Initial Severity of Injury Has Little Effect on the Temporal Profile of Long-Term Deficits in Locomotion, Anxiety, and Cognitive Function After Diffuse Traumatic Brain Injury.

Traumatic brain injury (TBI) is associated with persistent impairments in multiple domains, including cognitive and neuropsychiatric function. Previous literature has suggested that the risk of such impairments may differ as a function of the initial severity of injury, with moderate-severe TBI (msTBI) associated with more severe cognitive dysfunction and mild TBI (mTBI) associated with a higher risk of developing an anxiety disorder. Despite this, relatively few pre-clinical studies have investigated the time course of behavioral change after different severities of injury. The current study compared the temporal profile of functional deficits incorporating locomotion, cognition, and anxiety up to 12 months post-injury after an mTBI, repeated mild TBI (rmTBI), and single msTBI in an experimental model of diffuse TBI. Injury appeared to alter the effect of aging on locomotor activity, with both msTBI and rmTBI rats showing a decrease in locomotion at 12 months relative to their earlier performance on the task, an effect not observed in shams or after a single mTBI. Further, mTBI seemed to be associated with decreased anxiety over time, as measured by increased time spent in the open arm of the elevated plus maze from 3 to 12 months post-injury. No significant findings were observed on spatial memory or volumetric magnetic resonance imaging. Future studies will need to use a more comprehensive behavioral battery, capable of capturing subtle alterations in function, and longer time points, following rats into old age, in order to more fully assess the evolution of persistent behavioral deficits in key domains after different severities of TBI, as well as their accompanying neuroimaging changes. Given the prevalence and significance of such deficits post-TBI for a person's quality of life, as well as the elevated risk of neurodegenerative disease post-injury, such investigations may play a critical role in identifying optimal windows of therapeutic intervention post-injury.

Serum neurofilament light as a biomarker of vulnerability to a second mild traumatic brain injury.

A second mild traumatic brain injury (mTBI) sustained prior to neuropathological recovery can lead to exacerbated effects. Without objective indicators of this neuropathology, individuals may return to activities at risk of mTBI when their brain is still vulnerable. With axonal injury recognized as a neuropathological hallmark of mTBI, we hypothesized that serum levels of neurofilament light (NfL), a highly sensitive biomarker of axonal injury, may be predictive of vulnerability to worse outcomes in the event of a second mTBI. Given this hypothesis is difficult to test clinically, we used a two-hit model of mTBI in rats and staggered inter-injury intervals by 1-, 3-, 7-, or 14-days. Repeat-mTBI rats were dichotomized into NfLhigh (NfL>median at the time of re-injury) and NfLlow (NfL

A companion to the preclinical common data elements and case report forms for in vivo rodent neuroimaging: A report of the TASK3-WG3 Neuroimaging Working Group of the ILAE/AES Joint Translational Task Force.

The International League Against Epilepsy/American Epilepsy Society (ILAE/AES) Joint Translational Task Force established the TASK3 working groups to create common data elements (CDEs) for various aspects of preclinical epilepsy research studies, which could help improve the standardization of experimental designs. In this article, we discuss CDEs for neuroimaging data that are collected in rodent models of epilepsy, with a focus on adult rats and mice. We provide detailed CDE tables and case report forms (CRFs), and with this companion manuscript, we discuss the methodologies for several imaging modalities and the parameters that can be collected.

Platelet-targeted thrombolysis for treatment of acute ischemic stroke.

Thrombolysis with tissue-type plasminogen activator (tPA) is still the main treatment for acute ischemic stroke. Nevertheless, tPA intervention is limited by a short therapeutic window, low recanalization rates and a risk of intracranial haemorrhage (ICH), raising a clinical demand for improved thrombolytic drugs. We examined a novel thrombolytic agent termed 'SCE5-scuPA', comprising a single-chain urokinase plasminogen activator (scuPA) fused with a single-chain antibody (SCE5) that targets the activated GPIIb/IIIa platelet receptor, for its effects in experimental stroke. SCE5-scuPA was first tested in whole blood clot degradation assay to demonstrate the benefit of platelet-targeted thrombolysis. The tail bleeding time, blood clearance and biodistribution were then determined to inform the use of SCE5-scuPA in mouse models of photothrombotic stroke and Middle Cerebral Artery occlusion (MCAo) against tenecteplase (TNK-tPA). The impacts of SCE5-scuPA on motor function, ICH, blood-brain barrier (BBB) integrity and immunosuppression were evaluated. Infarct size was measured by Computed Tomography and Magnetic Resonance Imaging. SCE5-scuPA enhanced clot degradation ex vivo compared to its non-platelet-targeting control. The maximal SCE5-scuPA dose that maintained hemostasis and a rapid blood clearance were determined. SCE5-scuPA administration both prior and 2h after photothrombotic stroke reduced the infarct volume. SCE5-scuPA also improved neurological deficit, decreased intracerebral blood deposits, preserved the BBB and alleviated immunosuppression post-stroke. In MCAo, SCE5-scuPA did not worsen stroke outcomes or caused ICH, and protected the BBB. Our findings support the ongoing development of platelet-targeted thrombolysis with SCE5-scuPA as a novel emergency treatment for AIS with a promising safety profile.

Early and progressive dysfunction revealed by in vivo neurite imaging in the rNLS8 TDP-43 mouse model of ALS.

Amyotrophic lateral sclerosis (ALS) is characterized by transactive response DNA-binding protein 43 (TDP-43) pathology, progressive loss of motor neurons and muscle dysfunction. Symptom onset can be insidious and diagnosis challenging. Conventional neuroimaging is used to exclude ALS mimics, however more advanced neuroimaging techniques may facilitate an earlier diagnosis. Here, we investigate the potential for neurite orientation dispersion and density imaging and diffusion tensor imaging (DTI) to detect microstructural changes in an experimental model of ALS with neuronal doxycycline (Dox)-suppressible overexpression of human TDP-43 (hTDP-43). In vivo diffusion-weighted imaging (DWI) was acquired 1- and 3- weeks following the initiation of hTDP-43 expression (post-Dox) to investigate whether neurite density imaging (NDI) and orientation dispersion imaging (ODI) are affected early in this preclinical model of ALS and if so, how these metrics compare to those derived from the diffusion tensor. Tract-based spatial statistics at 1-week post-Dox, i.e. very early in the disease stage, demonstrated increased NDI in TDP-43 mice but no change in ODI or DTI metrics. At 3-weeks post-Dox, a reduced pattern of increased NDI was observed along with widespread increases in ODI, and decreased fractional anisotropy (FA), apparent diffusion coefficient (ADC) and axial diffusivity (AD). A hypothesis driven analysis of the bilateral corticospinal tracts demonstrated that at 1-week post-Dox, ODI was significantly increased caudally but decreased in the motor cortex of TDP-43 mice. Decreased cortical ODI had normalized by 3-weeks post-Dox and only significant increases were observed. A similar, but inverse pattern in FA was also observed. Together, these results suggest a non-monotonic relationship between DWI metrics and pathophysiological progression with TDP-43 mice exhibiting significantly altered diffusion metrics consistent with early inflammation followed by progressive axonal degeneration. Importantly, significant group-wise changes were observed in the earliest stages of disease when subtle pathology may be more elusive to traditional structural imaging techniques.

Sub-acute Changes on MRI Measures of Cerebral Blood Flow and Venous Oxygen Saturation in Concussed Australian Rules Footballers.

BACKGROUND: Sports-related concussion (SRC) is common in collision sport athletes. There is growing evidence that repetitive SRC can have serious neurological consequences, particularly when the repetitive injuries occur when the brain has yet to fully recover from the initial injury. Hence, there is a need to identify biomarkers that are capable of determining SRC recovery so that they can guide clinical decisions pertaining to return-to-play. Cerebral venous oxygen saturation (SvO2) and cerebral blood flow (CBF) can be measured using magnetic resonance imaging (MRI) and may provide insights into changing energy demands and recovery following SRC. RESULTS: In this study we therefore investigated SvO2 and CBF in a cohort of concussed amateur Australian Football athletes (i.e., Australia's most participated collision sport). Male and female Australian footballers (n = 13) underwent MRI after being cleared to return to play following a mandatory 13-day recovery period and were compared to a group of control Australian footballers (n = 16) with no recent history of SRC (i.e., > 3 months since last SRC). Despite the concussed Australian footballers being cleared to return to play at the time of MRI, we found evidence of significantly increased susceptibility in the global white matter (p = 0.020) and a trend (F5,21 = 2.404, p = 0.071) for reduced relative CBF (relCBF) compared to the control group. Further, there was evidence of an interaction between sex and injury in straight sinus susceptibility values (F1,25 = 3.858, p = 0.061) which were decreased in female SRC athletes (p = 0.053). Of note, there were significant negative correlations between straight sinus susceptibility and relCBF suggesting impaired metabolic function after SRC. CONCLUSIONS: These findings support the use of quantitative susceptibility mapping (QSM) and relCBF as sensitive indicators of SRC, and raise further concerns related to SRC guidelines that allow for return-to-play in less than two weeks.

Impaired glymphatic function in the early stages of disease in a TDP-43 mouse model of amyotrophic lateral sclerosis.

BACKGROUND: Multiple lines of evidence suggest possible impairment of the glymphatic system in amyotrophic lateral sclerosis (ALS). To investigate this, we used in vivo magnetic resonance imaging (MRI) to assess glymphatic function early in the course of disease in a transgenic mouse with doxycycline (Dox)-controlled expression of cytoplasmic human TDP-43 (hTDP-43ΔNLS), mimicking the key pathology implicated in ALS. METHODS: Adult TDP-43 transgenic and littermate monogenic control mice underwent longitudinal multimodal MRI one and three weeks after the cessation of Dox feed, together with weekly rotarod assessments of motor performance. Glymphatic function was assessed using dynamic contrast-enhanced MRI to track the clearance of an MR contrast agent injected into the cisterna magna. RESULTS: Compared to their littermate controls, TDP-43 mice exhibited progressive neurodegeneration including that within the primary motor cortex, primary somatosensory cortex and corticospinal tract, significant weight loss including gastrocnemius atrophy, and shortened telomere length. Furthermore, in the presence of this ALS-like phenotype, these mice have significantly disrupted glymphatic function. CONCLUSIONS: Although the relationship between glymphatic clearance and ALS disease progression remains to be elucidated, these changes occurred very early in the disease course. This provides initial evidence to suggest that the glymphatic system might be a potential therapeutic target in the treatment of ALS.

Ancient DNA and deep population structure in sub-Saharan African foragers.

Multiple lines of genetic and archaeological evidence suggest that there were major demographic changes in the terminal Late Pleistocene epoch and early Holocene epoch of sub-Saharan Africa1-4. Inferences about this period are challenging to make because demographic shifts in the past 5,000 years have obscured the structures of more ancient populations3,5. Here we present genome-wide ancient DNA data for six individuals from eastern and south-central Africa spanning the past approximately 18,000 years (doubling the time depth of sub-Saharan African ancient DNA), increase the data quality for 15 previously published ancient individuals and analyse these alongside data from 13 other published ancient individuals. The ancestry of the individuals in our study area can be modelled as a geographically structured mixture of three highly divergent source populations, probably reflecting Pleistocene interactions around 80-20 thousand years ago, including deeply diverged eastern and southern African lineages, plus a previously unappreciated ubiquitous distribution of ancestry that occurs in highest proportion today in central African rainforest hunter-gatherers. Once established, this structure remained highly stable, with limited long-range gene flow. These results provide a new line of genetic evidence in support of hypotheses that have emerged from archaeological analyses but remain contested, suggesting increasing regionalization at the end of the Pleistocene epoch.

Targeting the Cerebrovascular System: Next-Generation Biomarkers and Treatment for Mild Traumatic Brain Injury.

The diagnosis, prognosis, and treatment of mild traumatic brain injuries (mTBIs), such as concussions, are significant unmet medical issues. The kinetic forces that occur in mTBI adversely affect the cerebral vasculature, making cerebrovascular injury (CVI) a pathophysiological hallmark of mTBI. Given the importance of a healthy cerebrovascular system in overall brain function, CVI is likely to contribute to neurological dysfunction after mTBI. As such, CVI and related pathomechanisms may provide objective biomarkers and therapeutic targets to improve the clinical management and outcomes of mTBI. Despite this potential, until recently, few studies have focused on the cerebral vasculature in this context. This article will begin by providing a brief overview of the cerebrovascular system followed by a review of the literature regarding how mTBI can affect the integrity and function of the cerebrovascular system, and how this may ultimately contribute to neurological dysfunction and neurodegenerative conditions. We then discuss promising avenues of research related to mTBI biomarkers and interventions that target CVI, and conclude that a clinical approach that takes CVI into account could result in substantial improvements in the care and outcomes of patients with mTBI.

Pre-existing Toxoplasma gondii infection increases susceptibility to pentylenetetrazol-induced seizures independent of traumatic brain injury in mice.

Introduction: Post-traumatic epilepsy (PTE) is a debilitating chronic outcome of traumatic brain injury (TBI), and neuroinflammation is implicated in increased seizure susceptibility and epileptogenesis. However, how common clinical factors, such as infection, may modify neuroinflammation and PTE development has been understudied. The neurotropic parasite, Toxoplasma gondii (T. gondii) incurably infects one-third of the world's population. Thus, many TBI patients have a pre-existing T. gondii infection at the time of injury. T. gondii infection results in chronic low-grade inflammation and altered signaling pathways within the brain, and preliminary clinical evidence suggest that it may be a risk factor for epilepsy. Despite this, no studies have considered how a pre-existing T. gondii infection may alter the development of PTE. Methods: This study aimed to provide insight into this knowledge gap by assessing how a pre-existing T. gondii infection alters susceptibility to, and severity of, pentylenetetrazol (PTZ)-induced seizures (i.e., a surrogate marker of epileptogenesis/PTE) at a chronic stage of TBI recovery. We hypothesized that T. gondii will increase the likelihood and severity of seizures following PTZ administration, and that this would occur in the presence of intensified neuroinflammation. To test this, 6-week old male and female C57BL/6 Jax mice were intraperitoneally injected with 50,000 T. gondii tachyzoites or with the PBS vehicle only. At 12-weeks old, mice either received a severe TBI via controlled cortical impact or sham injury. At 18-weeks post-injury, mice were administered 40 mg/kg PTZ and video-recorded for evaluation of seizure susceptibility. Fresh cortical tissue was then collected for gene expression analyses. Results: Although no synergistic effects were evident between infection and TBI, chronic T. gondii infection alone had robust effects on the PTZ-seizure response and gene expression of markers related to inflammatory, oxidative stress, and glutamatergic pathways. In addition to this, females were more susceptible to PTZ-induced seizures than males. While TBI did not impact PTZ responses, injury effects were evident at the molecular level. Discussion: Our data suggests that a pre-existing T. gondii infection is an important modifier of seizure susceptibility independent of brain injury, and considerable attention should be directed toward delineating the mechanisms underlying this pro-epileptogenic factor.

Visitor Restrictions, Palliative Care, and Epistemic Agency: A Qualitative Study of Nurses' Relational Practice During the Coronavirus Pandemic.

Efforts to curb spread of COVID-19 has led to restrictive visitor policies in healthcare, which disrupt social connection between patients and their families at end of life. We interviewed 17 Canadian nurses providing palliative care, to solicit their descriptions of, and responses to, ethical issues experienced as a result of COVID-19 related circumstances. Our analysis was inductive and scaffolded on notions of nurses' moral agency, palliative care values, and our clinical practice in end-of-life care. Our findings reveal that while participants appreciated the need for pandemic measures, they found blanket policies separating patients and families to be antithetical to their philosophy of palliative care. In navigating this tension, nurses drew on the foundational values of their practice, engaging in ethical reasoning and action to integrate safety and humanity into their work. These findings underscore the epistemic agency of nurses and highlight the limits of a purely biomedical logic for guiding the nursing ethics of the pandemic response.

Pain in the Developing Brain: Early Life Factors Alter Nociception and Neurobiological Function in Adolescent Rats.

Although adverse early experiences prime individuals to be at increased risk for chronic pain, little research has examined the trauma-pain relationship in early life or the underlying mechanisms that drive pathology over time. Given that early experiences can potentiate the nociceptive response, this study aimed to examine the effects of a high-fat, high-sugar (HFHS) diet and early life stress (maternal separation [MS]) on pain outcomes in male and female adolescent rats. Half of the rats also underwent a plantar-incision surgery to investigate how the pain system responded to a mildly painful stimuli in adolescence. Compared with controls, animals that were on the HFHS diet, experienced MS, or had exposure to both, exhibited increased anxiety-like behavior and altered thermal and mechanical nociception at baseline and following the surgery. Advanced magnetic resonance imaging demonstrated that the HFHS diet and MS altered the maturation of the brain, leading to changes in brain volume and diffusivity within the anterior cingulate, amygdala, corpus callosum, nucleus accumbens, and thalamus, while also modifying the integrity of the corticospinal tracts. The effects of MS and HFHS diet were often cumulative, producing exacerbated pain sensitivity and increased neurobiological change. As early experiences are modifiable, understanding their role in pain may provide targets for early intervention/prevention.

White and Gray Matter Abnormalities in Australian Footballers With a History of Sports-Related Concussion: An MRI Study.

Sports-related concussion (SRC) is a form of mild traumatic brain injury that has been linked to long-term neurological abnormalities. Australian rules football is a collision sport with wide national participation and is growing in popularity worldwide. However, the chronic neurological consequences of SRC in Australian footballers remain poorly understood. This study investigated the presence of brain abnormalities in Australian footballers with a history of sports-related concussion (HoC) using multimodal MRI. Male Australian footballers with HoC (n = 26), as well as noncollision sport athletes with no HoC (n = 27), were recruited to the study. None of the footballers had sustained a concussion in the preceding 6 months, and all players were asymptomatic. Data were acquired using a 3T MRI scanner. White matter integrity was assessed using diffusion tensor imaging. Cortical thickness, subcortical volumes, and cavum septum pellucidum (CSP) were analyzed using structural MRI. Australian footballers had evidence of widespread microstructural white matter damage and cortical thinning. No significant differences were found regarding subcortical volumes or CSP. These novel findings provide evidence of persisting white and gray matter abnormalities in Australian footballers with HoC, and raise concerns related to the long-term neurological health of these athletes.

Early human impacts and ecosystem reorganization in southern-central Africa.

Modern Homo sapiens engage in substantial ecosystem modification, but it is difficult to detect the origins or early consequences of these behaviors. Archaeological, geochronological, geomorphological, and paleoenvironmental data from northern Malawi document a changing relationship between forager presence, ecosystem organization, and alluvial fan formation in the Late Pleistocene. Dense concentrations of Middle Stone Age artifacts and alluvial fan systems formed after ca. 92 thousand years ago, within a paleoecological context with no analog in the preceding half-million-year record. Archaeological data and principal coordinates analysis indicate that early anthropogenic fire relaxed seasonal constraints on ignitions, influencing vegetation composition and erosion. This operated in tandem with climate-driven changes in precipitation to culminate in an ecological transition to an early, pre-agricultural anthropogenic landscape.

Longitudinal hippocampal volumetric changes in mice following brain infarction.

Hippocampal atrophy is increasingly described in many neurodegenerative syndromes in humans, including stroke and vascular cognitive impairment. However, the progression of brain volume changes after stroke in rodent models is poorly characterized. We aimed to monitor hippocampal atrophy occurring in mice up to 48-weeks post-stroke. Male C57BL/6J mice were subjected to an intraluminal filament-induced middle cerebral artery occlusion (MCAO). At baseline, 3-days, and 1-, 4-, 12-, 24-, 36- and 48-weeks post-surgery, we measured sensorimotor behavior and hippocampal volumes from T2-weighted MRI scans. Hippocampal volume-both ipsilateral and contralateral-increased over the life-span of sham-operated mice. In MCAO-subjected mice, different trajectories of ipsilateral hippocampal volume change were observed dependent on whether the hippocampus contained direct infarction, with a decrease in directly infarcted tissue and an increase in non-infarcted tissue. To further investigate these volume changes, neuronal and glial cell densities were assessed in histological brain sections from the subset of MCAO mice lacking hippocampal infarction. Our findings demonstrate previously uncharacterized changes in hippocampal volume and potentially brain parenchymal cell density up to 48-weeks in both sham- and MCAO-operated mice.

Study protocol for a phase II randomised, double-blind, placebo-controlled trial of perampanel as an antiepileptogenic treatment following acute stroke.

INTRODUCTION: Stroke is a common cause of epilepsy that may be mediated via glutamate dysregulation. There is currently no evidence to support the use of antiseizure medications as primary prevention against poststroke epilepsy. Perampanel has a unique antiglutamatergic mechanism of action and may have antiepileptogenic properties. This study aims to evaluate the efficacy and safety of perampanel as an antiepileptogenic treatment in patients at high risk of poststroke epilepsy. METHODS AND ANALYSIS: Up to 328 patients with cortical ischaemic stroke or lobar haemorrhage will be enrolled, and receive their first treatment within 7 days of stroke onset. Patients will be randomised (1:1) to receive perampanel (titrated to 6 mg daily over 4 weeks) or matching placebo, stratified by stroke subtype (ischaemic or haemorrhagic). Treatment will be continued for 12 weeks after titration. 7T MRI will be performed at baseline for quantification of cerebral glutamate by magnetic resonance spectroscopy and glutamate chemical exchange saturation transfer imaging. Blood will be collected for measurement of plasma glutamate levels. Participants will be followed up for 52 weeks after randomisation.The primary study outcome will be the proportion of participants in each group free of late (more than 7 days after stroke onset) poststroke seizures by the end of the 12-month study period, analysed by Fisher's exact test. Secondary outcomes will include time to first seizure, time to treatment withdrawal and 3-month modified Rankin Scale score. Quality of life, cognitive function, mood and adverse events will be assessed by standardised questionnaires. Exploratory outcomes will include correlation between cerebral and plasma glutamate concentration and stroke and seizure outcomes. ETHICS AND DISSEMINATION: This study was approved by the Alfred Health Human Research Ethics Committee (HREC No 44366, Reference 287/18). TRIAL REGISTRATION NUMBER: ACTRN12618001984280; Pre-results.

Diffusion Imaging Reveals Sex Differences in the White Matter Following Sports-Related Concussion.

Sports-related concussion (SRC) is a serious health concern. However, the temporal profile of neuropathophysiological changes after SRC and how these relate to biological sex are still poorly understood. This preliminary study investigated whether diffusion-weighted magnetic resonance imaging (dMRI) was sensitive to neuropathophysiological changes following SRC; whether these changes were sex-specific; and whether they persisted beyond the resolution of self-reported symptoms. Recently concussed athletes (n = 14), and age- and education-matched nonconcussed control athletes (n = 16), underwent MRI 24-48-h postinjury and again at 2-week postinjury (i.e., when cleared to return-to-play). Male athletes reported more symptoms and greater symptom severity compared with females. dMRI revealed white matter differences between athletes with SRC and their nonconcussed counterparts at 48-h postinjury. These differences were still present at 2-week postinjury, despite SRC athletes being cleared to return to play and may indicate increased cerebral vulnerability beyond the resolution of subjective symptoms. Furthermore, we identified sex-specific differences, with male SRC athletes having significantly greater white matter disruption compared with female SRC athletes. These results have important implications for the management of concussion, including guiding return-to-play decisions, and further improve our understanding regarding the role of sex in SRC outcomes.

QSMART: Quantitative susceptibility mapping artifact reduction technique.

PURPOSE: Quantitative susceptibility mapping (QSM) is a novel MR technique that allows mapping of tissue susceptibility values from MR phase images. QSM is an ill-conditioned inverse problem, and although several methods have been proposed in the field, in the presence of a wide range of susceptibility sources, streaking artifacts appear around high susceptibility regions and contaminate the whole QSM map. QSMART is a post-processing pipeline that uses two-stage parallel inversion to reduce the streaking artifacts and remove banding artifact at the cortical surface and around the vasculature. METHOD: Tissue and vein susceptibility values were separately estimated by generating a mask of vasculature driven from the magnitude data using a Frangi filter. Spatially dependent filtering was used for the background field removal step and the two susceptibility estimates were combined in the final QSM map. QSMART was compared to RESHARP/iLSQR and V-SHARP/iLSQR inversion in a numerical phantom, 7T in vivo single and multiple-orientation scans, 9.4T ex vivo mouse data, and 4.7T in vivo rat brain with induced focal ischemia. RESULTS: Spatially dependent filtering showed better suppression of phase artifacts near cortex compared to RESHARP and V-SHARP, while preserving voxels located within regions of interest without brain edge erosion. QSMART showed successful reduction of streaking artifacts as well as improved contrast between different brain tissues compared to the QSM maps obtained by RESHARP/iLSQR and V-SHARP/iLSQR. CONCLUSION: QSMART can reduce QSM artifacts to enable more robust estimation of susceptibility values in vivo and ex vivo.

White matter changes following experimental pediatric traumatic brain injury: an advanced diffusion-weighted imaging investigation.

Pediatric traumatic brain injury (pTBI) is a major community health concern. Due to ongoing maturation, injury to the brain at a young age can have devastating consequences in later life. However, how pTBI affects brain development, including white matter maturation, is still poorly understood. Here, we used advanced diffusion weighted imaging (DWI) to assess chronic white matter changes after experimental pTBI. Mice at post-natal day 21 sustained a TBI using the controlled cortical impact model and magnetic resonance imaging (MRI) was performed at 6 months post-injury using a 4.7 T Bruker scanner. Four diffusion shells with 81 directions and b-values of 1000, 3000, 5000, and 7000s/mm2 were acquired and analyzed using MRtrix3 software. Advanced DWI metrics, including fiber density, fiber cross-section and a combined fiber density and cross-section measure, were investigated together with three track-weighted images (TWI): the average pathlength map, mean curvature and the track density image. These advanced metrics were compared to traditional diffusion tensor imaging (DTI) metrics which indicated that TBI injured mice had reduced fractional anisotropy and increased radial diffusivity in the white matter when compared to age-matched sham controls. Consistent with previous findings, fiber density and TWI metrics appeared to be more sensitive to white matter changes than DTI metrics, revealing widespread reductions in fiber density and TWI metrics in pTBI mice compared to sham controls. These results provide additional support for the use of advanced DWI metrics in assessing white matter degeneration following injury and highlight the chronic outcomes that can follow pTBI.