Acute thalamic connectivity precedes chronic post-concussive symptoms in mild traumatic brain injury.

Chronic post-concussive symptoms are common after mild traumatic brain injury (mTBI) and are difficult to predict or treat. Thalamic functional integrity is particularly vulnerable in mTBI and may be related to long-term outcomes but requires further investigation. We compared structural MRI and resting state functional MRI in 108 patients with a Glasgow Coma Scale (GCS) of 13-15 and normal CT, and 76 controls. We examined whether acute changes in thalamic functional connectivity were early markers for persistent symptoms and explored neurochemical associations of our findings using PET data. Of the mTBI cohort, 47% showed incomplete recovery 6 months post-injury. Despite the absence of structural changes, we found acute thalamic hyperconnectivity in mTBI, with specific vulnerabilities of individual thalamic nuclei. Acute fMRI markers differentiated those with chronic post-concussive symptoms, with time- and outcome-dependent relationships in a sub-cohort followed longitudinally. Moreover, emotional and cognitive symptoms were associated with changes in thalamic functional connectivity to known serotonergic and noradrenergic targets, respectively. Our findings suggest that chronic symptoms can have a basis in early thalamic pathophysiology. This may aid identification of patients at risk of chronic post-concussive symptoms following mTBI, provide a basis for development of new therapies and facilitate precision medicine application of these therapies.

Can quantitative susceptibility mapping help diagnose and predict recovery of concussion in children? An A-CAP study.

BACKGROUND: Quantitative susceptibility mapping (QSM) is an MRI technique that is a potential biomarker for concussion. We performed QSM in children following concussion or orthopaedic injury (OI), to assess QSM performance as a diagnostic and prognostic biomarker. METHODS: Children aged 8-17 years with either concussion (N=255) or OI (N=116) were recruited from four Canadian paediatric emergency departments and underwent QSM postacutely (2-33 days postinjury) using 3 Tesla MRI. QSM Z-scores within nine regions of interest (ROI) were compared between groups. QSM Z-scores were also compared with the 5P score, the current clinical benchmark for predicting persistent postconcussion symptoms (PPCS), at 4 weeks postinjury, with PPCS defined using reliable change methods based on both participant and parent reports. RESULTS: Concussion and OI groups did not differ significantly in QSM Z-scores for any ROI. Higher QSM Z-scores within frontal white matter (WM) independently predicted PPCS based on parent ratings of cognitive symptoms (p=0.001). The combination of frontal WM QSM Z-score and 5P score was better at predicting PPCS than 5P score alone (p=0.004). The area under the curve was 0.72 (95% CI 0.63 to 0.81) for frontal WM susceptibility, 0.69 (95% CI 0.59 to 0.79) for the 5P score and 0.74 (95% CI 0.65 to 0.83) for both. CONCLUSION: The findings suggest that QSM is a potential MRI biomarker that can help predict PPCS in children with concussion, over and above the current clinical benchmark, and thereby aid in clinical management. They also suggest a frontal lobe substrate for PPCS, highlighting the potential for QSM to clarify the neurophysiology of paediatric concussion.

Investigating cognitive reserve, symptom resolution and brain connectivity in mild traumatic brain injury.

BACKGROUND: A proportion of patients with mild traumatic brain injury (mTBI) suffer long-term consequences, and the reasons behind this are still poorly understood. One factor that may affect outcomes is cognitive reserve, which is the brain's ability to maintain cognitive function despite injury. It is often assessed through educational level or premorbid IQ tests. This study aimed to explore whether there were differences in post-concussion symptoms and symptom resolution between patients with mTBI and minor orthopedic injuries one week and three months after injury. Additional aims were to explore the relationship between cognitive reserve and outcome, as well as functional connectivity according to resting state functional magnetic resonance imaging (rs-fMRI). METHOD: Fifteen patients with mTBI and 15 controls with minor orthopedic injuries were recruited from the emergency department. Assessments, including Rivermead Post-Concussion Questionnaire (RPQ), neuropsychological testing, and rs-fMRI scans, were conducted on average 7 days (SD = 2) and 122 days (SD = 51) after injury. RESULTS: At the first time point, significantly higher rates of post-concussion symptoms (U = 40.0, p = 0.003), state fatigue (U = 56.5, p = 0.014), and fatigability (U = 58.5, p = 0.025) were observed among the mTBI group than among the controls. However, after three months, only the difference in post-concussion symptoms remained significant (U = 27.0, p = 0.003). Improvement in post-concussion symptoms was found to be significantly correlated with cognitive reserve, but only in the mTBI group (Spearman's rho = -0.579, p = .038). Differences in the trajectory of recovery were also observed for fatigability between the two groups (U = 36.5, p = 0.015). Moreover, functional connectivity differences in the frontoparietal network were observed between the groups, and for mTBI patients, functional connectivity differences in an executive control network were observed over time. CONCLUSION: The findings of this pilot study suggest that mTBI, compared to minor orthopedic trauma, is associated to both functional connectivity changes in the brain and concussion-related symptoms. While there is improvement in these symptoms over time, a small subgroup with lower cognitive reserve appears to experience more persistent and possibly worsening symptoms over time. This, however, needs to be validated in larger studies. TRIAL REGISTRATION: NCT05593172. Retrospectively registered.

Altered connectivity of default mode and executive control networks among female patients with persistent post-concussion symptoms.

OBJECTIVE: To examine the roles of the default mode network (DMN) and executive control network (ECN) in prolonged recovery after mild traumatic brain injury (mTBI), and relationships with indices of white matter microstructural injury. METHODS: Seventeen mTBI patients with persistent symptoms were imaged an average of 21.5 months post-injury, along with 23 healthy controls. Resting-state functional magnetic resonance imaging (rs-fMRI) was used to evaluate functional connectivity (FC) of the DMN and ECN. Diffusion tensor imaging (DTI) quantified fractional anisotropy, along with mean, axial and radial diffusivity of white matter tracts. RESULTS: Compared to controls, patients with mTBI had increased functional connectivity of the DMN and ECN to brain regions implicated in salience and frontoparietal networks, and increased white matter diffusivity within the cerebrum and brainstem. Among the patients, FC was correlated with better neurocognitive test scores, while diffusivity was correlated with more severe self-reported symptoms. The FC and diffusivity values within abnormal brain regions were not significantly correlated. CONCLUSION: For female mTBI patients with prolonged symptoms, hyper-connectivity may represent a compensatory response that helps to mitigate the effects of mTBI on cognition. These effects are unrelated to indices of microstructural injury, which are correlated with symptom severity, suggesting that rs-fMRI and DTI may capture distinct aspects of pathophysiology.

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.

Return to work after mild traumatic brain injury: association with positive CT and MRI findings.

BACKGROUND: Return to work (RTW) might be delayed in patients with complicated mild traumatic brain injury (MTBI), i.e., MTBI patients with associated traumatic intracranial lesions. However, the effect of different types of lesions on RTW has not studied before. We investigated whether traumatic intracranial lesions detected by CT and MRI are associated with return to work and post-concussion symptoms in patients with MTBI. METHODS: We prospectively followed up 113 adult patients with MTBI that underwent a brain MRI within 3-17 days after injury. Return to work was assessed with one-day accuracy up to one year after injury. Rivermead Post-Concussion Symptoms Questionnaire (RPQ) and Glasgow Outcome Scale Extended (GOS-E) were conducted one month after injury. A Kaplan-Meier log-rank analysis was performed to analyze the differences in RTW. RESULTS: Full RTW-% one year after injury was 98%. There were 38 patients with complicated MTBI, who had delayed median RTW compared to uncomplicated MTBI group (17 vs. 6 days), and more post-concussion symptoms (median RPQ 12.0 vs. 6.5). Further, RTW was more delayed in patients with multiple types of traumatic intracranial lesions visible in MRI (31 days, n = 19) and when lesions were detected in the primary CT (31 days, n = 24). There were no significant differences in GOS-E. CONCLUSIONS: The imaging results that were most clearly associated with delayed RTW were positive primary CT and multiple types of lesions in MRI. RTW-% of patients with MTBI was excellent and a single intracranial lesion does not seem to be a predictive factor of disability to work.

Diffusion and functional MRI findings and their relationship to behaviour in postconcussion syndrome: a scoping review.

Postconcussion syndrome (PCS) is a term attributed to the constellation of symptoms that fail to recover after a concussion. PCS is associated with a variety of symptoms such as headaches, concentration deficits, fatigue, depression and anxiety that have an enormous impact on patients' lives. There is currently no diagnostic biomarker for PCS. There have been attempts at identifying structural and functional brain changes in patients with PCS, using diffusion tensor imaging (DTI) and functional MRI (fMRI), respectively, and relate them to specific PCS symptoms. In this scoping review, we appraised, synthesised and summarised all empirical studies that (1) investigated structural or functional brain changes in PCS using DTI or fMRI, respectively, and (2) assessed behavioural alterations in patients with PCS. We performed a literature search in MEDLINE (Ovid), Embase (Ovid) and PsycINFO (Ovid) for primary research articles published up to February 2020. We identified 8306 articles and included 45 articles that investigated the relationship between DTI and fMRI parameters and behavioural changes in patients with PCS: 20 diffusion, 20 fMRI studies and 5 papers with both modalities. Most frequently studied structures were the corpus callosum, superior longitudinal fasciculus in diffusion and the dorsolateral prefrontal cortex and default mode network in the fMRI literature. Although some white matter and fMRI changes were correlated with cognitive or neuropsychiatric symptoms, there were no consistent, converging findings on the relationship between neuroimaging abnormalities and behavioural changes which could be largely due to the complex and heterogeneous presentation of PCS. Furthermore, the heterogeneity of symptoms in PCS may preclude discovery of one biomarker for all patients. Further research should take advantage of multimodal neuroimaging to better understand the brain-behaviour relationship, with a focus on individual differences rather than on group comparisons.

Microstructure of the Corpus Callosum Long after Pediatric Concussion.

OBJECTIVE: The long-term effects of pediatric concussion on white matter microstructure are poorly understood. This study investigated long-term changes in white matter diffusion properties of the corpus callosum in youth several years after concussion. METHODS: Participants were 8-19 years old with a history of concussion (n = 36) or orthopedic injury (OI) (n = 21). Mean time since injury for the sample was 2.6 years (SD = 1.6). Participants underwent diffusion magnetic resonance imaging, completed cognitive testing, and rated their post-concussion symptoms. Measures of diffusivity (fractional anisotropy, mean, axial, and radial diffusivity) were extracted from white matter tracts in the genu, body, and splenium regions of the corpus callosum. The genu and splenium tracts were further subdivided into 21 equally spaced regions along the tract and diffusion values were extracted from each of these smaller regions. RESULTS: White matter tracts in the genu, body, and splenium did not differ in diffusivity properties between youth with a history of concussion and those with a history of OI. No significant group differences were found in subdivisions of the genu and splenium after correcting for multiple comparisons. Diffusion metrics did not significantly correlate with symptom reports or cognitive performance. CONCLUSIONS: These findings suggest that at approximately 2.5 years post-injury, youth with prior concussion do not have differences in their corpus callosum microstructure compared to youth with OI. Although these results are promising from the perspective of long-term recovery, further research utilizing longitudinal study designs is needed to confirm the long-term effects of pediatric concussion on white matter microstructure.

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.

Cerebral blood flow in children and adolescents several years after concussion.

OBJECTIVES: The long-term effects of concussion in youth remain poorly understood. The objective of this study was to determine the association between history of concussion and cerebral blood flow (CBF) in youth. METHODS: A total of 53 children and adolescents with a history of concussion (n = 37) or orthopaedic injury (OI; n = 16) were considered. Measures included pseudo-continuous arterial spin labelling magnetic resonance imaging to quantify CBF, post-concussion symptoms, psychological symptoms, and cognitive testing. RESULTS: Participants (mean age: 14.4 years, 95% CI = 13.8-15.4, range = 8-19) were on average 2.7 years (95% CI = 2.2-3.1) post-injury. Youth with a history of concussion had higher parent-reported physical, cognitive, anxiety, and depression symptoms than children with OI, but the groups did not differ on self-reported symptoms (post-concussive or psychological) or cognitive testing. Global CBF did not differ between groups. Regional CBF analyses suggested that youth with a history of concussion had hypoperfusion in posterior and inferior regions and hyperperfusion in anterior/frontal/temporal regions as compared to those with OI. However, neither global nor regional CBF were significantly associated with demographics, pre-injury functioning, number of concussions, time since injury, post-concussive symptoms, psychological symptoms, or cognitive abilities. CONCLUSIONS: Youth with a history of concussion demonstrate differences in regional CBF (not global CBF), but without clear clinical expression.

Loss of consciousness and altered mental state predicting depressive and post-concussive symptoms after mild traumatic brain injury.

Objective: Limited studies exist on the association between loss of consciousness (LOC) and altered mental state (AMS) and development of depressive and post-concussive symptoms within six months after mild traumatic brain injury (mTBI). We tested the hypothesis that presence of both LOC and AMS predict the highest risk of symptoms within the first six months post-mTBI compared to either variable alone, and that LOC alone is more strongly associated with these symptoms. Research design: We analyzed data from 407 subjects with mTBI from the Head injury Serum Markers for Assessing Response to Trauma (HeadSMART) cohort, a prospective cohort of patients post-TBI presenting to two urban emergency departments. Results: There were higher rates of depressive (44%) and post-concussive symptoms (54%) at 1 month post-injury, among participants with both LOC and AMS compared to other groups. AMS was associated with depressive symptoms at one and six months (OR = 1.59, p = .038; OR = 1.60; p = .060) and post-concussive symptoms at one month (OR = 1.56, p = .053). LOC was associated only with post-concussive symptoms at one month (OR = 1.55;p = .048). Among those without LOC, AMS was associated with depressive symptoms at one month (OR = 2.24; p = .028). Conclusions: AMS predicts post-mTBI depressive symptoms both in the acute and chronic mTBI phases whereas LOC is a more sensitive predictor of post-concussive symptoms in the acute mTBI period.

Evaluating task-based brain network activity in pediatric subjects with an mTBI: mechanisms of functional compensation are symptom-level dependent.

The diagnosis of a mild traumatic brain injury (mTBI) places large emphasis on patient-reported symptoms which has restricted our ability to evaluate patients. Task-based functional magnetic resonance imaging has the potential to act as an objective measurement of abnormal brain activity and inform clinical decision-making; however, there is little research evaluating pediatric subjects as a function of mTBI-related symptoms. The objective of this study was to evaluate the extent to which brain activity during a spatial navigation task is different between children with mTBI and a group of healthy controls (HCs) based on symptom reporting. A group of patients with mTBI (n = 27) were divided into low- and high-symptom cohorts and compared with HCs (n = 27) on a task that required participants to locate specific landmarks. No difference was found in the level of symptoms reported between patients with low-symptom participants and HCs despite the low-symptom group showing increased activity within the frontal and occipital cortices. In participants with high-symptoms, an increase in the number of reported symptoms was found relative to HCs alongside an increase in the number of active brain regions. Findings suggest that persons with an mTBI may display unique symptom-dependent patterns of altered task-related brain activity.

Longitudinal Changes in Resting State Connectivity and White Matter Integrity in Adolescents With Sports-Related Concussion.

OBJECTIVES: The aim of this study was to investigate alterations in functional connectivity, white matter integrity, and cognitive abilities due to sports-related concussion (SRC) in adolescents using a prospective longitudinal design. METHODS: We assessed male high school football players (ages 14-18) with (n=16) and without (n=12) SRC using complementary resting state functional MRI (rs-fMRI) and diffusion tensor imaging (DTI) along with cognitive performance using the Immediate Post-Concussive Assessment and Cognitive Testing (ImPACT). We assessed both changes at the acute phase (<7 days post-SRC) and at 21 days later, as well as, differences between athletes with SRC and age- and team-matched control athletes. RESULTS: The results revealed rs-fMRI hyperconnectivity within posterior brain regions (e.g., precuneus and cerebellum), and hypoconnectivity in more anterior areas (e.g., inferior and middle frontal gyri) when comparing SRC group to control group acutely. Performance on the ImPACT (visual/verbal memory composites) was correlated with resting state network connectivity at both time points. DTI results revealed altered diffusion in the SRC group along a segment of the corticospinal tract and the superior longitudinal fasciculus in the acute phase of SRC. No differences between the SRC group and control group were seen at follow-up imaging. CONCLUSIONS: Acute effects of SRC are associated with both hyperconnectivity and hypoconnectivity, with disruption of white matter integrity. In addition, acute memory performance was most sensitive to these changes. After 21 days, adolescents with SRC returned to baseline performance, although chronic hyperconnectivity of these regions could place these adolescents at greater risk for secondary neuropathological changes, necessitating future follow-up. (JINS, 2018, 24, 781-792).

Diffusion MRI findings in patients with extensive and minimal post-concussion symptoms after mTBI and healthy controls: a cross sectional study.

PRIMARY OBJECTIVES: We hypothesized that the microstructure of the corpus callosum, thalamus and hippocampus, as measured with diffusion and Mean of the Kurtosis Tensor (MKT) MRI, differs between healthy subjects and patients with extensive and minimal post-concussion symptoms (PCS) and that MKT measures correlate with PCS severity and self-reported cognitive symptoms. RESEARCH DESIGN: A cross-sectional study comparing patients with extensive PCS and patients with minimal PCS 2-5 months after mild traumatic brain injury (mTBI) with each other and with an external healthy control group. METHODS AND PROCEDURES: Diffusion MRI was obtained in 25 patients with extensive PCS and in 25 patients with minimal PCS as measured by the Rivermead Post-concussion Symptoms Questionnaire. The patients were matched on age, sex and time since accident. Data from an external healthy control group (n = 27) was included. MAIN OUTCOME AND RESULTS: There was no difference in MKT between the two groups with mTBI and no correlation between MKT and PCS. There was no difference between the three groups in other diffusion measures. CONCLUSIONS: Our results did not point to microstructural changes in the corpus callosum, thalamus and hippocampus in relation to PCS after mTBI.

Small world properties changes in mild traumatic brain injury.

PURPOSE: To investigate local and global efficiency changes characterized by small-world properties based on resting-state functional MRI, such as centrality and clustering coefficient, in mild traumatic brain injury (MTBI) patients; and to associate these findings with axonal injury as measured by diffusion tensor imaging (DTI) as well as with post-concussive symptom (PCS). MATERIALS AND METHODS: Thirty patients (mean age 35 ± 13 years) with clinically defined MTBI and 45 age-matched healthy controls (mean age 37 ± 10 years) participated in the experiments. Resting-state functional MRI was performed using gradient echo planar imaging sequence with 3 Tesla MRI scanner to obtain functional small-world networks. Out of all participants, 20 MTBI patients and 20 controls had available DTI data with three b-values (0, 500, 1000) s/mm2 and 30 directions for diffuse axonal injury analyses. RESULTS: Compared with controls, MTBI patients showed lower relative betweenness centrality (P = 0.01), but significantly higher clustering coefficient (P = 0.04), and these two metrics correlated negatively in patients (r = -0.77; P < 0.001). Regions with lower betweenness centrality (e.g., frontal and occipital) corresponded with the regions of reduced FA in patients, while global FA reduction correlated with betweenness centrality (r = 0.48; P = 0.03) and clustering coefficient (r = -0.46; P = 0.04) in MTBI patients. In addition, there was significantly higher thalamocortical connectivity that correlated with clustering coefficient (r = 0.39; P = 0.03) in patients. Also, patients with higher clustering coefficient tended to have less PCS score with negative correlation (r = -0.4; P = 0.04). CONCLUSION: Our results demonstrated significant functional small-world properties changes in patients with MTBI, and suggest decreased global efficiency, possibly due to diffuse axonal injury and local network upregulation including increased thalamo-cortical connectivity. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;46:518-527.

Structural Connectivity Related to Persistent Symptoms After Mild TBI in Adolescents and Response to Aerobic Training: Preliminary Investigation.

OBJECTIVE: To quantify structural connectivity abnormalities in adolescents with mild traumatic brain injury (mTBI) and to investigate connectivity changes following aerobic training using graph theory and diffusion tensor imaging tractography. SETTING: Outpatient research setting. PARTICIPANTS: Twenty-two children (age: 15.83 ± 1.77 years, 10 females) with 4 to 16 weeks of persistent symptoms after mTBI and a matched healthy comparison group. DESIGN: Randomized clinical trial of aerobic training and stretching comparison combined with case-control comparison. MAIN MEASURES: (1) Five global network measures: global efficiency (Eglob), mean local efficiency, modularity, normalized clustering coefficient (γ), normalized characteristic path length (λ), and small-worldness (σ). (2) The self-reported Post-Concussion Symptom Inventory score. RESULTS: At initial enrollment, adolescents with mTBI had significantly lower Eglob and higher γ, λ, and σ (all P < .05) than healthy peers. After the intervention, significantly increased Eglob and decreased λ (both P < .05) were found in the aerobic training group. Improvement in Post-Concussion Symptom Inventory scores was significantly correlated with the Eglob increase and λ decrease in the aerobic training and λ decrease in the stretching comparison group (all P < .05). CONCLUSION: This pilot study showed initial evidence that structural connectivity analysis was sensitive to brain network abnormalities and may serve as an imaging biomarker in children with persistent symptoms after mTBI.

Concussion and its neurobehavioural sequelae.

A concussion results from a force to the brain that results in a transient loss of connectivity within the brain. Sport psychiatrists are increasingly called to be part of the concussion team and need to be prepared to manage issues related to concussion and its behavioural sequelae. Objectively, the best evidence available suggests that deficits in attention and/or in balance are the most reliable objective findings that a concussion has occurred. Prognosis after a concussion is generally very good, although a sub-set of patients that are yet well defined seem pre-disposed to delayed recovery. Neither head CT nor MRI are sufficiently sensitive to diagnose the type of injuries that pre-dispose patients to the neurobehavioural sequelae that have been associated with a concussion; confounding this is the finding that many of these signs and symptoms associated with concussion occur in other types of non-head injuries. Brain biomarkers and functional MRI (fMRI) hold promise in both diagnosis and prognosis of concussion, but are still research tools without validated clinical utility at this time. Finally, neurocognitive testing holds promise as a diagnostic criterion to demonstrate injury but, unfortunately, these tests are also limited in their prognostic utility and are of limited value.

Evidence of Ongoing Cerebral Microstructural Reorganization in Children With Persisting Symptoms Following Mild Traumatic Brain Injury: A NODDI DTI Analysis.

Approximately 300-550 children per 100,000 sustain a mild traumatic brain injury (mTBI) each year, of whom ∼25-30% have long-term cognitive problems. Following mTBI, free water (FW) accumulation occurs in white matter (WM) tracts. Diffusion tensor imaging (DTI) can be used to investigate structural integrity following mTBI. Compared with conventional DTI, neurite orientation dispersion and density imaging (NODDI) orientation dispersion index (ODI) and fraction of isolated free water (FISO) metrics may allow a more advanced insight into microstructural damage following pediatric mTBI. In this longitudinal study, we used NODDI to explore whole-brain and tract-specific differences in ODI and FISO in children with persistent symptoms after mTBI (n = 80) and in children displaying clinical recovery (n = 32) at 1 and 2-3 months post-mTBI compared with healthy controls (HCs) (n = 21). Two-way repeated measures analysis of variance (ANOVA) and voxelwise two-sample t tests were conducted to compare whole-brain and tract-specific diffusion across groups. All results were corrected at positive false discovery rate (pFDR) <0.05. We also examined the association between NODDI metrics and clinical outcomes, using logistical regression to investigate the value of NODDI metrics in predicting future recovery from mTBI. Whole-brain ODI was significantly increased in symptomatic participants compared with HCs at both 1 and 2 months post-injury, where the uncinate fasciculus (UF) and inferior fronto-occipital fasciculus (IFOF) were particularly implicated. Using region of interest (ROI) analysis in significant WM, bilateral IFOF and UF voxels, symptomatic participants had the highest ODI in all ROIs. ODI was lower in asymptomatic participants, and HCs had the lowest ODI in all ROIs. No changes in FISO were found across groups or over time. WM ODI was moderately correlated with a higher youth-reported post-concussion symptom inventory (PCSI) score. With 87% predictive power, ODI (1 month post-injury) and clinical predictors (age, sex, PCSI score, attention scores) were a more sensitive predictor of recovery at 2-3 months post-injury than fractional anisotropy (FA) and clinical predictors, or clinical predictors alone. FISO could not predict recovery at 2-3 months post-injury. Therefore, we found that ODI was significantly increased in symptomatic children following mTBI compared with HCs at 1 month post-injury, and progressively decreased over time alongside clinical recovery. We found no significant differences in FISO between groups or over time. WM ODI at 1 month was a more sensitive predictor of clinical recovery at 2-3 months post-injury than FA, FISO, or clinical measures alone. Our results show evidence of ongoing microstructural reorganization or neuroinflammation between 1 and 2-3 months post-injury, further supporting delayed return to play in children who remain symptomatic. We recommend future research examining the clinical utility of NODDI following mTBI to predict recovery or persistence of post-concussion symptoms and thereby inform management of mTBI.

Examining post-concussion white matter change in a pediatric sample.

Diffusion-Weight Imaging (DWI) is increasingly used to explore a range of outcomes in pediatric concussion, particularly the neurobiological underpinnings of symptom recovery. However, the DWI findings within the broader pediatric concussion literature are mixed, which can largely be explained by methodological heterogeneity. To address some of these limitations, the aim of the present study was to utilize internationally- recognized criteria for concussion and a consistent imaging timepoint to conduct a comprehensive, multi-parametric survey of white matter microstructure after concussion. Forty-three children presenting with concussion to the emergency department of a tertiary level pediatric hospital underwent neuroimaging and were classified as either normally recovering (n = 27), or delayed recovering (n = 14) based on their post-concussion symptoms at 2 weeks post-injury.We combined multiple DWI metrics across four modeling approaches using Linked Independent Component Analysis (LICA) to extract several independent patterns of covariation in tissue microstructure present in the study cohort. Our analysis did not identify significant differences between the symptomatic and asymptomatic groups and no component significantly predicted delayed recovery. If white matter microstructure changes are implicated in delayed recovery from concussion, these findings, alongside previous work, suggest that current diffusion techniques are insufficient to detect those changes at this time.

A Scoping Review of Magnetic Resonance Modalities Used in Detection of Persistent Postconcussion Symptoms in Pediatric Populations.

Up to 30% of youth with concussion experience PPCSs (PPCS) lasting 4 weeks or longer, and can significantly impact quality of life. Magnetic resonance imaging (MRI) has the potential to increase understanding of causal mechanisms underlying PPCS. However, there are no clear modalities to assist in detecting PPCS. This scoping review aims to synthesize findings on utilization of MRI among children and youth with PPCS, and summarize progress and limitations. Thirty-six studies were included from 4907 identified papers. Many studies used multiple modalities, including (1) structural (n = 27) such as T1-weighted imaging, diffusion weighted imaging, and susceptibility weighted imaging; and (2) functional (n = 23) such as functional MRI and perfusion-weighted imaging. Findings were heterogeneous among modalities and regions of interest, which warrants future reviews that report on the patterns and potential advancements in the field. Consideration of modalities that target PPCS prediction and sensitive modalities that can supplement a biopsychosocial approach to PPCS would benefit future research.