning Global Executive Composite score (ß = -208.9 mm3; 95% CI, -319.0 to -98.0 mm3; P = .008) and Metacognition Index score (ß = -202.5 mm3; 95% CI, -319.0 to -85.0 mm3; P = .02). In a subset of 185 participants with longitudinal data, younger msTBI participants exhibited cerebellum volume reductions (ß = 0.0052 mm3; 95% CI, 0.0013 to 0.0090 mm3; P = .01), and older participants slower growth rates. Poorer white matter organization in the first months postinjury was associated with decreases in cerebellum volume over time (ß=0.52 mm3; 95% CI, 0.19 to 0.84 mm3; P = .005). Conclusions and Relevance: In this cohort study of pediatric msTBI, our results demonstrated robust cerebellar volume alterations associated with pediatric TBI, localized to the posterior lobe. Furthermore, longitudinal cerebellum changes were associated with baseline diffusion tensor MRI metrics, suggesting secondary cerebellar atrophy. These results provide further understanding of secondary injury mechanisms and may point to new opportunities for intervention.

Long-term Participation and Functional Status in Children Who Experience Traumatic Brain Injury.

OBJECTIVE: To evaluate the effect of child and family factors on children's participation outcomes 2 to 3 years following traumatic brain injury (TBI). SETTING: Two level 1 pediatric trauma centers. PARTICIPANTS: Children aged 0 to 15 years with TBI at all severity levels or an orthopedic injury. DESIGN: Prospective cohort. MAIN MEASURES: Caregivers completed the Child and Adolescent Scale of Participation (CASP) at 2- and 3-year follow-ups. The CASP was categorized as more than 90 or 90 or less on a 100-point scale, with 90 or less representing the 10th percentile and below in this sample. Modified Poisson regression models were used to describe relative risk of the CASP at 90 or less at 2 to 3 years postinjury, adjusting for preinjury family environment variables and injury group. A secondary analysis only included children who were 31 months or older at injury (n = 441) to determine whether changes in functional outcome (Pediatric Injury Functional Outcome Scale, PIFOS) and executive functions (Behavior Rating Inventory of Executive Function, BRIEF) from preinjury to 1 year after injury predicted CASP scores at the 2- or 3-year follow-up. RESULTS: Seventy-eight percent (596/769) of children who had a completed preinjury survey had a completed CASP. In the adjusted model, children with severe TBI had a nearly 3 times higher risk (RR = 2.90; 95% CI, 1.43-5.87) of reduced participation than children with an orthopedic injury. In the secondary analysis, lower functional skills (5-point increase in 1-year postinjury PIFOS score) (RR = 1.36; 95% CI, 1.18-1.57) and less favorable family function (RR = 1.46; 95% CI, 1.02-2.10) were associated with reduced participation in both girls and boys. CONCLUSION: Participation in home, school, and community activities after TBI is related to multiple biopsychosocial factors. Participation-focused interventions are needed to reduce barriers to involvement and assist children and families to close the participation gap across settings.

Reducing Stress after Trauma (ReSeT): study protocol for a randomized, controlled trial of an online psychoeducational program and video therapy sessions for children hospitalized after trauma.

BACKGROUND: Post-traumatic stress symptoms develop in a quarter to half of injured children affecting their longer-term psychologic and physical health. Evidence-based care exists for post-traumatic stress; however, it is not readily available in some communities. We have developed an eHealth program consisting of online, interactive educational modules and telehealth therapist support based in trauma-focused cognitive behavioral therapy, the Reducing Stress after Trauma (ReSeT) program. We hypothesize that children with post-traumatic stress who participate in ReSeT will have fewer symptoms compared to the usual care control group. METHODS: This is a randomized controlled trial to test the effectiveness of the ReSeT intervention in reducing symptoms of post-traumatic stress compared to a usual care control group. One hundred and six children ages 8-17 years, who were admitted to hospital following an injury, with post-traumatic stress symptoms at 4 weeks post-injury, will be recruited and randomized from the four participating trauma centers. The outcomes compared across groups will be post-traumatic stress symptoms at 10 weeks (primary outcome) controlling for baseline symptoms and at 6 months post-randomization (secondary outcome). DISCUSSION: ReSeT is an evidence-based program designed to reduce post-traumatic stress symptoms among injured children using an eHealth platform. Currently, the American College of Surgeons standards suggest that trauma programs identify and treat patients at high risk for mental health needs in the trauma system. If effectiveness is demonstrated, ReSeT could help increase access to evidence-based care for children with post-traumatic stress within the trauma system. TRIAL REGISTRATION: ClinicalTrials.gov NCT04838977. 8 April 2021.

Longitudinal Developmental Outcomes of Infants and Toddlers With Traumatic Brain Injury.

Importance: Among children, infants and toddlers have some of the highest rates of traumatic brain injury (TBI), but longitudinal information on their developmental outcomes to guide postinjury surveillance is sparse. Objective: To evaluate infants' and toddlers' development over 3 years following TBI compared with those with orthopedic injury (OI). Design, Setting, and Participants: A longitudinal observational cohort study was conducted at 2 level 1 pediatric trauma centers from January 20, 2013, to September 30, 2015; data analysis was performed from May 12 to October 20, 2021. Participants included children injured when younger than 31 months with TBI or OI who received emergency department care. Exposures: Mild, moderate, or severe TBI or OI. Main Outcomes and Measures: Parents completed baseline measures representing preinjury status and 3-, 12-, 24-, and 36-month postinjury status, using the Ages & Stages Questionnaire-3 (ASQ-3), with a mean reference value of 50 and higher scores indicating more advanced development. Linear mixed models characterized children's outcomes for each ASQ-3 domain after adjustment for baseline ASQ-3, injury severity and group, age, injury mechanism (abuse or not), sex, prematurity, family function, social capital, and time. Interactions with time were evaluated. Results: Consent for participation was provided for 195 children; 184 parents (94%) completed a baseline survey. The cohort included 168 children who completed at least 1 follow-up survey: 48 (29%) mild; 54 (32%) complicated mild/moderate; 21 (13%) severe TBI; and 45 (27%) orthopedic injury. The cohort included 95 boys (57%), 49% injured before age 1 year; and 13% injured by abuse. Mean (SD) age at the time of injury was 13.9 (9.4) months. At 36 months, children with mild or complicated mild/moderate TBI performed similarly to children with OI across ASQ-3 domains. Children with severe TBI performed poorly as shown by negative mean differences in communication (-8.8; 95% CI, -13.8 to -3.8); gross motor (-10.1; 95% CI, -15.1 to -5.1); problem solving (-6.6; 95% CI, -11.2 to -1.9), and personal social (-6.3; 95% CI, -10.4 to -2.1) domains with little recovery over time. Children with abusive injury experienced decrements in ability over time in fine motor and personal social skills. Social capital was protective in communication (mean, 1.5; 95% CI, 0.3-2.7) and problem solving (mean, 1.2; 95% CI, 0.1-2.3) domains. Conclusions and Relevance: In this cohort study of children with TBI, children with severe injury showed little recovery. These findings suggest that early childhood intervention is needed, while children with milder injury remained on their developmental track and should continue routine developmental surveillance.

Novel Psychiatric Disorder 6 Months After Traumatic Brain Injury in Children and Adolescents.

OBJECTIVE: To investigate the factors predictive of novel psychiatric disorders in the interval 0-6 months following traumatic brain injury (TBI). METHODS: Children ages 5-14 years consecutively hospitalized for mild to severe TBI at five hospitals were recruited. Participants were evaluated at baseline (soon after injury) for pre-injury characteristics including psychiatric disorders, socioeconomic status (SES), psychosocial adversity, family function, family psychiatric history, and adaptive function. In addition to the psychosocial variables, injury severity and lesion location detected with acquisition of a research MRI were measured to develop a biopsychosocial predictive model for development of novel psychiatric disorders. Psychiatric outcome, including occurrence of a novel psychiatric disorder, was assessed 6 months after the injury. RESULTS: The recruited sample numbered 177 children, and 141 children (80%) returned for the six-month assessment. Of the 141 children, 58 (41%) developed a novel psychiatric disorder. In univariable analyses, novel psychiatric disorder was significantly associated with lower SES, higher psychosocial adversity, and lesions in frontal lobe locations, such as frontal white matter, superior frontal gyrus, inferior frontal gyrus, and orbital gyrus. Multivariable analyses found that novel psychiatric disorder was independently and significantly associated with frontal-lobe white matter, superior frontal gyrus, and orbital gyrus lesions. CONCLUSION: The results demonstrate that occurrence of novel psychiatric disorders following pediatric TBI requiring hospitalization is common and has identifiable psychosocial and specific biological predictors. However, only the lesion predictors were independently related to this adverse psychiatric outcome.

Stress Reactivity After Pediatric Traumatic Brain Injury: Relation With Behavioral Adjustment.

Traumatic injury is linked increasingly to alterations in both stress response systems and psychological health. We investigated reactivity of salivary analytes of the hypothalamic-pituitary-adrenal axis (cortisol) and autonomic nervous system (salivary alpha amylase, sAA) during a psychosocial stress procedure in relation to psychological health outcomes. In a prospective cohort design, stress reactivity of children ages 8 to 15 years hospitalized for traumatic brain injury (TBI; n = 74) or extracranial injury (EI; n = 35) was compared with healthy controls (n = 51) 7 months after injury. Area under the curve increase (AUCinc) assessed pre-stressor to post-stressor cortisol and sAA values. Multi-variable general linear models evaluated demographic, family functioning, group, cortisol, and sAA AUCinc, and their interactions in relation to concurrent child and parent ratings of emotion regulation and internalizing and externalizing problems. Although AUCinc values were similar across groups, their relations with outcomes varied by group. Higher stress reactivity is typically associated with fewer adjustment problems. Relative to controls, greater sAA reactivity was associated with greater emotion dysregulation after TBI. In contrast, the relation of sAA reactivity with internalizing and generalized anxiety scores was flatter for both TBI and EI groups. The flattened and/or reversed direction of sAA reactivity with psychological health outcomes after TBI, and to a lesser degree EI, suggests autonomic nervous system dysregulation. Across groups, sAA reactivity interacted with sex on several psychological health outcomes with greater dysregulation in girls than in boys. Our findings highlight altered sAA, but not cortisol reactivity, as a potential mechanism of biological vulnerability associated with poorer adjustment after TBI.

Novel Oppositional Defiant Disorder 12 Months After Traumatic Brain Injury in Children and Adolescents.

OBJECTIVE: The investigators examined the factors predictive of novel oppositional defiant disorder in the 6-12 months following traumatic brain injury (TBI). METHODS: Children ages 5-14 years old who experienced a TBI were recruited from consecutive admissions to five hospitals. Participants were evaluated soon after injury (baseline) for preinjury characteristics, including psychiatric disorders, adaptive function, family function, psychosocial adversity, family psychiatric history, socioeconomic status, and injury severity, to develop a biopsychosocial predictive model for development of novel oppositional defiant disorder. MRI analyses were conducted to examine potential brain lesions. Psychiatric outcome, including that of novel oppositional defiant disorder, was assessed 12 months after injury. RESULTS: Although 177 children were recruited for the study, 120 children without preinjury oppositional defiant disorder, conduct disorder, or disruptive behavior disorder not otherwise specified (DBD NOS) returned for the 12-month assessment. Of these 120 children, seven (5.8%) exhibited novel oppositional defiant disorder, and none developed conduct disorder or DBD NOS in the 6-12 months postinjury. Novel oppositional defiant disorder was significantly associated with lower socioeconomic status, higher psychosocial adversity, and lower preinjury adaptive functioning. CONCLUSIONS: These results demonstrate that novel oppositional defiant disorder following TBI selectively and negatively affects an identifiable group of children. Both proximal (preinjury adaptive function) and distal (socioeconomic status and psychosocial adversity) psychosocial variables significantly increase risk for this outcome.

Novel Oppositional Defiant Disorder 6 Months After Traumatic Brain Injury in Children and Adolescents.

OBJECTIVE: The investigators aimed to assess predictive factors of novel oppositional defiant disorder (ODD) among children and adolescents in the first 6 months following traumatic brain injury (TBI). METHODS: Children ages 5-14 years who experienced a TBI were recruited from consecutive admissions to five hospitals. Testing of a biopsychosocial model that may elucidate the development of novel ODD included assessment soon after injury (baseline) of preinjury characteristics, including psychiatric disorders, adaptive function, family function, psychosocial adversity, family psychiatric history, socioeconomic status, injury severity, and postinjury processing speed (which may be a proxy for brain injury). MRI analyses were also conducted to examine potential brain lesions. Psychiatric outcome, including that of novel ODD, was assessed 6 months after the injury. RESULTS: A total of 177 children and adolescents were recruited for the study, and 134 who were without preinjury ODD, conduct disorder, or disruptive behavior disorder not otherwise specified (DBD NOS) returned for the 6-month assessment. Of those who returned 6 months postinjury, 11 (8.2%) developed novel ODD, and none developed novel conduct disorder or DBD NOS. Novel ODD was significantly associated with socioeconomic status, preinjury family functioning, psychosocial adversity, and processing speed. CONCLUSIONS: These findings show that an important minority of children with TBI developed ODD. Psychosocial and injury-related variables, including socioeconomic status, lower family function, psychosocial adversity, and processing speed, significantly increase risk for this outcome.

Effective connectivity in the default mode network after paediatric traumatic brain injury.

Children who experience a traumatic brain injury (TBI) are at elevated risk for a range of negative cognitive and neuropsychological outcomes. Identifying which children are at greatest risk for negative outcomes can be difficult due to the heterogeneity of TBI. To address this barrier, the current study applied a novel method of characterizing brain connectivity networks, Bayesian multi-subject vector autoregressive modelling (BVAR-connect), which used white matter integrity as priors to evaluate effective connectivity-the time-dependent relationship in functional magnetic resonance imaging (fMRI) activity between two brain regions-within the default mode network (DMN). In a prospective longitudinal study, children ages 8-15 years with mild to severe TBI underwent diffusion tensor imaging and resting state fMRI 7 weeks after injury; post-concussion and anxiety symptoms were assessed 7 months after injury. The goals of this study were to (1) characterize differences in positive effective connectivity of resting-state DMN circuitry between healthy controls and children with TBI, (2) determine if severity of TBI was associated with differences in DMN connectivity and (3) evaluate whether patterns of DMN effective connectivity predicted persistent post-concussion symptoms and anxiety. Healthy controls had unique positive connectivity that mostly emerged from the inferior temporal lobes. In contrast, children with TBI had unique effective connectivity among orbitofrontal and parietal regions. These positive orbitofrontal-parietal DMN effective connectivity patterns also differed by TBI severity and were associated with persisting behavioural outcomes. Effective connectivity may be a sensitive neuroimaging marker of TBI severity as well as a predictor of chronic post-concussion symptoms and anxiety.

As Time Goes by: Understanding Child and Family Factors Shaping Behavioral Outcomes After Traumatic Brain Injury.

Objective: To model pre-injury child and family factors associated with the trajectory of internalizing and externalizing behavior problems across the first 3 years in children with pediatric traumatic brain injury (TBI) relative to children with orthopedic injuries (OI). Parent-reported emotional symptoms and conduct problems were expected to have unique and shared predictors. We hypothesized that TBI, female sex, greater pre-injury executive dysfunction, adjustment problems, lower income, and family dysfunction would be associated with less favorable outcomes. Methods: In a prospective longitudinal cohort study, we examined the level of behavior problems at 12 months after injury and rate of change from pre-injury to 12 months and from 12 to 36 months in children ages 4-15 years with mild to severe TBI relative to children with OI. A structural equation model framework incorporated injury characteristics, child demographic variables, as well as pre-injury child reserve and family attributes. Internalizing and externalizing behavior problems were indexed using the parent-rated Emotional Symptoms and Conduct Problems scales from the Strengths and Difficulties questionnaire. Results: The analysis cohort of 534 children [64% boys, M (SD) 8.8 (4.3) years of age] included 395 with mild to severe TBI and 139 with OI. Behavior ratings were higher after TBI than OI but did not differ by TBI severity. TBI, higher pre-injury executive dysfunction, and lower income predicted the level and trajectory of both Emotional Symptoms and Conduct Problems at 12 months. Female sex and poorer family functioning were vulnerability factors associated with greater increase and change in Emotional Symptoms by 12 months after injury; unique predictors of Conduct Problems included younger age and prior emotional/behavioral problems. Across the long-term follow-up from 12 to 36 months, Emotional Symptoms increased significantly and Conduct Problems stabilized. TBI was not a significant predictor of change during the chronic stage of recovery. Conclusions: After TBI, Emotional Symptoms and Conduct Problem scores were elevated, had different trajectories of change, increased or stayed elevated from 12 to 36 months after TBI, and did not return to pre-injury levels across the 3 year follow-up. These findings highlight the importance of addressing behavioral problems after TBI across an extended time frame.

White Matter Disruption in Pediatric Traumatic Brain Injury: Results from ENIGMA Pediatric Moderate to Severe Traumatic Brain Injury.

OBJECTIVE: Our study addressed aims: (1) test the hypothesis that moderate-severe TBI in pediatric patients is associated with widespread white matter (WM) disruption; (2) test the hypothesis that age and sex impact WM organization after injury; and (3) examine associations between WM organization and neurobehavioral outcomes. METHODS: Data from ten previously enrolled, existing cohorts recruited from local hospitals and clinics were shared with the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) Pediatric msTBI working group. We conducted a coordinated analysis of diffusion MRI (dMRI) data using the ENIGMA dMRI processing pipeline. RESULTS: Five hundred and seven children and adolescents (244 with complicated mild to severe TBI [msTBI] and 263 controls) were included. Patients were clustered into three post-injury intervals: acute/subacute - <2 months, post-acute - 2-6 months, chronic - 6+ months. Outcomes were dMRI metrics and post-injury behavioral problems as indexed by the Child Behavior Checklist (CBCL). Our analyses revealed altered WM diffusion metrics across multiple tracts and all post-injury intervals (effect sizes ranging between d=-0.5 to -1.3). Injury severity is a significant contributor to the extent of WM alterations but explained less variance in dMRI measures with increasing time post-injury. We observed a sex-by-group interaction: females with TBI had significantly lower fractional anisotropy in the uncinate fasciculus than controls (𝞫=0.043), which coincided with more parent-reported behavioral problems (𝞫=-0.0027). CONCLUSIONS: WM disruption after msTBI is widespread, persistent, and influenced by demographic and clinical variables. Future work will test techniques for harmonizing neurocognitive data, enabling more advanced analyses to identify symptom clusters and clinically-meaningful patient subtypes.

Post-Concussion and Post-Traumatic Stress Symptoms after Pediatric Traumatic Brain Injury: Shared Vulnerability Factors?

Following pediatric traumatic brain injury (TBI), post-concussion symptoms (PCS) and post-traumatic stress symptoms (PTSS) occur commonly; however, it is unknown to what degree they overlap. The study examined PCS and PTSS persisting 7 weeks after injury in children and adolescents ages 8-15 years with TBI (n = 89) or extracranial injury (EI; n = 40) after vehicle collisions. TBI was divided into mild, complicated-mild/moderate, and severe groups. Parents retrospectively rated children's pre-injury symptoms and behavior problems, and children completed self-report measures after injury. PCS and PTSS total scores were significantly correlated in TBI and EI groups, respectively, for child (rs = 0.75; rs = 0.44), and adolescent (rs = 0.61; rs = 0.67) cohorts. Generalized linear models examined whether injury type and severity, age, sex, and pre-injury symptom ratings predicted PCS and PTSS total scores and factor scores. Specific PCS and PTSS factor scores were elevated in different TBI severity groups, with most frequent problems following mild or severe TBI. PCS did not differ by age; however, girls had more emotional symptoms than boys. Only PTSS were predicted by pre-injury externalizing behavior. Significant age by sex interactions indicated that adolescent girls had more total, avoidance, and hyperarousal PTSS symptoms than younger girls or all boys. PCS and PTSS significantly overlapped in both TBI and EI groups, highlighting shared persistent symptoms after injury. Shared vulnerability factors included female sex, milder TBI, and poorer pre-injury adjustment. Older age was a unique vulnerability factor for PTSS. Psychological health interventions after injury should be customized to address comorbid symptoms.

Trajectories of Children's Executive Function After Traumatic Brain Injury.

Importance: Executive functions are critical for school and social success. Although these functions are adversely affected by pediatric traumatic brain injury (TBI), recovery patterns are not well established. Objective: To examine 3-year trajectories of selected children's executive functions after TBI. Design, Setting, and Participants: This prospective cohort study was conducted from January 22, 2013, to September 30, 2015, with 3-year follow-up at the level I pediatric trauma centers Primary Children's Hospital in Salt Lake City, Utah and Children's Memorial Hermann Hospital in Houston, Texas. Study participants included children aged 2 to 15 years with TBI or orthopedic injury (OI) who were treated at the participating hospitals. Children were consecutively recruited and stratified by injury severity and age group. A total of 625 children consented and completed a baseline survey; 559 (89%) children completed at least 1 follow-up and composed the analysis cohort. It was hypothesized that recovery would differ by injury severity, age at injury, and sex. Data analyses were performed from June to October 2019. Main Outcomes and Measures: Growth curve models examined the pattern of change in the Emotional Control, Inhibit, Working Memory, and Plan-Organize subscales of the Behavior Rating Inventory of Executive Function (BRIEF) or BRIEF-Preschool. For all BRIEF subscales, higher scores indicate worse symptoms, and a score of 65 or greater represents clinical impairment. Results: A total of 559 children (mean [SD] age, 8.6 [4.4] years; 356 boys [64%], 328 non-Hispanic White children [59%]) were included in the study: 155 (28%) children had mild TBI, 162 (29%) had complicated mild or moderate TBI, 90 (16%) had severe TBI, and 152 (27%) had OI. Growth curve trajectories varied by BRIEF subscale and injury severity. Overall, children with TBI did not return to their preinjury baseline, with a stepwise worsening of each outcome at 36 months by TBI severity compared with OI. Among children with severe TBI, trajectories accelerated fastest, indicating increased problems, from injury to 12 months for the Emotional Control (9.0 points; 95% CI, 6.0-11.9 points), Inhibit (3.6 points; 95% CI, 1.6-5.6 points), and Working Memory (7.0 points; 95% CI, 4.1-9.9 points) subscales. Their trajectories plateaued, with a secondary acceleration before 36 months for the Emotional Control and Working Memory subscales. Children with mild TBI had worse 36-month scores on all subscales except Inhibit compared with OI. Recovery patterns were similar for boys and girls. Conclusions and Relevance: In this longitudinal cohort study of children with TBI, trajectory analysis revealed that some children worsen after a recovery plateau, suggesting a need for longitudinal reassessment beyond 1 year postinjury.

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

Plasticity is often implicated as a reparative mechanism when addressing structural and functional brain development in young children following traumatic brain injury (TBI); however, conventional imaging methods may not capture the complexities of post-trauma development. The present study examined the cingulum bundles and perforant pathways using diffusion tensor imaging (DTI) in 21 children and adolescents (ages 10-18 years) 5-15 years after sustaining early childhood TBI in comparison with 19 demographically-matched typically-developing children. Verbal memory and executive functioning were also evaluated and analyzed in relation to DTI metrics. Beyond the expected direction of quantitative DTI metrics in the TBI group, we also found qualitative differences in the streamline density of both pathways generated from DTI tractography in over half of those with early TBI. These children exhibited hypertrophic cingulum bundles relative to the comparison group, and the number of tract streamlines negatively correlated with age at injury, particularly in the late-developing anterior regions of the cingulum; however, streamline density did not relate to executive functioning. Although streamline density of the perforant pathway was not related to age at injury, streamline density of the left perforant pathway was significantly and positively related to verbal memory scores in those with TBI, and a moderate effect size was found in the right hemisphere. DTI tractography may provide insight into developmental plasticity in children post-injury. While traditional DTI metrics demonstrate expected relations to cognitive performance in group-based analyses, altered growth is reflected in the white matter structures themselves in some children several years post-injury. Whether this plasticity is adaptive or maladaptive, and whether the alterations are structure-specific, warrants further investigation.

Frontostriatal White Matter Integrity Relations with "Cool" and "Hot" Self-Regulation after Pediatric Traumatic Brain Injury.

Traumatic brain injury (TBI) produces microstructural damage to white matter pathways connecting neural structures in pre-frontal and striatal regions involved in self-regulation (SR). Dorsal and ventral frontostriatal pathways have been linked to cognitive ("cool") and emotional ("hot") SR, respectively. We evaluated the relation of frontostriatal pathway fractional anisotropy (FA) 2 months post-TBI on cool and hot SR assessed 7 months post-TBI. Participants were 8-15 years of age, including children with uncomplicated mild TBI (mTBI; n = 24), more severe TBI (complicated-mild, moderate, severe [cms]TBI; n = 60), and typically developing (TD) children (n = 55). Diffusion tensor tractography was used to map frontostriatal pathways. Cool SR included focused and sustained attention performance, and parent-reported attention, whereas hot SR included risk-taking performance and parent-reported emotional control. Multivariate general linear models showed that children with cmsTBI had greater parent-reported cool and hot SR difficulties and lower dorsal and ventral FA than TD children. Focused attention, risk taking, and emotional control correlated with FA of specific dorsal and ventral pathways; however, only the effect of TBI on focused attention was mediated by integrity of dorsal pathways. Results suggest that frontostriatal FA may serve as a biomarker of risk for SR difficulties or to assess response to interventions targeting SR in pediatric TBI and in broader neurodevelopmental populations.

Functional outcome after severe childhood traumatic brain injury: Results of the TGE prospective longitudinal study.

BACKGROUND: Childhood severe traumatic brain injury (TBI) is a leading cause of long-lasting acquired disability, but little is known about functional outcome. OBJECTIVE: We aimed to 1) study clinical recovery and functional outcome over 24 months after severe childhood TBI, 2) identify early sociodemographic and severity factors influencing outcome, and 3) examine the clinical utility of the Pediatric Injury Functional Outcome Scale (PIFOS) to assess functional outcome. METHODS: Children (0-15 years) consecutively admitted in a trauma centre after accidental severe TBI over 3 years were included in a prospective longitudinal study (Traumatisme Grave de l'Enfant cohort). We measured clinical/neurological recovery, functional status (Pediatric Injury Functional Outcome Scale, [PIFOS]), overall disability (pediatric Glasgow Outcome Scale [GOS-Peds]) as well as intellectual ability (Wechsler scales) and educational outcome (mainstream school vs special education) of survivors at 1, 3, 12 and 24 months post-injury. RESULTS: For 45 children (aged 3 to 15 years at injury), functional impairments were severe within the first 3 months. Despite the initial rapid clinical recovery and significant improvement over the first year, substantial alterations persisted for most children at 12 months post-TBI, with no significant improvement up to 2 years. Up to 80% of children still had moderate or severe overall disability (GOS-Peds) at 24 months. The severity of functional impairments (PIFOS) at 12 and 24 months was mostly related to socio-emotional, cognitive and physical impairments, and was significantly correlated with clinical/neurological deficits and cognitive (intellectual, executive) and behavioural disorders. Initial TBI severity was the main prognostic factor associated with functional status over the first 2 years post-injury. CONCLUSIONS: Our results confirm the significant impact of severe childhood TBI on short- and medium-term functional outcomes and overall disability. All patients should benefit from systematic follow-up. The PIFOS appeared to be an accurate and reliable tool to assess functional impairment evolution and clinically meaningful outcomes over the first 2 years post-injury.

Developmental Alterations in Cortical Organization and Socialization in Adolescents Who Sustained a Traumatic Brain Injury in Early Childhood.

This study investigated patterns of cortical organization in adolescents who had sustained a traumatic brain injury (TBI) during early childhood to determine ways in which early head injury may alter typical brain development. Increased gyrification in other patient populations is associated with polymicrogyria and aberrant development, but this has not been investigated in TBI. Seventeen adolescents (mean age = 14.1 ± 2.4) who sustained a TBI between 1-8 years of age, and 17 demographically-matched typically developing children (TDC) underwent a high-resolution, T1-weighted 3-Tesla magnetic resonance imaging (MRI) at 6-15 years post-injury. Cortical white matter volume and organization was measured using FreeSurfer's Local Gyrification Index (LGI). Despite a lack of significant difference in white matter volume, participants with TBI demonstrated significantly increased LGI in several cortical regions that are among those latest to mature in normal development, including left parietal association areas, bilateral dorsolateral and medial frontal areas, and the right posterior temporal gyrus, relative to the TDC group. Additionally, there was no evidence of increased surface area in the regions that demonstrated increased LGI. Higher Vineland-II Socialization scores were associated with decreased LGI in right frontal and temporal regions. The present results suggest an altered pattern of expected development in cortical gyrification in the TBI group, with changes in late-developing frontal and parietal association areas. Such changes in brain structure may underlie cognitive and behavioral deficits associated with pediatric TBI. Alternatively, increased gyrification following TBI may represent a compensatory mechanism that allows for typical development of cortical surface area, despite reduced brain volume.