A Traumatic Brain Injury Prescreening Tool for Intimate Partner Violence Patients Using Initial Clinical Reports and Machine Learning.

Research studies have presented an unappreciated relationship between intimate partner violence (IPV) survivors and symptoms of traumatic brain injuries (TBI). Within these IPV survivors, resulting TBIs are not always identified during emergency room visits. This demonstrates a need for a prescreening tool that identifies IPV survivors who should receive TBI screening. We present a model that measures similarities to clinical reports for confirmed TBI cases to identify whether a patient should be screened for TBI. This is done through an ensemble of three supervised learning classifiers which work in two distinct feature spaces. Individual classifiers are trained on clinical reports and then used to create an ensemble that needs only one positive label to indicate a patient should be screened for TBI.

Repeat subconcussion in the adult rat gives rise to behavioral deficits similar to a single concussion but different depending upon sex.

Although concussions are a popular focus of neurotrauma research, subconcussions occur with higher frequency but are less well-studied. A subconcussion is an impact to the head that does not result in immediately diagnosable concussion but can result in later neurological consequences. Repeat subconcussions can produce behavioral impairments and neuropathology that is similar to or worse than those seen following a single concussion. The current study modified a previously established closed head injury model of concussion to create a subconcussion model and examines sex differences in behavioral responses to repeated subconcussion in the adult rat. Rats received a single concussion, single or repeat subconcussions, or no impact and behavior was monitored from 2 h through 31 days post-injury. A single concussion or repeat subconcussion resulted in deficits in locomotion, righting reflexes, and recognition memory. The degree of deficit induced by repeat subconcussions were either similar (righting reflexes) or greater/more persistent (locomotor deficits and recognition memory) than that of a concussion. Single subconcussion resulted in acute deficits that were mild and limited to righting reflexes and locomotion. Sex differences were observed in responses to repeat subconcussion: females showed greater deficits in righting reflexes, locomotion, and vestibular function, while males showed greater alterations in anxiety and depressive-like behavior. This study established a model of subconcussive impact where a single subconcussive impact resulted in minimal behavioral deficits but repeat subconcussions resulted in deficits similar to or worse than a single concussion. Our data also suggest sex differences in behavioral responses to both concussive and subconcussive impacts.

Testosterone treatment restores vestibular function by enhancing neuronal survival in an experimental closed-head repetitive mild traumatic brain injury model.

Repetitive mild traumatic brain injury (rmTBI) results in a myriad of symptoms, including vestibular impairment. The mechanisms underlying vestibular dysfunction in rmTBI patients remain poorly understood. Concomitantly, acute hypogonadism occurs following TBI and can persist chronically in many patients. Using a repetitive mild closed-head animal model of TBI, the role of testosterone on vestibular function was tested. Male Long Evans Hooded rats were randomly divided into sham or rmTBI groups. Significant vestibular deficits were observed both acutely and chronically in the rmTBI groups. Systemic testosterone was administered after the development of chronic vestibular dysfunction. rmTBI animals given testosterone showed improved vestibular function that was sustained for 175 days post-rmTBI. Significant vestibular neuronal cell loss was, however, observed in the rmTBI animals compared to Sham animals at 175 days post-rmTBI and testosterone treatment significantly improved vestibular neuronal survival. Taken together, these data demonstrate a critical restorative role of testosterone in vestibular function following rmTBI. This study has important clinical implications because it identifies testosterone treatment as a viable therapeutic strategy for the long-term recovery of vestibular function following TBI.

Sustained Hippocampal Synaptic Pathophysiology Following Single and Repeated Closed-Head Concussive Impacts.

Traumatic brain injury (TBI), and related diseases such as chronic traumatic encephalopathy (CTE) and Alzheimer's (AD), are of increasing concern in part due to enhanced awareness of their long-term neurological effects on memory and behavior. Repeated concussions, vs. single concussions, have been shown to result in worsened and sustained symptoms including impaired cognition and histopathology. To assess and compare the persistent effects of single or repeated concussive impacts on mediators of memory encoding such as synaptic transmission, plasticity, and cellular Ca2+ signaling, a closed-head controlled cortical impact (CCI) approach was used which closely replicates the mode of injury in clinical cases. Adult male rats received a sham procedure, a single impact, or three successive impacts at 48-hour intervals. After 30 days, hippocampal slices were prepared for electrophysiological recordings and 2-photon Ca2+ imaging, or fixed and immunostained for pathogenic phospho-tau species. In both concussion groups, hippocampal circuits showed hyper-excitable synaptic responsivity upon Schaffer collateral stimulation compared to sham animals, indicating sustained defects in hippocampal circuitry. This was not accompanied by sustained LTP deficits, but resting Ca2+ levels and voltage-gated Ca2+ signals were elevated in both concussion groups, while ryanodine receptor-evoked Ca2+ responses decreased with repeat concussions. Furthermore, pathogenic phospho-tau staining was progressively elevated in both concussion groups, with spreading beyond the hemisphere of injury, consistent with CTE. Thus, single and repeated concussions lead to a persistent upregulation of excitatory hippocampal synapses, possibly through changes in postsynaptic Ca2+ signaling/regulation, which may contribute to histopathology and detrimental long-term cognitive symptoms.

Assessment of the Effects of Altered Amyloid-Beta Clearance on Behavior following Repeat Closed-Head Brain Injury in Amyloid-Beta Precursor Protein Humanized Mice.

Traumatic brain injury (TBI) increases the risk for dementias including Alzheimer's disease (AD) and chronic traumatic encephalopathy. Further, both human and animal model data indicate that amyloid-beta (Aß) peptide accumulation and its production machinery are upregulated by TBI. Considering the clear link between chronic Aß elevation and AD as well as tau pathology, the role(s) of Aß in TBI is of high importance. Endopeptidases, including the neprilysin (NEP)-like enzymes, are key mediators of Aß clearance and may affect susceptibility to pathology post-TBI. Here, we use a "humanized" mouse model of Aß production, which expresses normal human amyloid-beta precursor protein (APP) under its natural transcriptional regulation and exposed them to a more clinically relevant repeated closed-head TBI paradigm. These transgenic mice also were crossed with mice deficient for the Aß degrading enzymes NEP or NEP2 to assess models of reduced cerebral Aß clearance in our TBI model. Our results show that the presence of the human form of Aß did not exacerbate motor (Rotarod) and spatial learning/memory deficits (Morris water maze) post-injuries, while potentially reduced anxiety (Open Field) was observed. NEP and NEP2 deficiency also did not exacerbate these deficits post-injuries and was associated with protection from motor (NEP and NEP2) and spatial learning/memory deficits (NEP only). These data suggest that normally regulated expression of wild-type human APP/Aß does not contribute to deficits acutely after TBI and may be protective at this stage of injury.

Specific Aims Workshop: Your Grant in a Sound Bite.

Grant writing is an essential component of research. In an increasingly competitive funding environment, writing successful grants has become an important focus of workshops and websites with each grant proposal component requiring detailed attention. The FUN 2017 Workshop session "Specific Aims: Your Grant in a Sound Bite" was dedicated to provide information and guidance in constructing and composing a Specific Aims document. This workshop drew on the presenters' collective combination of grant experience ranging from successful submissions to serving as grant reviewers. The focus of the session was to provide some key points with regards to the purpose of a Specific Aims document, the typical audience who will read the Specific Aims, and how to construct Specific Aims that catch the attention of reviewers and provide a clear and concise overview of the grant with the goal of attracting funding. The following is a brief summary of this workshop and includes links to additional resources to help construct a Specific Aims document that provides clarity and outlines the impact of proposed research.

A Clinically Relevant Closed-Head Model of Single and Repeat Concussive Injury in the Adult Rat Using a Controlled Cortical Impact Device.

Repeat concussions (RC) can result in significant long-term neurological consequences and increased risk for neurodegenerative disease compared with single concussion (SC). Mechanisms underlying this difference are poorly understood and best elucidated using an animal model. To the best of our knowledge, there is no closed-head model in the adult rat using a commercially available device. We developed a novel and clinically relevant closed-head injury (CHI) model of both SC and RC in the adult rat using a controlled cortical impact (CCI) device. Adult rats received either a single or repeat CHI (three injuries, 48 h apart), and acute deficits in sensorimotor and locomotor function (foot fault; open field), memory (novel object), and anxiety (open field; corticosterone [CORT]) were measured. Assessment of cellular pathology was also conducted. Within the first week post-CHI, rats with SC or RC showed similar deficits in motor coordination, decreased locomotion, and higher resting CORT levels. Rats with an SC had memory deficits post-injury day (PID) 3 that recovered to sham levels by PID 7; however, rats with RC continued to show memory deficits. No obvious gross pathology was observed on the cortical surface or in coronal sections. Further examination showed thinning of the cortex and corpus callosum in RC animals compared with shams and increased axonal pathology in the corpus callosum of both SC and RC animals. Our data present a model of CHI that results in clinically relevant markers of concussion and an early differentiation between SC and RC.

Combinatorial Motor Training Results in Functional Reorganization of Remaining Motor Cortex after Controlled Cortical Impact in Rats.

Cortical reorganization subsequent to post-stroke motor rehabilitative training (RT) has been extensively examined in animal models and humans. However, similar studies focused on the effects of motor training after traumatic brain injury (TBI) are lacking. We previously reported that after a moderate/severe TBI in adult male rats, functional improvements in forelimb use were accomplished only with a combination of skilled forelimb reach training and aerobic exercise, with or without nonimpaired forelimb constraint. Thus, the current study was designed to examine the relationship between functional motor cortical map reorganization after experimental TBI and the behavioral improvements resulting from this combinatorial rehabilitative regime. Adult male rats were trained to proficiency on a skilled reaching task, received a unilateral controlled cortical impact (CCI) over the forelimb area of the caudal motor cortex (CMC). Three days post-CCI, animals began RT (n = 13) or no rehabilitative training (NoRT) control procedures (n = 13). The RT group participated in daily skilled reach training, voluntary aerobic exercise, and nonimpaired forelimb constraint. This RT regimen significantly improved impaired forelimb reaching success and normalized reaching strategies, consistent with previous findings. RT also enlarged the area of motor cortical wrist representation, derived by intracortical microstimulation, compared to NoRT. These findings indicate that sufficient RT can greatly improve motor function and improve the functional integrity of remaining motor cortex after a moderate/severe CCI. When compared with findings from stroke models, these findings also suggest that more intense RT may be needed to improve motor function and remodel the injured cortex after TBI.

Combining Multiple Types of Motor Rehabilitation Enhances Skilled Forelimb Use Following Experimental Traumatic Brain Injury in Rats.

BACKGROUND: Neuroplasticity and neurorehabilitation have been extensively studied in animal models of stroke to guide clinical rehabilitation of stroke patients. Similar studies focused on traumatic brain injury (TBI) are lacking. OBJECTIVE: The current study was designed to examine the effects of individual and combined rehabilitative approaches, previously shown to be beneficial following stroke, in an animal model of moderate/severe TBI, the controlled cortical impact (CCI). METHODS: Rats received a unilateral CCI, followed by reach training, voluntary exercise, or unimpaired forelimb constraint, alone or in combination. Forelimb function was assessed at different time points post-CCI by tests of skilled reaching, motor coordination, and asymmetrical limb use. RESULTS: Following CCI, skilled reaching and motor coordination were significantly enhanced by combinations of rehabilitation strategies, not by individual approaches. The return of symmetrical limb use benefited from forelimb constraint alone. None of the rehabilitation strategies affected the size of injury, suggesting that enhanced behavioral function was not a result of neuroprotection. CONCLUSIONS: The current study has provided evidence that individual rehabilitation strategies shown to be beneficial in animal models of stroke are not similarly sufficient to enhance behavioral outcome in a model of TBI. Motor rehabilitation strategies for TBI patients may need to be more intense and varied. Future basic science studies exploring the underlying mechanisms of combined rehabilitation approaches in TBI as well as clinical studies comparing rehabilitation approaches for stroke versus TBI would prove fruitful.

The control of movement following traumatic brain injury.

Traumatic brain injury (TBI) results in a variety of impairments in cognition, mood, sensation, and movement, depending upon the location and severity of injury. Although not as extensively studied as cognitive impairments, motor impairments are common, especially in moderately to severely injured patients. The recovery of these deficits is not usually complete; however, extensive effort is put into the rehabilitation of motor skills to enhance independence and quality of life. Understanding the motor recovery process and how it can be influenced by rehabilitation has been extensively studied in animal models of stroke and focal lesions, albeit to a lesser extent following animal models of TBI. Injury-induced neural plasticity is intricately involved in motor recovery and influenced by behavioral compensation and rehabilitation following stroke and focal lesions. New studies in animal models of TBI indicate that neural plasticity and the processes of motor recovery and rehabilitation following brain injury may not mirror those processes shown to occur following stroke. Further examination of motor recovery, rehabilitation, and plasticity in animal models of TBI as well as in individuals with TBI will be necessary to fully understand the control of movement following brain injury.

Targeted gene inactivation of calpain-1 suppresses cortical degeneration due to traumatic brain injury and neuronal apoptosis induced by oxidative stress.

Calpains are calcium-regulated cysteine proteases that have been implicated in the regulation of cell death pathways. Here, we used our calpain-1 null mouse model to evaluate the function of calpain-1 in neural degeneration following a rodent model of traumatic brain injury. In vivo, calpain-1 null mice show significantly less neural degeneration and apoptosis and a smaller contusion 3 days post-injury than wild type littermates. Protection from traumatic brain injury corroborated with the resistance of calpain-1 neurons to apoptosis induced by oxidative stress. Biochemical analysis revealed that caspase-3 activation, extracellular calcium entry, mitochondrial membrane permeability, and release of apoptosis-inducing factor from mitochondria are partially blocked in the calpain-1 null neurons. These findings suggest that the calpain-1 knock-out mice may serve as a useful model system for neuronal protection and apoptosis in traumatic brain injury and other neurodegenerative disorders in which oxidative stress plays a role.

Use-dependent dendritic regrowth is limited after unilateral controlled cortical impact to the forelimb sensorimotor cortex.

Compensatory neural plasticity occurs in both hemispheres following unilateral cortical damage incurred by seizures, stroke, and focal lesions. Plasticity is thought to play a role in recovery of function, and is important for the utility of rehabilitation strategies. Such effects have not been well described in models of traumatic brain injury (TBI). We examined changes in immunoreactivity for neural structural and plasticity-relevant proteins in the area surrounding a controlled cortical impact (CCI) to the forelimb sensorimotor cortex (FL-SMC), and in the contralateral homotopic cortex over time (3-28 days). CCI resulted in considerable motor deficits in the forelimb contralateral to injury, and increased reliance on the ipsilateral forelimb. The density of dendritic processes, visualized with immunostaining for microtubule-associated protein-2 (MAP-2), were bilaterally decreased at all time points. Synaptophysin (SYN) immunoreactivity increased transiently in the injured hemisphere, but this reflected an atypical labeling pattern, and it was unchanged in the contralateral hemisphere compared to uninjured controls. The lack of compensatory neuronal structural plasticity in the contralateral homotopic cortex, despite behavioral asymmetries, is in contrast to previous findings in stroke models. In the cortex surrounding the injury (but not the contralateral cortex), decreases in dendrites were accompanied by neurodegeneration, as indicated by Fluoro-Jade B (FJB) staining, and increased expression of the growth-inhibitory protein Nogo-A. These studies indicate that, following unilateral CCI, the cortex undergoes neuronal structural degradation in both hemispheres out to 28 days post-injury, which may be indicative of compromised compensatory plasticity. This is likely to be an important consideration in designing therapeutic strategies aimed at enhancing plasticity following TBI.

Glial cell line-derived neurotrophic factor (GDNF) gene delivery protects cortical neurons from dying following a traumatic brain injury.

PURPOSE: The therapeutic potential of glial cell line-derived neurotrophic factor (GDNF) gene delivery was examined in a rodent model of traumatic brain injury (TBI), the controlled cortical impact (CCI). METHODS: An adenoviral vector harboring human GDNF (AdGDNF) or green fluorescent protein (AdGFP) was injected unilaterally into the forelimb sensorimotor cortex (FL-SMC) of the rat one week prior to a unilateral CCI. Tests of forelimb function and asymmetry were administered for 2 weeks post-injury. At 2 weeks post-injury, animals were sacrificed and contusion size, neuronal survival, neurodegeneration, and virally-mediated GDNF and GFP protein expression were measured. RESULTS: Rats injected with AdGDNF had significantly smaller contusions, more surviving neurons, and less neurodegeneration than AdGFP injected and uninjected injured animals. GDNF gene delivery also resulted in significantly faster recovery of forelimb coordination and a smaller initial preference for the uninjured forelimb during exploration of the walls of a platform. However, overall recovery of symmetrical forelimb use was not achieved. CONCLUSIONS: The discrepancy between neural protection and behavioral recovery suggests that while GDNF gene delivery provided a high degree of protection of damaged cortical neurons in this model of TBI, it may not have fully protected their terminals and synaptic functioning, resulting in only mild protection against behavioral deficits.

Differential activation of microglia in neurogenic versus non-neurogenic regions of the forebrain.

Proliferation decreases in the neurogenic subventricular zone (SVZ) of mice after aspiration lesions of the cerebral cortex. We hypothesized that microglial activation may contribute to this given microglial activation attenuates neurogenesis in the hippocampus. Using CD45, CD11b, IB4, and IL-6 immunohistochemistry (IHC), BrdU IHC, and fluorescent bead tracking of peripheral monocytes into the brain, we compared microglial activation in the SVZ to non-neurogenic forebrain regions. SVZ microglia exhibited greater constitutive activation and proliferation than did microglia in non-neurogenic regions. In contrast to the SVZ, the dentate gyrus (DG) contained relatively few CD45(+) cells. After aspiration cerebral cortex lesions, microglia became activated in the cerebral cortex, corpus callosum, and striatum. SVZ microglial activation did not increase, and similarly, microglia in the DG were less activated after injury than in adjacent non-neurogenic regions. We next showed that SVZ microglia are not categorically refractory to activation, since deep cortical contusion injuries increased SVZ microglial activation. Macrophages migrate into the brain during development, but it is unclear if this is recapitulated after injury. Infiltration of microbead-labeled macrophages into the brain did not change after injury, but resident SVZ microglia were induced to migrate toward the injury. Our data show that both constitutive and postlesion levels of microglial activation differ between neurogenic and non-neurogenic regions.

Cellular proliferation and migration following a controlled cortical impact in the mouse.

Neurogenesis following neural degeneration has been demonstrated in many models of disease and injury. The present study further examines the early proliferative and migratory response of the brain to a controlled cortical impact (CCI) model of traumatic brain injury. The CCI was centered over the forelimb sensorimotor cortex, unilaterally, in the adult mouse. To examine proliferation, bromo-deoxyuridine (BrdU) was injected i.p. immediately post-injury and on post-injury days 1, 2, and 3. To assess migration, we labeled SVZ cells with inert latex microspheres immediately post-injury. By combining microsphere labeling with BrdU, we determined if migrating cells had gone through the S-phase of the cell cycle after the lesion. In addition, we used a marker of neurogenesis and migration, doublecortin, to further characterize the response of the SVZ to the injury. Lastly, we determined whether subregions of the SVZ respond differentially to injury. The current study demonstrates that 3 days following CCI cellular proliferation is seen around the cortex, in the SVZ, corpus callosum, and subcortical areas anatomically connected to, but not directly damaged by the impact. It delineates that an increase in proliferation occurs in the dorsal-most aspect of the ipsilateral SVZ following impact. Lastly, it demonstrates that proliferating cells migrate from the SVZ to cortical and subcortical structures affected by the injury and that some of these cells are migrating neuroblasts.

Paradoxical effects of cortical impact injury on environmentally enriched rats.

Animals housed in an enriched environment develop thicker cortices, with increased numbers of dendrites, synapses, blood vessels, and glial cells. This study examines the responses of adult rats, developmentally reared in an enriched environment, to traumatic brain injury. Rats were placed in an enriched environment for 15 days, starting on postnatal day 21. Following enrichment, they were placed in standard vivarium conditions until adulthood. At 3 months of age, enriched and age-matched control rats received a mild unilateral controlled cortical impact and were allowed to recover for 41 days. During this time, they were examined for motor coordination deficits and for preferences in forelimb use. Results demonstrate that enriched animals had a larger contusion cavity and a greater initial deficit in forelimb use. However, this deficit quickly diminished in comparison to that seen in non-enriched injured rats. The deficit in motor coordination recovered more quickly in enriched rats, 1 week sooner than in controls. These data suggest that the response of enriched animals to brain injury results in more marked neurodegeneration and acute behavioral dysfunction, with a higher capacity for compensation and recovery.