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1.  The health and life priorities of individuals with spinal cord injury: A systematic review 
Journal of neurotrauma  2012;29(8):1548-1555.
Determining the priorities of individuals with spinal cord injury (SCI) can assist in aligning research priorities which ultimately improve these individuals’ quality of life. This systematic review examined studies that directly surveyed people with SCI to ascertain their health priorities and life domains of importance. Twenty-four studies (combined sample of 5262) that met the inclusion criteria were identified using electronic databases (Medline, EMBASE, CINAHL, PsycINFO). The questionnaire methods and domains of importance were reviewed and described. While the questionnaires varied across the studies, a consistent set of priorities emerged. Functional recovery priorities were identified for the following areas: motor function (including arm/hand function for individuals with tetraplegia and mobility for individuals with paraplegia), bowel, bladder and sexual function. In addition, health, as well as relationships emerged as important life domains. The information from this study, which identified the priorities and domains of importance by individuals with SCI, may be useful for informing healthcare and research agenda-setting activities.
doi:10.1089/neu.2011.2226
PMCID: PMC3501530  PMID: 22320160 CAMSID: cams2491
SCI; consumer priorities; quality of life; well-being
2.  Functional Reinnervation of the Canine Bladder after Spinal Root Transection and Immediate Somatic Nerve Transfer 
Journal of neurotrauma  2008;25(3):214-224.
This study was performed to determine whether nerve transfer immediately after spinal root transection would lead to bladder reinnervation in a canine model. In one animal, the left T12 intercostal nerve was mobilized, cut and attached to the severed ends of sacral roots inducing bladder contraction using a graft from the T11 intercostal nerve. On the right side and bilaterally in two other dogs, coccygeal roots innervating tail musculature were cut and attached to the severed bladder sacral roots (coccygeal nerve transfer [CG NT]). In four other dogs, bladder sacral roots were transected in the vertebral column, and the genitofemoral nerve was transferred within the abdomen to the pelvic nerve (genitofemoral nerve transfer [GF NT]). After 14 months for CG NT and 4.5 months for GF NT, electrical stimulation of the pelvic nerve induced bladder pressure and urethral fluid flow on the intercostal nerve transfer side, in each of the five CG NT sites and bilaterally in three of the four GF NT animals. Reinnervation was further shown by retrograde labeling of spinal cord neurons following fluorogold injections into the bladder wall and by histological examination of the root/nerve suture sites. In all CG NT animals, labeled neuronal cell bodies were located in ventral horns in lamina IX of coccygeal cord segments. In the three GF NT animals in which pelvic nerve stimulation induced bladder contraction, abundant labeled cell bodies were observed in lamina IX and lateral zona intermedia of upper lumbar cord. These results clearly demonstrate that bladder reinnervation can be accomplished by immediate nerve transfer of intercostal nerves or coccygeal spinal roots to severed bladder sacral roots, or by transfer of peripheral genitofemoral nerves (L1,2 origin) to pelvic nerves.
doi:10.1089/neu.2007.0328
PMCID: PMC3604734  PMID: 18352835
animal studies; axonal injury; neuroplasticity; peripheral nerve injury; regeneration
3.  Functional Reinnervation of the Canine Bladder after Spinal Root Transection and Genitofemoral Nerve Transfer at One and Three Months after Denervation 
Journal of neurotrauma  2008;25(4):401-409.
In the immediate management of patients with spinal cord injury (SCI), patients are typically observed for a period of time to determine whether voluntary control of bladder function returns. Therefore, bladder reinnervation surgeries are not likely to be performed immediately after the injury. We performed genitofemoral to pelvic nerve transfer (GF NT) surgery in canines at 1 and 3 months after bladder denervation (transection of S1 and S2 spinal roots) to determine whether this type of bladder reinnervation surgery has potential clinical feasibility. Nerve cuff electrodes were implanted on the genitofemoral nerves proximal to the pelvic nerve transfer site. Evidence for bladder reinnervation includes (1) increased bladder pressure and urethral fluid flow following electrical stimulation in four out of 20 nerve cuff electrodes implanted on the transferred GF nerves, (2) bilateral pelvic nerve stimulation induced bladder pressure and urethral fluid flow in three of four denervated animals with 1-month delay GF NT, and in five of six denervated animals with 3-month delay GF NT, and (3) abundant L1 and L2 spinal cord cell bodies (the origin of the GF nerve) retrogradely labeled with fluorogold injected into the bladder in all 10 of the GF NT animals, except one animal on one side. This study presents initial proof of concept that GF NT is a potentially viable clinical approach to reinnervation of the lower motor neuron–lesioned urinary bladder.
doi:10.1089/neu.2007.0335
PMCID: PMC3578297  PMID: 18373487
animal studies; neural injury; recovery; regeneration; traumatic spinal cord injury
4.  Functional Reinnervation of the Canine Bladder after Spinal Root Transection and Immediate End-on-End Repair 
Journal of Neurotrauma  2006;23(7):1125-1136.
The goal of this study was to transect and immediately repair ventral roots, selected by their ability to stimulate bladder contraction, to assess the feasibility of bladder reinnervation in a canine model. Brain-derived neurotrophic factor (BDNF) was delivered via an osmotic pump (0.5 or 5 mg/mL) to a cuff surrounding the reanastomosis site to the two root bundles on one side. Electrodes were implanted bilaterally immediately proximal to the site of surgical reanastomosis. Results were compared to four root-intact, control animals that also received bilateral electrode implantation. At 6–12 months post-surgery, five of eight nerve transected and repaired animals showed increased pressure and bladder emptying during electrical stimulation of the repaired ventral roots contralateral to the BDNF delivery side. Nerve tracing studies one year postoperatively determined the repaired roots to be S1 and S2 and showed regrowth of axons from the spinal cord to nerve sites proximal to the repair site and to the bladder, and the presence of neurofilament-labeled axons growing across the ventral root repair site. In conclusion, transected ventral and dorsal roots in the sacral spine can be repaired and are capable of functionally reinnervating the urinary bladder. This feasibility study paves the way for future studies utilizing other more proximal motor nerves to bypass the transection site for bladder reinnervation.
doi:10.1089/neu.2006.23.1125
PMCID: PMC3285498  PMID: 16866625
axon regeneration; cauda equina; motor neurons; neurogenic bladder; spinal injuries; ventral and dorsal root repair
5.  Perfusional deficit and the dynamics of cerebral edemas in experimental traumatic brain injury using perfusion and diffusion-weighted magnetic resonance imaging 
Journal of Neurotrauma  2007;24(8):1321-1330.
The aim of this work was to characterize edema dynamics, cerebral blood volume and flow alterations in an experimental model of brain trauma using quantitative diffusion and perfusion MRI. Associated with an influx of water in the intracellular space 1–5hours post trauma as demonstrated by the 40% reduction in apparent diffusion coefficient, a 70–80% reduction in cerebral blood flow is measured within the lesioned region. Transient hypoperfusion (40–50%) was also observed in the non-traumatized contralateral hemisphere although there was no evidence of oedma formation. After the initial cytotoxic edema, a clear evolution toward extracellular water accumulation was observed, demonstrated by an increase in apparent diffusion coefficient.
doi:10.1089/neu.2006.0136
PMCID: PMC3218539  PMID: 17711393
Animals; Blood Flow Velocity; physiology; Blood Volume; physiology; Brain Edema; etiology; pathology; physiopathology; Brain Injuries; complications; pathology; physiopathology; Cerebrovascular Circulation; physiology; Contrast Media; Diffusion Magnetic Resonance Imaging; Female; Meglumine; diagnostic use; Organometallic Compounds; diagnostic use; Rats; Rats, Sprague-Dawley; Time Factors; Traumatic brain injury; Edema; Quantitative magnetic resonance imaging; Diffusion; ADC; Perfusion; DSC; Fluid lateral percussion.
6.  Reorganization and Preservation of Motor Control of the Brain in Spinal Cord Injury: A Systematic Review 
Journal of neurotrauma  2009;26(11):2113-2126.
Reorganization of brain function in people with CNS damage has been identified as one of the fundamental mechanisms involved in the recovery of sensori-motor function. Spinal cord injury (SCI) brain mapping studies during motor tasks aim for assessing the reorganization and preservation of brain networks involved in motor control. Revealing the activation of cortical and sub-cortical brain areas in people with SCI can indicate principal patterns of brain reorganization when the neurotrauma is distal to the brain. This review assessed brain activation after SCI in terms of intensity, volume, and somatotopic localization, as well as preservation of activation during attempted and/or imagined movements. Twenty-five studies meeting the inclusion criteria could be identified in MEDLINE (1980 to January 2008). Relevant characteristics of studies (level of lesion, time after injury, motor task) and mapping techniques varied widely. Changes in brain activation were found in both cortical and subcortical areas of individuals with SCI. In addition, several studies described a shift in the region of brain activation. These patterns appeared to be dynamic and influenced by the level, completeness and time after injury, as well as extent of clinical recovery. In addition, several aspects of reorganization of brain function following SCI resembled those reported in stroke. This review demonstrates that brain networks involved in different demands of motor control remain responsive even in chronic paralysis. These findings imply that therapeutic strategies aiming for restoring spinal cord function even in people with chronic SCI can build on a preserved competent brain control.
doi:10.1089/neu.2008.0688
PMCID: PMC3167869  PMID: 19604097 CAMSID: cams1872
SCI; neuroimaging; reorganization; motor; plasticity
7.  EXPRESSION OF PROTEIN PHOSPHATASE 2B (CALCINEURIN) SUBUNIT A ISOFORMS IN RAT HIPPOCAMPUS FOLLOWING A TRAUMATIC BRAIN INJURY 
Journal of neurotrauma  2010;27(1):109-120.
Calcineurin (CaN) is a calcium/calmodulin dependent phosphatase directly activated by calcium as a result of neuronal activation that is important for neuronal function. CaN subunit isoforms are implicated in long term potentiation (LTP), long term depression (LTD), and structural plasticity. CaN inhibitors are also beneficial to cognitive outcomes in animal models of traumatic brain injury (TBI). There are known changes in the CaN A (CnA) subunit following fluid percussion injury (FP). The CnA subunit has two isoforms CnAα and CnAβ. The effect of moderate controlled cortical impact (CCI) on distribution of CnA isoforms was examined at 2 hours and 2 weeks post injury. CnA distribution was assayed by immunohistochemistry and graded for non-parametric analysis. Acutely CnA isoforms showed reduced immunoreactivity in stratum radiatum processes of the ipsilateral CA1 and CA1-2. There was also a significant alteration in the immunoreactivity of both CnA isoforms in the ipsilateral dentate gyrus, predominantly within the hidden blade. Alterations in CnA isoform regional distribution within the CA1, CA1-2, and dentate gyrus may have significant implications for persistent hippocampal dysfunction following TBI, including dysfunctions in hippocampal plasticity. Understanding alterations in CnA isoform distribution may help improve the targeting of current therapeutic interventions and/or the development of new treatments for TBI.
doi:10.1089/neu.2009.1072
PMCID: PMC2812667  PMID: 19751097
Calcineurin; TBI; hippocampus
8.  Expression of Protein Phosphatase 2B (Calcineurin) Subunit A Isoforms in Rat Hippocampus after Traumatic Brain Injury 
Journal of Neurotrauma  2010;27(1):109-120.
Abstract
Calcineurin (CaN) is a calcium/calmodulin-dependent phosphatase directly activated by calcium as a result of neuronal activation that is important for neuronal function. CaN subunit isoforms are implicated in long-term potentiation (LTP), long-term depression (LTD), and structural plasticity. CaN inhibitors are also beneficial to cognitive outcomes in animal models of traumatic brain injury (TBI). There are known changes in the CaN A (CnA) subunit following fluid percussion injury (FPI). The CnA subunit has two isoforms: CnAα and CnAβ. The effect of moderate controlled cortical impact (CCI) on distribution of CnA isoforms was examined at 2 h and 2 weeks post-injury. CnA distribution was assayed by immunohistochemistry and graded for non-parametric analysis. Acutely CnA isoforms showed reduced immunoreactivity in stratum radiatum processes of the ipsilateral CA1 and CA1–2. There was also a significant alteration in the immunoreactivity of both CnA isoforms in the ipsilateral dentate gyrus, predominantly within the hidden blade. Alterations in CnA isoform regional distribution within the CA1, CA1–2, and dentate gyrus may have significant implications for persistent hippocampal dysfunction following TBI, including dysfunction in hippocampal plasticity. Understanding alterations in CnA isoform distribution may help improve the targeting of current therapeutic interventions and/or the development of new treatments for TBI.
doi:10.1089/neu.2009.1072
PMCID: PMC2812667  PMID: 19751097
calcineurin; hippocampus; traumatic brain injury
9.  Full Tensor Diffusion Imaging Is Not Required To Assess the White-Matter Integrity in Mouse Contusion Spinal Cord Injury 
Journal of Neurotrauma  2010;27(1):253-262.
Abstract
In vivo diffusion tensor imaging (DTI) derived indices have been demonstrated to quantify accurately white-matter injury after contusion spinal cord injury (SCI) in rodents. In general, a full diffusion tensor analysis requires the acquisition of diffusion-weighted images (DWI) along at least six independent directions of diffusion-sensitizing gradients. Thus, DTI measurements of the rodent central nervous system are time consuming. In this study, diffusion indices derived using the two-direction DWI (parallel and perpendicular to axonal tracts) were compared with those obtained using six-direction DTI in a mouse model of SCI. It was hypothesized that the mouse spinal cord ventral-lateral white-matter (VLWM) tracts, T8–T10 in this study, aligned with the main magnet axis (z) allowing the apparent diffusion coefficient parallel and perpendicular to the axis of the spine to be derived with diffusion-weighting gradients in the z and y axes of the magnet coordinate respectively. Compared with six-direction full tensor DTI, two-direction DWI provided comparable diffusion indices in mouse spinal cords. The measured extent of spared white matter after injury, estimated by anisotropy indices, using both six-direction DTI and two-direction DWI were in close agreement and correlated well with histological staining and behavioral assessment. The results suggest that the two-direction DWI derived indices may be used, with significantly reduced imaging time, to estimate accurately spared white matter in mouse SCI.
doi:10.1089/neu.2009.1026
PMCID: PMC2824236  PMID: 19715399
assessment tools; biomarkers; in vivo studies; MRI; traumatic spinal cord injury
10.  Recovery of Afferent Function and Synaptic Strength in Hippocampal CA1 following Traumatic Brain Injury 
Journal of Neurotrauma  2009;26(12):2269-2278.
Abstract
Cortical contusion injury can result in the partial loss of ipsilateral CA3 neurons within 48 h, leading to a proportional reduction in the number of afferent fibers to CA1 stratum radiatum. While the loss of afferent input to CA1 exhibits a remarkable, albeit incomplete, recovery over the next few weeks, little is known about the functional status of presynaptic afferents during the depletion and recovery phases following injury. Here, we prepared hippocampal slices from adult Sprague Dawley rats at 2, 7, and 14 days after lateral cortical contusion injury and measured fiber volley (FV) amplitudes extracellularly in CA1 stratum radiatum. Field excitatory post-synaptic potentials (EPSPs) were also measured and plotted as a function of FV amplitude to assess relative synaptic strength of residual and/or regenerated synaptic contacts. At 2 days post-injury, FV amplitude and synaptic strength were markedly reduced in the ipsilateral, relative to the contralateral, hippocampus. FV amplitude in ipsilateral CA1 showed a complete recovery by 7 days, indicative of a post-injury sprouting response. Synaptic strength in ipsilateral CA1 also showed a dramatic recovery over this time; however, EPSP-to-FV curves remained slightly suppressed at both the 7 and 14 day time points. Despite these deficits, ipsilateral slices retained the capacity to express long-term potentiation, indicating that at least some mechanisms for synaptic plasticity remain intact, or are compensated for. These results are in agreement with anatomical evidence showing a profound deafferentation, followed by a remarkable re-enervation, of ipsilateral CA1 in the first few weeks after traumatic brain injury. Although plasticity mechanisms appear to remain intact, synaptic strength deficits in CA1 could limit information throughput in the hippocampus, leading to persistent memory dysfunction.
doi:10.1089/neu.2009.1029
PMCID: PMC2824230  PMID: 19604098
cortical contusion injury; deafferentation; excitatory postsynaptic potential; fiber volley; Schaffer collaterals
11.  Gait Analysis in Normal and Spinal Contused Mice Using the TreadScan System 
Journal of Neurotrauma  2009;26(11):2045-2056.
Abstract
Advances in spinal cord injury (SCI) research are dependent on quality animal models, which in turn rely on sensitive outcome measures able to detect functional differences in animals following injury. To date, most measurements of dysfunction following SCI rely either on the subjective rating of observers or the slow throughput of manual gait assessment. The present study compares the gait of normal and contusion-injured mice using the TreadScan® system. TreadScan utilizes a transparent treadmill belt and a high-speed camera to capture the footprints of animals and automatically analyze gait characteristics. Adult female C57Bl/6 mice were introduced to the treadmill prior to receiving either a standardized mild, moderate, or sham contusion spinal cord injury. TreadScan gait analyses were performed weekly for 10 weeks and compared with scores on the Basso Mouse Scale (BMS). Results indicate that this software successfully differentiates sham animals from injured animals on a number of gait characteristics, including hindlimb swing time, stride length, toe spread, and track width. Differences were found between mild and moderate contusion injuries, indicating a high degree of sensitivity within the system. Rear track width, a measure of the animal's hindlimb base of support, correlated strongly both with spared white matter percentage and with terminal BMS. TreadScan allows for an objective and rapid behavioral assessment of locomotor function following mild-moderate contusive SCI, where the majority of mice still exhibit hindlimb weight support and plantar paw placement during stepping.
doi:10.1089/neu.2009.0914
PMCID: PMC2813489  PMID: 19886808
behavioral assessments; locomotor function; spinal cord injury (SCI)
12.  Axon Regeneration through Scaffold into Distal Spinal Cord after Transection 
Journal of Neurotrauma  2009;26(10):1759-1771.
Abstract
We employed Fast Blue (FB) axonal tracing to determine the origin of regenerating axons after thoracic spinal cord transection injury in rats. Schwann cell (SC)-loaded, biodegradable, poly(lactic-co-glycolic acid) (PLGA) scaffolds were implanted after transection. Scaffolds loaded with solubilized basement membrane preparation (without SCs) were used for negative controls, and nontransected cords were positive controls. One or 2 months after injury and scaffold implantation, FB was injected 0–15 mm caudal or about 5 mm rostral to the scaffold. One week later, tissue was harvested and the scaffold and cord sectioned longitudinally (30 μm) on a cryostat. Trans-scaffold labeling of neuron cell bodies was identified with confocal microscopy in all cell-transplanted groups. Large (30–50 μm diameter) neuron cell bodies were predominantly labeled in the ventral horn region. Most labeled neurons were seen 1–10 mm rostral to the scaffold, although some neurons were also labeled in the cervical cord. Axonal growth occurred bidirectionally after cord transection, and axons regenerated up to 14 mm beyond the PLGA scaffolds and into distal cord. The extent of FB labeling was negatively correlated with distance from the injection site to the scaffold. Electron microscopy showed myelinated axons in the transverse sections of the implanted scaffold 2 months after implantation. The pattern of myelination, with extracellular collagen and basal lamina, was characteristic of SC myelination. Our results show that FB labeling is an effective way to measure the origin of regenerating axons.
doi:10.1089/neu.2008.0610
PMCID: PMC2763055  PMID: 19413501
axonal tracing; biodegradable polymers; Fast Blue; Schwann cells; spinal cord injury
13.  Activity-Based Therapies To Promote Forelimb Use after a Cervical Spinal Cord Injury 
Journal of Neurotrauma  2009;26(10):1719-1732.
Abstract
Significant interest exists in strategies for improving forelimb function following spinal cord injury. We investigated the effect of enriched housing combined with skilled training on the recovery of skilled and automatic forelimb function after a cervical spinal cord injury in adult rats. All animals were pretrained in skilled reaching, gridwalk crossing, and overground locomotion. Some received a cervical over-hemisection lesion at C4-5, interrupting the right side of the spinal cord and dorsal columns bilaterally, and were housed in standard housing alone or enriched environments with daily training. A subset of animals received rolipram to promote neuronal plasticity. Animals were tested weekly for 4 weeks to measure reaching, errors on the gridwalk, locomotion, and vertical exploration. Biotinylated dextran amine was injected into the cortex to label the corticospinal tract. Enriched environments/daily training significantly increased the number and success of left reaches compared to standard housing. Animals also made fewer errors on the gridwalk, a measure of coordinated forelimb function. However, there were no significant improvements in forelimb use during vertical exploration or locomotion. Likewise, rolipram did not improve any of the behaviors tested. Both enriched housing and rolipram increased plasticity of the corticospinal tract rostral to the lesion. These studies indicate that skilled training after a cervical spinal cord injury improves recovery of skilled forelimb use (reaching) and coordinated limb function (gridwalk) but does not improve automatic forelimb function (locomotion and vertical exploration). These studies suggest that rehabilitating forelimb function after spinal cord injury will require separate strategies for descending and segmental pathways.
doi:10.1089/neu.2008.0592
PMCID: PMC2788495  PMID: 19317604
anatomical plasticity; enriched environment; functional recovery; rehabilitation; skilled forelimb use
14.  Neurometabolite Concentrations in Gray and White Matter in Mild Traumatic Brain Injury: An 1H–Magnetic Resonance Spectroscopy Study 
Journal of Neurotrauma  2009;26(10):1635-1643.
Abstract
Single-voxel proton magnetic resonance imaging (1H-MRS) and proton MR spectroscopic imaging (1H-MRSI) were used to compare brain metabolite levels in semi-acute mild traumatic brain injury (mTBI) patients (n = 10) and matched healthy controls (n = 9). The 1H-MRS voxel was positioned in the splenium, a region known to be susceptible to axonal injury in TBI, and a single 1H-MRSI slice was positioned above the lateral ventricles. To increase sensitivity to the glutamate (Glu) and the combined glutamate-glutamine (Glx) signal, an inter-pulse echo time shown to emphasize the major Glu signals was used along with an analysis method that reduces partial volume errors by using water as a concentration standard. Our preliminary findings indicate significantly lower levels of gray matter Glx and higher levels of white matter creatine-phosphocreatine (Cr) in mTBI subjects relative to healthy controls. Furthermore, Cr levels were predictive of executive function and emotional distress in the combined groups. These results suggest that perturbations in Cr, a critical component of the brain's energy metabolism, and Glu, the brain's major neurotransmitter, may occur following mTBI. Moreover, the different pattern of results for gray and white matter suggests tissue-specific metabolic responses to mTBI.
doi:10.1089/neu.2009.0896
PMCID: PMC2822798  PMID: 19355814
cognitive; creatine; glutamate; mild traumatic brain injury; spectroscopy
15.  Erythrocyte-Bound Tissue Plasminogen Activator is Neuroprotective in Experimental Traumatic Brain Injury 
Journal of Neurotrauma  2009;26(9):1585-1592.
Abstract
The purpose of this study was to test the effects of exogenous tissue plasminogen activator (tPA) in traumatic brain injury (TBI). We tested two different tPA formulations, free tPA and tPA bound to erythrocytes (RBC/tPA). Vehicle and each of the tPA treatments were injected intravenously into anesthetized rats 15 min after moderate lateral fluid percussion injury. The animals were sacrificed at 2 days for calculating microclot burden (n = 13) and IgG staining area (n = 13) in the brain sections as indicators of post-traumatic thrombosis and blood–brain barrier (BBB) breakdown, respectively. Another set of injured animals treated in the same way were sacrificed at 7 days to compare cortical lesion volumes (n = 28) and CA3 hippocampal cell loss (n = 24). All evaluations were done blinded with respect to treatment. No significant differences were found with respect to microclot burden or IgG staining volume. Injection of wild-type tPA caused significantly (p < 0.05) larger cortical injuries and greater cerebral hemorrhage. In contrast, there was significantly less cortical injury (p < 0.01) and hippocampal cell loss (p < 0.01) in the RBC/tPA group than in all other groups. These results reveal that RBC/tPA is more neuroprotective in experimental TBI than is unbound tPA.
doi:10.1089/neu.2008.0720
PMCID: PMC2766435  PMID: 19331516
blood–brain barrier; microclots; tissue plasminogen activator; traumatic brain injury
16.  Temporal and Spatial Dynamics of Peroxynitrite-Induced Oxidative Damage after Spinal Cord Contusion Injury 
Journal of Neurotrauma  2009;26(8):1369-1378.
Abstract
The reactive nitrogen species peroxynitrite (PN) has been suggested to be an important mediator of the secondary oxidative damage that occurs following acute spinal cord injury (SCI). The PN decomposition products nitrogen dioxide (•NO2), hydroxyl radical (•OH), and carbonate radical (•CO3) are highly reactive with cellular lipids and proteins. In this immunohistochemical study, we examined the temporal (3, 24, and 72 h, and 1 and 2 weeks) and spatial relationships of PN-mediated oxidative damage in the contusion-injured rat thoracic spinal cord (IH device, 200 kdyn, T10) using 3-nitrotyrosine (3-NT), a marker for protein nitration by PN-derived •NO2 and 4-hydroxynonenal (4-HNE), an indicator of lipid peroxidation (LP) initiated by any of the PN radicals. Minimal 3-NT or 4-HNE immunostaining was seen in sham, non-injured spinal cords. In contrast, both markers showed a substantial increase at 3 h post-injury at the epicenter, that extended throughout the gray matter and into the surrounding white matter. At 24 and 72 h, the oxidative damage expanded circumferentially to involve all but a small rim of white matter tissue at the injury site, and longitudinally as much as 6–9 mm in the rostral and caudal directions. The staining was observed in neuronal soma, axons, and microvessels. At all time points except 3 h, there was no significant difference in the mean rostral or caudal extent of 3-NT and 4-HNE staining. By 1, and more so at 2 weeks, the longitudinal extent of the oxidative damage staining was greatly decreased. The spatial and temporal overlap of 3-NT and 4-HNE staining supports the concept that PN is involved in both damage produced by lipid peroxidation and protein nitration, and that antioxidant agents that target PN or PN-derived radicals should be effective neuroprotectants for acute SCI if administered during the first post-injury hours.
doi:10.1089/neu.2008.0870
PMCID: PMC2850290  PMID: 19419247
4-hydroxynonenal; lipid peroxidation; peroxynitrite; protein nitration; spinal cord injury; 3-nitrotyrosine
17.  Impact Speed Does Not Determine Severity of Spinal Cord Injury in Mice with Fixed Impact Displacement 
Journal of Neurotrauma  2009;26(8):1395-1404.
Abstract
The speed of three leading rodent SCI impacting devices—0.1 m/s (Infinite Horizon), 0.2 m/s (Ohio State University), and 0.4 m/s (New York University)—were investigated using a custom-fabricated impactor to determine its effect on mouse spinal cord injury severity. The spared white matter was examined at 7 and 21 days post-injury with in vivo diffusion tensor imaging (DTI) and post-mortem histology, respectively. The neurological outcome of the injured mice was longitudinally evaluated using the Basso mouse scale. In vivo DTI derived diffusion anisotropy maps provided excellent gray-white matter contrast enabling objective and noninvasive quantification of normal appearing white matter. In vivo DTI estimated spared white matter content correlated well with those determined using post-mortem histology. No significant difference in BMS was observed among injury groups of various impact speeds. The present results suggest that injury severity can be reproduced using speeds from 0.1 to 0.4 m/s at the fixed impact displacement.
doi:10.1089/neu.2008.0728
PMCID: PMC2850293  PMID: 19257804
BMS; contusion SCI; diffusion tensor imaging; impact speed; spared white matter
18.  Impact speed does not determine severity of spinal cord injury in mice with fixed impact displacement 
Journal of neurotrauma  2009;26(8):10.1089/neu.2008-0728.
The speed of three leading rodent SCI impacting devices: 0.1 m/s (Infinite Horizon), 0.2 m/s (Ohio State Univerity), and 0.4 m/s (New York University) were investigated using a custom-fabricated impactor to determine its effect on mouse spinal cord injury severity. The spared white matter was examined at 7 and 21 days post injury with in vivo diffusion tensor imaging (DTI) and postmortem histology respectively. The neurological outcome of the injured mice was longitudinally evaluated using the Basso Mouse Scale. In vivo DTI derived diffusion anisotropy maps provided excellent gray-white matter contrast enabling objective and noninvasive quantification of normal appearing white matter. In vivo DTI estimated spared white matter content correlated well with those determined using postmortem histology. No significant difference in BMS was observed among injury groups of various impact speeds. The present results suggest that injury severity can be reproduced using speeds from 0.1 – 0.4 m/s at the fixed impact displacement.
doi:10.1089/neu.2008-0728
PMCID: PMC2850293  PMID: 19257804
Contusion SCI; Impact speed; BMS; Diffusion tensor imaging; Spared white matter
19.  Temporal and Spatial Dynamics of Peroxynitrite-Induced Oxidative Damage after Spinal Cord Contusion Injury 
Journal of neurotrauma  2009;26(8):10.1089/neu.2008-0870.
The reactive nitrogen species peroxynitrite (PN) has been suggested to be an important mediator of the secondary oxidative damage that occurs following acute spinal cord injury (SCI). The PN decomposition products nitrogen dioxide (•NO2), hydroxyl radical (•OH), and carbonate radical (•CO3) are highly reactive with cellular lipids and proteins. In this immunohistochemical study, we examined the temporal (3, 24, and 72 h, and 1 and 2 weeks) and spatial relationships of PN-mediated oxidative damage in the contusion-injured rat thoracic spinal cord (IH device, 200 kdyn, T10) using 3-nitrotyrosine (3-NT), a marker for protein nitration by PN-derived •NO2 and 4-hydroxynonenal (4-HNE), an indicator of lipid peroxidation (LP) initiated by any of the PN radicals. Minimal 3-NT or 4-HNE immunostaining was seen in sham, non-injured spinal cords. In contrast, both markers showed a substantial increase at 3 h post-injury at the epicenter, that extended throughout the gray matter and into the surrounding white matter. At 24 and 72 h, the oxidative damage expanded circumferentially to involve all but a small rim of white matter tissue at the injury site, and longitudinally as much as 6–9 mm in the rostral and caudal directions. The staining was observed in neuronal soma, axons, and microvessels. At all time points except 3 h, there was no significant difference in the mean rostral or caudal extent of 3-NT and 4-HNE staining. By 1, and more so at 2 weeks, the longitudinal extent of the oxidative damage staining was greatly decreased. The spatial and temporal overlap of 3-NT and 4-HNE staining supports the concept that PN is involved in both damage produced by lipid peroxidation and protein nitration, and that antioxidant agents that target PN or PN-derived radicals should be effective neuroprotectants for acute SCI if administered during the first post-injury hours.
doi:10.1089/neu.2008-0870
PMCID: PMC2850290  PMID: 19419247
4-hydroxynonenal; lipid peroxidation; peroxynitrite; protein nitration; spinal cord injury; 3-nitrotyrosine
20.  Swim Training Initiated Acutely after Spinal Cord Injury Is Ineffective and Induces Extravasation In and Around the Epicenter 
Journal of Neurotrauma  2009;26(7):1017-1027.
Abstract
Activity-based rehabilitation is a promising strategy for improving functional recovery following spinal cord injury (SCI). While results from both clinical and animal studies have shown that a variety of approaches can be effective, debate still exists regarding the optimal post-injury period to apply rehabilitation. We recently demonstrated that rats with moderately severe thoracic contusive SCI can be re-trained to swim when training is initiated 2 weeks after injury and that swim training had no effect on the recovery of overground locomotion. We concluded that swim training is a task-specific model of post-SCI activity-based rehabilitation. In the present study, we ask if re-training initiated acutely is more or less effective than when initiated at 2 weeks post-injury. Using the Louisville Swim Scale, an 18-point swimming assessment, supplemented by kinematic assessment of hindlimb movement during swimming, we report that acute re-training is less effective than training initiated at 2 weeks. Using the bioluminescent protein luciferase as a blood-borne macromolecular marker, we also show a significant increase in extravasation in and around the site of SCI following only 8 min of swimming at 3 days post-injury. Taken together, these results suggest that acute re-training in a rat model of SCI may compromise rehabilitation efforts via mechanisms that may involve one or more secondary injury cascades, including acute spinal microvascular dysfunction.
doi:10.1089/neu.2008.0829
PMCID: PMC2848951  PMID: 19331515
activity-based rehabilitation; microvascular; rat; spinal cord injury; swimming
21.  Swim Training Initiated Acutely after Spinal Cord Injury Is Ineffective and Induces Extravasation In and Around the Epicenter 
Journal of neurotrauma  2009;26(7):10.1089/neu.2008-0829.
Activity-based rehabilitation is a promising strategy for improving functional recovery following spinal cord injury (SCI). While results from both clinical and animal studies have shown that a variety of approaches can be effective, debate still exists regarding the optimal post-injury period to apply rehabilitation. We recently demonstrated that rats with moderately severe thoracic contusive SCI can be re-trained to swim when training is initiated 2 weeks after injury and that swim training had no effect on the recovery of overground locomotion. We concluded that swim training is a task-specific model of post-SCI activity-based rehabilitation. In the present study, we ask if re-training initiated acutely is more or less effective than when initiated at 2 weeks post-injury. Using the Louisville Swim Scale, an 18-point swimming assessment, supplemented by kinematic assessment of hindlimb movement during swimming, we report that acute re-training is less effective than training initiated at 2 weeks. Using the bioluminescent protein luciferase as a blood-borne macromolecular marker, we also show a significant increase in extravasation in and around the site of SCI following only 8 min of swimming at 3 days post-injury. Taken together, these results suggest that acute re-training in a rat model of SCI may compromise rehabilitation efforts via mechanisms that may involve one or more secondary injury cascades, including acute spinal microvascular dysfunction.
doi:10.1089/neu.2008-0829
PMCID: PMC2848951  PMID: 19331515
activity-based rehabilitation; microvascular; rat; spinal cord injury; swimming
22.  Hemorrhagic Shock after Experimental Traumatic Brain Injury in Mice: Effect on Neuronal Death 
Journal of neurotrauma  2009;26(6):889-899.
Traumatic brain injury (TBI) from blast injury is often complicated by hemorrhagic shock (HS) in victims of terrorist attacks. Most studies of HS after experimental TBI have focused on intracranial pressure; few have explored the effect of HS on neuronal death after TBI and none have been done in mice. We hypothesized that neuronal death in CA1 hippocampus would be exacerbated by HS after experimental TBI. C57BL6J male mice were anesthetized with isoflurane, mean arterial blood pressure (MAP) was monitored, and controlled cortical impact (CCI) delivered to the left parietal cortex followed by 1) continued anesthesia (CCI only), or either 60 or 90 min of volume controlled HS. Parallel 60 or 90 min HS only groups were also studied. After HS (± CCI), 6% hetastarch was used targeting MAP ≥50 mmHg during a 30 min Pre-Hospital resuscitation phase. Then, shed blood was re-infused and hetastarch given targeting MAP ≥60 mmHg during a 30 min Definitive Care phase. Neurological injury was evaluated at 24h (fluorojade C) or 7 days (CA1 and CA3 hippocampal neuron counts). HS reduced MAP to 30−40 mmHg in all groups, p<0.05 vs CCI only. Ipsilateral CA1 neuron counts in the 90 min CCI+HS group were reduced at 16.5±14.1 vs 30.8±6.8, 32.3±7.6, 30.6±2.2, 28.1±2.2 neurons/100 Im in CCI only, 60 min HS only, 90 min HS only, and 60 min CCI+HS, respectively, all p<0.05. CA3 neuron counts did not differ between groups. Fluorojade C staining confirmed neurodegeneration in CA1 in the 90 min CCI+HS group. Our data suggest a critical time window for exacerbation of neuronal death by HS after CCI and may have implications for blast injury victims in austere environments where definitive management is delayed.
doi:10.1089/neu.2008.0512
PMCID: PMC2694227  PMID: 18781889
Controlled cortical impact; hypotension; secondary insult; blast; polytrauma; resuscitation; hippocampus; delayed neuronal death; selective vulnerability
23.  In-Vitro Approaches for Studying Blast-Induced Traumatic Brain Injury 
Journal of Neurotrauma  2009;26(6):861-876.
Abstract
Traumatic brain injury caused by explosive or blast events is currently divided into four phases: primary, secondary, tertiary, and quaternary blast injury. These phases of blast-induced traumatic brain injury (bTBI) are biomechanically distinct, and can be modeled in both in-vivo and in-vitro systems. The purpose of this review is to consider the mechanical phases of bTBI, how these phases are reproduced with in-vitro models, and to review findings from these models to assess how each phase of bTBI can be examined in more detail. Highlighted are some important gaps in the literature that may be addressed in the future to better identify the exact contributing mechanisms for bTBI. These in-vitro models, viewed in combination with in-vivo models and clinical studies, can be used to assess both the mechanisms and possible treatments for this type of trauma.
doi:10.1089/neu.2008.0645
PMCID: PMC2803321  PMID: 19397424
biomechanics; blast; brain injury; in-vitro models
24.  Hemorrhagic Shock after Experimental Traumatic Brain Injury in Mice: Effect on Neuronal Death 
Journal of Neurotrauma  2009;26(6):889-899.
Abstract
Traumatic brain injury (TBI) from blast injury is often complicated by hemorrhagic shock (HS) in victims of terrorist attacks. Most studies of HS after experimental TBI have focused on intracranial pressure; few have explored the effect of HS on neuronal death after TBI, and none have been done in mice. We hypothesized that neuronal death in CA1 hippocampus would be exacerbated by HS after experimental TBI. C57BL6J male mice were anesthetized with isoflurane, mean arterial blood pressure (MAP) was monitored, and controlled cortical impact (CCI) delivered to the left parietal cortex followed by continued anesthesia (CCI-only), or either 60 or 90 min of volume-controlled HS. Parallel 60- or 90-min HS-only groups were also studied. After HS (±CCI), 6% hetastarch was used targeting MAP of ≥50 mm Hg during a 30-min Pre-Hospital resuscitation phase. Then, shed blood was re-infused, and hetastarch was given targeting MAP of ≥60 mm Hg during a 30-min Definitive Care phase. Neurological injury was evaluated at 24 h (fluorojade C) or 7 days (CA1 and CA3 hippocampal neuron counts). HS reduced MAP to 30–40 mm Hg in all groups, p < 0.05 versus CCI-only. Ipsilateral CA1 neuron counts in the 90-min CCI+HS group were reduced at 16.5 ± 14.1 versus 30.8 ± 6.8, 32.3 ± 7.6, 30.6 ± 2.2, 28.1 ± 2.2 neurons/100 μm in CCI-only, 60-min HS-only, 90-min HS-only, and 60-min CCI+HS, respectively, all p < 0.05. CA3 neuron counts did not differ between groups. Fluorojade C staining confirmed neurodegeneration in CA1 in the 90-min CCI+HS group. Our data suggest a critical time window for exacerbation of neuronal death by HS after CCI and may have implications for blast injury victims in austere environments where definitive management is delayed.
doi:10.1089/neu.2008.0512
PMCID: PMC2694227  PMID: 18781889
blast; controlled cortical impact; delayed neuronal death; hippocampus; hypotension; mouse; polytrauma; resuscitation; secondary insult; selective vulnerability
25.  Neocortical post-traumatic epileptogenesis is associated with loss of GABAergic neurons 
Journal of neurotrauma  2009;26(5):799-812.
The subtle mechanisms of post-traumatic epileptogenesis remain unknown although the incidence of chronic epilepsy after penetrating cortical wounds is very high. Here, we investigated whether the increased frequency of seizures occurring within 6 weeks following partial deafferentation of the suprasylvian gyrus in cats is accompanied with a change in the ratio between the number of excitatory and inhibitory neurons. Immunohistochemical labeling of all neurons with neuronal-specific nuclear protein (NeuN) antibody, and of the GABAergic inhibitory neurons with either gamma-aminobutyric acid (GABA) or glutamic acid decarboxylase (GAD 65&67) antibodies, was performed on sections obtained from control and epileptic animals with chronically deafferented suprasylvian gyrus. Quantifications of labeled neurons were performed in control and at 2, 4 and 6 weeks following cortical deafferentation, in the suprasylvian and marginal gyri, both ipsi- and contra-lateral to the cortical trauma. In all epileptic animals the neuronal loss was circumscribed to the deafferented suprasylvian gyrus. Inhibitory GABAergic neurons were particularly more sensitive to cortical deafferentation than excitatory ones, leading to a progressively increasing ratio between excitation and inhibition towards excitation, which might explain the increased propensity to seizures in chronic undercut cortex.
doi:10.1089/neu.2008.0739
PMCID: PMC2735829  PMID: 19422294
brain injury; cortical deafferentation; epilepsy; GAD; GABA

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