Memory in repeat sports-related concussive injury and single-impact traumatic brain injury.

Background: Repeat sports-related concussive/subconcussive injury (RC/SCI) is related to memory impairment. Objective & Methods: We sought to determine memory differences between persons with RC/SCI, moderate-to-severe single-impact traumatic brain injury (SI-TBI), and healthy controls. MRI scans from a subsample of participants with SI-TBI were used to identify the neuroanatomical correlates of observed memory process differences between the brain injury groups. Results: Both brain injury groups evidenced worse learning and recall in contrast to controls, although SI-TBI group had poorer memory than the RC/SCI group. Regarding memory process differences, in contrast to controls, the SI-TBI group evidenced difficulties with encoding, consolidation, and retrieval, while the RC/SCI group showed deficits in consolidation and retrieval. Delayed recall was predicted by encoding, with consolidation as a secondary predictor in the SI-TBI group. In the RC/SCI group, delayed recall was only predicted by consolidation. MRI data showed that the consolidation index we used mapped onto hippocampal atrophy. Conclusions: RC/SCI is primarily associated with consolidation deficits, which differs from SI-TBI. Given the role of the hippocampus in memory consolidation and the fact that hyperphosphorylated tau tends to accumulate in the medial temporal lobe in RC/SCI, consolidation deficits may be a cognitive marker of chronic traumatic encephalopathy in athletes.

Acute glucose and lactate metabolism are associated with cognitive recovery following traumatic brain injury.

Traumatic brain injury (TBI) is associated with acute cerebral metabolic crisis (ACMC). ACMC-related atrophy appears to be prominent in frontal and temporal lobes following moderate-to-severe TBI. This atrophy is correlated with poorer cognitive outcomes in TBI. The current study investigated ability of acute glucose and lactate metabolism to predict long-term recovery of frontal-temporal cognitive function in participants with moderate-to-severe TBI. Cerebral metabolic rate of glucose and lactate were measured by the Kety-Schmidt method on days 0-7 post-injury. Indices of frontal-temporal cognitive processing were calculated for six months post-injury; 12 months post-injury; and recovery (the difference between the six- and 12-month scores). Glucose and lactate metabolism were included in separate regression models, as they were highly intercorrelated. Also, glucose and lactate values were centered and averaged and included in a final regression model. Models for the prediction frontal-temporal cognition at six and 12 months post-injury were not significant. However, average glucose and lactate metabolism predicted recovery of frontal-temporal cognition, accounting for 23% and 22% of the variance, respectively. Also, maximum glucose metabolism, but not maximum lactate metabolism, was an inverse predictor in the recovery of frontal-temporal cognition, accounting for 23% of the variance. Finally, the average of glucose and lactate metabolism predicted frontal-temporal cognitive recovery, accounting for 22% of the variance. These data indicate that acute glucose and lactate metabolism both support cognitive recovery from TBI. Also, our data suggest that control of endogenous fuels and/or supplementation with exogenous fuels may have therapeutic potential for cognitive recovery from TBI.

Influence of Glycemic Control on Endogenous Circulating Ketone Concentrations in Adults Following Traumatic Brain Injury.

BACKGROUND: The objective was to investigate the impact of targeting tight glycemic control (4.4-6.1 mM) on endogenous ketogenesis in severely head-injured adults. METHODS: The data were prospectively collected during a randomized, within-patient crossover study comparing tight to loose glycemic control, defined as 6.7-8.3 mM. Blood was collected periodically during both tight and loose glycemic control epochs. Post hoc analysis of insulin dose and total nutritional provision was performed. RESULTS: Fifteen patients completed the crossover study. Total ketones were increased 81 µM ([38 135], p < 0.001) when blood glucose was targeted to tight (4.4-6.1 mM) compared with loose glycemic control (6.7-8.3 mM), corresponding to a 60 % increase. There was a significant decrease in total nutritional provisions (p = 0.006) and a significant increase in insulin dose (p = 0.008). CONCLUSIONS: Permissive underfeeding was tolerated when targeting tight glycemic control, but total nutritional support is an important factor when treating hyperglycemia.

Potentially neuroprotective gene modulation in an in vitro model of mild traumatic brain injury.

In this study, we investigated the hypothesis that mild traumatic brain injury (mTBI) triggers a controlled gene program as an adaptive response finalized to neuroprotection, similar to that found in hibernators and in ischemic preconditioning. A stretch injury device was used to produce an equi-biaxial strain field in rat organotypic hippocampal slice cultures at a specified Lagrangian strain of 10 % and a constant strain rate of 20 s(-1). After 24 h from injury, propidium iodide staining, HPLC analysis of metabolites and microarray analysis of cDNA were performed to evaluate cell viability, cell energy state and gene expression, respectively. Compared to control cultures, 10 % stretch injured cultures showed no change in viability, but demonstrated a hypometabolic state (decreased ATP, ATP/ADP, and nicotinic coenzymes) and a peculiar pattern of gene modulation. The latter was characterized by downregulation of genes encoding for proteins of complexes I, III, and IV of the mitochondrial electron transport chain and of ATP synthase; downregulation of transcriptional and translational genes; downregulation and upregulation of genes controlling the synthesis of glutamate and GABA receptors, upregulation of calmodulin and calmodulin-binding proteins; proper modulation of genes encoding for proapoptotic and antiapoptotic proteins. These results support the hypothesis that, following mTBI, a hibernation-type response is activated in non-hibernating species. Unlike in hibernators and ischemic preconditioning, this adaptive gene programme, aimed at achieving maximal neuroprotection, is not triggered by decrease in oxygen availability. It seems rather activated to avoid increase in oxidative/nitrosative stress and apoptosis during a transient period of mitochondrial malfunctioning.

Metabolomic analysis of cerebral spinal fluid from patients with severe brain injury.

Proton nuclear magnetic resonance (H-NMR) spectroscopic analysis of cerebral spinal fluid provides a quick, non-invasive modality for evaluating the metabolic activity of brain-injured patients. In a prospective study, we compared the CSF of 44 TBI patients and 13 non-injured control subjects. CSF was screened for ten parameters: ß-glucose (Glu), lactate (Lac), propylene glycol (PG), glutamine (Gln), alanine (Ala), α-glucose (A-Glu), pyruvate (PYR), creatine (Cr), creatinine (Crt), and acetate (Ace). Using mixed effects measures, we discovered statistically significant differences between control and trauma concentrations (mM). TBI patients had significantly higher concentrations of PG, while statistical trends existed for lactate, glutamine, and creatine. TBI patients had a significantly decreased concentration of total creatinine. There were no significant differences between TBI patients and non-injured controls regarding ß- or α-glucose, alanine, pyruvate or acetate. Correlational analysis between metabolites revealed that the strongest significant correlations in non-injured subjects were between ß- and α-glucose (r = 0.74), creatinine and pyruvate (r = 0.74), alanine and creatine (r = 0.62), and glutamine and α-glucose (r = 0.60). For TBI patients, the strongest significant correlations were between lactate and α-glucose (r = 0.54), lactate and alanine (r = 0.53), and α-glucose and alanine (r = 0.48). The GLM and multimodel inference indicated that the combined metabolites of PG, glutamine, α-glucose, and creatinine were the strongest predictors for CMRO2, ICP, and GOSe. By analyzing the CSF of patients with TBI, our goal was to create a metabolomic fingerprint for brain injury.

Tight glycemic control increases metabolic distress in traumatic brain injury: a randomized controlled within-subjects trial.

OBJECTIVE: To determine the effects of tight glycemic control on brain metabolism after traumatic brain injury using brain positron emission tomography and microdialysis. DESIGN: Single-center, randomized controlled within-subject crossover observational trial. SETTING: Academic intensive care unit. METHODS: We performed a prospective, unblinded randomized controlled within-subject crossover trial of tight (80-110 mg/dL) vs. loose (120-150 mg/dL) glycemic control in patients with severe traumatic brain injury to determine the effects of glycemic control on brain glucose metabolism, as measured by [18F] deoxy-D-glucose brain positron emission tomography. Brain microdialysis was done simultaneously. MEASUREMENTS AND MAIN RESULTS: Thirteen severely injured traumatic brain injury patients underwent the study between 3 and 8 days (mean 4.8 days) after traumatic brain injury. In ten of these subjects, global brain and gray matter tissues demonstrated higher glucose metabolic rates while glucose was under tight control as compared with loose control (3.2 ± 0.6 vs. 2.4 + 0.4, p = .02 [whole brain] and 3.8 ± 1.4 vs. 2.9 ± 0.8, p = .05 [gray matter]). However, the responses were heterogeneous with pericontusional tissue demonstrating the least state-dependent change. Cerebral microdialysis demonstrated more frequent critical reductions in glucose (p = .02) and elevations of lactate/pyruvate ratio (p = .03) during tight glycemic control. CONCLUSION: Tight glycemic control results in increased global glucose uptake and an increased cerebral metabolic crisis after traumatic brain injury. The mechanisms leading to the enhancement of metabolic crisis are unclear, but delivery of more glucose through mild hyperglycemia may be necessary after traumatic brain injury.

A pediatric perspective on concussion pathophysiology.

PURPOSE OF REVIEW: According to recent Centers for Disease Control (CDC) data, the annual incidence of traumatic brain injury (TBI) in the United States is 1.6-3.2 million, of which the majority is classified as mild. Over half of these injuries occur in the pediatric population, and can often be attributed to a sports-related mechanism. Although postconcussion symptoms are usually short-lived, more lasting deficits can occur, which can be particularly disruptive to the developing brain. Recent literature detailing the pathophysiology of mild TBI (mTBI), with attention to pediatric studies, is presented. RECENT FINDINGS: Although concussion generally does not produce any structural damage on conventional computed tomography (CT) or MRI, advanced neuroimaging modalities reveal microstructural and functional neurobiological changes. Diffuse axonal injury, metabolic impairment, alterations in neural activation and cerebral blood flow perturbations can occur and may contribute to acute symptomatology. Although these physiological changes usually recover to baseline in 7-10 days, sustaining recurrent injury before full recovery may increase the potential for persistent deficits. SUMMARY: Understanding the pathophysiology of concussion in the pediatric population can potentially open therapeutic avenues to decrease symptom persistence and prevent further injury. Future studies in the pediatric population are necessary given the pathophysiologic differences between the developing and adult brains.

The linear relationship between transcranial Doppler pulsatility indices and intracranial pressure is influenced by traumatic brain injury and vasospasm.

The pulsatility index (PI) and the intracranial -pressure (ICP) may or may not be correlated; the evidence to date differs widely. A study of multiple measures of PI and the corresponding ICP in patients with severe traumatic brain injury (TBI) showed that some of the relationships were moderately strong when calculated as conventional Pearson correlation coefficients. However, that method makes no adjustment of any kind for statistical outliers in the data. With the TBI patients demonstrating a large fraction of skewed measurements, a set of robust correlations were calculated that demonstrated that the apparent relationships between PI and ICP were entirely attributable to the statistical outliers. We conclude that the fundamental relationship of PI to ICP is weakly positive at best.

Increased Fear Generalization and Amygdala AMPA Receptor Proteins in Chronic Traumatic Brain Injury.

Cognitive impairments and emotional lability are common long-term consequences of traumatic brain injury (TBI). How TBI affects interactions between sensory, cognitive, and emotional systems may reveal mechanisms that underlie chronic mental health comorbidities. Previously, we reported changes in auditory-emotional network activity and enhanced fear learning early after TBI. In the current study, we asked whether TBI has long-term effects on fear learning and responses to novel stimuli. Four weeks following lateral fluid percussion injury (FPI) or sham surgery, adult male rats were fear conditioned to either white noise-shock or tone-shock pairing, or shock-only control and subsequently were tested for freezing to context and to the trained or novel auditory cues in a new context. FPI groups showed greater freezing to their trained auditory cue, indicating long-term TBI enhanced fear. Interestingly, FPI-Noise Shock animals displayed robust fear to the novel, untrained tone compared with Sham-Noise Shock across both experiments. Shock Only groups did not differ in freezing to either auditory stimulus. These findings suggest that TBI precipitates maladaptive associative fear generalization rather than non-associative sensitization. Basolateral amygdala (BLA) α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAr) subunits GluA1 and GluA2 levels were analyzed and the FPI-Noise Shock group had increased GluA1 (but not GluA2) levels that correlated with the level of tone fear generalization. This study illustrates a unique chronic TBI phenotype with both a cognitive impairment and increased fear and possibly altered synaptic transmission in the amygdala long after TBI, where stimulus generalization may underlie maladaptive fear and hyperarousal.

Region-Dependent Modulation of Neural Plasticity in Limbic Structures Early after Traumatic Brain Injury.

Traumatic brain injury (TBI)-induced disruptions in synaptic function within brain regions and across networks in the limbic system may underlie a vulnerability for maladaptive plasticity and contribute to behavioral comorbidities. In this study we measured how synaptic proteins respond to lateral fluid percussion injury (FPI) brain regions known to regulate emotion and memory, including the basolateral amygdala (BLA), dorsal and ventral hippocampus (DH, VH), and medial prefrontal cortex (PFC). We investigated proteins involved in regulating plasticity, including synaptic glutamatergic a-amino-3-hydroxy5-methyl-4-isoxazolepropionic acid (AMPA; GluA1, GluA2) and N-methyl-D-aspartate (NMDA; NR1, NR2A, NR2B) receptor subunits as well as inhibitory gamma-aminobutyric acid (GABA) synthetic enzymes (GAD67, GAD65) via western blot. Adult male rats received a mild-moderate lateral FPI or sham surgery and ipsi- and contralateral BLA, DH, VH, and PFC were collected 6 h, 24 h, 48 h, and 7 days post-injury. In the ipsilateral BLA, there was a significant decrease in NR1 and GluA2 24 h after injury, whereas NR2A and NR2B were increased in the contralateral BLA at 48 h compared with sham. GAD67 was increased ipsilaterally at 24 h, but decreased contralaterally at 48 h in the BLA. In the DH, both NMDA (NR2A, NR2B) and GABA-synthetic (GAD65, GAD67) proteins were increased acutely at 6 h compared with sham. GAD67 was also robustly increased in the ipsilateral VH at 6 h. In the contralateral VH, NR2A significantly increased between 6 h and 24 h after FPI, whereas GAD65 was decreased across the same time-points in the contralateral VH. In the medial PFC at 24 h we saw bilateral increases in GAD67 and a contralateral decrease in GluA1. Later, there was a significant decrease in GAD67 in contralateral PFC from 48 h to 7 days post-injury. Collectively, these data suggest that lateral FPI causes a dynamic homeostatic response across limbic networks, leading to an imbalance of the proteins involved in plasticity in neural systems underlying cognitive and emotional regulation.

Molecular and physiological responses to juvenile traumatic brain injury: focus on growth and metabolism.

Traumatic brain injury (TBI), one of the most frequent causes of neurologic and neurobehavioral morbidity in the pediatric population, can result in lifelong challenges not only for patients, but also for their families. Survivors of a brain injury experienced during childhood - when the brain is undergoing a period of rapid development - frequently experience unique challenges as the consequences of their injuries are overlaid on normal developmental changes. Experimental studies have significantly advanced our understanding of the mechanisms and underlying molecular underpinnings of the injury response and recovery process following a TBI in the developing brain. In this paper, normal and TBI-related alterations in growth, development and metabolism are comprehensively reviewed in the postweanling/juvenile age range in the rat (postnatal days 21-60). As part of this review, TBI-related changes in gene expression are presented, with a focus on the injury-induced alterations related to cerebral growth and metabolism, and discussed in the context of existing literature related to physiological and behavioral responses to experimental TBI. Increasing evidence from the existing literature and from our own gene microarray data indicates that molecular responses related to growth, development and metabolism may play a particularly important role in the injury response and the recovery trajectory following developmental TBI. While gene expression analysis shows many of these changes occur at the level of transcription, a comprehensive review of other studies suggests that the control of metabolic substrates may preferentially be regulated through changes in transporters and enzymatic activity. The interrelation between cellular metabolism and activity-dependent neuroplasticity shows great promise as an area for future study for an optimal translation of experimental data to clinical TBI, with the ultimate goal of guiding therapeutic interventions.

Controlled contusion injury alters molecular systems associated with cognitive performance.

We investigated whether a learning impairment after a controlled cortical impact (CCI) injury was associated with alterations in molecules involved in synaptic plasticity and learning and memory. Adult male rats with moderate CCI to the left parietal cortex, tested in a Morris water maze (MWM) beginning at postinjury day 10, showed impaired cognitive performance compared with sham-treated rats. Tissue was extracted for mRNA analysis on postinjury day 21. The expression of brain-derived neurotrophic factor (BDNF), synapsin I, cyclic-AMP response element binding protein (CREB), and calcium-calmodulin-dependent protein kinase II (alpha-CAMKII) were all significantly decreased compared with sham injury levels within the ipsilateral hippocampus after CCI. No significant molecular level changes were found in the contralateral hippocampus. Decreased expression of BDNF and synapsin I was also found within the ipsilateral parietal cortex of CCI-injured rats compared with shams. However, BDNF and synapsin I expressions were significantly increased in the contralateral parietal cortex of the CCI rats. CREB expression was significantly decreased within the contralateral cortex of the CCI group. These findings show enduring reductions in the expression of BDNF, synapsin I, CREB, and alpha-CAMKII ipsilateral to a CCI injury, which seem associated with the spatial learning deficits observed in this injury model. In addition, the delayed increase in the expression of BDNF and synapsin I within the cortex contralateral to CCI may reflect restorative processes in areas homotypical to the injury.

Ontogeny of Rat Recognition Memory measured by the novel object recognition task.

Detection of novelty is an essential component of recognition memory, which develops throughout cerebral maturation. To better understand the developmental aspects of this memory system, the novel object recognition task (NOR) was used with the immature rat and ontogenically profiled. It was hypothesized that object recognition would vary across development and be inferior to adult performance. The NOR design was made age-appropriate by downsizing the testing objects and arena. Weanling (P20-23), juvenile (P29-40), and adult (P50+) rats were tested after 0.25, 1, 24, and 48 hr delays. Weanlings exhibited novel object recognition at 0.25 and 1 hr, while older animals showed a preference for the novel object out to 24 hr. These findings are consistent with previous research performed in humans and monkeys, as well as to studies using the NOR after medial temporal lobe damage in adult rats.

Sensory sensitivity as a link between concussive traumatic brain injury and PTSD.

Traumatic brain injury (TBI) is one of the most common injuries to military personnel, a population often exposed to stressful stimuli and emotional trauma. Changes in sensory processing after TBI might contribute to TBI-post traumatic stress disorder (PTSD) comorbidity. Combining an animal model of TBI with an animal model of emotional trauma, we reveal an interaction between auditory sensitivity after TBI and fear conditioning where 75 dB white noise alone evokes a phonophobia-like phenotype and when paired with footshocks, fear is robustly enhanced. TBI reduced neuronal activity in the hippocampus but increased activity in the ipsilateral lateral amygdala (LA) when exposed to white noise. The white noise effect in LA was driven by increased activity in neurons projecting from ipsilateral auditory thalamus (medial geniculate nucleus). These data suggest that altered sensory processing within subcortical sensory-emotional circuitry after TBI results in neutral stimuli adopting aversive properties with a corresponding impact on facilitating trauma memories and may contribute to TBI-PTSD comorbidity.

Bridging the gap: Mechanisms of plasticity and repair after pediatric TBI.

Traumatic brain injury is the leading cause of death and disability in the United States, and may be associated with long lasting impairments into adulthood. The multitude of ongoing neurobiological processes that occur during brain maturation confer both considerable vulnerability to TBI but may also provide adaptability and potential for recovery. This review will examine and synthesize our current understanding of developmental neurobiology in the context of pediatric TBI. Delineating this biology will facilitate more targeted initial care, mechanism-based therapeutic interventions and better long-term prognostication and follow-up.

pH-weighted molecular MRI in human traumatic brain injury (TBI) using amine proton chemical exchange saturation transfer echoplanar imaging (CEST EPI).

Cerebral acidosis is a consequence of secondary injury mechanisms following traumatic brain injury (TBI), including excitotoxicity and ischemia, with potentially significant clinical implications. However, there remains an unmet clinical need for technology for non-invasive, high resolution pH imaging of human TBI for studying metabolic changes following injury. The current study examined 17 patients with TBI and 20 healthy controls using amine chemical exchange saturation transfer echoplanar imaging (CEST EPI), a novel pH-weighted molecular MR imaging technique, on a clinical 3T MR scanner. Results showed significantly elevated pH-weighted image contrast (MTRasym at 3 ppm) in areas of T2 hyperintensity or edema (P < 0.0001), and a strong negative correlation with Glasgow Coma Scale (GCS) at the time of the MRI exam (R2 = 0.4777, P = 0.0021), Glasgow Outcome Scale - Extended (GOSE) at 6 months from injury (R2 = 0.5334, P = 0.0107), and a non-linear correlation with the time from injury to MRI exam (R2 = 0.6317, P = 0.0004). This evidence suggests clinical feasibility and potential value of pH-weighted amine CEST EPI as a high-resolution imaging tool for identifying tissue most at risk for long-term damage due to cerebral acidosis.

Persistent metabolic crisis as measured by elevated cerebral microdialysis lactate-pyruvate ratio predicts chronic frontal lobe brain atrophy after traumatic brain injury.

OBJECTIVE: To determine whether persistent metabolic dysfunction in normal-appearing frontal lobe tissue is correlated with long-term tissue atrophy. DESIGN: Prospective monitoring with retrospective data analysis. SETTING: Single-center academic neurointensive care unit. PATIENTS: Fifteen patients with moderate to severe traumatic brain injury (Glasgow Coma Scale score 3-12). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Hourly cerebral microdialysis was performed for the initial 96 hrs after trauma to determine extracellular levels of glucose, glutamate, glycerol, lactate, and pyruvate in normal appearing frontal lobes. Six months after injury, the anatomical outcome was assessed by measures of global and regional cerebral atrophy using volumetric brain magnetic resonance imaging. The lactate/pyruvate ratio was elevated >40 after traumatic brain injury in most patients, with a mean percent time of 32 +/- 29% of hours monitored. At 6 months after traumatic brain injury, there was a mean frontal lobe atrophy of 12 +/- 11% and global brain atrophy of 8.5 +/- 4.5%. The percentage of time of elevated lactate/pyruvate ratio correlated with the extent of frontal lobe brain atrophy (r = -.56, p < 0.01), but not global brain atrophy (r = -.31, p = 0.20). The predictive effect of lactate/pyruvate ratio was independent of patient age, Glasgow Coma Scale score, and volume of frontal lobe contusion. CONCLUSION: Persistent metabolic crisis, as reflected by an elevated lactate/pyruvate ratio, in normal appearing posttraumatic frontal lobe, is predictive of the degree of tissue atrophy at 6 months.

Duration of ATP reduction affects extent of CA1 cell death in rat models of fluid percussion injury combined with secondary ischemia.

Secondary ischemia (SI) following traumatic brain injury (TBI) increases damage to the brain in both animals and humans. The current study determined if SI after TBI alters the extent or duration of reduced energy production within the first 24 h post-injury and hippocampal cell loss at one week post-injury. Adult male rats were subjected to sham injury, lateral (LFPI) or central fluid percussion injury (CFPI) only, or to combined LFPI or CFPI with SI. The SI was 8 min of bilateral forebrain ischemia combined with hemorrhagic hypotension, applied at 1 h following FPI. After LFPI alone adenosine triphosphate (ATP) levels within the ipsilateral CA1 were reduced at 2 h (p < 0.05) and subsequently recovered. After LFPI+SI the ATP reductions in CA1 ipsilateral to FPI persisted for 24 h (p < 0.01). ATP levels in the contralateral CA1 were not affected by LFPI alone or LFPI+SI. After CFPI alone CA1 ATP levels were depressed bilaterally only at 2 h (p < 0.05). Similar to the LFPI paradigm, CFPI+SI reduced ATP levels for 24 h (p < 0.01), with bilateral ATP reductions seen after CFPI+SI. Cell counts in the CA1 region at 7 days post-injury revealed no significant neuronal cell loss after LFPI or CFPI alone. Significant neuronal cell loss was present only within the ipsilateral (p < 0.001) CA1 after LFPI+SI, but cell loss was bilateral (p < 0.001) after CFPI+SI. Thus, SI prolongs ATP reductions induced by LFPI and CFPI within the CA1 region and this SI-induced energy reduction appears to adversely affect regional neuronal viability.

The impact of substance abuse on mortality in patients with severe traumatic brain injury.

BACKGROUND: Drug and alcohol use are common in neurotrauma patients. Despite growing methamphetamine use there are few studies of the impact of methamphetamine use on outcome after traumatic brain injury (TBI). METHODS: We conducted a retrospective review of 5-years of data from a trauma database. Inclusion criteria included severe TBI and diagnosis codes indicating head injury. The entire database was analyzed and then a subset of patients with complete toxicology data were examined separately. Primary outcome was mortality. RESULTS: Four hundred eighty-three patients were included. Toxicology results were available for 52.6% of patients. Alcohol, amphetamines, and cannabis were the most commonly detected substances. Overall mortality was 50.9%. When the group with complete tox screen data were analyzed, a toxicology screen that was positive for alcohol or amphetamine was associated with decreased mortality with an odds ratio of 0.23 (CI: 0.10-0.56, p = 0.001) and 0.25 (CI: 0.08-0.79, p = 0.02), respectively. When the subset of patients for whom toxicology data were available was analyzed the amphetamine-positive group was more likely to use cannabis and less likely to use alcohol. CONCLUSIONS: We unexpectedly found alcohol and methamphetamine use to be associated with decreased mortality. Neurotoxic and possible neuroprotective mechanisms of these substances are discussed as well as possible interactions between cannabis and methamphetamine. The potential influence of psycho-social factors are also considered. Prospective studies are needed to further investigate the effects of drug and alcohol use on outcome after severe TBI.

Craniectomy Effects on Resting State Functional Connectivity and Cognitive Performance in Immature Rats.

Experimental models have been proven to be valuable tools to understand downstream cellular mechanisms of Traumatic Brain Injury (TBI). The models allow for reduction of confounding variables and tighter control of varying parameters. It has been recently reported that craniectomy induces pro-inflammatory responses, which therefore needs to be properly addressed given the fact that craniectomy is often considered a control procedure for experimental TBI models. The current study aims to determine whether a craniectomy induces alterations in Resting State Network (RSN) in a developmental rodent model. Functional Magnetic Resonance Imaging (fMRI) data-driven RSN show clusters of peak differences (left caudate putamen, somatosensory cortex, amygdala and piriform cortex) between craniectomy and control group, four days post-craniectomy. In addition, the Novel Object Recognition (NOR) task revealed impaired working memory in the craniectomy group. This evidence supports craniectomy-induced neurological changes which need to be carefully addressed, considering the frequent use of craniectomy as a control procedure for experimental models of TBI.