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.

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.

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.

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.

Increased severity of the CHIMERA model induces acute vascular injury, sub-acute deficits in memory recall, and chronic white matter gliosis.

Traumatic brain injury (TBI) is a leading cause of death and disability in modern societies. Diffuse axonal and vascular injury are nearly universal consequences of mechanical energy impacting the head and contribute to disability throughout the injury severity spectrum. CHIMERA (Closed Head Impact Model of Engineered Rotational Acceleration) is a non-surgical, impact-acceleration model of rodent TBI that reliably produces diffuse axonal injury characterized by white matter gliosis and axonal damage. At impact energies up to 0.7 joules, which result in mild TBI in mice, CHIMERA does not produce detectable vascular or grey matter injury. This study was designed to expand CHIMERA's capacity to induce more severe injuries, including vascular damage and grey matter gliosis. This was made possible by designing a physical interface positioned between the piston and animal's head to allow higher impact energies to be transmitted to the head without causing skull fracture. Here, we assessed interface-assisted single CHIMERA TBI at 2.5 joules in wild-type mice using a study design that spanned 6 h-60 d time points. Injured animals displayed robust acute neurological deficits, elevated plasma total tau and neurofilament-light levels, transiently increased proinflammatory cytokines in brain tissue, blood-brain barrier (BBB) leakage and microstructural vascular abnormalities, and grey matter microgliosis. Memory deficits were evident at 30 d and resolved by 60 d. Intriguingly, white matter injury was not remarkable at acute time points but evolved over time, with white matter gliosis being most extensive at 60 d. Interface-assisted CHIMERA thus enables experimental modeling of distinct endophenotypes of TBI that include acute vascular and grey matter injury in addition to chronic evolution of white matter damage, similar to the natural history of human TBI.

Depletion of microglia immediately following traumatic brain injury in the pediatric rat: Implications for cellular and behavioral pathology.

The inflammatory response is a significant component of the pathophysiology of pediatric traumatic brain injury. High levels of inflammatory mediators have been found in the cerebrospinal fluid of brain-injured children which have been linked to poor prognosis. Targeting aspects of the inflammatory response in the hopes of finding a viable post-injury therapeutic option has gained attention. Microglia are largely responsible for perpetuating the injury-induced inflammatory response but in the developing brain they play beneficial roles in both normal and disease states. Following closed head injury in the neonate rat, depletion of microglia with intracerebral injections of liposomes containing clodronate was associated with an increase in neurodegeneration in the early post-injury period (3 days) relative to those injected with empty liposomes suggestive of a decrease in clearance of dying cells. In sham-injured animals, microglia repopulated the clodrosome-mediated depleted brain regions over a period of 2-4 weeks and exhibited morphology typical of a resting phenotype. In brain-injured animals, the repopulated microglia in clodrosome-injected animals exhibited rod-like and amoeboid morphologies. However, fluoro-Jade B reactivity in these brain regions was more extensive than in empty liposome-injected animals suggesting that the active microglia may be unable to clear dying neurons. This was accompanied by an induction of hyperexcitability in the local cortical circuitry. Depletion of microglia within the white matter tracts and the thalamus did not affect the extent of injury-induced traumatic axonal injury. Increased neurodegeneration in the dorsal subiculum was not accompanied by any changes to injury-induced deficits in spatial learning and memory. These data suggest that activation of microglia may be important for removal of dying neurons in the traumatically-injured immature brain.

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.

Repetitive closed-head impact model of engineered rotational acceleration (CHIMERA) injury in rats increases impulsivity, decreases dopaminergic innervation in the olfactory tubercle and generates white matter inflammation, tau phosphorylation and degeneration.

Traumatic brain injury (TBI) affects at least 3 M people annually. In humans, repetitive mild TBI (rmTBI) can lead to increased impulsivity and may be associated with chronic traumatic encephalopathy. To better understand the relationship between repetitive TBI (rTBI), impulsivity and neuropathology, we used CHIMERA (Closed-Head Injury Model of Engineered Rotational Acceleration) to deliver five TBIs to rats, which were continuously assessed for trait impulsivity using the delay discounting task and for neuropathology at endpoint. Compared to sham controls, rats with rTBI displayed progressive impairment in impulsive choice. Histological analyses revealed reduced dopaminergic innervation from the ventral tegmental area to the olfactory tubercle, consistent with altered impulsivity neurocircuitry. Consistent with diffuse axonal injury generated by CHIMERA, white matter inflammation, tau immunoreactivity and degeneration were observed in the optic tract and corpus callosum. Finally, pronounced grey matter microgliosis was observed in the olfactory tubercle. Our results provide insight into the mechanisms by which rTBI leads to post-traumatic psychiatric-like symptoms in a novel rat TBI platform.

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.

Utility of repeat head computed tomography after mild head trauma: influence on short- and long-term prognosis and health-related quality of life.

The aim of this study was to investigate the utility of repeat head CT in a large population of patients with non-isolated blunt mild head trauma (MTBI), especially in the presence of intracranial injury. This is a study of a cohort of 478 non-isolated MTBI patients admitted to the High Dependency Unit of the Emergency Department of the University-Hospital of Florence from July 2008 to December 2013. Results of initial and subsequent head CT scans, and indications for repeat head CT scan (routine vs. neurologic change) were recorded. The study population was divided into two subgroups: 28 (6 %) patients with neurological change or persistently reduced GCS (group GCS-) and 450 (94 %) patients with normal or improving GCS (group GCS+). After 6 months from the event, a telephone interview using SF12 questionnaire was conducted. Among GCS- patients, the admission CT scan showed intracranial lesions (ICI) in 16 (57 %) patients; only two patients had a TBI-related neurosurgical intervention. Among GCS+ patients, the first CT scan showed an ICI in 133 patients; in a significant proportion of patients with ICI at the first CT scan, the injury worsened (40/133, 30 %, p < 0.0001). However, no GCS+ patient had any neurosurgical intervention. We observed a significant reduction in both MCS and PCS scores after the injury compared with the previous period. The number of repeat CT scan was high in patients who presented ICI at the first CT scan; however, no patient with ICI and normal or improving GCS score needed a neurosurgical intervention.

Studying self-awareness in children: validation of the Questionnaire of Executive Functioning (QEF).

OBJECTIVE: People with accurate representations of their own cognitive functioning (i.e. cognitive self-awareness) tend to use appropriate strategies to regulate their behavior. Due to the lack of appropriate instruments, few studies have examined the development of this ability among children. METHOD: This study tested the measurement properties of the self-rating and other-rating forms of the Questionnaire of Executive Functioning (QEF), designed to tap children's knowledge of their executive functioning. Specifically, the construct, convergent, and discriminant validities were investigated and a self-other discrepancy score was computed to assess children's executive self-awareness. Participants were 317 children aged 7-14 years old. RESULTS: Confirmatory factor analyses carried out on the QEF confirmed the eight-factor structure of both versions. There were significant correlations between the QEF and the parent versions of the Behavior Rating Inventory of Executive Function, the Dysexecutive Questionnaire for Children, and the Childhood Executive Functioning Inventory. Both forms of the QEF were able to distinguish between children who had sustained a traumatic brain injury (TBI) and control participants. A statistical difference was observed between the TBI and control groups on this score, suggesting that TBI may trigger self-awareness impairments in children. CONCLUSION: The good psychometric properties of the two forms of the QEF were established. Furthermore, results of the analyses carried out on the different discrepancy scores seem to indicate that the QEF could help clinicians to detect patients with self-awareness deficits.

Perceptual organization deficits in traumatic brain injury patients.

Traumatic brain injury (TBI) is a prevalent condition and there is limited visual perception research with this population. Here, we investigated perceptual organization changes in a rather homogeneous sample of closed head TBI outpatients with diffuse axonal injury only and no other known comorbidities. Patients had normal or corrected visual acuity. Perceptual organization was measured with the Leuven Perceptual Organization Screening Test (L-POST), a coherent motion task (CM) and the Leuven Embedded Figures Test (L-EFT). These tests were chosen to screen for deficits in different aspects of perceptual organization (L-POST), to evaluate local and global processing (L-EFT) and grouping in a dynamic set of stimuli (CM). TBI patients were significantly impaired compared to controls in all measures for both response time and accuracy, except for CM thresholds and object recognition subtests. The TBI group was similarly affected in all aspects of the L-EFT. TBI was also similarly affected in all perceptual factors of the L-POST. No significant correlations were found between scores and time post-injury, except for CM thresholds (rs=-0.74), which might explain the lack of group-level differences. The only score significantly correlated to IQ was L-EFT response time (rs=-0.67). These findings demonstrate that perceptual organization is diffusely affected in TBI and this effect has no substantial correlations with IQ. As many of the neuropsychological tests used to measure different cognitive functions involve some level of visual discrimination and perceptual organization demands, these results must be taken into account in the general neuropsychological evaluation of TBI patients.

Impoverished descriptions of familiar routes in three cases of hippocampal/medial temporal lobe amnesia.

Recent research has challenged classic theories of hippocampal function in spatial memory with findings that the hippocampus may be necessary for detailed representations of environments learned long ago, but not for remembering the gist or schematic aspects that are sufficient for navigating within those environments (Rosenbaum et al., 2000; Rosenbaum, Winocur, Binns, & Moscovitch, 2012). We aimed to probe further distinctions between detailed and schematic representations of familiar environments in three cases of hippocampal/medial temporal lobe (MTL) amnesia by testing them on a route description task and mental navigation tasks that assess the identity and location of landmarks, and distances and directions between them. The amnesic cases could describe basic directions along known, imagined routes, estimate distance and direction between well-known landmarks, and produce sketch maps with accurate layouts, suggestive of intact schematic representations. However, findings that their route descriptions lack richness of detail, along with impoverished sketch maps and poor landmark recognition, substantiates previous findings that detailed representations are hippocampus-dependent.

Decreased microvascular cerebral blood flow assessed by diffuse correlation spectroscopy after repetitive concussions in mice.

Repetitive concussions are associated with long-term cognitive dysfunction that can be attenuated by increasing the time intervals between concussions; however, biomarkers of the safest rest interval between injuries remain undefined. We hypothesize that deranged cerebral blood flow (CBF) is a candidate biomarker for vulnerability to repetitive concussions. Using a mouse model of human concussion, we examined the effect of single and repetitive concussions on cognition and on an index of CBF (CBFi) measured with diffuse correlation spectroscopy. After a single mild concussion, CBFi was reduced by 35±4% at 4 hours (P<0.01 versus baseline) and returned to preinjury levels by 24 hours. After five concussions spaced 1 day apart, CBFi was also reduced from preinjury levels 4 hours after each concussion but had returned to preinjury levels by 72 hours after the final concussion. Interestingly, in this repetitive concussion model, lower CBFi values measured both preinjury and 4 hours after the third concussion were associated with worse performance on the Morris water maze assessed 72 hours after the final concussion. We conclude that low CBFi measured either before or early on in the evolution of injury caused by repetitive concussions could be a useful predictor of cognitive outcome.

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.