Greater neurodegeneration and behavioral deficits after single closed head traumatic brain injury in adolescent versus adult male mice.

Traumatic brain injury (TBI) is a major public health concern affecting 2.8 million people per year in the United States, of whom about 1 million are children under 19 years old. Animal models of TBI have been developed and used in multiple ages of animals, but direct comparisons of adult and adolescent populations are rare. The current studies were undertaken to directly compare outcomes between adult and adolescent male mice, using a closed head, single-impact model of TBI. Six-week-old adolescent and 9-week-old adult male mice were subjected to mild-moderate TBI. Histological measures for neurodegeneration, gliosis, and microglial neuroinflammation, and behavioral tests of locomotion and memory were performed. Adolescent TBI mice have increased mortality (Χ2  = 20.72, p < 0.001) compared to adults. There is also evidence of hippocampal neurodegeneration in adolescents that is not present in adults. Hippocampal neurodegeneration correlates with histologic activation of microglia, but not with increased astrogliosis. Adults and adolescents have similar locomotion deficits after TBI that recover by 16 days postinjury. Adolescents have memory deficits as evidenced by impaired novel object recognition between 3-4 and 4-16 days postinjury (F1,26  = 5.23, p = 0.031) while adults do not. In conclusion, adults and adolescents within a close age range (6-9 weeks) respond to TBI differently. Adolescents are more severely affected by mortality, neurodegeneration, and inflammation in the hippocampus compared to adults. Adolescents, but not adults, have worse memory performance after TBI that lasts at least 16 days postinjury.

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

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

Case Series of Adolescents With Stroke-Like Symptoms Following Head Trauma.

BACKGROUND: Studies cite the incidence of pediatric blunt cerebrovascular injuries (BCVI) ranges from 0.03% to 1.3%. While motor vehicle incidents are a known high-risk mechanism, we are the first to report on football injuries resulting in BCVI. CASE REPORT: Case 1 is a 14-year-old male football player who presented with slurred speech and facial droop 16 h after injury that had resulted in unilateral stinger on the field. The patient had a negative brain computed tomography (CT) at the onset of symptoms. Given progression of symptoms over the next 24 h, re-evaluation with CT angiography (CTA) of brain and neck showed left internal carotid artery (ICA) dissection, and magnetic resonance imaging of the brain showed left middle cerebral artery infarct. Case 2 is a 16-year-old male football player who presented with headache and right hemiparesis immediately following a tackle injury. CT brain and neck were negative at an outside hospital, but he was transferred to us for progressive symptoms, and then CTA showed a left ICA dissection with distal emboli, including occlusive involvement of the intracranial left ICA. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: The diagnosis of BCVI requires a high level of suspicion. Focal neurologic deficits are consistently a risk factor across all screening criteria, including the Denver, Utah, Memphis, and Eastern Association for the Surgery of Trauma. These current screening criteria, however, may not be sufficient to diagnosis BCVI in children. The addition of the mechanism of injury and attention to the patient's clinical presentation and examination are important to prevent missed diagnosis and poor neurologic outcomes.

Closed head injury in an age-related Alzheimer mouse model leads to an altered neuroinflammatory response and persistent cognitive impairment.

Epidemiological studies have associated increased risk of Alzheimer's disease (AD)-related clinical symptoms with a medical history of head injury. Currently, little is known about pathophysiology mechanisms linked to this association. Persistent neuroinflammation is one outcome observed in patients after a single head injury. Neuroinflammation is also present early in relevant brain regions during AD pathology progression. In addition, previous mechanistic studies in animal models link neuroinflammation as a contributor to neuropathology and cognitive impairment in traumatic brain injury (TBI) or AD-related models. Therefore, we explored the potential interplay of neuroinflammatory responses in TBI and AD by analysis of the temporal neuroinflammatory changes after TBI in an AD model, the APP/PS1 knock-in (KI) mouse. Discrete temporal aspects of astrocyte, cytokine, and chemokine responses in the injured KI mice were delayed compared with the injured wild-type mice, with a peak neuroinflammatory response in the injured KI mice occurring at 7 d after injury. The neuroinflammatory responses were more persistent in the injured KI mice, leading to a chronic neuroinflammation. At late time points after injury, KI mice exhibited a significant impairment in radial arm water maze performance compared with sham KI mice or injured wild-type mice. Intervention with a small-molecule experimental therapeutic (MW151) that selectively attenuates proinflammatory cytokine production yielded improved cognitive behavior outcomes, consistent with a link between neuroinflammatory responses and altered risk for AD-associated pathology changes with head injury.

Prevalence of traumatic brain injury in cocaine-dependent research volunteers.

BACKGROUND: There is a high prevalence of traumatic brain injury (TBI) among those with substance dependence. However, TBI often remains undiagnosed in these individuals, due to lack of routine screening in substance use treatment settings or due to overlap in some of the cognitive sequelae (eg impulsivity, disinhibition) of TBI and cocaine dependence. METHODS: The prevalence of self-reported mild to moderate TBI in a group of cocaine-dependent (n = 95) and a group of healthy volunteers (n = 75) enrolled at the same facility was assessed. Additionally, the relationship between TBI and clinically relevant correlates, including impulsivity, cocaine use history, and treatment outcome in the cocaine-dependent group was also examined. RESULTS: A higher proportion of individuals with cocaine dependence (29.5%) reported having suffered a TBI in their lifetime compared to controls (8%) on a Closed Head Injury scale. Among cocaine users, the average age of sustaining TBI was significantly lower than the age of initiating cocaine use. Presence of TBI was not associated with higher impulsivity on the Barratt Impulsiveness Scale-11 or self-reported years of cocaine use. No differences were noted on treatment outcome for cocaine dependence as measured by treatment effectiveness scores (TES) between cocaine users with TBI and their non-TBI counterparts. CONCLUSIONS: These results are the first to highlight the high prevalence of TBI among individuals with cocaine dependence. This study underscores the possible role of TBI history as a risk factor for onset of cocaine use, however, more research is needed to determine the impact of co-morbid TBI as a complicating factor in the substance abuse treatment setting.

Spectral power, source localization and microstates to quantify chronic deficits from 'mild' closed head injury: correlation with classic neuropsychological tests.

PRIMARY OBJECTIVE: To explore the quantitative relationship between neuropsychological impairment and spectral QEEG power, source localization (s-LORETA) and microstate duration in patients who 'fail to adapt' years after mild closed head injury. METHODS AND PROCEDURES: Differences in classic psychometric measures, QEEG measures, s-LORETA indicators and microstate durations were compared for three levels of neuropsychological impairment ∼(average) 6 years after injury. RESULTS: Patients who displayed the moderate-to-severe neuropsychological impairments typical of mild TBIs exhibited shorter microstates, less power within the alpha band and lower power within the theta and delta bands within caudal regions. There were conspicuous differences in the configurations of microstates, their source localizations and frequency bands. CONCLUSIONS: The systematic relationship between neuropsychological impairment as inferred by classic psychometric measures that can require tens of hours to collect and modern configurational analyses of brain activity that require ∼30 minutes suggests that the latter might be useful in discerning the area of dysfunction and potential focus of treatment for patients with closed head injury years after the event.

Does acute TBI-related sleep disturbance predict subsequent neuropsychiatric disturbances?

PRIMARY OBJECTIVE: To determine whether sleep disturbance in the acute post-traumatic brain injury (TBI) period predicts symptoms of depression, anxiety or apathy measured 6 and 12 months after TBI. RESEARCH DESIGN: Longitudinal, observational study. METHODS AND PROCEDURES: First time closed-head injury patients (n = 101) were recruited and evaluated within 3 months of injury and followed longitudinally, with psychiatric evaluations at 6 and 12 months post-injury. Pre- and post-injury sleep disturbances were measured via the Medical Outcome Scale (MOS) for Sleep. Subjects were also assessed for anxiety, depression, apathy, medical comorbidity and severity of TBI. MAIN OUTCOMES AND RESULTS: Sleep disturbance in the acute TBI period was associated with increased symptoms of depression, anxiety and apathy 12 months post-injury. CONCLUSIONS: Sleep disturbances experienced soon after trauma (i.e. <3 months after injury) predicted neuropsychiatric symptoms 1 year after injury, raising two important clinical questions: (1) Is sleep disturbance soon after trauma a prognostic marker of subsequent neuropsychiatric symptoms? and (2) Can early treatment of sleep disturbance during the post-TBI period reduce subsequent development of neuropsychiatric symptoms? Future studies with larger sample sizes and appropriate control groups could help to answer these questions, using evidence-based methods for evaluating and treating sleep disturbances.

Parental anxiety and affecting factors in acute paediatric blunt head injury.

OBJECTIVE: This study is designed to investigate the factors affecting parental anxiety regarding their children with head injury in the emergency department (ED). MATERIALS AND METHODS: This prospective observational study enrolled all consecutive paediatric patients admitted to the university-based ED with the presenting chief complaint of paediatric blunt head injury (PBHI). The parents were asked to respond to the 10-item questionnaire during both presentation and discharge. Anxiety and persuasion scores of the parents were calculated and magnitudes of the decreases in anxiety and persuasion scores were analysed with respect to sociodemographic and clinical variables. RESULTS: The study sample included 341 patients admitted to the ED. The anxiety and persuasion scores of mothers and fathers were not significantly different from each other on presentation while the extent of decrease in anxiety scores of mothers were significantly smaller than that of the fathers (p=0.003). The parents' education levels had significant impact on anxiety and persuasion scores recorded on presentation. The anxiety and persuasion scores were inversely related to education levels of the parents on presentation (p=0.002 and p=0.000, respectively). In addition, lower education levels were found to be associated with a greater decrease in anxiety and persuasion scores. Neurosurgical consultation also affected the magnitude of the decrease in anxiety and persuasion scores of the parents. The changes in the scores were affected negatively by the parents' age. CONCLUSIONS: Radiological investigations had no significant impact on the decrease in anxiety and persuasion scores of the parents by themselves, while neurosurgical consultation had significant impact on them. Emergency physicians should tailor their strategy to institute effective communication with the parents of children to cut down unnecessary investigations in PBHI.

[The German guideline "legal evaluation after closed head injury"]. / Die leitlinie "begutachtung nach gedecktem schädel-hirntrauma".

In 2005, the "Deutsche Gesellschaft für Neurowissenschaftliche Begutachtung" (German Society for Neuroscientific Legal Evaluation) together with other Societies published a guideline for the legal evaluation of patients with closed head injuries. Meanwhile, not only scientific progress in imaging techniques but also in other fields such as neuropsychology has necessitated a revision, which is presented here. In the mean time, the handling of guidelines has been systematised in Germany so that a registration with the Cooperation of German Medical Learned Societies is applied for and publication in the German Guideline Registry is expected.

Emergence of complex partial epilepsy-like experiences following closed head injuries: personality variables and neuropsychological profiles.

To pursue Richard Roberts' epileptic spectrum disorder (ESD) and the emergence of complex partial epilepsy-like experiences, items and total scores for the ESD Inventory were examined for 185 patients who had sustained mechanical impacts (and were diagnosed with or without neuropsychological impairment) and a reference group (n=68) of university students. Results from neuropsychological, personality, neurological screening, and interview data supported the role of temporal lobe origins for these experiences. The incidences of these experiences were sufficient to adversely affect adaptation and to produce psychiatric profiles. Although only 70% of the patients who were impaired versus not impaired could be differentiated by items from the ESD Inventory, >95% of the patients with scores >100 on the ESD Inventory displayed abnormal scores on more than four Minnesota Multiphasic Personality Inventory scales. These results support Roberts' ESD concept and strongly suggest that persistent, subclinical occurrence of these experiences could be the cause or major correlate of neuropsychological impairment for these patients.

[Depressive disorders after closed craniocerebral injury].

71 patients were under the observation (37 male and 34 female) aged 30-74 years old (average age 51). Depression developed after 3-6 months after the cranial injury. 20 patients with vertebrogeneous lumbargy without injury were included into the comparing group. Neurological, pathopsycological and psychometric examination were carried out (according to Gamilton's, Bek's, Spilberger-Hanyn's scales). It was demonstrated that average depression level in patiens after cranial injury was the same as in patients without injury and it didn't depend on injury terms and neurological deficiency. Clinicaly manifested, severe, depression was noticed in 22% patients. Its degree was higher in cases of the right hemisphere localization of traumatic process. It was determined that psycosocial factors (lonlines) were the most significant for depression pathogenesis. Conditions of depression occurences were aftertraumatic intellect and high anxiety level. Loss of job didn't influence the patients condition.

[Medical care to patients with remote consequences of traumatic craniocerebral injury using methods of reflexology].

Head injury--is an important medical and social problem. In recent years Ukraine prevalence rate of patients with TBI is growing and now is 4-4,2 cases per 100 thousand population. In 50-80% or 2 of the 3 victims formed long-term consequences of closed head injuries that occur with frequent decompensation states with a temporary disability, often (11-12% of patients) have a strong disability. Use in osnovnovnomu acupuncture points of general application, segmental acupuncture points in the head, neck and scalp area. Treatment ought to be lengthy, with mnohorazovym conducting repeated courses. Most often, the following AND: VB(XI)20, VB(XI)21, T(XII)14, T(XII)20, GI(II)11, GI(II)15, GI(II)10, IG(VI)3, IG(VI)15, IG(VI)16, TR(X)5, TR(X)9, C(V)5, MC(IX)5, MC(IX)6, V(VII)40, V(VII)62, VB(XI)34, VB(XI)30, E(III)36, RP(IV)6. Take Effect braking method.

Emergency department prediction of post-concussive syndrome following mild traumatic brain injury--an international cross-validation study.

BACKGROUND: Between 20-50% of those suffering a mild traumatic brain injury (MTBI) will suffer symptoms beyond 3 months or post-concussive disorder (PCD). Researchers in Sydney conducted a prospective controlled study which identified that bedside recordings of memory impairment together with recordings of moderate or severe pain could predict those who would suffer PCS with 80% sensitivity and specificity of 76%. PRIMARY OBJECTIVE: This study is a cross-validation study of the Sydney predictive model conducted at Montreal General Hospital, Montreal, Canada. METHODS: One hundred and seven patients were assessed in the Emergency Department following a MTBI and followed up by phone at 3 months. The Rivermead Post-Concussive Questionnaire was the main outcome measure. RESULTS: Regression analysis showed that immediate verbal recall and quantitative recording of headache was able to predict PCD with a sensitivity of 71.4% and a specificity of 63.3%. In the combined MTBI groups from Sydney and Montreal the sensitivity was 70.2% and the specificity was 64.2%. CONCLUSION: This is the first study to compare populations from different countries with diverse language groups using a predictive model for identifying PCD following MTBI. The model may be able to identify an 'at risk' population to whom pre-emptive treatment can be offered.

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.

Ketogenic Diet as a potential treatment for traumatic brain injury in mice.

Traumatic brain injury (TBI) is a brain dysfunction without present treatment. Previous studies have shown that animals fed ketogenic diet (KD) perform better in learning tasks than those fed standard diet (SD) following brain injury. The goal of this study was to examine whether KD is a neuroprotective in TBI mouse model. We utilized a closed head injury model to induce TBI in mice, followed by up to 30 days of KD/SD. Elevated levels of ketone bodies were confirmed in the blood following KD. Cognitive and behavioral performance was assessed post injury and molecular and cellular changes were assessed within the temporal cortex and hippocampus. Y-maze and Novel Object Recognition tasks indicated that mTBI mice maintained on KD displayed better cognitive abilities than mTBI mice maintained on SD. Mice maintained on SD post-injury demonstrated SIRT1 reduction when compared with uninjured and KD groups. In addition, KD management attenuated mTBI-induced astrocyte reactivity in the dentate gyrus and decreased degeneration of neurons in the dentate gyrus and in the cortex. These results support accumulating evidence that KD may be an effective approach to increase the brain's resistance to damage and suggest a potential new therapeutic strategy for treating TBI.

Systemic Elevation of n-3 Polyunsaturated Fatty Acids (n-3-PUFA) Is Associated with Protection against Visual, Motor, and Emotional Deficits in Mice following Closed-Head Mild Traumatic Brain Injury.

Traumatic brain injury (TBI) causes neuroinflammation and neurodegeneration leading to various pathological complications such as motor and sensory (visual) deficits, cognitive impairment, and depression. N-3 polyunsaturated fatty acid (n-3 PUFA) containing lipids are known to be anti-inflammatory, whereas the sphingolipid, ceramide (Cer), is an inducer of neuroinflammation and degeneration. Using Fat1+-transgenic mice that contain elevated levels of systemic n-3 PUFA, we tested whether they are resistant to mild TBI-mediated sensory-motor and emotional deficits by subjecting Fat1-transgenic mice and their WT littermates to focal cranial air blast (50 psi) or sham blast (0 psi, control). We observed that visual function in WT mice was reduced significantly following TBI but not in Fat1+-blast animals. We also found Fat1+-blast mice were resistant to the decline in motor functions, depression, and fear-producing effects of blast, as well as the reduction in the area of oculomotor nucleus and increase in activated microglia in the optic tract in brain sections seen following blast in WT mice. Lipid and gene expression analyses confirmed an elevated level of the n-3 PUFA eicosapentaenoic acid (EPA) in the plasma and brain, blocking of TBI-mediated increase of Cer in the brain, and decrease in TBI-mediated induction of Cer biosynthetic and inflammatory gene expression in the brain of the Fat1+ mice. Our results demonstrate that suppression of ceramide biosynthesis and inflammatory factors in Fat1+-transgenic mice is associated with significant protection against the visual, motor, and emotional deficits caused by mild TBI. This study suggests that n-3 PUFA (especially, EPA) has a promising therapeutic role in preventing neurodegeneration after TBI.

Mode of occurrence of traumatic head injuries in male patients with cluster headache or migraine: Is there a connection with lifestyle?

INTRODUCTION: Our study objective was to investigate the mode of occurrence of traumatic head injury in episodic cluster headache and migraine patients. METHODS: We conducted a retrospective study on 400 male patients, 200 with cluster headache (cases) and 200 with migraine (controls). We investigated the frequency and mode of occurrence of traumatic head injury and some lifestyle habits. RESULTS: The number of traumatic head injuries was significantly higher in cases than in controls (adjusted odds ratio [OR] = 2.0; 95% confidence interval [CI] = 1.5-2.8). Cases were more often responsible for the head traumas (adjusted OR = 2.6; 95% CI = 1.3-4.9) and reported a significantly higher proportion of injuries during scuffles or brawls (OR = 6.5; 95% CI = 2.9-14.8). Compared with other cluster headache patients, cases responsible for traumatic head injuries were more frequently heavy alcohol (p = .000), heavy tobacco (p = .03) and heavy coffee consumers (p = .003). CONCLUSIONS: Cluster headache patients (a) had traumatic head injuries more frequently than migraineurs; and (b) were more often responsible for them, perhaps due to particular behaviours related to their lifestyles.

Repeatable battery for the assessment of neuropsychological status (RBANS) may be valid in men ages 18 to 201.

The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) provides standardized scores for adults ages 20 to 89 years. However, there are situations in which the use of the RBANS for adults ages 18 to 20 years may be appropriate and have practical advantages. Thus, at present, an examiner who uses the RBANS for adult patients must rely on an entirely different evaluation tool for those adult patients under the age of 20 years. This preliminary investigation suggests the RBANS is a valid measure for men ages 18 to 20 years.

Coping and Health-Related Quality of Life after Closed Head Injury.

OBJECTIVES: In the present study the relationship between illness coping and health-related quality of life (HRQOL) in patients after closed head injury (CHI) was analyzed. Furthermore, the study was performed to assess the relative significance of clinical, neuroradiological, psychosocial variables and coping activities after CHI. We hypothesized that the effect of a depressive coping style is significantly stronger than that of all other variables considered. PATIENTS AND METHODS: This cross-sectional study took place at the outpatient clinic of the Department of Neurosurgery of the University of Technology (RWTH) Aachen, Germany. Of a total of 98 patients 1-2 years after CHI living in the catchment area of the university hospital fulfilling the inclusion criteria 63 individuals (mean age 40.6 years; 46 males) with a mean of 17.6 months after CHI took part in the study. HRQOL was assessed by means of the Aachen Life Quality Questionnaire (ALQI) and illness coping by the Freiburger Fragebogen zur Krankheitsverarbeitung (FKV). RESULTS: The patients complained most frequently of impairments in their HRQOL in the areas of free-time activities and social contact. The most intensely used coping activities were distraction and self-management, active problem-oriented coping and religion and looking for sense. Regression analyses revealed exclusively the depressive coping style as the most important predictor of subjectively impaired HRQOL explaining up to 44% of the variance. There was only a modest relationship between patient age and active problem-oriented coping (r = .43; p < .01). The degree of education was negatively associated (r= -.35; p < .01) with depressive coping. A moderate severity of the injury led to significantly more intense activities in the area of minimizing and wishful thinking as compared to a mild CHI (p < .05). CONCLUSIONS: In patients after CHI rehabilitation measures should focus to the HRQOL areas of free-time activities and social contact. Specific psychological interventions are called for in order to tackle the obviously dysfunctional depressive coping style.

The effects of mild closed head injuries on tauopathy and cognitive deficits in rodents: Primary results in wild type and rTg4510 mice, and a systematic review.

In humans, the majority of sustained traumatic brain injuries (TBIs) are classified as 'mild' and most often a result of a closed head injury (CHI). The effects of a non-penetrating CHI are not benign and may lead to chronic pathology and behavioral dysfunction, which could be worsened by repeated head injury. Clinical-neuropathological correlation studies provide evidence that conversion of tau into abnormally phosphorylated proteotoxic intermediates (p-tau) could be part of the pathophysiology triggered by a single TBI and enhanced by repeated TBIs. However, the link between p-tau and CHI in rodents remains controversial. To address this question experimentally, we induced a single CHI or two CHIs to WT or rTg4510 mice. We found that 2× CHI increased tau phosphorylation in WT mice and rTg4510 mice. Behavioral characterization in WT mice found chronic deficits in the radial arm water maze in 2× CHI mice that had partially resolved in the 1× CHI mice. Moreover, using Manganese-Enhanced Magnetic Resonance Imaging with R1 mapping - a novel functional neuroimaging technique - we found greater deficits in the rTg4510 mice following 2× CHI compared to 1× CHI. To integrate our findings with prior work in the field, we conducted a systematic review of rodent mild repetitive CHI studies. Following Prisma guidelines, we identified 25 original peer-reviewed papers. Results from our experiments, as well as our systematic review, provide compelling evidence that tau phosphorylation is modified by experimental mild TBI studies; however, changes in p-tau levels are not universally reported. Together, our results provide evidence that repetitive TBIs can result in worse and more persistent neurological deficits compared to a single TBI, but the direct link between the worsened outcome and elevated p-tau could not be established.