Discovery of Alpha-1-Antichymotrypsin as a Marker of Delayed Recovery from Concussion in Children.

Of the four million children who experience a concussion each year, 30-50% of children will experience delayed recovery, where they will continue to experience symptoms more than two weeks after their injury. Delayed recovery from concussion encompasses emotional, behavioral, physical, and cognitive symptoms, and as such, there is an increased focus on developing an objective tool to determine risk of delayed recovery. This study aimed to identify a blood protein signature predictive of delayed recovery from concussion in children. Plasma samples were collected from children who presented to the Emergency Department at the Royal Children's Hospital, Melbourne, within 48h post-concussion. This study involved a discovery and validation phase. For the discovery phase, untargeted proteomics analysis was performed using single window acquisition of all theoretical mass spectra to identify blood proteins differentially abundant in samples from children with and without delayed recovery from concussion. A subset of these proteins was then validated in a separate participant cohort using multiple reaction monitoring and enzyme linked immunosorbent assay. A blood protein signature predictive of delayed recovery from concussion was modeled using a Support Vector Machine, a machine learning approach. In the discovery phase, 22 blood proteins were differentially abundant in age- and sex-matched samples from children with (n = 9) and without (n = 9) delayed recovery from concussion, six of whom were chosen for validation. In the validation phase, alpha-1-ACT was shown to be significantly lower in children with delayed recovery (n = 12) compared with those without delayed recovery (n = 28), those with orthopedic injuries (n = 7) and healthy controls (n = 33). A model consisting of alpha-1-ACT concentration stratified children based on recovery from concussion with an 0.88 area under the curve. We have identified that alpha-1-ACT differentiates between children at risk of delayed recovery from those without delayed recovery from concussion. To our knowledge, this is the first study to identify alpha-1-ACT as a potential marker of delayed recovery from concussion in children. Multi-site studies are required to further validate this finding before use in a clinical setting.

Updates to the Melbourne Children's Regional Infant Brain Software Package (M-CRIB-S).

The delineation of cortical areas on magnetic resonance images (MRI) is important for understanding the complexities of the developing human brain. The previous version of the Melbourne Children's Regional Infant Brain (M-CRIB-S) (Adamson et al. Scientific Reports, 10(1), 10, 2020) is a software package that performs whole-brain segmentation, cortical surface extraction and parcellation of the neonatal brain. Available cortical parcellation schemes in the M-CRIB-S are the adult-compatible 34- and 31-region per hemisphere Desikan-Killiany (DK) and Desikan-Killiany-Tourville (DKT), respectively. We present a major update to the software package which achieves two aims: 1) to make the voxel-based segmentation outputs derived from the Freesurfer-compatible M-CRIB scheme, and 2) to improve the accuracy of whole-brain segmentation and cortical surface extraction. Cortical surface extraction has been improved with additional steps to improve penetration of the inner surface into thin gyri. The improved cortical surface extraction is shown to increase the robustness of measures such as surface area, cortical thickness, and cortical volume.

Investigating Associations Between Maternal Behavior and the Development of Functional Connectivity During the Transition From Late Childhood to Early Adolescence.

BACKGROUND: Parenting behavior is thought to affect child brain development, with implications for mental health. However, longitudinal studies that use whole-brain approaches are lacking. In this study, we investigated associations between parenting behavior, age-related changes in whole-brain functional connectivity, and psychopathology symptoms in children and adolescents. METHODS: Two hundred forty (126 female) children underwent resting-state functional magnetic resonance imaging at up to two time points, providing a total of 398 scans covering the age range 8 to 13 years. Parenting behavior was self-reported at baseline. Parenting factors (positive parenting, inattentive parenting, and harsh and inconsistent discipline) were identified based on a factor analysis of self-report parenting questionnaires. Longitudinal measures of child internalizing and externalizing symptoms were collected. Network-based R-statistics was used to identify associations between parenting and age-related changes in functional connectivity. RESULTS: Higher maternal inattentive behavior was associated with lower decreases in connectivity over time, particularly between regions of the ventral attention and default mode networks and frontoparietal and default mode networks. However, this association was not significant after strict correction for multiple comparisons. CONCLUSIONS: While results should be considered preliminary, they suggest that inattentive parenting may be associated with a reduction in the normative pattern of increased network specialization that occurs with age. This may reflect a delayed development of functional connectivity.

The relationship between cognition and white matter tract damage after mild traumatic brain injury in a premorbidly healthy, hospitalised adult cohort during the post-acute period.

Introduction: Recent developments in neuroimaging techniques enable increasingly sensitive consideration of the cognitive impact of damage to white matter tract (WMT) microstructural organisation after mild traumatic brain injury (mTBI). Objective: This study investigated the relationship between WMT microstructural properties and cognitive performance. Participants setting and design: Using an observational design, a group of 26 premorbidly healthy adults with mTBI and a group of 20 premorbidly healthy trauma control (TC) participants who were well-matched on age, sex, premorbid functioning and a range of physical, psychological and trauma-related variables, were recruited following hospital admission for traumatic injury. Main measures: All participants underwent comprehensive unblinded neuropsychological examination and structural neuroimaging as outpatients 6-10 weeks after injury. Neuropsychological examination included measures of speed of processing, attention, memory, executive function, affective state, pain, fatigue and self-reported outcome. The WMT microstructural properties were estimated using both diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) modelling techniques. Tract properties were compared between the corpus callosum, inferior longitudinal fasciculus, uncinate fasciculus, anterior corona radiata and three segmented sections of the superior longitudinal fasciculus. Results: For the TC group, in all investigated tracts, with the exception of the uncinate fasciculus, two DTI metrics (fractional anisotropy and apparent diffusion coefficient) and one NODDI metric (intra-cellular volume fraction) revealed expected predictive linear relationships between extent of WMT microstructural organisation and processing speed, memory and executive function. The mTBI group showed a strikingly different pattern relative to the TC group, with no relationships evident between WMT microstructural organisation and cognition on most tracts. Conclusion: These findings indicate that the predictive relationship that normally exists in adults between WMT microstructural organisation and cognition, is significantly disrupted 6-10 weeks after mTBI and suggests that WMT microstructural organisation and cognitive function have disparate recovery trajectories.

Hypothalamus volumes in adolescent Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): impact of self-reported fatigue and illness duration.

Adolescent Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex illness of unknown aetiology. Emerging theories suggest ME/CFS may reflect a progressive, aberrant state of homeostasis caused by disturbances within the hypothalamus, yet few studies have investigated this using magnetic resonance imaging in adolescents with ME/CFS. We conducted a volumetric analysis to investigate whether whole and regional hypothalamus volumes in adolescents with ME/CFS differed compared to healthy controls, and whether these volumes were associated with fatigue severity and illness duration. 48 adolescents (25 ME/CFS, 23 controls) were recruited. Lateralised whole and regional hypothalamus volumes, including the anterior-superior, superior tubular, posterior, anterior-inferior and inferior tubular subregions, were calculated from T1-weighted images. When controlling for age, sex and intracranial volume, Bayesian linear regression models revealed no evidence for differences in hypothalamus volumes between groups. However, in the ME/CFS group, a weak linear relationship between increased right anterior-superior volumes and fatigue severity was identified, which was absent in controls. In addition, Bayesian quantile regression revealed a likely-positive association between illness duration and right superior tubular volumes in the ME/CFS group. While these findings suggest overall comparability in regional and whole hypothalamus volumes between adolescents with ME/CFS and controls, preliminary evidence was identified to suggest greater fatigue severity and longer illness duration were associated with greater right anterior-superior and superior-tubular volumes, respectively. These regions contain the anterior and superior divisions of the paraventricular nucleus, involved in the neuroendocrine response to stress, suggesting involvement in ME/CFS pathophysiology. However, replication in a larger, longitudinal cohort is required.

Cerebral microhaemorrhage count is related to processing speed, but not level of symptom reporting, independently of age, psychological status and premorbid functioning, after first-ever mild traumatic brain injury.

Cerebral microhaemorrhage is a commonly identified neuropathological consequence of mild traumatic brain injury (mTBI) and can be identified in vivo using susceptibility weighted imaging (SWI). This study aimed to determine whether SWI-detected microhaemorrhages are more common in individuals after a single, first-ever, mTBI event relative to trauma controls (TC) and to investigate whether a linear relationship exists between microhaemorrhage numbers and cognition or symptom reporting in the post-acute period after injury, independently of age, psychological status and premorbid level of functioning. Microhaemorrhagic lesions were identified by expert clinical examination of SWI for 78 premorbidly healthy adult participants who were admitted to hospital after a traumatic injury and had suffered a first-ever mTBI (n = 47) or no head strike (n = 31). Participants underwent objective cognitive examination of processing speed, attention, memory, and executive function as well as self-reported post-concussion symptomatology. Bootstrapping analyses were used as data were not normally distributed. Analyses revealed that the mTBI group had significantly more microhaemorrhages than the TC group (Cohen's d = 0.559). These lesions were only evident in 28% of individuals. The mTBI participants demonstrated a significant linear association between number of microhaemorrhages and processing speed, independently of age, psychological status, or premorbid level of functioning. This study shows that a single mTBI causes cerebral microhaemorrhages to occur in a minority of premorbidly healthy individuals. Greater microhaemorrhage count is independently associated with slower processing speed, but not symptom reporting, during the post-acute injury period.

Blood biomarkers of secondary outcomes following concussion: A systematic review.

Introduction: Blood biomarkers have been identified as an alternative tool for predicting secondary outcomes following concussion. This systematic review aimed to summarize the literature on blood biomarkers of secondary outcomes following concussion in both pediatric and adult cohorts. Methods: A literature search of Embase, Medline and PubMed was conducted. Two reviewers independently assessed retrieved studies to determine inclusion in systematic review synthesis. Results: A total of 1771 unique studies were retrieved, 58 of which were included in the final synthesis. S100B, GFAP and tau were identified as being associated with secondary outcomes following concussion. Seventeen percent of studies were performed in a solely pediatric setting. Conclusions: Validation of biomarkers associated with secondary outcomes following concussion have been largely limited by heterogeneous study cohorts and definitions of concussion and mTBI, presenting a hurdle for translation of these markers into clinical practice. Additionally, there was an underrepresentation of studies which investigated pediatric cohorts. Adult markers are not appropriate for children, therefore pediatric specific markers of secondary outcomes following concussion present the biggest gap in this field.

Maternal warmth is associated with network segregation across late childhood: A longitudinal neuroimaging study.

The negative impact of adverse experiences in childhood on neurodevelopment is well documented. Less attention however has been given to the impact of variations in "normative" parenting behaviors. The influence of these parenting behaviors is likely to be marked during periods of rapid brain reorganization, such as late childhood. The aim of the current study was to investigate associations between normative parenting behaviors and the development of structural brain networks across late childhood. Data were collected from a longitudinal sample of 114 mother-child dyads (54% female children, M age 8.41 years, SD = 0.32 years), recruited from low socioeconomic areas of Melbourne, Australia. At the first assessment parenting behaviors were coded from two lab-based interaction tasks and structural magnetic resonance imaging (MRI) scans of the children were performed. At the second assessment, approximately 18 months later (M age 9.97 years, SD = 0.37 years) MRI scans were repeated. Cortical thickness (CT) was extracted from T1-weighted images using FreeSurfer. Structural covariance (SC) networks were constructed from partial correlations of CT estimates between brain regions and estimates of network efficiency and modularity were obtained for each time point. The change in these network measures, from Time 1 to Time 2, was also calculated. At Time 2, less positive maternal affective behavior was associated with higher modularity (more segregated networks), while negative maternal affective behavior was not related. No support was found for an association between local or global efficacy and maternal affective behaviors at Time 2. Similarly, no support was demonstrated for associations between maternal affective behaviors and change in network efficiency and modularity, from Time 1 to Time 2. These results indicate that normative variations in parenting may influence the development of structural brain networks in late childhood and extend current knowledge about environmental influences on structural connectivity in a developmental context.

Brain White Matter Development Over the First 13 Years in Very Preterm and Typically Developing Children Based on the T 1-w/T 2-w Ratio.

BACKGROUND AND OBJECTIVES: To investigate brain regional white matter development in full-term (FT) and very preterm (VP) children at term equivalent and 7 and 13 years of age based on the ratio of T 1- and T 2-weighted MRI (T 1-w/T 2-w), including (1) whether longitudinal changes differ between birth groups or sexes, (2) associations with perinatal risk factors in VP children, and (3) relationships with neurodevelopmental outcomes at 13 years. METHODS: Prospective longitudinal cohort study of VP (born <30 weeks' gestation or <1,250 g) and FT infants born between 2001 and 2004 and followed up at term equivalent and 7 and 13 years of age, including MRI studies and neurodevelopmental assessments. T 1-w/T 2-w images were parcellated into 48 white matter regions of interest. RESULTS: Of 224 VP participants and 76 FT participants, 197 VP and 55 FT participants had useable T 1-w/T 2-w data from at least one timepoint. T 1-w/T 2-w values increased between term equivalent and 13 years of age, with little evidence that longitudinal changes varied between birth groups or sexes. VP birth, neonatal brain abnormalities, being small for gestational age, and postnatal infection were associated with reduced regional T 1-w/T 2-w values in childhood and adolescence. Increased T 1-w/T 2-w values across the white matter at 13 years were associated with better motor and working memory function for all children. Within the FT group only, larger increases in T 1-w/T 2-w values from term equivalent to 7 years were associated with poorer attention and executive function, and higher T 1-w/T 2-w values at 7 years were associated with poorer mathematics performance. DISCUSSION: VP birth and multiple known perinatal risk factors are associated with long-term reductions in the T 1-w/T 2-w ratio in white matter regions in childhood and adolescence, which may relate to alterations in microstructure and myelin content. Increased T 1-w/T 2-w ratio at 13 years appeared to be associated with better motor and working memory function and there appeared to be developmental differences between VP and FT children in the associations for attention, executive functioning, and mathematics performance.

Auditory Dysfunction Among Individuals With Neurofibromatosis Type 1.

Importance: Neurofibromatosis type 1 (NF1) affects hearing through disruption of central auditory processing. The mechanisms, functional severity, and management implications are unclear. Objective: To investigate auditory neural dysfunction and its perceptual consequences in individuals with NF1. Design, Setting, and Participants: This case-control study included children and adults with NF1 and control participants matched on age, sex, and hearing level. Patients were recruited through specialist neurofibromatosis and neurogenetic outpatient clinics between April and September 2019. An evaluation of auditory neural activity, monaural/binaural processing, and functional hearing was conducted. Diffusion-weighted magnetic resonance imaging (MRI) data were collected from a subset of participants (10 children with NF1 and 10 matched control participants) and evaluated using a fixel-based analysis of apparent fiber density. Main Outcomes and Measures: Type and severity of auditory dysfunction evaluated via laboratory testing and questionnaire data. Results: A total of 44 participants (18 [41%] female individuals) with NF1 with a mean (SD) age of 16.9 (10.7) years and 44 control participants (18 [41%] female individuals) with a mean (SD) age of 17.2 (10.2) years were included in the study. Overall, 11 participants (25%) with NF1 presented with evidence of auditory neural dysfunction, including absent, delayed, or low amplitude electrophysiological responses from the auditory nerve and/or brainstem, compared with 1 participant (2%) in the control group (odds ratio [OR], 13.03; 95% CI, 1.59-106.95). Furthermore, 14 participants (32%) with NF1 showed clinically abnormal speech perception in background noise compared with 1 participant (2%) in the control group (OR, 20.07; 95% CI, 2.50-160.89). Analysis of diffusion-weighted MRI data of participants with NF1 showed significantly lower apparent fiber density within the ascending auditory brainstem pathways. The regions identified corresponded to the neural dysfunction measured using electrophysiological assessment. Conclusions and Relevance: The findings of this case-control study could represent new neurobiological and clinical features of NF1. Auditory dysfunction severe enough to impede developmental progress in children and restrict communication in older participants is a common neurobiological feature of the disorder.

A systematic review of brain MRI findings in monogenic disorders strongly associated with autism spectrum disorder.

BACKGROUND: Research on monogenic forms of autism spectrum disorder (autism) can inform our understanding of genetic contributions to the autism phenotype; yet, there is much to be learned about the pathways from gene to brain structure to behavior. This systematic review summarizes and evaluates research on brain magnetic resonance imaging (MRI) findings in monogenic conditions that have strong association with autism. This will improve understanding of the impact of genetic variability on brain structure and related behavioral traits in autism. METHODS: The search strategy for this systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Risk of bias (ROB) assessment was completed on included studies using the Newcastle-Ottawa Scales. RESULTS: Of 4,287 studies screened, 69 were included pertaining to 13 of the top 20 genes with the strongest association with autism. The greatest number of studies related to individuals with PTEN variants and autism. Brain MRI abnormalities were reported for 12 of the 13 genes studied, and in 51.7% of participants across all 13 genes, including 100% of participants with ARID1B variants. Specific MRI findings were highly variable, with no clear patterns emerging within or between the 13 genes, although white matter abnormalities were the most common. Few studies reported specific details about methods for acquisition and processing of brain MRI, and descriptors for brain abnormalities were variable. ROB assessment indicated high ROB for all studies, largely due to small sample sizes and lack of comparison groups. CONCLUSIONS: Brain abnormalities are common in this population of individuals, in particular, children; however, a range of different brain abnormalities were reported within and between genes. Directions for future neuroimaging research in monogenic autism are suggested.

The development of structural covariance networks during the transition from childhood to adolescence.

Structural covariance conceptualizes how morphologic properties of brain regions are related to one another (across individuals). It can provide unique information to cortical structure (e.g., thickness) about the development of functionally meaningful networks. The current study investigated how structural covariance networks develop during the transition from childhood to adolescence, a period characterized by marked structural re-organization. Participants (N = 192; scans = 366) completed MRI assessments between 8.5 and 14.5 years of age. A sliding window approach was used to create "age-bins", and structural covariance networks (based on cortical thickness) were created for each bin. Next, generalized additive models were used to characterize trajectories of age-related changes in network properties. Results revealed nonlinear trajectories with "peaks" in mean correlation and global density that are suggestive of a period of convergence in anatomical properties across the cortex during early adolescence, prior to regional specialization. "Hub" regions in sensorimotor cortices were present by late childhood, but the extent and strength of association cortices as "hubs" increased into mid-adolescence. Moreover, these regional changes were found to be related to rates of thinning across the cortex. In the context of neurocognitive networks, the frontoparietal, default mode, and attention systems exhibited age-related increases in within-network and between-network covariance. These regional and modular developmental patterns are consistent with continued refinement of socioemotional and other complex executive functions that are supported by higher-order cognitive networks during early adolescence.

Individual variation underlying brain age estimates in typical development.

Typical brain development follows a protracted trajectory throughout childhood and adolescence. Deviations from typical growth trajectories have been implicated in neurodevelopmental and psychiatric disorders. Recently, the use of machine learning algorithms to model age as a function of structural or functional brain properties has been used to examine advanced or delayed brain maturation in healthy and clinical populations. Termed 'brain age', this approach often relies on complex, nonlinear models that can be difficult to interpret. In this study, we use model explanation methods to examine the cortical features that contribute to brain age modelling on an individual basis. In a large cohort of n = 768 typically-developing children (aged 3-21 years), we build models of brain development using three different machine learning approaches. We employ SHAP, a model-agnostic technique to identify sample-specific feature importance, to identify regional cortical metrics that explain errors in brain age prediction. We find that, on average, brain age prediction and the cortical features that explain model predictions are consistent across model types and reflect previously reported patterns of regions brain development. However, while several regions are found to contribute to brain age prediction error, we find little spatial correspondence between individual estimates of feature importance, even when matched for age, sex and brain age prediction error. We also find no association between brain age error and cognitive performance in this typically-developing sample. Overall, this study shows that, while brain age estimates based on cortical development are relatively robust and consistent across model types and preprocessing strategies, significant between-subject variation exists in the features that explain erroneous brain age predictions on an individual level.

No Evidence of a Difference in Susceptibility-Weighted Imaging Lesion Burden or Functional Network Connectivity between Children with Typical and Delayed Recovery Two Weeks Post-Concussion.

Susceptibility weighted imaging (SWI) and resting state functional magnetic resonance imaging have been highlighted as two novel neuroimaging modalities that have been underutilized when attempting to predict whether a child with concussion will recover normally or have a delayed recovery course. This study aimed to investigate whether there was a difference between children who recover normally from a concussion and children with delayed recovery in terms of SWI lesion burden and resting state network makeup. Forty-one children who presented to the emergency department of a tertiary level pediatric hospital with concussion participated in this study as a part of a larger prospective, longitudinal observational cohort study into concussion assessment and recovery. Children underwent neuroimaging 2 weeks post-injury 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. No participants showed lesions detected using SWI; therefore, no group differences could be assessed. No between-group resting state network differences were uncovered using dual regression analysis. These findings, alongside previously published work, suggest that potential causes of delayed recovery from concussion may not be found using current neuroimaging paradigms.

Investigating the brain structural connectome following working memory training in children born extremely preterm or extremely low birth weight.

Children born extremely preterm (EP, <28 weeks' gestation) or extremely low birth weight (ELBW, <1,000 g) are a vulnerable population at high risk of working memory impairments. We aimed to examine changes in the brain structural connectivity networks thought to underlie working memory performance, after completion of a working memory training program (Cogmed) compared with a placebo program in EP/ELBW children. This was a double-blind, placebo-controlled randomized trial (the Improving Memory in a Preterm Randomised Intervention Trial). Children born EP/ELBW received either the Cogmed or placebo program at 7 years of age (n = 91). A subset of children had magnetic resonance imaging of the brain immediately pre- and 2 weeks post-training (Cogmed n = 28; placebo n = 27). T1 -weighted and diffusion-weighted images were used to perform graph theoretical analysis of structural connectivity networks. Changes from pre-training to post-training in structural connectivity metrics were generally similar between randomized groups. There was little evidence that changes in structural connectivity metrics were related to changes in working memory performance from pre- to post-training. Overall, our results provide little evidence that the Cogmed working memory training program has training-specific effects on structural connectivity networks in EP/ELBW children.

Towards understanding neurocognitive mechanisms of parenting: Maternal behaviors and structural brain network organization in late childhood.

A substantial body of knowledge suggests that exposure to adverse family environments - including violence and neglect - influences many aspects of brain development. Relatively less attention has been directed toward the influence of "normative" differences in parenting behaviors. Given the rapid brain reorganization during late childhood, parenting behaviors are particularly likely to impact the structure of the brain during this time. This study investigated associations between maternal parenting behaviors and the organization of structural brain networks in late childhood, as measured by structural covariance. One hundred and forty-five typically developing 8-year-olds and their mothers completed questionnaire measures and two observed interaction tasks; magnetic resonance imaging (MRI) scans were obtained from the children. Measures of maternal negative, positive, and communicative behavior were derived from the interaction tasks. Structural covariance networks based on partial correlations between cortical thickness estimates were constructed and estimates of modularity were obtained using graph theoretical analysis. High levels of negative maternal behavior were associated with low modularity. Minimal support was found for an association between positive maternal behaviors and modularity and between maternal communicative behaviors and modularity. Our findings suggest that variation in negative maternal behavior is associated with the structural organization of brain networks in children.

A longitudinal analysis of puberty-related cortical development.

The brain undergoes extensive structural changes during adolescence, concurrent to puberty-related physical and hormonal changes. While animal research suggests these biological processes are related to one another, our knowledge of brain development in humans is largely based on age-related processes. Thus, the current study characterized puberty-related changes in human brain structure, by combining data from two longitudinal neuroimaging cohorts. Beyond normative changes in cortical thickness, we examined whether individual differences in the rate of pubertal maturation (or "pubertal tempo") was associated with variations in cortical trajectories. Participants (N = 192; scans = 366) completed up to three waves of MRI assessments between 8.5 and 14.5 years of age, as well as questionnaire assessments of pubertal stage at each wave. Generalized additive mixture models were used to characterize trajectories of cortical development. Results revealed widespread linear puberty-related changes across much of the cortex. Many of these changes, particularly within the frontal and parietal cortices, were independent of age-related development. Males exhibiting faster pubertal tempo demonstrated greater thinning in the precuneus and frontal cortices than same-aged and -sex peers. Findings suggest that the unique influence of puberty on cortical development may be more extensive than previously identified, and also emphasize important individual differences in the coupling of these developmental processes.

Investigating White Matter Tract Microstructural Changes at Six-Twelve Weeks following Mild Traumatic Brain Injury: A Combined Diffusion Tensor Imaging and Neurite Orientation Dispersion and Density Imaging Study.

Using diffusion-weighted imaging (DWI), research has demonstrated changes suggestive of damage to white matter tracts (WMT) following mild traumatic brain injury (mTBI). Yet due to the predominant use of the diffusion tensor imaging (DTI) model, which has numerous well-established limitations, it has not yet been possible to clearly examine the nature of changes to WMT microstructure following mTBI. This study used a second DWI-based technique, neurite orientation dispersion and density imaging (NODDI), in combination with DTI to measure microstructural changes within the corpus callosum, three long association and one projection WMTs at 6-12 weeks following mTBI, compared with matched trauma controls (TC). Between-groups differences were identified across all WMT for the DTI metric fractional anisotropy (FA), and the NODDI metrics orientation dispersion index (ODI) and isotropic volume fraction (ISO). No statistically significant between-groups differences were found for other DTI and NODDI metrics. Our study revealed that reduced FA was accompanied by increased ODI, suggesting that mTBI results in reduced coherence of axonal fiber bundles within the studied WMTs. These between-groups differences in WMT microstructure were found at 6-12 weeks post-injury, which suggests that structural recovery is not yet complete towards end of the typical 3-month recovery period.

Longitudinal patterns of white matter fibre density and morphology in children are associated with age and pubertal stage.

The pubertal period involves dynamic white matter development. This period also corresponds with rapid gains in higher cognitive functions including attention, as well as increased risk of developing mental health difficulties. This longitudinal study comprised children aged 9-13 years (n = 130). Diffusion magnetic resonance imaging (dMRI) data were acquired (b = 2800s/mm2, 60 directions) at two time-points. We derived measures of fibre density and morphology using the fixel-based analysis framework and performed a tract-based mixed-effects modelling analysis to understand patterns of white matter development with respect to age, sex, pubertal stage, and the change in pubertal stage. We observed significant increases in apparent fibre density across a large number of white matter pathways, including major association and commissural pathways. We observed a linear relationship between pubertal stage and fibre density and morphology in the right superior longitudinal fasciculus, and fibre morphology in the right inferior longitudinal fasciculus. Finally, we report a significant interaction between the change in pubertal stage and age in the development of fibre density, for left-lateralised association tracts. Overall, white matter development across ages 9-13 years involves the expansion of major white matter fibre pathways, with key association pathways linked with pubertal stage.

Neuroimaging in paediatric mild traumatic brain injury: a systematic review.

Neuroimaging is being increasingly applied to the study of paediatric mild traumatic brain injury (mTBI) to uncover the neurobiological correlates of delayed recovery post-injury. The aims of this systematic review were to: (i) evaluate the neuroimaging research investigating neuropathology post-mTBI in children and adolescents from 0-18 years, (ii) assess the relationship between advanced neuroimaging abnormalities and PCS in children, (iii) assess the quality of the evidence by evaluating study methodology and reporting against best practice guidelines, and (iv) provide directions for future research. A literature search of MEDLINE, PsycINFO, EMBASE, and PubMed was conducted. Abstracts and titles were screened, followed by full review of remaining articles where specific eligibility criteria were applied. This systematic review identified 58 imaging studies which met criteria. Based on several factors including methodological heterogeneity and relatively small sample sizes, the literature currently provides insufficient evidence to draw meaningful conclusions about the relationship between MRI findings and clinical outcomes. Future research is needed which incorporates prospective, longitudinal designs, minimises potential confounds and utilises multimodal imaging techniques.