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1.  Nrf2 Activation in Astrocytes Contributes to Spinal Cord Ischemic Tolerance Induced by Hyperbaric Oxygen Preconditioning 
Journal of Neurotrauma  2014;31(15):1343-1353.
Abstract
In this study, we investigated whether nuclear factor erythroid 2-related factor 2 (Nrf2) activation in astrocytes contributes to the neuroprotection induced by a single hyperbaric oxygen preconditioning (HBO-PC) against spinal cord ischemia/reperfusion (SCIR) injury. In vivo: At 24 h after a single HBO-PC at 2.5 atmospheres absolute for 90 min, the male ICR mice underwent SCIR injury by aortic cross-clamping surgery and observed for 48 h. HBO-PC significantly improved hindlimb motor function, reduced secondary spinal cord edema, ameliorated the reactivity of spinal motor-evoked potentials, and slowed down the process of apoptosis to exert neuroprotective effects against SCIR injury. At 12 h or 24 h after HBO-PC without aortic cross-clamping surgery, Western blot, enzyme-linked immunosorbent assay, realtime-polymerase chain reaction and double-immunofluorescence staining were used to detect the Nrf2 activity of spinal cord tissue, such as mRNA level, protein content, DNA binding activity, and the expression of downstream gene, such as glutamate-cysteine ligase, γ-glutamyltransferase, multidrug resistance protein 1, which are key proteins for intracellular glutathione synthesis and transit. The Nrf2 activity and downstream genes expression were all enhanced in normal spinal cord with HBO-PC. Glutathione content of spinal cord tissue with HBO-PC significantly increased at all time points after SCIR injury. Moreover, Nrf2 overexpression mainly occurs in astrocytes. In vitro: At 24 h after HBO-PC, the primary spinal astrocyte-neuron co-cultures from ICR mouse pups were subjected to oxygen-glucose deprivation (OGD) for 90 min to simulate the ischemia-reperfusion injury. HBO-PC significantly increased the survival rate of neurons and the glutathione content in culture medium, which was mainly released from asctrocytes. Moreover, the Nrf2 activity and downstream genes expression induced by HBO-PC were mainly enhanced in astrocytes, but not in neurons. In conclusion, our findings demonstrated that spinal cord ischemic tolerance induced by HBO-PC may be mainly related to Nrf2 activation in astrocytes.
doi:10.1089/neu.2013.3222
PMCID: PMC4120927  PMID: 24716787
astrocyte; hyperbaric oxygen preconditioning; neuroprotection; Nrf2; oxygen-glucose deprivation; spinal cord ischemia/reperfusion
2.  Diffusion Tensor Imaging as a Predictor of Locomotor Function after Experimental Spinal Cord Injury and Recovery 
Journal of Neurotrauma  2014;31(15):1362-1373.
Abstract
Traumatic spinal cord injury (SCI) causes long-term disability with limited functional recovery linked to the extent of axonal connectivity. Quantitative diffusion tensor imaging (DTI) of axonal integrity has been suggested as a potential biomarker for prognostic and therapeutic evaluation after trauma, but its correlation with functional outcomes has not been clearly defined. To examine this application, female Sprague-Dawley rats underwent midthoracic laminectomy followed by traumatic spinal cord contusion of differing severities or laminectomy without contusion. Locomotor scores and hindlimb kinematic data were collected for 4 weeks post-injury. Ex vivo DTI was then performed to assess axonal integrity using tractography and fractional anisotropy (FA), a numerical measure of relative white matter integrity, at the injury epicenter and at specific intervals rostral and caudal to the injury site. Immunohistochemistry for tissue sparing was also performed. Statistical correlation between imaging data and functional performance was assessed as the primary outcome. All injured animals showed some recovery of locomotor function, while hindlimb kinematics revealed graded deficits consistent with injury severity. Standard T2 magnetic resonance sequences illustrated conventional spinal cord morphology adjacent to contusions while corresponding FA maps indicated graded white matter pathology within these adjacent regions. Positive correlations between locomotor (Basso, Beattie, and Bresnahan score and gait kinematics) and imaging (FA values) parameters were also observed within these adjacent regions, most strongly within caudal segments beyond the lesion. Evaluation of axonal injury by DTI provides a mechanism for functional recovery assessment in a rodent SCI model. These findings suggest that focused DTI analysis of caudal spinal cord should be studied in human cases in relationship to motor outcome to augment outcome biomarkers for clinical cases.
doi:10.1089/neu.2013.3238
PMCID: PMC4120934  PMID: 24779685
diffusion tensor imaging; fractional anisotropy; kinematics; spinal cord injury; rat; tractography
3.  Effects of Serotonergic Medications on Locomotor Performance in Humans with Incomplete Spinal Cord Injury 
Journal of Neurotrauma  2014;31(15):1334-1342.
Abstract
Incomplete spinal cord injury (iSCI) often results in significant motor impairments that lead to decreased functional mobility. Loss of descending serotonergic (5HT) input to spinal circuits is thought to contribute to motor impairments, with enhanced motor function demonstrated through augmentation of 5HT signaling. However, the presence of spastic motor behaviors in SCI is attributed, in part, to changes in spinal 5HT receptors that augment their activity in the absence of 5HT, although data demonstrating motor effects of 5HT agents that deactivate these receptors are conflicting. The effects of enhancement or depression of 5HT signaling on locomotor function have not been thoroughly evaluated in human iSCI. Therefore, the aim of the current study was to investigate acute effects of 5HT medications on locomotion in 10 subjects with chronic (>1 year) iSCI. Peak overground and treadmill locomotor performance, including measures of gait kinematics, electromyographic (EMG) activity, and oxygen consumption, were assessed before and after single-dose administration of either a selective serotonin reuptake inhibitor (SSRI) or a 5HT antagonist using a double-blinded, randomized, cross-over design. Results indicate that neither medication led to improvements in locomotion, with a significant decrease in peak overground gait speed observed after 5HT antagonists (from 0.8±0.1 to 0.7±0.1 m/s; p=0.01). Additionally, 5-HT medications had differential effects on EMG activity, with 5HT antagonists decreasing extensor activity and SSRIs increasing flexor activity. Our data therefore suggest that acute manipulation of 5HT signaling, despite changes in muscle activity, does not improve locomotor performance after iSCI.
doi:10.1089/neu.2013.3206
PMCID: PMC4121052  PMID: 24742292
locomotor function; neurotransmitters; rehabilitation; spinal cord injury
4.  Real-Time Monitoring of Changes in Brain Extracellular Sodium and Potassium Concentrations and Intracranial Pressure after Selective Vasopressin-1a Receptor Inhibition following Focal Traumatic Brain Injury in Rats 
Journal of Neurotrauma  2014;31(14):1258-1267.
Abstract
Brain swelling and increased intracranial pressure (ICP) following traumatic brain injury (TBI) contribute to poor outcome. Vasopressin-1a receptors (V1aR) and aquaporin-4 (AQP4) regulate water transport and brain edema formation, perhaps in part by modulating cation fluxes. After focal TBI, V1aR inhibitors diminish V1aR and AQP4, reduce astrocytic swelling and brain edema. We determined whether V1aR inhibition with SR49059 after lateral controlled-cortical-impact (CCI) injury affects extracellular Na+ and K+ concentrations ([Na+]e; [K+]e). Ion-selective Na+ and K+ electrodes (ISE) and an ICP probe were implanted in rat parietal cortex, and [Na+]e, [K+]e, and physiological parameters were monitored for 5 h post-CCI. Sham-vehicle-ISE, CCI-vehicle-ISE and CCI-SR49059-ISE groups were studied, and SR49059 was administered 5 min to 5 h post-injury. We found a significant injury-induced decrease in [Na+]e to 80.1±15 and 87.9±7.9 mM and increase in [K+]e to 20.9±3.8 and 13.4±3.4 mM at 5 min post-CCI in CCI-vehicle-ISE and CCI-SR49059-ISE groups, respectively (p<0.001 vs. baseline; ns between groups). Importantly, [Na+]e in CCI-SR49059-ISE was reduced 5–20 min post-injury and increased to baseline at 25 min, whereas recovery in CCI-vehicle-ISE required more than 1 hr, suggesting SR49059 accelerated [Na+]e recovery. In contrast, [K+]e recovery took 45 min in both groups. Further, ICP was lower in the CCI-SR49059-ISE group. Thus, selective V1aR inhibition allowed faster [Na+]e recovery and reduced ICP. By augmenting the [Na+]e recovery rate, SR49059 may reduce trauma-induced ionic imbalance, blunting cellular water influx and edema after TBI. These findings suggest SR49059 and V1aR inhibitors are potential tools for treating cellular edema post-TBI.
doi:10.1089/neu.2013.3063
PMCID: PMC4108937  PMID: 24635833
AQP4; cations; TBI; V1a receptor; vasopressin
5.  Inhibition of Src Family Kinases Protects Hippocampal Neurons and Improves Cognitive Function after Traumatic Brain Injury 
Journal of Neurotrauma  2014;31(14):1268-1276.
Abstract
Traumatic brain injury (TBI) is often associated with intracerebral and intraventricular hemorrhage. Thrombin is a neurotoxin generated at bleeding sites fater TBI and can lead to cell death and subsequent cognitive dysfunction via activation of Src family kinases (SFKs). We hypothesize that inhibiting SFKs can protect hippocampal neurons and improve cognitive memory function after TBI. To test these hypotheses, we show that moderate lateral fluid percussion (LFP) TBI in adult rats produces bleeding into the cerebrospinal fluid (CSF) in both lateral ventricles, which elevates oxyhemoglobin and thrombin levels in the CSF, activates the SFK family member Fyn, and increases Rho-kinase 1(ROCK1) expression. Systemic administration of the SFK inhibitor, PP2, immediately after moderate TBI blocks ROCK1 expression, protects hippocampal CA2/3 neurons, and improves spatial memory function. These data suggest the possibility that inhibiting SFKs after TBI might improve clinical outcomes.
doi:10.1089/neu.2013.3250
PMCID: PMC4108941  PMID: 24428562
cognitive memory deficits; hemorrhage; Src family kinases (SFKs); thrombin; traumatic brain injury (TBI)
6.  Sleep Problems and Their Relationship to Cognitive and Behavioral Outcomes in Young Children with Traumatic Brain Injury 
Journal of Neurotrauma  2014;31(14):1305-1312.
Abstract
This study examined the effect of traumatic brain injury (TBI) in young children on sleep problems and the relationship of sleep problems to neuropsychological and psychosocial functioning. Participants were drawn from an ongoing longitudinal study of injury in young children recruited from 3 to 6 years of age. They constituted three groups: orthopedic injury (OI; n=92), complicated mild/moderate TBI (mTBI; n=55); and severe TBI (sTBI; n=20). Caregivers completed the Children's Sleep Habits Questionnaire (CSHQ), as well as ratings of behavioral adjustment, adaptive functioning, and everyday executive function at 1, 6, 12, and 18 months postinjury. Retrospective ratings of preinjury sleep and psychosocial functioning were obtained at the initial assessment. Children completed neuropsychological testing at all occasions. Children with complicated mTBI demonstrated more total sleep problems than children with OI at 6 months postinjury, but not at 12 or 18 months. Children with sTBI displayed more bedtime resistance and shorter sleep duration than those with complicated mTBI or OI at several occasions. Across groups, total sleep problems predicted more emotional and behavioral problems and worse everyday executive function as rated by parents across follow-up occasions. In contrast, sleep problems were generally not related to neuropsychological test performance. The results suggest that young children with TBI demonstrate more sleep problems than children with injuries not involving the head. Sleep problems, in turn, significantly increase the risk of poor psychosocial outcomes across time, but are not associated with worse neuropsychological test performance.
doi:10.1089/neu.2013.3275
PMCID: PMC4108979  PMID: 24665961
behavior; cognitive ability; preschool; sleep; traumatic brain injury
7.  Using the Olfactory System as an In Vivo Model To Study Traumatic Brain Injury and Repair 
Journal of Neurotrauma  2014;31(14):1277-1291.
Abstract
Loss of olfactory function is an early indicator of traumatic brain injury (TBI). The regenerative capacity and well-defined neural maps of the mammalian olfactory system enable investigations into the degeneration and recovery of neural circuits after injury. Here, we introduce a unique olfactory-based model of TBI that reproduces many hallmarks associated with human brain trauma. We performed a unilateral penetrating impact to the mouse olfactory bulb and observed a significant loss of olfactory sensory neurons (OSNs) in the olfactory epithelium (OE) ipsilateral to the injury, but not contralateral. By comparison, we detected the injury markers p75NTR, β-APP, and activated caspase-3 in both the ipsi- and contralateral OE. In the olfactory bulb (OB), we observed a graded cell loss, with ipsilateral showing a greater reduction than contralateral and both significantly less than sham. Similar to OE, injury markers in the OB were primarily detected on the ipsilateral side, but also observed contralaterally. Behavioral experiments measured 4 days after impact also demonstrated loss of olfactory function, yet following a 30-day recovery period, we observed a significant improvement in olfactory function and partial recovery of olfactory circuitry, despite the persistence of TBI markers. Interestingly, by using the M71-IRES-tauLacZ reporter line to track OSN organization, we further determined that inducing neural activity during the recovery period with intense odor conditioning did not enhance the recovery process. Together, these data establish the mouse olfactory system as a new model to study TBI, serving as a platform to understand neural disruption and the potential for circuit restoration.
doi:10.1089/neu.2013.3296
PMCID: PMC4108980  PMID: 24694002
apoptosis; APP; biomarker; circuit repair; mouse model; olfactory system; p75NTR; regeneration; traumatic brain injury
8.  Exposure of the Thorax to a Sublethal Blast Wave Causes a Hydrodynamic Pulse That Leads to Perivenular Inflammation in the Brain 
Journal of Neurotrauma  2014;31(14):1292-1304.
Abstract
Traumatic brain injury (TBI) caused by an explosive blast (blast-TBI) is postulated to result, in part, from transvascular transmission to the brain of a hydrodynamic pulse (a.k.a., volumetric blood surge, ballistic pressure wave, hydrostatic shock, or hydraulic shock) induced in major intrathoracic blood vessels. This mechanism of blast-TBI has not been demonstrated directly. We tested the hypothesis that a blast wave impacting the thorax would induce a hydrodynamic pulse that would cause pathological changes in the brain. We constructed a Thorax-Only Blast Injury Apparatus (TOBIA) and a Jugular-Only Blast Injury Apparatus (JOBIA). TOBIA delivered a collimated blast wave to the right lateral thorax of a rat, precluding direct impact on the cranium. JOBIA delivered a blast wave to the fluid-filled port of an extracorporeal intravenous infusion device whose catheter was inserted retrograde into the jugular vein, precluding lung injury. Long Evans rats were subjected to sublethal injury by TOBIA or JOBIA. Blast injury induced by TOBIA was characterized by apnea and diffuse bilateral hemorrhagic injury to the lungs associated with a transient reduction in pulse oximetry signals. Immunolabeling 24 h after injury by TOBIA showed up-regulation of tumor necrosis factor alpha, ED-1, sulfonylurea receptor 1 (Sur1), and glial fibrillary acidic protein in veins or perivenular tissues and microvessels throughout the brain. The perivenular inflammatory effects induced by TOBIA were prevented by ligating the jugular vein and were reproduced using JOBIA. We conclude that blast injury to the thorax leads to perivenular inflammation, Sur1 up-regulation, and reactive astrocytosis resulting from the induction of a hydrodynamic pulse in the vasculature.
doi:10.1089/neu.2013.3016
PMCID: PMC4108981  PMID: 24673157
blast-TBI; ED-1; GFAP; perivenular inflammation; Sur1, TNF-α
9.  Activation of NF-κB Mediates Astrocyte Swelling and Brain Edema in Traumatic Brain Injury 
Journal of Neurotrauma  2014;31(14):1249-1257.
Abstract
Brain edema and associated increased intracranial pressure are major consequences of traumatic brain injury (TBI). While astrocyte swelling (cytotoxic edema) represents a major component of the brain edema in the early phase of TBI, its mechanisms are unclear. One factor known to be activated by trauma is nuclear factor-κB (NF-κB). Because this factor has been implicated in the mechanism of cell swelling/brain edema in other neurological conditions, we examined whether NF-κB might also be involved in the mediation of post-traumatic astrocyte swelling/brain edema. Here we show an increase in NF-κB activation in cultured astrocytes at 1 and 3 h after trauma (fluid percussion injury, FPI), and that BAY 11–7082, an inhibitor of NF-κB, significantly blocked the trauma-induced astrocyte swelling. Increased activities of nicotinamide adenine dinucleotide phosphate-oxidase and the Na+, K+, 2Cl- cotransporter were also observed in cultured astrocytes after trauma, and BAY 11–7082 reduced these effects. We also examined the role of NF-κB in the mechanism of cell swelling by using astrocyte cultures derived from transgenic (Tg) mice with a functional inactivation of astrocytic NF-κB. Exposure of cultured astrocytes from wild-type mice to in vitro trauma (3 h) caused a significant increase in cell swelling. By contrast, traumatized astrocyte cultures derived from NF-κB Tg mice showed no swelling. We also found increased astrocytic NF-κB activation and brain water content in rats after FPI, while BAY 11-7082 significantly reduced such effects. Our findings strongly suggest that activation of astrocytic NF-κB represents a key element in the process by which cytotoxic brain edema occurs after TBI.
doi:10.1089/neu.2013.3169
PMCID: PMC4108982  PMID: 24471369
astrocyte swelling; NF-κB, traumatic brain injury; transgenic mice
10.  PEG-PDLLA Micelle Treatment Improves Axonal Function of the Corpus Callosum following Traumatic Brain Injury 
Journal of Neurotrauma  2014;31(13):1172-1179.
Abstract
The initial pathological changes of diffuse axonal injury following traumatic brain injury (TBI) include membrane disruption and loss of ionic homeostasis, which further lead to dysfunction of axonal conduction and axon disconnection. Resealing the axolemma is therefore a potential therapeutic strategy for the early treatment of TBI. Monomethoxy poly (ethylene glycol)-poly (D, L–lactic acid) di-block copolymer micelles (mPEG-PDLLA) have been shown to restore depressed compound action potentials (CAPs) of spinal axons and promote functional recovery after spinal cord injury. Here, we evaluate the effect of the micelles on repairing the injured cortical axons following TBI. Adult mice subjected to controlled cortical impact (CCI) were treated with intravenous injection of the micelles at 0 h or 4 h after injury. Evoked CAPs were recorded from the corpus callosum of coronal cortical slices at 2 days after injury. The CCI caused significant decreases in the amplitudes of two CAP peaks that were respectively generated by the faster myelinated axons and slower unmyelinated axons. Micelle treatment at both 0 h and 4 h after CCI resulted in significant increases in both CAP peak amplitudes. Injection of fluorescent dye-labeled micelles revealed high fluorescent staining in cortical gray and white matters underneath the impact site. Labeling membrane-perforated neurons by injecting a membrane impermeable dye Texas Red-labeled dextran into lateral ventricles at 2 h post-CCI revealed that immediate micelle injection after CCI did not reduce the number of dye-stained cortical neurons and dentate granule cells of the hippocampus, indicating its ineffectiveness in repairing plasma membrane of neuronal somata. We conclude that intravenous administration of mPEG-PDLLA micelles immediately or at 4 h after TBI allows brain penetration via the compromised blood brain–barrier, and thereby improves the function of both myelinated and unmyelinated axons of the corpus callosum.
doi:10.1089/neu.2013.3147
PMCID: PMC4082361  PMID: 24579802
axon; CAP; cerebral cortex; micelles; TBI
11.  Prevalence of Pituitary Hormone Dysfunction, Metabolic Syndrome, and Impaired Quality of Life in Retired Professional Football Players: A Prospective Study 
Journal of Neurotrauma  2014;31(13):1161-1171.
Abstract
Hypopituitarism is common after moderate and severe traumatic brain injury (TBI). Herein, we address the association between mild TBI (mTBI) and pituitary and metabolic function in retired football players. Retirees 30–65 years of age, with one or more years of National Football League (NFL) play and poor quality of life (QoL) based on Short Form 36 (SF-36) Mental Component Score (MCS) were prospectively enrolled. Pituitary hormonal and metabolic syndrome (MetS) testing was performed. Using a glucagon stimulation test, growth hormone deficiency (GHD) was defined with a standard cut point of 3 ng/mL and with a more stringent body mass index (BMI)-adjusted cut point. Subjects with and without hormonal deficiency (HD) were compared in terms of QoL, International Index of Erectile Function (IIEF) scores, metabolic parameters, and football career data. Of 74 subjects, 6 were excluded because of significant non-football-related TBIs. Of the remaining 68 subjects (mean age, 47.3±10.2 years; median NFL years, 5; median NFL concussions, 3; mean BMI, 33.8±6.0), 28 (41.2%) were GHD using a peak GH cutoff of <3 ng/mL. However, with a BMI-adjusted definition of GHD, 13 of 68 (19.1%) were GHD. Using this BMI-adjusted definition, overall HD was found in 16 (23.5%) subjects: 10 (14.7%) with isolated GHD; 3 (4.4%) with isolated hypogonadism; and 3 (4.4%) with both GHD and hypogonadism. Subjects with HD had lower mean scores on the IIEF survey (p=0.016) and trended toward lower scores on the SF-36 MCS (p=0.113). MetS was present in 50% of subjects, including 5 of 6 (83%) with hypogonadism, and 29 of 62 (46.8%) without hypogonadism (p=0.087). Age, BMI, median years in NFL, games played, number of concussions, and acknowledged use of performance-enhancing steroids were similar between HD and non-HD groups. In summary, in this cohort of retired NFL players with poor QoL, 23.5% had HD, including 19% with GHD (using a BMI-adjusted definition), 9% with hypogonadism, and 50% had MetS. Although the cause of HD is unclear, these results suggest that GHD and hypogonadism may contribute to poor QoL, erectile dysfunction, and MetS in this population. Further study of pituitary function is warranted in athletes sustaining repetitive mTBI.
doi:10.1089/neu.2013.3212
PMCID: PMC4082350  PMID: 24552537
growth hormone deficiency; hypogonadism; metabolic syndrome; mild traumatic brain injury; professional football
12.  Temporal and Spatial Dynamics of Nrf2-Antioxidant Response Elements Mediated Gene Targets in Cortex and Hippocampus after Controlled Cortical Impact Traumatic Brain Injury in Mice 
Journal of Neurotrauma  2014;31(13):1194-1201.
Abstract
The pathophysiological importance of oxidative damage after traumatic brain injury (TBI) has been extensively demonstrated. The transcription factor nuclear factor erythoid related factor 2 (Nrf2) mediates antioxidant and cytoprotective genes by binding to antioxidant response elements (ARE) present in nuclear DNA. In this study, we characterized the time course of Nrf2-ARE–mediated expression in the cortex and hippocampus using a unilateral controlled cortical impact model of focal TBI. Ipsilateral hippocampal and cortical tissue was collected for Western-blot protein analysis (n=6/group) or quantitative reverse transcription-polymerase chain reaction for mRNA (n=3/group) at 3, 6, 12, 24, 48, and 72 h or 1 week post-injury. Multiple genes mediated by Nrf2-ARE were altered post-TBI. Specifically, Nrf2 mRNA increased significantly post-TBI at 48 and 72 h in the cortex and at 48 and 72 h and 1 week in the hippocampus with a coincident increase in glial fibrillary acidic protein mRNA, thereby implying this response is likely occurring in astrocytes. Presumably linked to Nrf2 activation, heme-oxygenase-1, nicotinamide adenine dinucleotide phosphate-quinone-oxidoreductase 1, glutathione reductase, and catalase mRNA overlap throughout the post-injury time course. This study demonstrates the first evidence of such changes during the first week after focal TBI and that increases in expression of some Nrf2-ARE–mediated cytoprotective genes are not observed until 24–48 h post-injury. Unfortunately, this does not precede, but rather coincides with, the occurrence of lipid peroxidative damage. This is the first known comparison between the time course of peroxidative damage and that of Nrf2-ARE activation during the first week post-TBI. These results underscore the necessity to discover pharmacological agents to accelerate and amplify Nrf2-ARE–mediated expression early post-TBI.
doi:10.1089/neu.2013.3218
PMCID: PMC4082355  PMID: 24628668
4-hydroxy-2-nonenal; gene expression; lipid peroxidation; Nrf2; oxidative damage; traumatic brain injury
13.  MMP-9 Inhibitor SB-3CT Attenuates Behavioral Impairments and Hippocampal Loss after Traumatic Brain Injury in Rat 
Journal of Neurotrauma  2014;31(13):1225-1234.
Abstract
The aim of this study was to evaluate the potential efficacy of SB-3CT, a matrix metallopeptidase 9 inhibitor, on behavioral and histological outcomes after traumatic brain injury (TBI) in rats. Adult male Sprague-Dawley rats were randomly divided into three groups (n=15/group): TBI with SB-3CT treatment, TBI with saline, and sham injury. The TBI model was induced by a fluid percussion TBI device. SB-3CT (50 mg/kg in 10% dimethyl sulfoxide) was administered intraperitoneally at 30 min, 6 h, and 12 h after the TBI. Motor function (beam-balance/beam-walk tests) and spatial learning/memory (Morris water maze) were assessed on post-operative Days 1−5 and 11–15, respectively. Fluoro-Jade staining, immunofluorescence, and cresyl violet-staining were carried out for histopathological evaluation at 24 h, 72 h, and 15 days after TBI, respectively. It was shown that TBI can result in significant behavioral deficit induced by acute neurodegeneration, increased expression of cleaved caspase-3, and long-term neuronal loss. SB-3CT intervention via the current regime provides robust behavioral protection and hippocampal neurons preservation from the deleterious effects of TBI. Hence, the efficacy of SB-3CT on TBI prognosis could be ascertained. It is believed that the current study adds to the growing literature in identifying SB-3CT as a potential therapy for human brain injury.
doi:10.1089/neu.2013.3230
PMCID: PMC4082357  PMID: 24661104
hippocampus; neuroprotection; SB-3CT; traumatic brain injury
14.  Linking Traumatic Brain Injury to Chronic Traumatic Encephalopathy: Identification of Potential Mechanisms Leading to Neurofibrillary Tangle Development 
Journal of Neurotrauma  2014;31(13):1129-1138.
Abstract
Significant attention has recently been drawn to the potential link between head trauma and the development of neurodegenerative disease, namely chronic traumatic encephalopathy (CTE). The acute neurotrauma associated with sports-related concussions in athletes and blast-induced traumatic brain injury in soldiers elevates the risk for future development of chronic neurodegenerative diseases such as CTE. CTE is a progressive disease distinguished by characteristic tau neurofibrillary tangles (NFTs) and, occasionally, transactive response DNA binding protein 43 (TDP43) oligomers, both of which have a predilection for perivascular and subcortical areas near reactive astrocytes and microglia. The disease is currently only diagnosed postmortem by neuropathological identification of NFTs. A recent workshop sponsored by National Institute of Neurological Disorders and Stroke emphasized the need for premortem diagnosis, to better understand disease pathophysiology and to develop targeted treatments. In order to accomplish this objective, it is necessary to discover the mechanistic link between acute neurotrauma and the development of chronic neurodegenerative and neuropsychiatric disorders such as CTE. In this review, we briefly summarize what is currently known about CTE development and pathophysiology, and subsequently discuss injury-induced pathways that warrant further investigation. Understanding the mechanistic link between acute brain injury and chronic neurodegeneration will facilitate the development of appropriate diagnostic and therapeutic options for CTE and other related disorders.
doi:10.1089/neu.2013.3303
PMCID: PMC4089022  PMID: 24499307
chronic traumatic encephalopathy; neurofibrillary tangles
15.  Assessment of Depression in a Rodent Model of Spinal Cord Injury 
Journal of Neurotrauma  2014;31(12):1107-1121.
Abstract
Despite an increased incidence of depression in patients after spinal cord injury (SCI), there is no animal model of depression after SCI. To address this, we used a battery of established tests to assess depression after a rodent contusion injury. Subjects were acclimated to the tasks, and baseline scores were collected before SCI. Testing was conducted on days 9–10 (acute) and 19–20 (chronic) postinjury. To categorize depression, subjects' scores on each behavioral measure were averaged across the acute and chronic stages of injury and subjected to a principal component analysis. This analysis revealed a two-component structure, which explained 72.2% of between-subjects variance. The data were then analyzed with a hierarchical cluster analysis, identifying two clusters that differed significantly on the sucrose preference, open field, social exploration, and burrowing tasks. One cluster (9 of 26 subjects) displayed characteristics of depression. Using these data, a discriminant function analysis was conducted to derive an equation that could classify subjects as “depressed” on days 9–10. The discriminant function was used in a second experiment examining whether the depression-like symptoms could be reversed with the antidepressant, fluoxetine. Fluoxetine significantly decreased immobility in the forced swim test (FST) in depressed subjects identified with the equation. Subjects that were depressed and treated with saline displayed significantly increased immobility on the FST, relative to not depressed, saline-treated controls. These initial experiments validate our tests of depression, generating a powerful model system for further understanding the relationships between molecular changes induced by SCI and the development of depression.
doi:10.1089/neu.2013.3204
PMCID: PMC4062114  PMID: 24564232
contusion; depression; fluoxetine; quality of life; spinal cord injury
16.  Functional Near-Infrared Spectroscopy Reveals Reduced Interhemispheric Cortical Communication after Pediatric Concussion 
Journal of Neurotrauma  2015;32(11):833-840.
Abstract
Concussion, or mild traumatic brain injury (mTBI), is a growing concern, especially among the pediatric population. By age 25, as many as 30% of the population are likely to have had a concussion. Many result in long-term disability, with some evolving to postconcussion syndrome. Treatments are being developed, but are difficult to assess given the lack of measures to quantitatively monitor concussion. There is no accepted quantitative imaging metric for monitoring concussion. We hypothesized that because cognitive function and fiber tracks are often impacted in concussion, interhemispheric brain communication may be impaired. We used functional near-infrared spectroscopy (fNIRS) to quantify functional coherence between the left and right motor cortex as a marker of interhemispheric communication. Studies were undertaken during the resting state and with a finger-tapping task to activate the motor cortex. Pediatric patients (ages 12–18) had symptoms for 31–473 days, compared to controls, who have not had reported a previous concussion. We detected differences between patients and controls in coherence between the contralateral motor cortices using measurements of total hemoglobin and oxy-hemoglobin with a p<0.01 (n=8, control; n=12 mTBI). Given the critical need for a quantitative biomarker for recovery after a concussion, we present these data to highlight the potential of fNIRS coupled with interhemispheric coherence analysis as a biomarker of concussion injury.
doi:10.1089/neu.2014.3577
PMCID: PMC4449632  PMID: 25387354
coherence; concussion; fNIRS; mild traumatic brain injury; near infrared spectroscopy
17.  Significant Improvements in Cognitive Performance Post-Transcranial, Red/Near-Infrared Light-Emitting Diode Treatments in Chronic, Mild Traumatic Brain Injury: Open-Protocol Study 
Journal of Neurotrauma  2014;31(11):1008-1017.
Abstract
This pilot, open-protocol study examined whether scalp application of red and near-infrared (NIR) light-emitting diodes (LED) could improve cognition in patients with chronic, mild traumatic brain injury (mTBI). Application of red/NIR light improves mitochondrial function (especially in hypoxic/compromised cells) promoting increased adenosine triphosphate (ATP) important for cellular metabolism. Nitric oxide is released locally, increasing regional cerebral blood flow. LED therapy is noninvasive, painless, and non-thermal (cleared by the United States Food and Drug Administration [FDA], an insignificant risk device). Eleven chronic, mTBI participants (26–62 years of age, 6 males) with nonpenetrating brain injury and persistent cognitive dysfunction were treated for 18 outpatient sessions (Monday, Wednesday, Friday, for 6 weeks), starting at 10 months to 8 years post- mTBI (motor vehicle accident [MVA] or sports-related; and one participant, improvised explosive device [IED] blast injury). Four had a history of multiple concussions. Each LED cluster head (5.35 cm diameter, 500 mW, 22.2 mW/cm2) was applied for 10 min to each of 11 scalp placements (13 J/cm2). LEDs were placed on the midline from front-to-back hairline; and bilaterally on frontal, parietal, and temporal areas. Neuropsychological testing was performed pre-LED, and at 1 week, and 1 and 2 months after the 18th treatment. A significant linear trend was observed for the effect of LED treatment over time for the Stroop test for Executive Function, Trial 3 inhibition (p=0.004); Stroop, Trial 4 inhibition switching (p=0.003); California Verbal Learning Test (CVLT)-II, Total Trials 1–5 (p=0.003); and CVLT-II, Long Delay Free Recall (p=0.006). Participants reported improved sleep, and fewer post-traumatic stress disorder (PTSD) symptoms, if present. Participants and family reported better ability to perform social, interpersonal, and occupational functions. These open-protocol data suggest that placebo-controlled studies are warranted.
doi:10.1089/neu.2013.3244
PMCID: PMC4043367  PMID: 24568233
executive function; mTBI; photobiomodulation; treatment for mTBI
18.  Methylene Blue Is Neuroprotective against Mild Traumatic Brain Injury 
Journal of Neurotrauma  2014;31(11):1063-1071.
Abstract
Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Methylene blue (MB) has known energy-enhancing and antioxidant properties. This study tested the hypothesis that MB treatment reduces lesion volume and behavioral deficits in a rat model of mild TBI. In a randomized double-blinded design, animals received either MB (n=5) or vehicle (n=6) after TBI. Studies were performed on 0, 1, 2, 7, and 14 days following an impact to the primary forelimb somatosensory cortex. MRI lesion was not apparent 1 h after TBI, became apparent 3 h after TBI, and peaked at 2 days for both groups. The MB-treated animals showed significantly smaller MRI lesion volume than the vehicle-treated animals at all time points studied. The MB-treated animals exhibited significantly improved scores on forelimb placement asymmetry and foot fault tests than did the vehicle-treated animals at all time points studied. Smaller numbers of dark-stained Nissl cells and Fluoro-Jade® positive cells were observed in the MB-treated group than in vehicle-treated animals 14 days post-TBI. In conclusion, MB treatment minimized lesion volume, behavioral deficits, and neuronal degeneration following mild TBI. MB is already approved by the United States Food and Drug Administration (FDA) to treat a number of indications, likely expediting future clinical trials in TBI.
doi:10.1089/neu.2013.3193
PMCID: PMC4043255  PMID: 24479842
antioxidant; mitochondria; MRI; oxidative stress; vasogenic edema
19.  Addressing the Challenges of Obtaining Functional Outcomes in Traumatic Brain Injury Research: Missing Data Patterns, Timing of Follow-Up, and Three Prognostic Models 
Journal of Neurotrauma  2014;31(11):1029-1038.
Abstract
Traumatic brain injury (TBI) is common and debilitating. Randomized trials of interventions for TBI ideally assess effectiveness by using long-term functional neurological outcomes, but such outcomes are difficult to obtain and costly. If there is little change between functional status at hospital discharge versus 6 months, then shorter-term outcomes may be adequate for use in future clinical trials. Using data from a previously published multi-center, randomized, placebo-controlled TBI clinical trial, we evaluated patterns of missing outcome data, changes in functional status between hospital discharge and 6 months, and three prognostic models to predict long-term functional outcome from covariates available at hospital discharge (functional measures, demographics, and injury characteristics). The Resuscitation Outcomes Consortium Hypertonic Saline trial enrolled 1282 TBI patients, obtaining the primary outcome of 6-month Glasgow Outcome Score Extended (GOSE) for 85% of patients, but missing the primary outcome for the remaining 15%. Patients with missing outcomes had less-severe injuries, higher neurological function at discharge (GOSE), and shorter hospital stays than patients whose GOSE was obtained. Of 1066 (83%) patients whose GOSE was obtained both at hospital discharge and at 6-months, 71% of patients had the same dichotomized functional status (severe disability/death vs. moderate/no disability) after 6 months as at discharge, 28% had an improved functional status, and 1% had worsened. Performance was excellent (C-statistic between 0.88 and 0.91) for all three prognostic models and calibration adequate for two models (p values, 0.22 and 0.85). Our results suggest that multiple imputation of the standard 6-month GOSE may be reasonable in TBI research when the primary outcome cannot be obtained through other means.
doi:10.1089/neu.2013.3122
PMCID: PMC4043258  PMID: 24552494
clinical trial design; functional outcomes; prognostic models; traumatic brain injury
20.  Old Dog, New Tricks: The Attentional Set-Shifting Test as a Novel Cognitive Behavioral Task after Controlled Cortical Impact Injury 
Journal of Neurotrauma  2014;31(10):926-937.
Abstract
Cognitive impairment associated with prefrontal cortical dysfunction is a major component of disability in traumatic brain injury (TBI) survivors. Specifically, deficits of cognitive flexibility and attentional set-shifting are present across all levels of injury severity. Though alterations in spatial learning have been extensively described in experimental models of TBI, studies investigating more complex cognitive deficits are relatively scarce. Hence, the aim of this preclinical study was to expand on this important issue by evaluating the effect of three injury levels on executive function and behavioral flexibility performance as assessed using an attentional set-shifting test (AST). Isoflurane-anesthetized male rats received a controlled cortical impact (CCI) injury (2.6, 2.8, and 3.0 mm cortical depth at 4 m/sec) or sham injury, whereas an additional group had no surgical manipulation (naïve). Four weeks postsurgery, rats were tested on the AST, which involved a series of discriminative tasks of increasing difficulty, such as simple and compound discriminations, stimulus reversals, and intra- and extradimensional (ED) shifts. TBI produced accompanying impact depth-dependent increases in cortical lesion volumes, with the 3.0-mm cortical depth group displaying significantly larger injury volumes than the 2.6-mm group (p=0.05). Further, injury severity-induced deficits in ED set-shifting and stimulus reversals, as well as increases in total response error rates and total set loss errors, were observed. These novel findings demonstrate executive function and behavioral flexibility deficits in our animal model of CCI injury and provide the impetus to integrate the AST in the standard neurotrauma behavioral battery to further evaluate cognitive dysfunction after TBI. Ongoing experiments in our laboratory are assessing AST performance after pharmacological and rehabilitative therapies post-TBI, as well as elucidating possible mechanisms underlying the observed neuropsychological deficits.
doi:10.1089/neu.2013.3295
PMCID: PMC4012626  PMID: 24397572
attentional set-shifting; behavior; controlled cortical impact; executive function; traumatic brain injury
21.  Environmental Enrichment as a Viable Neurorehabilitation Strategy for Experimental Traumatic Brain Injury 
Journal of Neurotrauma  2014;31(10):873-888.
Abstract
Environmental enrichment (EE) emerged as a robust independent variable capable of influencing behavioral outcome in experimental studies after the fortuitous observation by renowned neuropsychologist Donald O. Hebb that rats raised as pets in his home performed markedly better on problem-solving tasks than those kept in the laboratory. In the subsequent years, numerous studies ensued demonstrating that EE was also capable of inducing neuroplasticity in normal (i.e., noninjured) rats. These behavioral and neural alterations provided the impetus for investigating EE as a potential therapy for traumatic brain injury (TBI), which, over the past two decades, has resulted in several reports. Hence, the aim of this review is to integrate the findings and present the current state of EE as a viable neurorehabilitation strategy for TBI. Using the specific key term searches “traumatic brain injury” and “environmental enrichment” or “enriched environment,” 30 and 30 experimental TBI articles were identified by PubMed and Scopus, respectively. Of these, 27 articles were common to both search engines. An additional article was found on PubMed using the key terms “enriched environment” and “fluid percussion.” A review of the bibliographies in the 34 articles did not yield additional citations. The overwhelming consensus of the 34 publications is that EE benefits behavioral and histological outcome after brain injury produced by various models. Further, the enhancements are observed in male and female as well as adult and pediatric rats and mice. Taken together, these cumulative findings provide strong support for EE as a generalized and robust preclinical model of neurorehabilitation. However, to further enhance the model and to more accurately mimic the clinic, future studies should continue to evaluate EE during more rehabilitation-relevant conditions, such as delayed and shorter time periods, as well as in combination with other therapeutic approaches, as we have been doing for the past few years.
doi:10.1089/neu.2014.3328
PMCID: PMC4012629  PMID: 24555571
behavior; brain injury; cognition, environmental enrichment; functional recovery; rehabilitation; water maze
22.  Diffusion Tensor Imaging Reveals White Matter Injury in a Rat Model of Repetitive Blast-Induced Traumatic Brain Injury 
Journal of Neurotrauma  2014;31(10):938-950.
Abstract
Blast-induced traumatic brain injury (bTBI) is one of the most common combat-related injuries seen in U.S. military personnel, yet relatively little is known about the underlying mechanisms of injury. In particular, the effects of the primary blast pressure wave are poorly understood. Animal models have proven invaluable for the study of primary bTBI, because it rarely occurs in isolation in human subjects. Even less is known about the effects of repeated primary blast wave exposure, but existing data suggest cumulative increases in brain damage with a second blast. MRI and, in particular, diffusion tensor imaging (DTI), have become important tools for assessing bTBI in both clinical and preclinical settings. Computational statistical methods such as voxelwise analysis have shown promise in localizing and quantifying bTBI throughout the brain. In this study, we use voxelwise analysis of DTI to quantify white matter injury in a rat model of repetitive primary blast exposure. Our results show a significant increase in microstructural damage with a second blast exposure, suggesting that primary bTBI may sensitize the brain to subsequent injury.
doi:10.1089/neu.2013.3144
PMCID: PMC4012630  PMID: 24392843
blast neurotrauma; diffusion tensor imaging; MRI; traumatic brain injury; voxelwise analysis
23.  Patterns of Early Emotional and Neuropsychological Sequelae after Mild Traumatic Brain Injury 
Journal of Neurotrauma  2014;31(10):914-925.
Abstract
Although mild traumatic brain injury (mTBI) is now recognized as a major health issue, there have been relatively few studies of its acute effects. Previous studies of mTBI assessed at 1 week or less post-injury have produced inconsistent results, spanning reports of no ill effects to findings of robust dysfunction. These gross disparities reflect study differences such as the criteria for mTBI diagnosis and selection of comparison groups. In consideration of these issues, this study investigated outcome in the first 96 hours after injury in adolescents and adults ages 12–30 years with mTBI (n=73) compared with orthopedically injured (OI, n=65) and typically developing controls (TDC, n=40). The mTBI group reported significantly greater general psychological distress, post-concussion symptom severity, and post-traumatic stress severity than OI (all p<0.0001) and TDC (all p<0.0001); the OI and TDC groups responded similarly on these variables. There was a significant Group×Age interaction on the Total score (p<0.009), and the Cognitive (p=0.01) and Somatic (p<0.032) subscales of the Rivermead Post Concussion Symptoms Questionnaire where increasing symptom severity was associated with increasing age in the mTBI group. On neuropsychological assessment, the mTBI group performed significantly more poorly compared with OI for Verbal Selective Reminding Test (delayed recall, p=0.0003) and Symbol-Digit Modalities Test (SDMT written p=0.03; oral, p=0.001). The TDC group more robustly outperformed the mTBI group on these measures and also on the Brief Visuospatial Memory Test (delayed recall, p<0.04), Letter Fluency (p<0.02), and Category Switching (p<0.04). The TDC group outperformed the OI group on SDMT and Letter Fluency. These findings are consistent with previous reports of acute deficits in episodic memory and processing speed acutely after mTBI. Notably, however, these data also demonstrate the challenges of comparison group selection because differences were also found between the TDC and OI groups.
doi:10.1089/neu.2012.2826
PMCID: PMC4012631  PMID: 24344952
memory; mild traumatic brain injury; post-concussion syndrome; post-traumatic stress disorder; processing speed
24.  Comparison of the Effect of Minocycline and Simvastatin on Functional Recovery and Gene Expression in a Rat Traumatic Brain Injury Model 
Journal of Neurotrauma  2014;31(10):961-975.
Abstract
The goal of this study was to compare the effects of minocycline and simvastatin on functional recovery and brain gene expression after a cortical contusion impact (CCI) injury. Dosage regimens were designed to provide serum concentrations in a rat model in the range obtained with clinically approved doses; minocycline 60 mg/kg q12h and simvastatin 10 mg/kg q12h for 72 h. Functional recovery was assessed using motor and spatial learning tasks and neuropathological measurements. Microarray-based transcriptional profiling was used to determine the effect on gene expression at 24 h, 72 h, and 7 days post-CCI. Gene Ontology analysis (GOA) was used to evaluate the effect on relevant biological pathways. Both minocycline and simvastatin improved fine motor function, but not gross motor or cognitive function. Minocycline modestly decreased lesion size with no effect of simvastatin. At 24 h post-CCI, GOA identified a significant effect of minocycline on chemotaxis, blood circulation, immune response, and cell to cell signaling pathways. Inflammatory pathways were affected by minocycline only at the 72 h time point. There was a minimal effect of simvastatin on gene expression 24 h after injury, with increasing effects at 72 h and 7 days. GOA identified a significant effect of simvastatin on inflammatory response at 72 h and 7 days. In conclusion, treatment with minocycline and simvastatin resulted in significant effects on gene expression in the brain reflecting adequate brain penetration without producing significant neurorestorative effects.
doi:10.1089/neu.2013.3119
PMCID: PMC4012634  PMID: 24308531
cortical contusion injury model; gene expression; minocycline; simvastatin; traumatic brain injury
25.  Granulocyte-Macrophage Colony-Stimulating Factor Is Neuroprotective in Experimental Traumatic Brain Injury 
Journal of Neurotrauma  2014;31(10):976-983.
Abstract
Traumatic brain injury (TBI) is an international health concern with a complex pathogenesis resulting in major long-term neurological, neurocognitive, and neuropsychiatric outcomes. Although neuroinflammation has been identified as an important pathophysiological process resulting from TBI, the function of specific inflammatory mediators in the aftermath of TBI remains poorly understood. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is an inflammatory cytokine that has been reported to have neuroprotective effects in various animal models of neurodegenerative disease that share pathological similarities with TBI. The importance of GM-CSF in TBI has yet to be studied, however. We examined the role of GM-CSF in TBI by comparing the effects of a lateral fluid percussion (LFP) injury or sham injury in GM-CSF gene deficient (GM-CSF-/-) versus wild-type (WT) mice. After a 3-month recovery interval, mice were assessed using neuroimaging and behavioral outcomes. All mice given a LFP injury displayed significant brain atrophy and behavioral impairments compared with those given sham-injuries; however, this was significantly worse in the GM-CSF-/- mice compared with the WT mice. GM-CSF-/- mice given LFP injury also had reduced astrogliosis compared with their WT counterparts. These novel findings indicate that the inflammatory mediator, GM-CSF, may have significant protective properties in the chronic sequelae of experimental TBI and suggest that further research investigating GM-CSF and its potential benefits in the injured brain is warranted.
doi:10.1089/neu.2013.3106
PMCID: PMC4012635  PMID: 24392832
animal studies; cytokine; inflammation; models of injury; MRI; traumatic brain injury

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