Widespread White Matter Abnormalities in Concussed Athletes Detected by 7T Diffusion Magnetic Resonance Imaging.

Sports-related concussions may cause white matter injuries and persistent post-concussive symptoms (PPCS). We hypothesized that athletes with PPCS would have neurocognitive impairments and white matter abnormalities that could be revealed by advanced neuroimaging using ultra-high field strength diffusion tensor (DTI) and diffusion kurtosis (DKI) imaging metrics and cerebrospinal fluid (CSF) biomarkers. A cohort of athletes with PPCS severity limiting the ability to work/study and participate in sport school and/or social activities for ≥6 months completed 7T magnetic resonance imaging (MRI) (morphological T1-weighed volumetry, DTI and DKI), extensive neuropsychological testing, symptom rating, and CSF biomarker sampling. Twenty-two athletes with PPCS and 22 controls were included. Concussed athletes performed below norms and significantly lower than controls on all but one of the psychometric neuropsychology tests. Supratentorial white and gray matter, as well as hippocampal volumes did not differ between concussed athletes and controls. However, of the 72 examined white matter tracts, 16% of DTI and 35% of DKI metrics (in total 28%) were significantly different between concussed athletes and controls. DKI fractional anisotropy and axial kurtosis were increased, and DKI radial diffusivity and radial kurtosis decreased in concussed athletes when compared with controls. CSF neurofilament light (NfL; an axonal injury marker), although not glial fibrillary acidic protein, correlated with several diffusion metrics. In this first 7T DTI and DKI study investigating PPCS, widespread microstructural alterations were observed in the white matter, correlating with CSF markers of axonal injury. More white matter changes were observed using DKI than using DTI. These white matter alterations may indicate persistent pathophysiological processes following concussion in sport.

Thalamocortical coherence predicts persistent postconcussive symptoms.

The pathogenetic mechanism of persistent post-concussive symptoms (PCS) following concussion remains unclear. Thalamic damage is known to play a role in PCS prolongation while the evidence and biomarkers that trigger persistent PCS have never been elucidated. We collected longitudinal neuroimaging and behavior data from patients and rodents after concussion, complemented with rodents' histological staining data, to unravel the early biomarkers of persistent PCS. Diffusion tensor imaging (DTI) were acquired to investigated the thalamic damage, while quantitative thalamocortical coherence was derived through resting-state functional MRI for evaluating thalamocortical functioning and predicting long-term behavioral outcome. Patients with prolonged symptoms showed abnormal DTI-derived indices at the boundaries of bilateral thalami (peri-thalamic regions). Both patients and rats with persistent symptoms demonstrated enhanced thalamocortical coherence between different thalamocortical circuits, which disrupted thalamocortical multifunctionality. In rodents, the persistent DTI abnormalities were validated in thalamic reticular nucleus (TRN) through immunohistochemistry, and correlated with enhanced thalamocortical coherence. Strong predictive power of these coherence biomarkers for long-term PCS was also validated using another patient cohort. Postconcussive events may begin with persistent TRN injury, followed by disrupted thalamocortical coherence and prolonged PCS. Functional MRI-based coherence measures can be surrogate biomarkers for early prediction of long-term PCS.

Structural brain network deviations predict recovery after traumatic brain injury.

OBJECTIVE: Traumatic brain injury results in diffuse axonal injury and the ensuing maladaptive alterations in network function are associated with incomplete recovery and persistent disability. Despite the importance of axonal injury as an endophenotype in TBI, there is no biomarker that can measure the aggregate and region-specific burden of axonal injury. Normative modeling is an emerging quantitative case-control technique that can capture region-specific and aggregate deviations in brain networks at the individual patient level. Our objective was to apply normative modeling in TBI to study deviations in brain networks after primarily complicated mild TBI and study its relationship with other validated measures of injury severity, burden of post-TBI symptoms, and functional impairment. METHOD: We analyzed 70 T1-weighted and diffusion-weighted MRIs longitudinally collected from 35 individuals with primarily complicated mild TBI during the subacute and chronic post-injury periods. Each individual underwent longitudinal blood sampling to characterize blood protein biomarkers of axonal and glial injury and assessment of post-injury recovery in the subacute and chronic periods. By comparing the MRI data of individual TBI participants with 35 uninjured controls, we estimated the longitudinal change in structural brain network deviations. We compared network deviation with independent measures of acute intracranial injury estimated from head CT and blood protein biomarkers. Using elastic net regression models, we identified brain regions in which deviations present in the subacute period predict chronic post-TBI symptoms and functional status. RESULTS: Post-injury structural network deviation was significantly higher than controls in both subacute and chronic periods, associated with an acute CT lesion and subacute blood levels of glial fibrillary acid protein (r = 0.5, p = 0.008) and neurofilament light (r = 0.41, p = 0.02). Longitudinal change in network deviation associated with change in functional outcome status (r = -0.51, p = 0.003) and post-concussive symptoms (BSI: r = 0.46, p = 0.03; RPQ: r = 0.46, p = 0.02). The brain regions where the node deviation index measured in the subacute period predicted chronic TBI symptoms and functional status corresponded to areas known to be susceptible to neurotrauma. CONCLUSION: Normative modeling can capture structural network deviations, which may be useful in estimating the aggregate and region-specific burden of network changes induced by TAI. If validated in larger studies, structural network deviation scores could be useful for enrichment of clinical trials of targeted TAI-directed therapies.

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.

Blood-Brain Barrier Disruption in Mild Traumatic Brain Injury Patients with Post-Concussion Syndrome: Evaluation with Region-Based Quantification of Dynamic Contrast-Enhanced MR Imaging Parameters Using Automatic Whole-Brain Segmentation.

OBJECTIVE: This study aimed to investigate the blood-brain barrier (BBB) disruption in mild traumatic brain injury (mTBI) patients with post-concussion syndrome (PCS) using dynamic contrast-enhanced (DCE) magnetic resonance (MR) imaging and automatic whole brain segmentation. MATERIALS AND METHODS: Forty-two consecutive mTBI patients with PCS who had undergone post-traumatic MR imaging, including DCE MR imaging, between October 2016 and April 2018, and 29 controls with DCE MR imaging were included in this retrospective study. After performing three-dimensional T1-based brain segmentation with FreeSurfer software (Laboratory for Computational Neuroimaging), the mean Ktrans and vp from DCE MR imaging (derived using the Patlak model and extended Tofts and Kermode model) were analyzed in the bilateral cerebral/cerebellar cortex, bilateral cerebral/cerebellar white matter (WM), and brainstem. Ktrans values of the mTBI patients and controls were calculated using both models to identify the model that better reflected the increased permeability owing to mTBI (tendency toward higher Ktrans values in mTBI patients than in controls). The Mann-Whitney U test and Spearman rank correlation test were performed to compare the mean Ktrans and vp between the two groups and correlate Ktrans and vp with neuropsychological tests for mTBI patients. RESULTS: Increased permeability owing to mTBI was observed in the Patlak model but not in the extended Tofts and Kermode model. In the Patlak model, the mean Ktrans in the bilateral cerebral cortex was significantly higher in mTBI patients than in controls (p = 0.042). The mean vp values in the bilateral cerebellar WM and brainstem were significantly lower in mTBI patients than in controls (p = 0.009 and p = 0.011, respectively). The mean Ktrans of the bilateral cerebral cortex was significantly higher in patients with atypical performance in the auditory continuous performance test (commission errors) than in average or good performers (p = 0.041). CONCLUSION: BBB disruption, as reflected by the increased Ktrans and decreased vp values from the Patlak model, was observed throughout the bilateral cerebral cortex, bilateral cerebellar WM, and brainstem in mTBI patients with PCS.

Expert Panel Survey to Update the American Congress of Rehabilitation Medicine Definition of Mild Traumatic Brain Injury.

OBJECTIVE: As part of an initiative led by the Brain Injury Special Interest Group Mild Traumatic Brain Injury (TBI) Task Force of the American Congress of Rehabilitation Medicine (ACRM) to update the 1993 ACRM definition of mild TBI, the present study aimed to characterize current expert opinion on diagnostic considerations. DESIGN: Cross-sectional web-based survey. SETTING: Not applicable. PARTICIPANTS: An international, interdisciplinary group of clinician-scientists (N=31) with expertise in mild TBI completed the survey by invitation between May and July 2019 (100% completion rate). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Ratings of agreement with statements related to the diagnosis of mild TBI and ratings of the importance of various clinical signs, symptoms, test findings, and contextual factors for increasing the likelihood that the individual sustained a mild TBI, on a scale ranging from 1 ("not at all important") to 10 ("extremely important"). RESULTS: Men (n=25; 81%) and Americans (n=21; 68%) were over-represented in the sample. The survey revealed areas of expert agreement (eg, acute symptoms are diagnostically useful) and disagreement (eg, whether mild TBI with abnormal structural neuroimaging should be considered the same diagnostic entity as "concussion"). Observable signs were generally rated as more diagnostically important than subjective symptoms (Wilcoxon signed ranks test, Z=3.77; P<.001; r=0.68). Diagnostic importance ratings for individual symptoms varied widely, with some common postconcussion symptoms (eg, fatigue) rated as unhelpful (<75% of respondents indicated at least 5 out of 10 importance). Certain acute test findings (eg, cognitive and balance impairments) and contextual factors (eg, absence of confounds) were consistently rated as highly important for increasing the likelihood of a mild TBI diagnosis (≥75% of respondents indicated at least 7 out of 10). CONCLUSIONS: The expert survey findings identified several potential revisions to consider when updating the ACRM mild TBI definition, including preferentially weighing observable signs in a probabilistic framework, incorporating symptoms and test findings, and adding differential diagnosis considerations.

Neural Correlates of Sleep Recovery following Melatonin Treatment for Pediatric Concussion: A Randomized Controlled Trial.

Evidence-based treatments for children with persistent post-concussion symptoms (PPCS) are few and limited. Common PPCS complaints such as sleep disturbance and fatigue could be ameliorated via the supplementation of melatonin, which has significant neuroprotective and anti-inflammatory properties. This study aims to identify neural correlates of melatonin treatment with changes in sleep disturbances and clinical recovery in a pediatric cohort with PPCS. We examined structural and functional neuroimaging (fMRI) in 62 children with PPCS in a randomized, double-blind, placebo-controlled trial of 3 mg or 10 mg of melatonin (NCT01874847). The primary outcome was the total youth self-report Post-Concussion Symptom Inventory (PCSI) score after 28 days of treatment. Secondary outcomes included the change in the sleep domain PCSI score and sleep-wake behavior (assessed using wrist-worn actigraphy). Whole-brain analyses of (1) functional connectivity (FC) of resting-state fMRI, and (2) structural gray matter volumes via voxel-based morphometry were assessed immediately before and after melatonin treatment and compared with placebo to identify neural effects of melatonin treatment. Increased FC of posterior default mode network (DMN) regions with visual, somatosensory, and dorsal networks was detected in the melatonin groups over time. The FC increases also corresponded with reduced wake periods (r = -0.27, p = 0.01). Children who did not recover (n = 39) demonstrated significant FC increases within anterior DMN and limbic regions compared with those who did recover (i.e., PCSI scores returned to pre-injury level, n = 23) over time, (p = 0.026). Increases in GM volume within the posterior cingulate cortex were found to correlate with reduced wakefulness after sleep onset (r = -0.32, p = 0.001) and sleep symptom improvement (r = 0.29, p = 0.02). Although the melatonin treatment trial was negative and did not result in PPCS recovery (with or without sleep problems), the relationship between melatonin and improvement in sleep parameters was linked to changes in function-structure within and between brain regions interacting with the DMN.

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

INTRODUCTION: Mild traumatic brain injury (TBI) is a global public health concern that affects millions of children annually. Mild TBI tends to result in subtle and diffuse alterations in brain tissue, which challenges accurate clinical detection and prognostication. Diffusion tensor imaging (DTI) holds promise as a diagnostic and prognostic tool, but little research has examined DTI in post-acute mild TBI. The current study compared post-acute white matter microstructure in children with mild TBI versus those with mild orthopedic injury (OI), and examined whether post-acute DTI metrics can predict post-acute and chronic post-concussive symptoms (PCS). MATERIALS AND METHODS: Children aged 8-16.99 years with mild TBI (n = 132) or OI (n = 69) were recruited at emergency department visits to two children's hospitals, during which parents rated children's pre-injury symptoms retrospectively. Children completed a post-acute (<2 weeks post-injury) assessment, which included a 3T MRI, and 3- and 6-month post-injury assessments. Parents and children rated PCS at each assessment. Mean diffusivity (MD) and fractional anisotropy (FA) were derived from diffusion-weighted MRI using Automatic Fiber Quantification software. Multiple multivariable linear and negative binomial regression models were used to test study aims, with False Discovery Rate (FDR) correction for multiple comparisons. RESULTS: No significant group differences were found in any of the 20 white matter tracts after FDR correction. DTI metrics varied by age and sex, and site was a significant covariate. No interactions involving group, age, and sex were significant. DTI metrics in several tracts robustly predicted PCS ratings at 3- and 6-months post-injury, but only corpus callosum genu MD was significantly associated with post-acute PCS after FDR correction. Significant group by DTI metric interactions on chronic PCS ratings indicated that left cingulum hippocampus and thalamic radiation MD was positively associated with 3-month PCS in the OI group, but not in the mild TBI group. CONCLUSIONS: Post-acute white matter microstructure did not differ for children with mild TBI versus OI after correcting for multiple comparisons, but was predictive of post-acute and chronic PCS in both injury groups. These findings support the potential prognostic utility of this advanced DTI technique.

Default mode network anatomy and function is linked to pediatric concussion recovery.

OBJECTIVE: To determine whether anatomical and functional brain features relate to key persistent post-concussion symptoms (PPCS) in children recovering from mild traumatic brain injuries (mTBI), and whether such brain indices can predict individual recovery from PPCS. METHODS: One hundred and ten children with mixed recovery following mTBI were seen at the concussion clinic at Neurology department Alberta Children's Hospital. The primary outcome was the Post-Concussion Symptom Inventory (PCSI, parent proxy). Sleep disturbance scores (PCSI subdomain) and the Neurocognition Index (CNS Vital Signs) were also measured longitudinally. PPCS was assessed at 4 weeks postinjury and 8-10 weeks postinjury. Gray matter volumes were assessed using magnetic resonance imaging (MRI) and voxel-based morphometry at 4 weeks postinjury. Functional connectivity was estimated at the same timepoint using resting-state MRI. Two complementary machine learning methods were used to assess if the combination of gray matter and functional connectivity indices carried meaningful prognostic information. RESULTS: Higher scores on a composite index of sleep disturbance, including fatigue, were associated with converging decreases in gray matter volume and local functional connectivity in two key nodes of the default mode network: the posterior cingulate cortex and the medial prefrontal cortex. Sleep-related disturbances also significantly correlated with reductions in functional connectivity between these brain regions. The combination of structural and functional brain indices associated to individual variations in the default mode network accurately predicted clinical outcomes at follow-up (area under the curve = 0.86). INTERPRETATION: These results highlight that the function-structure profile of core default mode regions underpins sleep-related problems following mTBI and carries meaningful prognostic information for pediatric concussion recovery.

Patients with Mild Traumatic Brain Injury Recruited from Both Hospital and Primary Care Settings: A Controlled Longitudinal Magnetic Resonance Imaging Study.

With an emphasis on traumatic axonal injury (TAI), frequency and evolution of traumatic intracranial lesions on 3T clinical magnetic resonance imaging (MRI) were assessed in a combined hospital and community-based study of patients with mild traumatic brain injury (mTBI). The findings were related to post-concussion symptoms (PCS) at 3 and 12 months. Prospectively, 194 patients (16-60 years of age) were recruited from the emergency departments at a level 1 trauma center and a municipal outpatient clinic into the Trondheim mTBI follow-up study. MRI was acquired within 72 h (n = 194) and at 3 (n = 165) and 12 months (n = 152) in patients and community controls (n = 78). The protocol included T2, diffusion weighted imaging, fluid attenuated inversion recovery (FLAIR), and susceptibility weighted imaging (SWI). PCS was assessed with British Columbia Post Concussion Symptom Inventory in patients and controls. Traumatic lesions were present in 12% on very early MRI, and in 5% when computed tomography (CT) was negative. TAI was found in 6% and persisted for 12 months on SWI, whereas TAI lesions on FLAIR disappeared or became less conspicuous on follow-up. PCS occurred in 33% of patients with lesions on MRI and in 19% in patients without lesions at 3 months (p = 0.12) and in 21% with lesions and 14% without lesions at 12 months (p = 0.49). Very early MRI depicted cases of TAI in patients with mTBI with microbleeds persisting for 12 months. Patients with traumatic lesions may have a more protracted recovery, but the study was underpowered to detect significant differences for PCS because of the low frequency of trauma-related MRI lesions.

Longitudinal Changes in Diffusion Tensor Imaging Following Mild Traumatic Brain Injury and Correlation With Outcome.

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.

Protocol for a prospective, longitudinal, cohort study of recovery pathways, acute biomarkers and cost for children with persistent postconcussion symptoms: the Take CARe Biomarkers study.

INTRODUCTION: The majority of children who sustain a concussion will recover quickly, but a significant minority will experience ongoing postconcussive symptoms, known as postconcussion syndrome (PCS). These symptoms include emotional, behavioural, cognitive and physical symptoms and can lead to considerable disability. The neurobiological underpinnings of PCS are poorly understood, limiting potential clinical interventions. As such, patients and families frequently re-present to clinical services, who are often ill equipped to address the multifactorial nature of PCS. This contributes to the high cost of concussion management and the disability of children experiencing PCS. The aims of the present study are: (1) to plot and contrast recovery pathways for children with concussion from time of injury to 3 months postinjury, (ii) evaluate the contribution of acute biomarkers (ie, blood, MRI) to delayed recovery postconcussion and (3) estimate financial costs of child concussion to patients attending the emergency department (ED) of a tertiary children's hospital and factors predicting high cost. METHODS AND ANALYSIS: Take C.A.Re is a prospective, longitudinal study at a tertiary children's hospital, recruiting and assessing 525 patients aged 5-<18 years (400 concussion, 125 orthopaedic injury) who present to the ED with a concussion and following them at 1-4 days, 2 weeks, 1 month and 3 months postinjury. Multiple domains are assessed: preinjury and postinjury, clinical, MRI, blood samples, neuropsychological, psychological and economic. PCS is defined as the presence of ≥2 symptoms on the Post Concussive Symptoms Inventory rated as worse compared with baseline 1 month postinjury. Main analyses comprise longitudinal Generalised Estimating Equation models and regression analyses of predictors of recovery and factors predicting high economic costs. ETHICS AND DISSEMINATION: Ethical approval has been obtained through the Royal Children's Hospital Melbourne Human Research Ethics Committee (33122). We aim to disseminate the findings through international conferences, international peer-reviewed journals and social media. TRIAL REGISTRATION NUMBER: ACTRN12615000316505; Results.

Diffusion kurtosis imaging in mild traumatic brain injury and postconcussional syndrome.

Aims of this study were to investigate white matter (WM) and thalamus microstructure 72 hr and 3 months after mild traumatic brain injury (TBI) with diffusion kurtosis imaging (DKI) and diffusion tensor imaging (DTI), and to relate DKI and DTI findings to postconcussional syndrome (PCS). Twenty-five patients (72 hr = 24; 3 months = 23) and 22 healthy controls were recruited, and DKI and DTI data were analyzed with Tract-Based Spatial Statistics (TBSS) and a region-of-interest (ROI) approach. Patients were categorized into PCS or non-PCS 3 months after injury according to the ICD-10 research criteria for PCS. In TBSS analysis, significant differences between patients and controls were seen in WM, both in the acute stage and 3 months after injury. Fractional anisotropy (FA) reductions were more widespread than kurtosis fractional anisotropy (KFA) reductions in the acute stage, while KFA reductions were more widespread than the FA reductions at 3 months, indicating the complementary roles of DKI and DTI. When comparing patients with PCS (n = 9), without PCS (n = 16), and healthy controls, in the ROI analyses, no differences were found in the acute DKI and DTI metrics. However, near-significant differences were observed for several DKI metrics obtained in WM and thalamus concurrently with symptom assessment (3 months after injury). Our findings indicate a combined utility of DKI and DTI in detecting WM microstructural alterations after mild TBI. Moreover, PCS may be associated with evolving alterations in brain microstructure, and DKI may be a promising tool to detect such changes.

Factors associated with persistent post-concussion symptoms following mild traumatic brain injury in adults.

OBJECTIVES: Debate regarding factors associated with persistent symptoms following mild traumatic brain injury continues. Nested within a trial aiming to change practice in emergency department management of mild traumatic brain injury, this study investigated the nature of persistent symptoms, work/study outcomes, anxiety and quality of life and factors associated with persistent symptoms following injury, including the impact of receiving information about mild traumatic brain injuries in the emergency department. METHODS: A total of 343 individuals with mild traumatic brain injury completed the Rivermead Post-Concussion Symptom Questionnaire, Hospital Anxiety Depression Scale - Anxiety Scale, and Quality of Life - Short Form in average 7 months post-injury. RESULTS: Overall, 18.7% of participants reported 3 or more post-concussional symptoms, most commonly fatigue (17.2%) and forgetfulness (14.6%). Clinically significant anxiety was reported by 12.8%, and was significantly associated with symptom reporting, as were mental and physical quality of life scores. Significant predictors of post-concussional symptoms at follow-up were pre-injury psychological issues, experiencing loss of consciousness, and having no recall of receiving information about brain injury in the emergency department. CONCLUSION: This study confirms that loss of consciousness and pre-injury psychological issues are associated with persistent symptom reporting. Not receiving injury information in the emergency department may also negatively influence symptom reporting.

Impact of Body Mass Index on Postconcussion Symptoms in Teenagers Aged 13 to 18 Years.

CONTEXT: Adolescent obesity and sports-related concussion are rising in prevalence, yet there is minimal research exploring the relationship between these two conditions. OBJECTIVE: To assess the impact of body mass index (BMI) percentile on duration of recovery and reported symptoms after sports-related concussion in adolescents. DESIGN: Retrospective chart review at a regional concussion program located at an academic medical center. Medical records of all patients aged 13 to 18 years treated from March 2006 through January 2012 were reviewed. Two hundred fifty-two patients met the inclusion criteria of sports-related concussion and having BMI data. MAIN OUTCOME MEASURES: Outcome variables included reported emotional symptoms, sleep-related symptoms, physical symptoms (headache), and time to recovery after a concussion. Explanatory variables in this analysis were BMI percentile and sex. RESULTS: More male patients were obese and overweight than were females (42% vs 27%, p = 0.02). There was no statistically significant difference in recovery time between obese and overweight patients and others. Obese and overweight patients were more likely than healthy-weight patients to report symptoms of irritability (p = 0.05) and impulsivity (p = 0.01), and less likely to report headache (p = 0.03). CONCLUSION: After concussion, irritability and impulsivity may be more likely than headaches in overweight and obese patients. There was no difference in recovery time between obese and healthy-weight teens. These findings may have importance in the evaluation, treatment, and anticipatory guidance of patients with concussions.

Traumatic Brain Injury-Related Symptoms Reported by Parents: Clinical, Imaging, and Host Predictors in Children with Impairments in Consciousness Less than 24 Hours.

This study examined the relationship between acute neuroimaging, host and injury factors, and parent-reported traumatic brain injury (TBI)-related symptoms in children with noncritical head injury at two weeks and three months after injury. Data were collected prospectively on 45 subjects aged three to 16 years old enrolled in the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study. Subjects had rapid recovery of mental status (Glasgow Coma Score [GCS] = 15 within 24 h), and had no clinical need for neurosurgical intervention. Intra- or extra-axial magnetic resonance imaging (MRI) lesions were categorized using Common Data Elements (CDE) definitions. Host and acute injury factors including neurobehavioral history, race, extracranial injuries, loss of consciousness (LOC), and GCS were analyzed while controlling for pre-injury symptoms, age, sex, and socioeconomic status. Parent-reported cognitive and somatic symptoms were measured by the Health and Behavior Inventory (HBI). Forty-nine percent of children had MRI lesions, most of which were relatively small. LOC predicted increased cognitive and somatic symptoms at two weeks. At three months, pre-injury neurobehavioral history predicted increased cognitive and somatic symptoms. Neuroimaging findings did not predict parent-reported symptom severity, except at three months where extra-axial lesions were associated with less severe cognitive symptoms. While structural MRI lesions do not predict increased parent-reported symptoms in this population, age-specific child performance measures may be more sensitive outcome measures and require further study. Children with pre-injury neurobehavioral problems have more severe symptoms at three months and thus may benefit from longer follow-up and monitoring after traumatic brain injury.

The effect of an acute systemic inflammatory insult on the chronic effects of a single mild traumatic brain injury.

A small but significant proportion of mild traumatic brain injury (mTBI) sufferers will report persistent symptoms, including depression, anxiety and cognitive deficits, in the months, or even years, following the initial event. This is known as post-concussion syndrome and its pathogenesis is not yet known. This study sought to investigate the role of a peripheral inflammatory insult in the development of ongoing behavioral symptoms following a mTBI. To investigate, male Sprague-Dawley rats were administered a single mTBI using the diffuse impact-acceleration model to generate ∼100G of force. Sham animals underwent surgery only. At 5days following surgery, rats were given either the TLR4 agonist, lipopolysaccharide (LPS, 0.1mg/kg), or saline via an intraperitoneal injection. mTBI animals showed an exaggerated response to LPS, with an increase in the expression of pro-inflammatory cytokines within the hippocampus at 24h post-dose, an effect not seen in sham animals. This was associated with the development of persistent behavioral deficits in the mTBI:LPS animals at 3 months post-injury. These behavioral deficits consisted of increased time spent immobile on the forced swim-test, indicative of depressive like behavior, impaired cognitive performance on the Barnes Maze and decreased anxiety on the Elevated Plus Maze. In contrast, animals administered mTBI alone had no deficits. This study provides evidence that a peripheral inflammatory stimulus can facilitate ongoing symptoms following a mTBI. As such this provides a basis for further exploration of exogenous factors which promote immune system activation as potential targets for intervention to allow the resolution of symptoms following a mTBI.

Decreased Number of Self-Paced Saccades in Post-Concussion Syndrome Associated with Higher Symptom Burden and Reduced White Matter Integrity.

The aim of this study was to examine the potential utility of a self-paced saccadic eye movement as a marker of post-concussion syndrome (PCS) and monitoring the recovery from PCS. Fifty-nine persistently symptomatic participants with at least two concussions performed the self-paced saccade (SPS) task. We evaluated the relationships between the number of SPSs and 1) number of self-reported concussion symptoms, and 2) integrity of major white matter (WM) tracts (as measured by fractional anisotropy [FA] and mean diffusivity) that are directly or indirectly involved in saccadic eye movements and often affected by concussion. These tracts included the uncinate fasciculus (UF), cingulum (Cg) and its three subcomponents (subgenual, retrosplenial, and parahippocampal), superior longitudinal fasciculus, and corpus callosum. Mediation analyses were carried out to examine whether specific WM tracts (left UF and left subgenual Cg) mediated the relationship between the number of SPSs and 1) interval from last concussion or 2) total number of self-reported symptoms. The number of SPSs was negatively correlated with the total number of self-reported symptoms (r = -0.419, p = 0.026). The number of SPSs were positively correlated with FA of left UF and left Cg (r = 0.421, p = 0.013 and r = 0.452, p = 0.008; respectively). FA of the subgenual subcomponent of the left Cg partially mediated the relationship between the total number of symptoms and the number of SPSs, while FA of the left UF mediated the relationship between interval from last concussion and the number of SPSs. In conclusion, SPS testing as a fast and objective assessment may reflect symptom burden in patients with PCS. In addition, since the number of SPSs is associated with the integrity of some WM tracts, it may be useful as a diagnostic biomarker in patients with PCS.

Neuropsychological alterations and neuroradiological findings in patients with post-traumatic concussion: Results of a pilot study. / Alteraciones neuropsicológicas y hallazgos neurorradiológicos en pacientes con conmoción cerebral postraumática. Resultados de un estudio piloto.

INTRODUCTION: Mild traumatic brain injury (mTBI) has traditionally been considered to cause no significant brain damage since symptoms spontaneously remit after a few days. However, this idea is facing increasing scrutiny. The purpose of this study is to demonstrate the presence of early cognitive alterations in a series of patients with mTBI and to link these findings to different markers of brain damage. METHODS: We conducted a prospective study of a consecutive series of patients with mTBI who were evaluated over a 12-month period. Forty-one (3.7%) of the 1144 included patients had experienced a concussion. Patients underwent a routine clinical evaluation and a brain computed tomography (CT) scan, and were also administered a standardised test for post-concussion symptoms within the first 24hours of mTBI and also 1 to 2 weeks later. The second assessment also included a neuropsychological test battery. The results of these studies were compared to those of a control group of 28 healthy volunteers with similar characteristics. Twenty patients underwent an MRI scan. RESULTS: Verbal memory and learning were the cognitive functions most affected by mTBI. Seven out of the 20 patients with normal CT findings displayed structural alterations on MR images, which were compatible with diffuse axonal injury in 2 cases. CONCLUSIONS: Results from this pilot study suggest that early cognitive alterations and structural brain lesions affect a considerable percentage of patients with post-concussion syndrome following mTBI.

Prevalence of Abnormal Magnetic Resonance Imaging Findings in Children with Persistent Symptoms after Pediatric Sports-Related Concussion.

A subset of patients experience persistent symptoms after pediatric concussion, and magnetic resonance imaging (MRI) is commonly used to evaluate for pathology. The utility of this practice is unclear. We conducted a retrospective cohort study to describe the MRI findings in children with concussion. A registry of all patients seen at our institution from January 2010 through March 2016 with pediatric sports-related concussion was cross-referenced with a database of radiographical studies. Radiology reports were reviewed for abnormal findings. Patients with abnormal computed tomographies or MRI scans ordered for reasons other than concussion were excluded. Among 3338 children identified with concussion, 427 underwent MRI. Only 2 (0.5%) had findings compatible with traumatic injury, consisting in both of microhemorrhage. Sixty-one patients (14.3%) had abnormal findings unrelated to trauma, including 24 nonspecific T2 changes, 15 pineal cysts, eight Chiari I malformations, and five arachnoid cysts. One child underwent craniotomy for a cerebellar hemangioblastoma after presenting with ataxia; another had cortical dysplasia resected after seizure. The 2 patients with microhemorrhage each had three previous concussions, significantly more than patients whose scans were normal (median, 1) or abnormal without injury (median, 1.5; p = 0.048). MRI rarely revealed intracranial injuries in children post-concussion, and the clinical relevance of these uncommon findings remains unclear. Abnormalities unrelated to trauma are usually benign. However, MRI should be thoughtfully considered in children who present with concerning or atypical symptoms.