Characterizing microstructural alterations in a ratmodel of mild traumatic brain injury

1. INTRODUCTION Traumatic brain injury (TBI) is an acquired brain injury that contributes to a substantial number of deaths (mortality rate: 15 per 100 000 in Europe) and a high number of cases of permanent disability (incidence rate: 235 per 100 000 in Europe). Most of the TBI patients have mild TBI (mTBI), a condition that shows no abnormalities on conventional imaging but can result in persisting cognitive defects. Diffusion imaging is an MRI technique sensitive to diffusion of water molecules in the brain and can detect subtle changes in white matter organization. The aim of this study is to investigate whether advanced diffusion MRI scanning can be used to detect microstructural changes in a rat model of mTBI. 2. MATERIALS AND METHODS 2.1 Animal model Nine female Wistar rats weighing 250 ± 19.6 g obtained mTBI utilizing the Marmarou weight drop model [1]. In brief, in anesthetized rats a steel helmet was fixed on the skull 1/3 before and 2/3 behind bregma. The rat was positioned under a 450 g brass weight on a foam bed. The weight was dropped from a height of 1m guided through a plexiglass column. The foam bed together with the rat was rapidly removed away from the column to prevent a second injury. Rats were allowed to recover for one week. 2.2 Imaging and data analysis MRI data was acquired on a 7T MRI scanner (PharmaScan, Bruker, Ettlingen) before and 1 week after injury. T2-weighted images were acquired for anatomical reference. Multishell diffusion data was acquired with multiple directions (b=800, 1500 and 2000; 32, 46 and 64 directions, respectively). Diffusion weighted images were corrected for EPI, motion and eddy current distortions and quantitative maps were calculated for the diffusion tensor and diffusion kurtosis model in ExploreDTI [2]. Furthermore diffusion kurtosis tensor estimation was done using weighted linear least squares method and maps for white matter metrics were calculated using the model of Fieremans et al. [3]. The maps were co-registered in SPM12 with a template based on the local population and a volume-of-interest analysis was performed in the hippocampus, cingulum and corpus callosum using Amide toolbox [4]. Differences between the two time points were calculated for each map using the Wilcoxon signed-rank test in SPSS. P < 0.05 was considered significant. 3. RESULTS AND DISCUSSION The DTI and DKI metrics were not significantly different between the two time points. The axonal water fraction (AWF) was significantly increased in the cingulum, corpus callosum and hippocampus after mTBI and could be explained by axonal swelling. To verify this hypothesis, histological analysis is currently ongoing. Sections will be stained for synapses, astrocytes, neurons and myelin. References Marmarou, A. et al. A new model of diffuse brain injury in rats: Part I. J Neuroscience, 80, 291-300, 1994. Leemans, A. et al. ExploreDTI: a graphical toolbox for processing, analyzing, and visualizing diffusion MR data. In: 17th Annual Meeting of Intl Soc Mag Reson Med, p. 3537, Hawaii, USA, 2009 Fieremans, E. et al. White matter characterization with diffusional kurtosis imaging, Neuroimage 58(1): 177-188, 2011. Loening, AM. et al. AMIDE: A Free Software Tool for Multimodality Medical Image Analysis. Molecular Imaging, 2(3):131-137, 2003

Exploration of gray matter correlates of cognitive training benefit in adolescents with chronic traumatic brain injury

Sustaining a traumatic brain injury (FBI) during adolescence has a profound effect on brain development and can result in persistent executive functioning deficits in daily life. Cognitive recovery from pediatric-TBI relies on the potential of neuroplasticity, which can be fostered by restorative training-programs. However the structural mechanisms underlying cognitive recovery in the immature brain are poorly understood. This study investigated gray matter plasticity following 2 months of cognitive training in young patients with TBI. Sixteen adolescents in the chronic stage of moderate-severe-TBI (9 male, mean age = 15y8m +/- 1y7m) were enrolled in a cognitive computerized training program for 8 weeks (5 times/week, 40 min/session). Pre-and post-intervention, and 6 months after completion of the training, participants underwent a comprehensive neurocognitive test-battery and anatomical Magnetic Resonance Imaging scans. We selected 9 cortical-subcortical Regions-Of-Interest associated with Executive Functioning (EF-ROIs) and 3 control regions from the Desikan-Killiany atlas. Baseline analyses showed significant decreased gray matter density in the superior frontal gyri p = 0.033, superior parietal gyri p = 0.015 and thalamus p = 0.006 in adolescents with TBI compared to age and gender matched controls. Linear mixed model analyses of longitudinal volumetric data of the EF-ROI revealed no strong evidence of training-related changes in the group with TBI. However, compared to the change over time in the control regions between post-intervention and 6 months follow-up, the change in the EF-ROIs showed a significant difference. Exploratory analyses revealed a negative correlation between the change on the Digit Symbol Substitution test and the change in volume of the putamen (r = - 0.596, p = 0.015). This preliminary study contributes to the insights of training-related plasticity mechanisms after pediatric-TBI

Network diffusion modeling predicts neurodegeneration in traumatic brain injury

Objective Traumatic brain injury (TBI) is a heterogeneous disease with multiple neurological deficits that evolve over time. It is also associated with an increased incidence of neurodegenerative diseases. Accordingly, clinicians need better tools to predict a patient’s long‐term prognosis. Methods Diffusion‐weighted and anatomical MRI data were collected from 17 adolescents (mean age = 15y8mo) with moderate‐to‐severe TBI and 19 healthy controls. Using a network diffusion model (NDM), we examined the effect of progressive deafferentation and gray matter thinning in young TBI patients. Moreover, using a novel automated inference method, we identified several injury epicenters in order to determine the neural degenerative patterns in each TBI patient. Results We were able to identify the subject‐specific patterns of degeneration in each patient. In particular, the hippocampus, temporal cortices, and striatum were frequently found to be the epicenters of degeneration across the TBI patients. Orthogonal transformation of the predicted degeneration, using principal component analysis, identified distinct spatial components in the temporal–hippocampal network and the cortico‐striatal network, confirming the vulnerability of these networks to injury. The NDM model, best predictive of the degeneration, was significantly correlated with time since injury, indicating that NDM can potentially capture the pathological progression in the chronic phase of TBI. Interpretation These findings suggest that network spread may help explain patterns of distant gray matter thinning, which would be consistent with Wallerian degeneration of the white matter connections (i.e., “diaschisis”) from diffuse axonal injuries and multifocal contusive injuries, and the neurodegenerative patterns of abnormal protein aggregation and transmission, which are hallmarks of brain changes in TBI. NDM approaches could provide highly subject‐specific biomarkers relevant for disease monitoring and personalized therapies in TBI

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Prefrontal and temporal cortical thickness in adolescents with traumatic brain injury

Aim To investigate the impact of traumatic injury on the developing prefrontal‐temporal adolescent cortex, and correlated brain structural measures with neurocognitive functioning. Method Nineteen adolescents (12 males, 7 females, age range: 11–17y, mean 15y 8mo, standard deviation 1y 7mo, median 15y 11mo) with traumatic brain injury (TBI) were included. Cortical thickness of frontal and temporal lobes was assessed using magnetic resonance imaging. We correlated cortical thickness of prefrontal‐temporal regions with age, time since injury, and neurocognitive functioning, and compared these results with a matched control cohort without TBI. Results We found thinner prefrontal (p=0.039) and temporal cortices (p=0.002) in adolescents with TBI compared to typically developing children. Furthermore, significant age effect was observed on the prefrontal (r=−0.75, p=0.003) and temporal (r=−0.66, p=0.013) cortical thickness in typically developing adolescents, but not in adolescents with TBI. Executive function (measured using the Behaviour Rating Inventory of Executive Function questionnaire, with lower scores meaning higher functioning) was correlated with prefrontal cortical thickness in typically developing adolescents (r=0.72, p=0.009). Opposite trends were found for correlations between cortical thickness and executive function in the TBI and control cohort. Interpretation Structural maturation in typically developing adolescents correlates with functional development: the older the adolescent, the thinner the prefrontal cortex, the better executive function. In adolescents with TBI we observed an opposite trend, that appeared significantly different from the control group: the thinner the prefrontal and temporal cortex, the worse executive functioning

Cognitive training benefit depends on brain injury location in adolescents with traumatic brain injury: A pilot study

BACKGROUND: Executive dysfunction after pediatric traumatic brain injury (TBI) has been linked to poor outcomes in school performance, social functioning and employment. The credibility of training-induced cognitive enhancement in TBI is threatened by its limited proof of benefit in executive skills of daily living. AIM: Our primary aim was to investigate if cognitive intervention for improving impairments in executive functions in the chronic stage of TBI is effective during adolescence. The secondary aim was to explore whether training benefit is driven by injury location. DESIGN: Prospective observational study. SETTING: Child Rehabilitation Center of a University Hospital. POPULATION: Sixteen adolescents with moderate to severe TBI (mean age 15 years and 8 months) and 16 age and gender matched healthy peers were included. METHODS: Effects of a new cognitive training program (BrainGames) were assessed postintervention and 6 months later utilizing a comprehensive neuropsychological test-battery and the Behavior Rating Inventory of Executive Function. In addition, subgroup analyses were performed to determine long-term training benefit in the presence of lesions in corpus callosum, deep-brain-nuclei and prefrontal cortex. RESULTS: Adolescents with TBI showed significant improvements on measures of executive functioning at completion of the training and at follow-up compared with the pre-tests. The presence or absence of diffuse-axonal-injuries (DAI) in the deep brain nuclei determined a significant difference in long-term training benefit. CONCLUSIONS: This study provides preliminary evidence that cognitive training, beyond the acute rehabilitation period in adolescents with TBI is effective to boost executive functioning in daily living. Furthermore, we indicated that DAI in deep brain nuclei may jeopardize long-term benefit from cognitive training. CLINICAL REHABILITATION IMPACT: Individualized rehabilitation programs are crucial in adolescents with different locations of TBI-lesions. Long term follow-up of pediatric TBI is essential

Is diffuse axonal injury on susceptibility weighted imaging a biomarker for executive functioning in adolescents with traumatic brain injury?

Traumatic brain injury (TBI) is a heterogeneous disorder in which diffuse axonal injury (DAI) is an important component contributing to executive dysfunction. During adolescence, developing brain networks are especially vulnerable to acceleration-deceleration forces. We aimed to examine the correlation between DAI (number and localization) and executive functioning in adolescents with TBI. We recruited 18 adolescents with a mean age of 15y8m (SD = 1y7m), averaging 2.5 years after sustaining a moderate-to-severe TBI with documented DAI. Susceptibility Weighted Imaging sequence was administered to localize the DAI lesions. The adolescents performed a neurocognitive test-battery, addressing different aspects of executive functioning (working memory, attention, processing speed, planning ability) and their parents completed the Behavior Rating Inventory of Executive Function (BRIEF) - questionnaire. Executive performance of the TBI-group was compared with an age and gender matched control group of typically developing peers. Based on these results we focused on the Stockings of Cambridge test and the BRIEF to correlate with the total number and location of DAI. Results revealed that the anatomical distribution of DAI, especially in the corpus callosum and the deep brain nuclei, may have more implications for executive functioning than the total amount of DAI in adolescents. Results of this study may help guide targeted rehabilitation to redirect the disturbed development of executive function in adolescents with TBI

Corrigendum to “Is diffuse axonal injury on susceptibility weighted imaging a biomarker for executive functioning in adolescents with traumatic brain injury?” [Eur. J. Paediatr. Neurol. (2019) 525–536] (European Journal of Paediatric Neurology (2019) 23(3) (525–536), (S1090379818304872), (10.1016/j.ejpn.2019.04.003))

The authors regret that the at publication the authors name had been inverted thus was incorrect. The above is the correct authorship list which has been updated online. The authors would like to apologise for any inconvenience caused