Diverging volumetric trajectories following pediatric traumatic brain injury.
ABSTRACT: Traumatic brain injury (TBI) is a significant public health concern, and can be especially disruptive in children, derailing on-going neuronal maturation in periods critical for cognitive development. There is considerable heterogeneity in post-injury outcomes, only partially explained by injury severity. Understanding the time course of recovery, and what factors may delay or promote recovery, will aid clinicians in decision-making and provide avenues for future mechanism-based therapeutics. We examined regional changes in brain volume in a pediatric/adolescent moderate-severe TBI (msTBI) cohort, assessed at two time points. Children were first assessed 2-5 months post-injury, and again 12 months later. We used tensor-based morphometry (TBM) to localize longitudinal volume expansion and reduction. We studied 21 msTBI patients (5 F, 8-18 years old) and 26 well-matched healthy control children, also assessed twice over the same interval. In a prior paper, we identified a subgroup of msTBI patients, based on interhemispheric transfer time (IHTT), with significant structural disruption of the white matter (WM) at 2-5 months post injury. We investigated how this subgroup (TBI-slow, N = 11) differed in longitudinal regional volume changes from msTBI patients (TBI-normal, N = 10) with normal WM structure and function. The TBI-slow group had longitudinal decreases in brain volume in several WM clusters, including the corpus callosum and hypothalamus, while the TBI-normal group showed increased volume in WM areas. Our results show prolonged atrophy of the WM over the first 18 months post-injury in the TBI-slow group. The TBI-normal group shows a different pattern that could indicate a return to a healthy trajectory.
Project description:<h4>Objective</h4>To examine longitudinal trajectories of white matter organization in pediatric moderate/severe traumatic brain injury (msTBI) over a 12-month period.<h4>Methods</h4>We studied 21 children (16 M/5 F) with msTBI, assessed 2-5 months postinjury and again 13-19 months postinjury, as well as 20 well-matched healthy control children. We assessed corpus callosum function through interhemispheric transfer time (IHTT), measured using event-related potentials, and related this to diffusion-weighted MRI measures of white matter (WM) microstructure. At the first time point, half of the patients with TBI had significantly slower IHTT (TBI-slow-IHTT, n = 11) and half were in the normal range (TBI-normal-IHTT, n = 10).<h4>Results</h4>The TBI-normal-IHTT group did not differ significantly from healthy controls, either in WM organization in the chronic phase or in the longitudinal trajectory of WM organization between the 2 evaluations. In contrast, the WM organization of the TBI-slow-IHTT group was significantly lower than in healthy controls across a large portion of the WM. Longitudinal analyses showed that the TBI-slow-IHTT group experienced a progressive decline between the 2 evaluations in WM organization throughout the brain.<h4>Conclusions</h4>We present preliminary evidence suggesting a potential biomarker that identifies a subset of patients with impaired callosal organization in the first months postinjury who subsequently experience widespread continuing and progressive degeneration in the first year postinjury.
Project description:<h4>Importance</h4>Moderate to severe traumatic brain injury (msTBI) is a major cause of death and disability in the US and worldwide. Few studies have enabled prospective, longitudinal outcome data collection from the acute to chronic phases of recovery after msTBI.<h4>Objective</h4>To prospectively assess outcomes in major areas of life function at 2 weeks and 3, 6, and 12 months after msTBI.<h4>Design, setting, and participants</h4>This cohort study, as part of the Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study, was conducted at 18 level 1 trauma centers in the US from February 2014 to August 2018 and prospectively assessed longitudinal outcomes, with follow-up to 12 months postinjury. Participants were patients with msTBI (Glasgow Coma Scale scores 3-12) extracted from a larger group of patients with mild, moderate, or severe TBI who were enrolled in TRACK-TBI. Data analysis took place from October 2019 to April 2021.<h4>Exposures</h4>Moderate or severe TBI.<h4>Main outcomes and measures</h4>The Glasgow Outcome Scale-Extended (GOSE) and Disability Rating Scale (DRS) were used to assess global functional status 2 weeks and 3, 6, and 12 months postinjury. Scores on the GOSE were dichotomized to determine favorable (scores 4-8) vs unfavorable (scores 1-3) outcomes. Neurocognitive testing and patient reported outcomes at 12 months postinjury were analyzed.<h4>Results</h4>A total of 484 eligible patients were included from the 2679 individuals in the TRACK-TBI study. Participants with severe TBI (n = 362; 283 men [78.2%]; median [interquartile range] age, 35.5 [25-53] years) and moderate TBI (n = 122; 98 men [80.3%]; median [interquartile range] age, 38 [25-53] years) were comparable on demographic and premorbid variables. At 2 weeks postinjury, 36 of 290 participants with severe TBI (12.4%) and 38 of 93 participants with moderate TBI (41%) had favorable outcomes (GOSE scores 4-8); 301 of 322 in the severe TBI group (93.5%) and 81 of 103 in the moderate TBI group (78.6%) had moderate disability or worse on the DRS (total score ≥4). By 12 months postinjury, 142 of 271 with severe TBI (52.4%) and 54 of 72 with moderate TBI (75%) achieved favorable outcomes. Nearly 1 in 5 participants with severe TBI (52 of 270 [19.3%]) and 1 in 3 with moderate TBI (23 of 71 [32%]) reported no disability (DRS score 0) at 12 months. Among participants in a vegetative state at 2 weeks, 62 of 79 (78%) regained consciousness and 14 of 56 with available data (25%) regained orientation by 12 months.<h4>Conclusions and relevance</h4>In this study, patients with msTBI frequently demonstrated major functional gains, including recovery of independence, between 2 weeks and 12 months postinjury. Severe impairment in the short term did not portend poor outcomes in a substantial minority of patients with msTBI. When discussing prognosis during the first 2 weeks after injury, clinicians should be particularly cautious about making early, definitive prognostic statements suggesting poor outcomes and withdrawal of life-sustaining treatment in patients with msTBI.
Project description:<h4>Objective</h4>Traumatic brain injury (TBI) is a common disabling condition with limited treatment options. Diffusion tensor imaging measures recovery of axonal injury in white matter (WM) tracts after TBI. Growth hormone deficiency (GHD) after TBI may impair axonal and neuropsychological recovery, and serum insulin-like growth factor-I (IGF-I) may mediate this effect. We conducted a longitudinal study to determine the effects of baseline serum IGF-I concentrations on WM tract and neuropsychological recovery after TBI.<h4>Methods</h4>Thirty-nine adults after TBI (84.6% male, median age?=?30.5 years, 87.2% moderate-severe, median time since TBI?=?16.3 months, n?=?4 with GHD) were scanned twice, 13.3 months (range?=?12.1-14.9) apart, and 35 healthy controls were scanned once. Symptom and quality of life questionnaires and cognitive assessments were completed at both visits (n?=?33). Our main outcome measure was fractional anisotropy (FA), a measure of WM tract integrity, in a priori regions of interest: splenium of corpus callosum (SPCC) and posterior limb of internal capsule (PLIC).<h4>Results</h4>At baseline, FA was reduced in many WM tracts including SPCC and PLIC following TBI compared to controls, indicating axonal injury, with longitudinal increases indicating axonal recovery. There was a significantly greater increase in SPCC FA over time in patients with serum IGF-I above versus below the median for age. Only the higher IGF-I group had significant improvements in immediate verbal memory recall over time.<h4>Interpretation</h4>WM recovery and memory improvements after TBI were greater in patients with higher serum IGF-I at baseline. These findings suggest that the growth hormone/IGF-I system may be a potential therapeutic target following TBI. Ann Neurol 2017;82:30-43.
Project description:<h4>Background</h4>Traumatic brain injury (TBI) is the leading cause of death and disability in children, but effective tools for predicting outcome remain elusive. Although many pediatric patients receive early magnetic resonance imaging (MRI), data on its utility in prognostication are lacking. Diffuse axonal injury (DAI) is a hallmark of TBI detected on early MRI and was shown previously to improve prognostication in adult patients with TBI. In this exploratory study, we investigated whether DAI grade correlates with functional outcome and improves prognostic accuracy when combined with core clinical variables and computed tomography (CT) biomarkers in pediatric patients with moderate-severe TBI (msTBI).<h4>Methods</h4>Pediatric patients (≤ 19 years) who were admitted to two regional level one trauma centers with a diagnosis of msTBI (Glasgow Coma Scale [GCS] score < 13) between 2011 and 2019 were identified through retrospective chart review. Patients who underwent brain MRI within 30 days of injury and had documented clinical follow-up after discharge were included. Age, pupil reactivity, and initial motor GCS score were collected as part of the International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) model. Imaging was reviewed to calculate the Rotterdam score (CT) and DAI grade (MRI) and to evaluate for presence of hypoxic-ischemic injury (MRI). The primary outcome measure was the Pediatric Cerebral Performance Category Scale (PCPCS) score at 6 months after TBI, with favorable outcome defined as PCPCS scores 1-3 and unfavorable outcome defined as PCPCS scores 4-6. The secondary outcome measure was discharge disposition to home versus to an inpatient rehabilitation facility.<h4>Result</h4>Of 55 patients included in the study, 45 (82%) had severe TBI. The most common mechanism of injury was motor vehicle collision (71%). Initial head CT scans showed acute hemorrhage in 84% of patients. MRI was acquired a median of 5 days after injury, and hemorrhagic DAI lesions were detected in 87% of patients. Each 1-point increase in DAI grade increased the odds of unfavorable functional outcome by 2.4-fold. When controlling for core IMPACT clinical variables, neither the DAI grade nor the Rotterdam score was independently correlated with outcome and neither significantly improved outcome prediction over the IMPACT model alone.<h4>Conclusions</h4>A higher DAI grade on early MRI is associated with worse 6-month functional outcome and with discharge to inpatient rehabilitation in children with acute msTBI in a univariate analysis but does not independently correlate with outcome when controlling for the GCS score. Addition of the DAI grade to the core IMPACT model does not significantly improve prediction of poor neurological outcome. Further study is needed to elucidate the utility of early MRI in children with msTBI.
Project description:The chronic consequences of traumatic brain injury (TBI) may contribute to the increased risk for early cognitive decline and dementia, primarily due to diffusion axonal injury. Previous studies in mild TBI (mTBI) have been controversial in describing the white matter tract integrity changes occurring at acute and subacute post-injury. In this prospective longitudinal study, we aim to investigate the longitudinal changes of white matter (WM) using diffusion tensor imaging (DTI) and their correlations with neuropsychological tests. Thirty-three patients with subacute mTBI and 31 matched healthy controls were studied with an extensive imaging and clinical battery. Neuroimaging was obtained within 7 days post-injury for acute scans and repeated at 1 and 3 months post-injury. Using a region-of-interest-based approach, tract-based spatial statistics was used to conduct voxel-wise analysis on diffusion changes in mTBI and was compared to those of healthy matched controls, scanned during the same time period and rescanned with an interval similar to that of patients. We found decreased fractional anisotropy (FA) values in the left anterior limb of internal capsule (ALIC) and right inferior fronto-occipital fasciculus (IFOF) during the 7 days post-injury, which showed longitudinal evidence of recovery following 1 month post-injury. Increased FA values in these two tracts at 1 month post-injury were positively associated with better performance on cognitive information processing speed at initial assessment. By contrast, there were also some tracts (right anterior corona radiata, forceps major, and body of corpus callosum) exhibiting the continuing loss of integrity sustaining even beyond 3 months, which can predict the persisting post-concussion syndromes. Continuing loss of structural integrity in some tracts may contribute to the persistent post-concussion syndromes in mTBI patients, suggesting certain tracts providing an objective biomarker for tracking the pathological recovery process following mTBI.
Project description:<h4>Background and purpose</h4>Diffusion tensor imaging (DTI) can noninvasively quantify white matter (WM) integrity. Although its application in adult traumatic brain injury (TBI) is common, few studies in children have been reported. The purposes of this study were to examine the alteration of fractional anisotropy (FA) in children with TBI experienced during early childhood and to quantify the association between FA and injury severity.<h4>Materials and methods</h4>FA was assessed in 9 children with TBI (age = 7.89 +/- 1.00 years; Glasgow Coma Scale [GCS] = 10.11 +/- 4.68) and a control group of 12 children with orthopedic injuries without central nervous system involvement (age = 7.51 +/- 0.95 years). All of the subjects were at minimum 12 months after injury. We examined group differences in a series of predetermined WM regions of interest with t test analysis. We subsequently conducted a voxel-wise comparison with Spearman partial correlation analysis. Correlations between FA and injury severity were also calculated on a voxel-wise basis.<h4>Results</h4>FA values were significantly reduced in the TBI group in genu of corpus callosum (CC), posterior limb of internal capsule (PLIC), superior longitudinal fasciculus (SLF), superior fronto-occipital fasciculus (SFO), and centrum semiovale (CS). GCS scores were positively correlated with FA in several WM areas including CC, PLIC, SLF, CS, SFO, and inferior fronto-occipital fasciculus (IFO).<h4>Conclusion</h4>This DTI study provides evidence that WM integrity remains abnormal in children with moderate-to-severe TBI experienced during early childhood and that injury severity correlated strongly with FA.
Project description:The cholinergic nuclei in the basal forebrain innervate frontal cortical structures regulating attention. Our aim was to investigate if cognitive test results measuring attention relate to the longitudinal volume change of cholinergically innervated structures following traumatic brain injury (TBI). During the prospective, observational TBIcare project patients with all severities of TBI (n = 114) and controls with acute orthopedic injuries (n = 17) were recruited. Head MRI was obtained in both acute (mean 2 weeks post-injury) and late (mean 8 months) time points. T1-weighted 3D MR images were analyzed with an automatic segmentation method to evaluate longitudinal, structural brain volume change. The cognitive outcome was assessed with the Cambridge Neuropsychological Test Automated Battery (CANTAB). Analyses included 16 frontal cortical structures, of which four showed a significant correlation between post-traumatic volume change and the CANTAB test results. The strongest correlation was found between the volume loss of the supplementary motor cortex and motor screening task results (R-sq 0.16, p < 0.0001), where poorer test results correlated with greater atrophy. Of the measured sum structures, greater cortical gray matter atrophy rate showed a significant correlation with the poorer CANTAB test results. TBI caused volume loss of frontal cortical structures that are heavily innervated by cholinergic neurons is associated with neuropsychological test results measuring attention.
Project description:Traumatic brain injury (TBI) causes neuroendocrine dysregulation in up to 40% of humans, which is related to impaired function of the hypothalamo-hypophyseal axis and contributes to TBI-related co-morbidities. Our objective was to investigate whether hypophyseal atrophy can be recapitulated in rat lateral fluid-percussion injury model of human TBI. High-resolution structural magnetic resonance images (MRI) were acquired from rats at 2 days and 5 months post-TBI. To measure the lobe-specific volumetric changes, manganese-enhanced MRI (MEMRI) scans were acquired from rats at 8 months post-TBI, which also underwent the pentylenetetrazol (PTZ) seizure susceptibility and Morris water-maze spatial memory tests. MRI revealed no differences in the total hypophyseal volume between TBI and controls at 2 days, 5 months or 8 months post-TBI. Surprisingly, MEMRI at 8 months post-TBI indicated a 17% reduction in neurohypophyseal volume in the TBI group as compared to controls (1.04?±?0.05?mm3 vs 1.25?±?0.05?mm3, p?<?0.05). Moreover, neurohypophyseal volume inversely correlated with the number of PTZ-induced epileptiform discharges and the mean latency to platform in the Morris water-maze test. Our data demonstrate that TBI leads to neurohypophyseal lobe-specific atrophy and may serve as a prognostic biomarker for post-TBI outcome.
Project description:<h4>Purpose</h4>Our purpose was to investigate the association between imaging biomarkers of radiation-induced white matter (WM) injury within perisylvian regions and longitudinal language decline in patients with brain tumors.<h4>Methods and materials</h4>Patients with primary brain tumors (n = 44) on a prospective trial underwent brain magnetic resonance imaging, diffusion-weighted imaging, and language assessments of naming (Boston Naming Test [BNT]) and fluency (Delis-Kaplan Executive Function System Category Fluency [DKEFS-CF]) at baseline and 3, 6, and 12 months after fractionated radiation therapy (RT). Reliable change indices of language function (0-6 months), accounting for practice effects (RCI-PE), evaluated decline. Bilateral perisylvian WM regions (superficial WM subadjacent to Broca's area and the superior temporal gyrus [STG], inferior longitudinal fasciculus [ILF], inferior fronto-occipital fasciculus [IFOF], and arcuate fasciculus) were autosegmented. We quantified volume and diffusion measures of WM microstructure: fractional anisotropy (FA; lower values indicate disruption) and mean diffusivity (MD; higher values indicate injury). Linear mixed-effects models assessed mean dose as predictor of imaging biomarker change and imaging biomarkers as longitudinal predictors of language scores.<h4>Results</h4>DKEFS-CF scores declined at 6 months post-RT (RCI-PE, -0.483; P = .01), whereas BNT scores improved (RCI-PE, 0.262; P = .04). Higher mean dose to left and right regions was predictive of decreased volume (left-STG, P = .02; right-ILF and IFOF, P = .03), decreased FA (left-WM tracts, all P < .01; right-STG and IFOF, P < .02), and increased MD of left-WM tracts (all P < .03). Volume loss within left-Broca's area (P = .01), left-ILF (P = .01), left-IFOF (P = .01), and left-arcuate fasciculus (P = .04) was associated with lower BNT scores. Lower FA correlated with poorer DKEFS-CF and BNT scores within left-ILF (P = .02, not significant), left-IFOF (P = .02, .04), and left-arcuate fasciculus (P = .01, .01), respectively. Poorer DKEFS-CF scores correlated with increased MD values within the left-arcuate fasciculus (P = .03). Right-sided biomarkers did not correlate with language scores.<h4>Conclusions</h4>Patients with primary brain tumors experience language fluency decline post-RT. Poorer fluency and naming function may be explained by microstructural injury to left-sided perisylvian WM, representing potential dose-avoidance targets for language preservation.
Project description:Post-concussion symptoms often occur after TBI, persist and cause disabilities. The Rivermead Post-Concussion Symptoms Questionnaire (RPQ) is widely used in this population, but little is known about the comparability of the symptoms over time, i.e., longitudinal measurement invariance (MI). The objectives of this study were to analyze the longitudinal MI of RPQ symptoms from three to twelve months after TBI and to find factors related to RPQ symptoms. The study involved 1023 individuals after TBI who took part in the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) study and completed the RPQ at three, six and twelve months post-injury. Longitudinal confirmatory factor analysis showed that the three-factor structure (somatic, emotional and cognitive) remains stable within one year after TBI. Linear mixed models revealed that sex, injury cause and prior psychiatric problems were related to the RPQ three-factor structure as well as to the RPQ total score. The study strengthens evidence for the RPQ’s factorial structure stability within one year after TBI and identifies sex, injury cause and prior psychiatric problems as important factors that may help clinicians to prevent future complications of symptomatology after TBI.