Hippocampal interneuronal dysfunction and hyperexcitability in a porcine model of concussion.

Cognitive impairment is a common symptom following mild traumatic brain injury (mTBI or concussion) and can persist for years in some individuals. Hippocampal slice preparations following closed-head, rotational acceleration injury in swine have previously demonstrated reduced axonal function and hippocampal circuitry disruption. However, electrophysiological changes in hippocampal neurons and their subtypes in a large animal mTBI model have not been examined. Using in vivo electrophysiology techniques, we examined laminar oscillatory field potentials and single unit activity in the hippocampal network 7 days post-injury in anesthetized minipigs. Concussion altered the electrophysiological properties of pyramidal cells and interneurons differently in area CA1. While the firing rate, spike width and amplitude of CA1 interneurons were significantly decreased post-mTBI, these parameters were unchanged in CA1 pyramidal neurons. In addition, CA1 pyramidal neurons in TBI animals were less entrained to hippocampal gamma (40-80 Hz) oscillations. Stimulation of the Schaffer collaterals also revealed hyperexcitability across the CA1 lamina post-mTBI. Computational simulations suggest that reported changes in interneuronal physiology may be due to alterations in voltage-gated sodium channels. These data demonstrate that a single concussion can lead to significant neuronal and circuit level changes in the hippocampus, which may contribute to cognitive dysfunction following mTBI.

Early posttraumatic brain injury tranexamic acid prevents blood-brain barrier hyperpermeability and improves surrogates of neuroclinical recovery.

BACKGROUND: Tranexamic acid (TXA) given early, but not late, after traumatic brain injury (TBI) appears to improve survival. This may be partly related to TXA-driven profibrinolysis and increased leukocyte (LEU)-mediated inflammation when administered late post-injury. We hypothesized that early TXA (1 hour post-TBI), blunts penumbral, blood-brain barrier (BBB) leukocyte-endothelial cell (LEU-EC) interactions and microvascular permeability, in vivo when compared with late administration (24 hours post-TBI). METHODS: CD1 male mice (n = 35) were randomized to severe TBI (injury by controlled cortical impact; injury: velocity, 6 m/s; depth, 1 mm; diameter, 3 mm) or sham craniotomy followed by intravenous saline (placebo) at 1 hour, or TXA (30 mg/kg) at 1 hour or 24 hours. At 48 hours, in vivo pial intravital microscopy visualized live penumbral LEU-EC interactions and BBB microvascular fluorescent albumin leakage. Neuroclinical recovery was assessed by the Garcia Neurological Test (motor, sensory, reflex, and balance assessments) and body weight loss recovery at 1 and 2 days after injury. Analysis of variance with Bonferroni correction assessed intergroup differences ( p < 0.05). RESULTS: One-hour, but not 24-hour, TXA improved Garcia Neurological Test performance on day 1 post-TBI compared with placebo. Both 1 hour and 24 hours TXA similarly improved day 1 weight loss recovery, but only 1 hour TXA significantly improved weight loss recovery on day 2 compared with placebo ( p = 0.04). No intergroup differences were found in LEU rolling or adhesion between injured animal groups. Compared with untreated injured animals, only TXA at 1 hour reduced BBB permeability. CONCLUSION: Only early post-TBI TXA consistently improves murine neurological recovery. Tranexamic acid preserves BBB integrity but only when administered early. This effect appears independent of LEU-EC interactions and demonstrates a time-sensitive effect that supports only early TXA administration.

Alzheimer's Disease-Related Dementias Summit 2022: National Research Priorities for the Investigation of Post-Traumatic Brain Injury Alzheimer's Disease and Related Dementias.

Traumatic Brain Injury (TBI) is a risk factor for Alzheimer's disease and Alzheimer's disease related dementias (AD/ADRD) and otherwise classified post-traumatic neurodegeneration (PTND). Targeted research is needed to elucidate the circumstances and mechanisms through which TBI contributes to the initiation, development, and progression of AD/ADRD pathologies including multiple etiology dementia (MED). The National Institutes of Health hosts triennial ADRD summits to inform a national research agenda, and TBI was included for a second time in 2022. A multidisciplinary expert panel of TBI and dementia researchers was convened to re-evaluate the 2019 research recommendations for understanding TBI as an AD/ADRD risk factor and to assess current progress and research gaps in understanding post-TBI AD/ADRD. Refined and new recommendations were presented during the MED special topic session at the virtual ADRD Summit in March 2022. Final research recommendations incorporating broad stakeholder input are organized into four priority areas as follows: (1) Promote interdisciplinary collaboration and data harmonization to accelerate progress of rigorous, clinically meaningful research; (2) Characterize clinical and biological phenotypes of PTND associated with varied lifetime TBI histories in diverse populations to validate multimodal biomarkers; (3) Establish and enrich infrastructure to support multimodal longitudinal studies of individuals with varied TBI exposure histories and standardized methods including common data elements (CDEs) for ante-mortem and post-mortem clinical and neuropathological characterization; and (4) Support basic and translational research to elucidate mechanistic pathways, development, progression, and clinical manifestations of post-TBI AD/ADRDs. Recommendations conceptualize TBI as a contributor to MED and emphasize the unique opportunity to study AD/ADRD following known exposure, to inform disease mechanisms and treatment targets for shared common AD/ADRD pathways.

Concussion leads to widespread axonal sodium channel loss and disruption of the node of Ranvier.

Despite being a major health concern, little is known about the pathophysiological changes that underly concussion. Nonetheless, emerging evidence suggests that selective damage to white matter axons, or diffuse axonal injury (DAI), disrupts brain network connectivity and function. While voltage-gated sodium channels (NaChs) and their anchoring proteins at the nodes of Ranvier (NOR) on axons are key elements of the brain's network signaling machinery, changes in their integrity have not been studied in context with DAI. Here, we utilized a clinically relevant swine model of concussion that induces evolving axonal pathology, demonstrated by accumulation of amyloid precursor protein (APP) across the white matter. Over a two-week follow-up post-concussion with this model, we found widespread loss of NaCh isoform 1.6 (Nav1.6), progressive increases in NOR length, the appearance of void and heminodes and loss of ßIV-spectrin, ankyrin G, and neurofascin 186 or their collective diffusion into the paranode. Notably, these changes were in close proximity, yet distinct from APP-immunoreactive swollen axonal profiles, potentially representing a unique, newfound phenotype of axonal pathology in DAI. Since concussion in humans is non-fatal, the clinical relevance of these findings was determined through examination of post-mortem brain tissue from humans with higher levels of acute traumatic brain injury. Here, a similar loss of Nav1.6 and changes in NOR structures in brain white matter were observed as found in the swine model of concussion. Collectively, this widespread and progressive disruption of NaChs and NOR appears to be a form of sodium channelopathy, which may represent an important substrate underlying brain network dysfunction after concussion.

Non-Linear Device Head Coupling and Temporal Delays in Large Animal Acceleration Models of Traumatic Brain Injury.

Accurate characterization of head kinematics following an external blow represents a fundamental aspect of traumatic brain injury (TBI) research. The majority of previous large animal studies have assumed an equivalent relationship between the device delivering the impulsive load and subsequent head kinematics rather than performing direct measurement (sensors or videography). The current study therefore examined factors affecting device/head coupling kinematics in an acceleration TBI model. Experiment 1 indicated ~ 50% reduction in peak angular velocity for swine head relative to the device, with an approximate doubling in temporal duration. The peak angular velocity for the head was not significantly altered by variations in restraint device (straps vs. cables), animal positioning or body mass. In Experiment 2, reducing the impulsive load by 32% resulted in only a 14% reduction in angular velocity of the head (approximately 69% head/device coupling ratio), with more pronounced differences qualitatively observed for angular momentum. A temporal delay was identified in initial device/head coupling, potentially a result of soft tissue deformation. Finally, similar head kinematics were obtained regardless of mounting the sensor directly to the skull or through the scalp (Experiment 3). Current findings highlight the importance of direct measurement of head kinematics for future studies.

Modeling links softening of myelin and spectrin scaffolds of axons after a concussion to increased vulnerability to repeated injuries.

Damage to the microtubule lattice, which serves as a rigid cytoskeletal backbone for the axon, is a hallmark mechanical initiator of pathophysiology after concussion. Understanding the mechanical stress transfer from the brain tissue to the axonal cytoskeleton is essential to determine the microtubule lattice's vulnerability to mechanical injury. Here, we develop an ultrastructural model of the axon's cytoskeletal architecture to identify the components involved in the dynamic load transfer during injury. Corroborative in vivo studies were performed using a gyrencephalic swine model of concussion via single and repetitive head rotational acceleration. Computational analysis of the load transfer mechanism demonstrates that the myelin sheath and the actin/spectrin cortex play a significant role in effectively shielding the microtubules from tissue stress. We derive failure maps in the space spanned by tissue stress and stress rate to identify physiological conditions in which the microtubule lattice can rupture. We establish that a softer axonal cortex leads to a higher susceptibility of the microtubules to failure. Immunohistochemical examination of tissue from the swine model of single and repetitive concussion confirms the presence of postinjury spectrin degradation, with more extensive pathology observed following repetitive injury. Because the degradation of myelin and spectrin occurs over weeks following the first injury, we show that softening of the myelin layer and axonal cortex exposes the microtubules to higher stress during repeated incidences of traumatic brain injuries. Our predictions explain how mechanical injury predisposes axons to exacerbated responses to repeated injuries, as observed in vitro and in vivo.

Reproducibility and Characterization of Head Kinematics During a Large Animal Acceleration Model of Traumatic Brain Injury.

Acceleration parameters have been utilized for the last six decades to investigate pathology in both human and animal models of traumatic brain injury (TBI), design safety equipment, and develop injury thresholds. Previous large animal models have quantified acceleration from impulsive loading forces (i.e., machine/object kinematics) rather than directly measuring head kinematics. No study has evaluated the reproducibility of head kinematics in large animal models. Nine (five males) sexually mature Yucatan swine were exposed to head rotation at a targeted peak angular velocity of 250 rad/s in the coronal plane. The results indicated that the measured peak angular velocity of the skull was 51% of the impulsive load, was experienced over 91% longer duration, and was multi- rather than uni-planar. These findings were replicated in a second experiment with a smaller cohort (N = 4). The reproducibility of skull kinematics data was mostly within acceptable ranges based on published industry standards, although the coefficients of variation (8.9% for peak angular velocity or 12.3% for duration) were higher than the impulsive loading parameters produced by the machine (1.1 vs. 2.5%, respectively). Immunohistochemical markers of diffuse axonal injury and blood-brain barrier breach were not associated with variation in either skull or machine kinematics, suggesting that the observed levels of variance in skull kinematics may not be biologically meaningful with the current sample sizes. The findings highlight the reproducibility of a large animal acceleration model of TBI and the importance of direct measurements of skull kinematics to determine the magnitude of angular velocity, refine injury criteria, and determine critical thresholds.

COllaborative Neuropathology NEtwork Characterizing ouTcomes of TBI (CONNECT-TBI).

Efforts to characterize the late effects of traumatic brain injury (TBI) have been in progress for some time. In recent years much of this activity has been directed towards reporting of chronic traumatic encephalopathy (CTE) in former contact sports athletes and others exposed to repetitive head impacts. However, the association between TBI and dementia risk has long been acknowledged outside of contact sports. Further, growing experience suggests a complex of neurodegenerative pathologies in those surviving TBI, which extends beyond CTE. Nevertheless, despite extensive research, we have scant knowledge of the mechanisms underlying TBI-related neurodegeneration (TReND) and its link to dementia. In part, this is due to the limited number of human brain samples linked to robust demographic and clinical information available for research. Here we detail a National Institutes for Neurological Disease and Stroke Center Without Walls project, the COllaborative Neuropathology NEtwork Characterizing ouTcomes of TBI (CONNECT-TBI), designed to address current limitations in tissue and research access and to advance understanding of the neuropathologies of TReND. As an international, multidisciplinary collaboration CONNECT-TBI brings together multiple experts across 13 institutions. In so doing, CONNECT-TBI unites the existing, comprehensive clinical and neuropathological datasets of multiple established research brain archives in TBI, with survivals ranging minutes to many decades and spanning diverse injury exposures. These existing tissue specimens will be supplemented by prospective brain banking and contribute to a centralized route of access to human tissue for research for investigators. Importantly, each new case will be subject to consensus neuropathology review by the CONNECT-TBI Expert Pathology Group. Herein we set out the CONNECT-TBI program structure and aims and, by way of an illustrative case, the approach to consensus evaluation of new case donations.

Post-traumatic brain injury antithrombin III recovers Morris water maze cognitive performance, improving cued and spatial learning.

BACKGROUND: Neuroinflammation and cerebral edema development following severe traumatic brain injury (TBI) affect subsequent cognitive recovery. Independent of its anticoagulant effects, antithrombin III (AT-III) has been shown to block neurovascular inflammation after severe TBI, reduce cerebral endothelial-leukocyte interactions, and decrease blood-brain barrier permeability. We hypothesized that AT-III administration after TBI would improve post-TBI cognitive recovery, specifically enhancing learning, and memory. METHODS: Fifteen CD1 male mice were randomized to undergo severe TBI (controlled cortical impact [CCI]: velocity, 6 m/s; depth, 1 mm; diameter, 3 mm) or sham craniotomy and received either intravenous AT-III (250 IU/kg) or vehicle (VEH/saline) 15 minutes and 24 hours post-TBI. Animals underwent Morris water maze testing from 6 to 14 days postinjury consisting of cued learning trials (platform visible), spatial learning trials (platform invisible, spatial cues present), and probe (memory) trials (platform removed, spatial cues present). Intergroup differences were assessed by the Kruskal-Wallis test (p < 0.05). RESULTS: Morris water maze testing demonstrated that cumulative cued learning (overall mean time in seconds to reach the platform on days 6-8) was worst in CCI-VEH animals (26.1 ± 2.4 seconds) compared with CCI-AT-III counterparts (20.3 ± 2.1 seconds, p < 0.01). Cumulative noncued spatial learning was also worst in the CCI-VEH group (23.4 ± 1.8 seconds) but improved with AT-III (17.6 ± 1.5 seconds, p < 0.01). In probe trials, AT-III failed to significantly improve memory ability. Animals that underwent sham craniotomy demonstrated preserved learning and memory compared with all CCI counterparts (p < 0.05). CONCLUSION: Antithrombin III improves neurocognitive recovery weeks after TBI. This improvement is particularly related to improvement in learning but not memory function. Pharmacologic support of enhanced learning may support new skill acquisition or relearning to improve outcomes after TBI. LEVEL OF EVIDENCE: Therapeutic/care management, level II.

Antithrombin III ameliorates post-traumatic brain injury cerebral leukocyte mobilization enhancing recovery of blood brain barrier integrity.

BACKGROUND: Acute traumatic coagulopathy often accompanies traumatic brain injury (TBI) and may impair cognitive recovery. Antithrombin III (AT-III) reduces the hypercoagulability of TBI. Antithrombin III and heparinoids such as enoxaparin (ENX) demonstrate potent anti-inflammatory activity, reducing organ injury and modulating leukocyte (LEU) activation, independent of their anticoagulant effect. It is unknown what impact AT-III exerts on cerebral LEU activation and blood-brain barrier (BBB) permeability after TBI. We hypothesized that AT-III reduces live microcirculatory LEU-endothelial cell (EC) interactions and leakage at the BBB following TBI. METHODS: CD1 mice (n = 71) underwent either severe TBI (controlled cortical impact (CCI), 6-m/s velocity, 1-mm depth, and 4-mm diameter) or sham craniotomy and then received either AT-III (250 IU/kg), ENX (1.5 mg/kg), or vehicle (saline) every 24 hours. Forty-eight hours post-TBI, cerebral intravital microscopy visualized in vivo penumbral microvascular LEU-EC interactions and microvascular leakage to assess BBB inflammation/permeability. Body weight loss and the Garcia neurological test (motor, sensory, reflex, balance) served as surrogates of clinical recovery. RESULTS: Both AT-III and ENX similarly reduced in vivo penumbral LEU rolling and adhesion (p < 0.05). Antithrombin III also reduced live BBB leakage (p < 0.05). Antithrombin III animals demonstrated the least 48-hour body weight loss (8.4 ± 1%) versus controlled cortical impact and vehicle (11.4 ± 0.5%, p < 0.01). Garcia neurological test scores were similar among groups. CONCLUSION: Antithrombin III reduces post-TBI penumbral LEU-EC interactions in the BBB leading to reduced neuromicrovascular permeability. Antithrombin III further reduced body weight loss compared with no therapy. Further study is needed to determine if these AT-III effects on neuroinflammation affect longer-term neurocognitive recovery after TBI.

Survival Rates and Biomarkers in a Large Animal Model of Traumatic Brain Injury Combined With Two Different Levels of Blood Loss.

INTRODUCTION: The pathology resulting from concurrent traumatic brain injury (TBI) and hemorrhagic shock (HS; TBI+HS) are leading causes of mortality and morbidity worldwide following trauma. However, the majority of large animal models of TBI+HS have utilized focal/contusional injuries rather than incorporating the types of brain trauma (closed-head injury caused by dynamic acceleration) that typify human injury. OBJECTIVE: To examine survival rates and effects on biomarkers from rotational TBI with two levels of HS. METHODS: Twenty-two sexually mature Yucatan swine (30.39 ±â€Š2.25 kg; 11 females) therefore underwent either Sham trauma procedures (n = 6) or a dynamic acceleration TBI combined with either 55% (n = 8) or 40% (n = 8) blood loss in this serial study. RESULTS: Survival rates were significantly higher for the TBI+40% (87.5%) relative to TBI+55% (12.5%) cohort, with the majority of TBI+55% animals expiring within 2 h post-trauma from apnea. Blood-based neural biomarkers and immunohistochemistry indicated evidence of diffuse axonal injury (increased NFL/Aß42), blood-brain barrier breach (increased immunoglobulin G) and inflammation (increased glial fibrillary acidic protein/ionized calcium-binding adaptor molecule 1) in the injured cohorts relative to Shams. Invasive hemodynamic measurements indicated increased shock index and decreased pulse pressure in both injury cohorts, with evidence of partial recovery for invasive hemodynamic measurements in the TBI+40% cohort. Similarly, although both injury groups demonstrated ionic and blood gas abnormalities immediately postinjury, metabolic acidosis continued to increase in the TBI+55% group ∼85 min postinjury. Somewhat surprisingly, both neural and physiological biomarkers showed significant changes within the Sham cohort across the multi-hour experimental procedure, most likely associated with prolonged anesthesia. CONCLUSION: Current results suggest the TBI+55% model may be more appropriate for severe trauma requiring immediate medical attention/standard fluid resuscitation protocols whereas the TBI+40% model may be useful for studies of prolonged field care.

Pre-Clinical Common Data Elements for Traumatic Brain Injury Research: Progress and Use Cases.

Traumatic brain injury (TBI) is an extremely complex condition due to heterogeneity in injury mechanism, underlying conditions, and secondary injury. Pre-clinical and clinical researchers face challenges with reproducibility that negatively impact translation and therapeutic development for improved TBI patient outcomes. To address this challenge, TBI Pre-clinical Working Groups expanded upon previous efforts and developed common data elements (CDEs) to describe the most frequently used experimental parameters. The working groups created 913 CDEs to describe study metadata, animal characteristics, animal history, injury models, and behavioral tests. Use cases applied a set of commonly used CDEs to address and evaluate the degree of missing data resulting from combining legacy data from different laboratories for two different outcome measures (Morris water maze [MWM]; RotorRod/Rotarod). Data were cleaned and harmonized to Form Structures containing the relevant CDEs and subjected to missing value analysis. For the MWM dataset (358 animals from five studies, 44 CDEs), 50% of the CDEs contained at least one missing value, while for the Rotarod dataset (97 animals from three studies, 48 CDEs), over 60% of CDEs contained at least one missing value. Overall, 35% of values were missing across the MWM dataset, and 33% of values were missing for the Rotarod dataset, demonstrating both the feasibility and the challenge of combining legacy datasets using CDEs. The CDEs and the associated forms created here are available to the broader pre-clinical research community to promote consistent and comprehensive data acquisition, as well as to facilitate data sharing and formation of data repositories. In addition to addressing the challenge of standardization in TBI pre-clinical studies, this effort is intended to bring attention to the discrepancies in assessment and outcome metrics among pre-clinical laboratories and ultimately accelerate translation to clinical research.

Mechanisms of Local Stress Amplification in Axons near the Gray-White Matter Interface.

Diffuse axonal injury is a primary neuropathological feature of concussion and is thought to greatly contribute to the classical symptoms of decreased processing speed and memory dysfunction. Although previous studies have investigated the injury biomechanics at the micro- and mesoscale of concussion, few have addressed the multiscale transmission of mechanical loading at thresholds that can induce diffuse axonal injury. Because it has been recognized that axonal pathology is commonly found at anatomic interfaces across all severities of traumatic brain injury, we combined computational, analytical, and experimental approaches to investigate the potential mechanical vulnerability of axons that span the gray-white tissue interface. Our computational models predict that material heterogeneities at the gray-white interface lead to a highly nonuniform distribution of stress in axons, which was most amplified in axonal regions near the interface. This mechanism was confirmed using an analytical model of an individual fiber in a strained bimaterial interface. Comparisons of these collective data with histopathological evaluation of a swine model of concussion demonstrated a notably similar pattern of axonal damage adjacent to the gray-white interface. The results suggest that the tissue property mismatch at the gray-white matter interface places axons crossing this region at greater risk of mechanical damage during brain tissue deformation from traumatic brain injury.

Traumatic Brain Injury Preserves Firing Rates But Disrupts Laminar Oscillatory Coupling and Neuronal Entrainment in Hippocampal CA1.

While hippocampal-dependent learning and memory are particularly vulnerable to traumatic brain injury (TBI), the functional status of individual hippocampal neurons and their interactions with oscillations are unknown following injury. Using the most common rodent TBI model and laminar recordings in CA1, we found a significant reduction in oscillatory input into the radiatum layer of CA1 after TBI. Surprisingly, CA1 neurons maintained normal firing rates despite attenuated input, but did not maintain appropriate synchronization with this oscillatory input or with local high-frequency oscillations. Normal synchronization between these coordinating oscillations was also impaired. Simultaneous recordings of medial septal neurons known to participate in theta oscillations revealed increased GABAergic/glutamatergic firing rates postinjury under anesthesia, potentially because of a loss of modulating feedback from the hippocampus. These results suggest that TBI leads to a profound disruption of connectivity and oscillatory interactions, potentially disrupting the timing of CA1 neuronal ensembles that underlie aspects of learning and memory.

Tau immunophenotypes in chronic traumatic encephalopathy recapitulate those of ageing and Alzheimer's disease.

Traumatic brain injury (TBI) is a risk factor for neurodegenerative disease, including chronic traumatic encephalopathy (CTE). Preliminary consensus criteria define the pathognomonic lesion of CTE as patchy tau pathology within neurons and astrocytes at the depths of cortical sulci. However, the specific tau isoform composition and post-translational modifications in CTE remain largely unexplored. Using immunohistochemistry, we performed tau phenotyping of CTE neuropathologies and compared this to a range of tau pathologies, including Alzheimer's disease, primary age-related tauopathy, ageing-related tau astrogliopathy and multiple subtypes of frontotemporal lobar degeneration with tau inclusions. Cases satisfying preliminary consensus diagnostic criteria for CTE neuropathological change (CTE-NC) were identified (athletes, n = 10; long-term survivors of moderate or severe TBI, n = 4) from the Glasgow TBI Archive and Penn Neurodegenerative Disease Brain Bank. In addition, material from a range of autopsy-proven ageing-associated and primary tauopathies in which there was no known history of exposure to TBI was selected as non-injured controls (n = 32). Each case was then stained with a panel of tau antibodies specific for phospho-epitopes (PHF1, CP13, AT100, pS262), microtubule-binding repeat domains (3R, 4R), truncation (Tau-C3) or conformation (GT-7, GT-38) and the extent and distribution of staining assessed. Cell types were confirmed with double immunofluorescent labelling. Results demonstrate that astroglial tau pathology in CTE is composed of 4R-immunoreactive thorn-shaped astrocytes, echoing the morphology and immunophenotype of astrocytes encountered in ageing-related tau astrogliopathy. In contrast, neurofibrillary tangles of CTE contain both 3R and 4R tau, with post-translational modifications and conformations consistent with Alzheimer's disease and primary age-related tauopathy. Our observations establish that the astroglial and neurofibrillary tau pathologies of CTE are phenotypically distinct from each other and recapitulate the tau immunophenotypes encountered in ageing and Alzheimer's disease. As such, the immunohistochemical distinction of CTE neuropathology from other mixed 3R/4R tauopathies of Alzheimer's disease and ageing may rest solely on the pattern and distribution of pathology.

Modeling traumatic brain injury with human brain organoids.

Traumatic brain injury (TBI) remains a prominent public health concern despite several decades of attempts to develop therapies for the associated neurological and cognitive deficits. Effective models of this condition are imperative for better defining its pathophysiology and testing therapeutics. Human brain organoids are stem cell-derived neural tissues that recapitulate many of the steps of normal neurodevelopment, resulting in the reproduction of a substantial degree of brain architecture. Organoids are highly relevant to clinical conditions because of their human nature and three-dimensional tissue structure, yet they are easier to manipulate and interrogate experimentally than animals. Thus, they have the potential to serve as a novel platform for studying TBI. In this article, we discuss available in vitro models of TBI, active areas of inquiry on brain organoids, and how these two concepts could be merged.

Astroglial tau pathology alone preferentially concentrates at sulcal depths in chronic traumatic encephalopathy neuropathologic change.

Current diagnostic criteria for the neuropathological evaluation of the traumatic brain injury-associated neurodegeneration, chronic traumatic encephalopathy, define the pathognomonic lesion as hyperphosphorylated tau-immunoreactive neuronal and astroglial profiles in a patchy cortical distribution, clustered around small vessels and showing preferential localization to the depths of sulci. However, despite adoption into diagnostic criteria, there has been no formal assessment of the cortical distribution of the specific cellular components defining chronic traumatic encephalopathy neuropathologic change. To address this, we performed comprehensive mapping of hyperphosphorylated tau-immunoreactive neurofibrillary tangles and thorn-shaped astrocytes contributing to chronic traumatic encephalopathy neuropathologic change. From the Glasgow Traumatic Brain Injury Archive and the University of Pennsylvania Center for Neurodegenerative Disease Research Brain Bank, material was selected from patients with known chronic traumatic encephalopathy neuropathologic change, either following exposure to repetitive mild (athletes n = 17; non-athletes n = 1) or to single moderate or severe traumatic brain injury (n = 4), together with material from patients with previously confirmed Alzheimer's disease neuropathologic changes (n = 6) and no known exposure to traumatic brain injury. Representative sections were stained for hyperphosphorylated or Alzheimer's disease conformation-selective tau, after which stereotypical neurofibrillary tangles and thorn-shaped astrocytes were identified and mapped. Thorn-shaped astrocytes in chronic traumatic encephalopathy neuropathologic change were preferentially distributed towards sulcal depths [sulcal depth to gyral crest ratio of thorn-shaped astrocytes 12.84 ± 15.47 (mean ± standard deviation)], with this pathology more evident in material from patients with a history of survival from non-sport injury than those exposed to sport-associated traumatic brain injury (P = 0.009). In contrast, neurofibrillary tangles in chronic traumatic encephalopathy neuropathologic change showed a more uniform distribution across the cortex in sections stained for either hyperphosphorylated (sulcal depth to gyral crest ratio of neurofibrillary tangles 1.40 ± 0.74) or Alzheimer's disease conformation tau (sulcal depth to gyral crest ratio 1.64 ± 1.05), which was comparable to that seen in material from patients with known Alzheimer's disease neuropathologic changes (P = 0.82 and P = 0.91, respectively). Our data demonstrate that in chronic traumatic encephalopathy neuropathologic change the astroglial component alone shows preferential distribution to the depths of cortical sulci. In contrast, the neuronal pathology of chronic traumatic encephalopathy neuropathologic change is distributed more uniformly from gyral crest to sulcal depth and echoes that of Alzheimer's disease. These observations provide new insight into the neuropathological features of chronic traumatic encephalopathy that distinguish it from other tau pathologies and suggest that current diagnostic criteria should perhaps be reviewed and refined.

Chronic traumatic encephalopathy is a common co-morbidity, but less frequent primary dementia in former soccer and rugby players.

Chronic traumatic encephalopathy (CTE) is reported at high prevalence in selected autopsy case series of former contact sports athletes. Nevertheless, the contribution of CTE pathology to clinical presentation and its interaction with co-morbid neurodegenerative pathologies remain unclear. To address these issues, we performed comprehensive neuropathology assessments on the brains of former athletes with dementia and considered these findings together with detailed clinical histories to derive an integrated clinicopathological diagnosis for each case. Consecutive, autopsy-acquired brains from former soccer and rugby players with dementia were assessed for neurodegenerative pathologies using established and preliminary consensus protocols. Thereafter, next of kin interviews were conducted to obtain detailed accounts of the patient's clinical presentation and course of disease to inform a final, integrated clinicopathological diagnosis. Neuropathologic change consistent with CTE (CTE-NC) was confirmed in five of seven former soccer and three of four former rugby players' brains, invariably in combination with mixed, often multiple neurodegenerative pathologies. However, in just three cases was the integrated dementia diagnosis consistent with CTE, the remainder having alternate diagnoses, with the most frequent integrated diagnosis Alzheimer's disease (AD) (four cases; one as mixed AD and vascular dementia). This consecutive autopsy series identifies neuropathologic change consistent with preliminary diagnostic criteria for CTE (CTE-NC) in a high proportion of former soccer and rugby players dying with dementia. However, in the majority, CTE-NC appears as a co-morbidity rather than the primary, dementia causing pathology. As such, we suggest that while CTE-NC might be common in former athletes with dementia, in many cases its clinical significance remains uncertain.

Multichannel Silicon Probes for Awake Hippocampal Recordings in Large Animals.

Decoding laminar information across deep brain structures and cortical regions is necessary in order to understand the neuronal ensembles that represent cognition and memory. Large animal models are essential for translational research due to their gyrencephalic neuroanatomy and significant white matter composition. A lack of long-length probes with appropriate stiffness allowing penetration to deeper structures with minimal damage to the neural interface is one of the major technical limitations to applying the approaches currently utilized in lower order animals to large animals. We therefore tested the performance of multichannel silicon probes of various solutions and designs that were developed specifically for large animal electrophysiology. Neurophysiological signals from dorsal hippocampus were recorded in chronically implanted awake behaving Yucatan pigs. Single units and local field potentials were analyzed to evaluate performance of given silicon probes over time. EDGE-style probes had the highest yields during intra-hippocampal recordings in pigs, making them the most suitable for chronic implantations and awake behavioral experimentation. In addition, the cross-sectional area of silicon probes was found to be a crucial determinant of silicon probe performance over time, potentially due to reduction of damage to the neural interface. Novel 64-channel EDGE-style probes tested acutely produced an optimal single unit separation and a denser sampling of the laminar structure, identifying these research silicon probes as potential candidates for chronic implantations. This study provides an analysis of multichannel silicon probes designed for large animal electrophysiology of deep laminar brain structures, and suggests that current designs are reaching the physical thresholds necessary for long-term (∼1 month) recordings with single-unit resolution.