Outcome measures from experimental traumatic brain injury in male rats vary with the complete temporal biomechanical profile of the injury event.

Millions suffer a traumatic brain injury (TBI) each year wherein the outcomes associated with injury can vary greatly between individuals. This study postulates that variations in each biomechanical parameter of a head trauma lead to differences in histological and behavioral outcome measures that should be considered collectively in assessing injury. While trauma severity typically scales with the magnitude of injury, much less is known about the effects of rate and duration of the mechanical insult. In this study, a newly developed voice-coil fluid percussion injury system was used to investigate the effects of injury rate and fluid percussion impulse on a collection of post-injury outcomes in male rats. Collectively the data suggest a potential shift in the specificity and progression of neuronal injury and function rather than a general scaling of injury severity. While a faster, shorter fluid percussion first presents as a mild TBI, neuronal loss and some behavioral tasks were similar among the slower and faster fluid percussion injuries. This study concludes that the sequelae of neuronal degeneration and behavioral outcomes are related to the complete temporal profile of the fluid percussion and do not scale only with peak pressure.

In vitro mechanical strain trauma alters neuronal calcium responses: Implications for posttraumatic epilepsy.

Traumatic brain injury (TBI) is known to initiate a series of chemical cascades resulting in neuronal dysfunction and death. Epidemiology studies have found that a prior incidence of TBI is the most important cause of remote symptomatic epilepsy in young adults and children. TBI-induced changes in neuronal sensitivity to stimulation may contribute to acute seizures and the eventual generation of epilepsy. This study examined TBI-induced changes in neuronal sensitivity to stimulation by measuring intracellular calcium ([Ca(++) ](i) ) responses in neurons during glutamate application in vitro. Initial experiments examined neuronal and glial cell death and determined that a 31% mechanical strain trauma to mixed neuronal-astrocyte rat cortical cultures produced a trend, but no significant cell death at 48 h after injury. Subsequent experiments utilized this magnitude of trauma to examine the sensitivity of cortical neurons to changes in [Ca(++) ](i) in response to 100-µm glutamate at five time points postinjury (1, 6, 24, 48, and 72 h). Traumatically strain-injured neurons responded with a dynamic change in the accumulation of [Ca(++) ](i) , with a significant increase at 48 h and a significant decrease at 72 h as compared to uninjured cultures. These data highlight that TBI leads to abnormal responsiveness to stimulation, an indicator of neuronal dysfunction in surviving cells. Such changes in sensitivity to stimulation may also be associated with changes in excitability in the first hours to days after TBI, and may play a role in early posttraumatic seizures observed in patients with TBI. In addition, this study provides an in vitro paradigm for testing the function of surviving cells following treatment interventions targeted at reducing cell death and dysfunction.

Combined Inhibition of Fyn and c-Src Protects Hippocampal Neurons and Improves Spatial Memory via ROCK after Traumatic Brain Injury.

Our previous studies demonstrated that traumatic brain injury (TBI) and ventricular administration of thrombin caused hippocampal neuron loss and cognitive dysfunction via activation of Src family kinases (SFKs). Based on SFK localization in brain, we hypothesized SFK subtypes Fyn and c-Src, as well as SFK downstream molecule Rho-associated protein kinase (ROCK), contribute to cell death and cognitive dysfunction after TBI. We administered nanoparticle wrapped small interfering RNA (siRNA)-Fyn and siRNA-c-Src, or ROCK inhibitor Y-27632 to adult rats subjected to moderate lateral fluid percussion (LFP)-induced TBI. Spatial memory function was assessed from 12 to 16 days, and NeuN stained hippocampal neurons were assessed 16 days after TBI. The combination of siRNA-Fyn and siRNA-c-Src, but neither alone, prevented hippocampal neuron loss and spatial memory deficits after TBI. The ROCK inhibitor Y-27632 also prevented hippocampal neuronal loss and spatial memory deficits after TBI. The data suggest that the combined actions of three kinases (Fyn, c-Src, ROCK) mediate hippocampal neuronal cell death and spatial memory deficits produced by LFP-TBI, and that inhibiting this pathway prevents the TBI-induced cell death and memory deficits.

Functional interferometric diffusing wave spectroscopy of the human brain.

Cerebral blood flow (CBF) is essential for brain function, and CBF-related signals can inform us about brain activity. Yet currently, high-end medical instrumentation is needed to perform a CBF measurement in adult humans. Here, we describe functional interferometric diffusing wave spectroscopy (fiDWS), which introduces and collects near-infrared light via the scalp, using inexpensive detector arrays to rapidly monitor coherent light fluctuations that encode brain blood flow index (BFI), a surrogate for CBF. Compared to other functional optical approaches, fiDWS measures BFI faster and deeper while also providing continuous wave absorption signals. Achieving clear pulsatile BFI waveforms at source-collector separations of 3.5 cm, we confirm that optical BFI, not absorption, shows a graded hypercapnic response consistent with human cerebrovascular physiology, and that BFI has a better contrast-to-noise ratio than absorption during brain activation. By providing high-throughput measurements of optical BFI at low cost, fiDWS will expand access to CBF.

Differential hippocampal protection when blocking intracellular sodium and calcium entry during traumatic brain injury in rats.

This study investigated the contributions of the reverse mode of the sodium-calcium exchanger (NCX) and the type 1 sodium-proton antiporter (NHE-1) to acute astrocyte and neuronal pathology in the hippocampus following fluid percussion traumatic brain injury (TBI) in the rat. KB-R7943, EIPA, or amiloride, which respectively inhibit NCX, NHE-1, or NCX, NHE-1, and ASIC1a (acid-sensing ion channel type 1a), was infused intraventricularly over a 60-min period immediately prior to TBI. Astrocytes were immunostained for glial fibrillary acidic protein (GFAP), and degenerating neurons were identified by Fluoro-Jade staining at 24 h after injury. Stereological analysis of the CA2/3 sub-regions of the hippocampus demonstrated that higher doses of KB-R7943 (2 and 20 nmoles) significantly reduced astrocyte GFAP immunoreactivity compared to vehicle-treated animals. EIPA (2-200 nmoles) did not alter astrocyte GFAP immunoreactivity. Amiloride (100 nmoles) significantly attenuated the TBI-induced acute reduction in astrocyte GFAP immunoreactivity. Of the three compounds examined, only amiloride (100 nmoles) reduced hippocampal neuronal degeneration assessed with Fluoro-Jade. The results provide additional evidence of acute astrocyte pathology in the hippocampus following TBI, while suggesting that activation of NHE-1 and the reverse mode of NCX contribute to both astrocyte and neuronal pathology following experimental TBI.

Dicyclomine, an M1 muscarinic antagonist, reduces biomarker levels, but not neuronal degeneration, in fluid percussion brain injury.

Recent studies indicate that alphaII-spectrin breakdown products (SBDPs) have utility as biological markers of traumatic brain injury (TBI). However, the utility of SBDP biomarkers for detecting effects of therapeutic interventions has not been explored. Acetylcholine plays a role in pathological neuronal excitation and TBI-induced muscarinic cholinergic receptor activation may contribute to excitotoxic processes. In experiment I, regional and temporal changes in calpain-mediated alpha-spectrin degradation were evaluated at 3, 12, 24, and 48 h using immunostaining for 145-kDa SBDP. Immunostaining of SBDP-145 was only evident in the hemisphere ipsilateral to TBI and was generally limited to the cortex except at 24 h when immunostaining was also prominent in the dentate gyrus and striatum. In Experiment II, cerebral spinal fluid (CSF) samples were analyzed for various SBDPs 24 h after moderate lateral fluid percussion TBI. Rats were administered either dicyclomine (5 mg/kg i.p.) or saline vehicle (n = 8 per group) 5 min prior to injury. Injury produced significant increases (p < 0.001) of 300%, 230%, and >1000% in SBDP-150, -145, and -120, respectively in vehicle-treated rats compared to sham. Dicyclomine treatment produced decreases of 38% (p = 0.077), 37% (p = 0.028), and 63% (p = 0.051) in SBDP-150, -145, and -120, respectively, compared to vehicle-treated injury. Following CSF extraction, coronal brain sections were processed for detecting degenerating neurons using Fluoro-Jade histofluorescence. Stereological techniques were used to quantify neuronal degeneration in the dorsal hippocampus CA2/3 region and in the parietal cortex. No significant differences were detected in numbers of degenerating neurons in the dorsal CA2/3 hippocampus or the parietal cortex between saline and dicyclomine treatment groups. The percent weight loss following TBI was significantly reduced by dicyclomine treatment. These data provide additional evidence that, as TBI biomarkers, SBDPs are able to detect a therapeutic intervention even in the absence of changes in neuronal cell degeneration measured by Fluoro-jade.

Dimethyl sulfoxide provides neuroprotection in a traumatic brain injury model.

PURPOSE: The objective of this study was to evaluate the neuroprotective potential of the antioxidant, curcumin compared to alpha-tocopherol in a rat model of traumatic brain injury (TBI). METHODS: Male Sprague-Dawley rats were administered curcumin (3, 30, 300 mg/kg), alpha-tocopherol (100 mg/kg), DMSO vehicle, or saline, 30 min prior to and 30 and 90 min after moderate lateral fluid percussion TBI. Rats were euthanized at 24 hours after injury and coronal brain sections were stained with Fluoro-Jade to identify degenerating neurons. Degenerating neurons in the CA2-3 sector of the dorsal hippocampus were quantified in 10 sections spaced 300 microm apart in each rat. RESULTS: One way ANOVA revealed a significant difference (p = 0.01) between groups. The curcumin, alpha-tocopherol, and DMSO groups had significantly reduced numbers of degenerating neurons compared to the saline-treated group. No significant differences were observed between any of the drug treatment groups or the DMSO group. CONCLUSIONS: Since protection in the DMSO vehicle group was equal to that of the experimental groups, no conclusions about neuroprotection regarding alpha-tocopherol or curcumin can be made from this study. The results suggest that DMSO may be acting as an overriding neuroprotectant in this experiment. We conclude that DMSO is a viable neuroprotective agent against secondary cell death in TBI.

HDAC inhibitor increases histone H3 acetylation and reduces microglia inflammatory response following traumatic brain injury in rats.

Traumatic brain injury (TBI) produces a rapid and robust inflammatory response in the brain characterized in part by activation of microglia. A novel histone deacetylase (HDAC) inhibitor, 4-dimethylamino-N-[5-(2-mercaptoacetylamino)pentyl]benzamide (DMA-PB), was administered (0, 0.25, 2.5, 25 mg/kg) systemically immediately after lateral fluid percussion TBI in rats. Hippocampal CA2/3 tissue was processed for acetyl-histone H3 immunolocalization, OX-42 immunolocalization (for microglia), and Fluoro-Jade B histofluorescence (for degenerating neurons) at 24 h after injury. Vehicle-treated TBI rats exhibited a significant reduction in acetyl-histone H3 immunostaining in the ipsilateral CA2/3 hippocampus compared to the sham TBI group (p<0.05). The reduction in acetyl-histone H3 immunostaining was attenuated by each of the DMA-PB dosage treatment groups. Vehicle-treated TBI rats exhibited a high density of phagocytic microglia in the ipsilateral CA2/3 hippocampus compared to sham TBI in which none were observed. All doses of DMA-PB significantly reduced the density of phagocytic microglia (p<0.05). There was a trend for DMA-PB to reduce the number of degenerating neurons in the ipsilateral CA2/3 hippocampus (p=0.076). We conclude that the HDAC inhibitor DMA-PB is a potential novel therapeutic for inhibiting neuroinflammation associated with TBI.

Astroglia: important mediators of traumatic brain injury.

Traumatic brain injury (TBI) research to date has focused almost exclusively on the pathophysiology of injured neurons with very little attention paid to non-neuronal cells. However in the past decade, exciting discoveries have challenged this century-old view of passive glial cells and have led to a reinterpretation of the role of glial cells in central nervous system (CNS) biology and pathology. In this chapter we review several lines of evidence, indicating that glial cells, particularly astrocytes, are active partners to neurons in the brain, and summarize recent findings that detail the significance of astrocyte pathology in traumatic brain injury.

Phosphorylation of calcium calmodulin-dependent protein kinase II following lateral fluid percussion brain injury in rats.

Traumatic brain injury (TBI) can dramatically increase levels of intracellular calcium ([Ca(2+)](i)). One consequence of increased [Ca(2+)](i) would be altered activity and function of calcium-regulated proteins, including calcium-calmodulin-dependent protein kinase II (CaMKII), which is autophosphorylated on Thr(286)(pCaMKII(286)) in the presence of calcium and calmodulin. Therefore, we hypothesized that TBI would result in increased levels of pCaMKII(286), and that such increases would occur early after injury in brain regions known to be damaged following lateral fluid percussion TBI (i.e., hippocampus and cortex). In order to test this hypothesis, immunostaining of CaMKII was examined in rat hippocampus and cortex after lateral fluid percussion (LFP) injury using an antibody directed against pCaMKII(286). LFP injury produced a marked increase in pCaMKII(286) immunostaining in the hippocampus and overlying cortex 30 min after TBI. The pattern of increased immunostaining was uneven, and unexpectedly absent in some hippocampal CA3 pyramidal neurons. This suggests that phosphatase activity may also increase following TBI, resulting in dephosphorylation of pCaMKII(286) in subpopulations of CA3 pyramidal neurons. Western blotting confirmed a rapid increase in levels of pCaMKII(286) at 10 and 30 min after brain injury, and that it was transient and no longer significantly elevated when examined at 3, 8, and 24 h. These results demonstrate that TBI alters the autophosphorylation state of CaMKII, an important neuronal regulator of critical cell functions, including enzyme activities, cell structure, gene expression, and neuronal plasticity, and provide a molecular mechanism that is likely to contribute to cell injury and impaired plasticity after TBI.

Sex and Electrode Configuration in Transcranial Electrical Stimulation.

Transcranial electrical stimulation (tES) can be an effective non-invasive neuromodulation procedure. Unfortunately, the considerable variation in reported treatment outcomes, both within and between studies, has made the procedure unreliable for many applications. To determine if individual differences in cranium morphology and tissue conductivity can account for some of this variation, the electrical density at two cortical locations (temporal and frontal) directly under scalp electrodes was modeled using a validated MRI modeling procedure in 23 subjects (12 males and 11 females). Three different electrode configurations (non-cephalic, bi-cranial, and ring) commonly used in tES were modeled at three current intensities (0.5, 1.0, and 2.0 mA). The aims were to assess the effects of configuration and current intensity on relative current received at a cortical brain target directly under the stimulating electrode and to characterize individual variation. The different electrode configurations resulted in up to a ninefold difference in mean current densities delivered to the brains. The ring configuration delivered the least current and the non-cephalic the most. Female subjects showed much less current to the brain than male subjects. Individual differences in the current received and differences in electrode configurations may account for significant variability in current delivered and, thus, potentially a significant portion of reported variation in clinical outcomes at two commonly targeted regions of the brain.

Electrical Guidance of Human Stem Cells in the Rat Brain.

Limited migration of neural stem cells in adult brain is a roadblock for the use of stem cell therapies to treat brain diseases and injuries. Here, we report a strategy that mobilizes and guides migration of stem cells in the brain in vivo. We developed a safe stimulation paradigm to deliver directional currents in the brain. Tracking cells expressing GFP demonstrated electrical mobilization and guidance of migration of human neural stem cells, even against co-existing intrinsic cues in the rostral migration stream. Transplanted cells were observed at 3 weeks and 4 months after stimulation in areas guided by the stimulation currents, and with indications of differentiation. Electrical stimulation thus may provide a potential approach to facilitate brain stem cell therapies.

Inhibition of Src family kinases improves cognitive function after intraventricular hemorrhage or intraventricular thrombin.

Intraventricular hemorrhage causes spatial memory loss, but the mechanism remains unknown. Our recent studies demonstrated that traumatic brain injury activates Src family kinases, which cause spatial memory loss. To test whether the spatial memory loss was due to blood in the ventricles, which activated Src family kinases, we infused autologous whole blood or thrombin into the lateral ventricles of adult rats to model non-traumatic intraventricular hemorrhage. Hippocampal neuron loss was examined 1 day to 5 weeks later. Spatial memory function was assessed 29 to 33 days later using the Morris water maze. Five weeks after the ventricular injections of blood or thrombin, there was death of most hippocampal neurons and significant memory deficits compared with sham operated controls. These data show that intraventricular thrombin is sufficient to kill hippocampal neurons and produce spatial memory loss. In addition, systemic administration of the non-specific Src family kinase inhibitor PP2 or intraventricular injection of siRNA-Fyn, a Src family kinase family member, prevented hippocampal neuronal loss and spatial memory deficits following intraventricular hemorrhage. The data support the conclusions that thrombin mediates the hippocampal neuronal cell death and spatial memory deficits produced by intraventricular blood and that these can be blocked by non-specific inhibition of Src family kinases or by inhibiting Fyn.

Historical Review of the Fluid-Percussion TBI Model.

Traumatic brain injury (TBI) is a major health concern worldwide. Laboratory studies utilizing animal models of TBI are essential for addressing pathological mechanisms of brain injury and development of innovative treatments. Over the past 75 years, pioneering head injury researchers have devised and tested a number of fluid percussive methods to reproduce the concussive clinical syndrome in animals. The fluid-percussion brain injury technique has evolved from early investigations that applied a generalized loading of the brain to more recent computer-controlled systems. Of the many preclinical TBI models, the fluid-percussion technique is one of the most extensively characterized and widely used models. Some of the most important advances involved the development of the Stalhammer device to produce concussion in cats and the later characterization of this device for application in rodents. The goal of this historical review is to provide readers with an appreciation for the time and effort expended by the pioneering researchers who have led to today's state of the art fluid-percussion animal models of TBI.

Lateral (Parasagittal) Fluid Percussion Model of Traumatic Brain Injury.

Fluid percussion was first conceptualized in the 1940s and has evolved into one of the leading laboratory methods for studying experimental traumatic brain injury (TBI). Over the decades, fluid percussion has been used in numerous species and today is predominantly applied to the rat. The fluid percussion technique rapidly injects a small volume of fluid, such as isotonic saline, through a circular craniotomy onto the intact dura overlying the brain cortex. In brief, the methods involve surgical production of a circular craniotomy, attachment of a fluid-filled conduit between the dura overlying the cortex and the outlet port of the fluid percussion device. A fluid pulse is then generated by the free-fall of a pendulum striking a piston on the fluid-filled cylinder of the device. The fluid enters the cranium, producing a compression and displacement of the brain parenchyma resulting in a sharp, high magnitude elevation of intracranial pressure that is propagated diffusely through the brain. This results in an immediate and transient period of traumatic unconsciousness as well as a combination of focal and diffuse damage to the brain, which is evident upon histological and behavioral analysis. Numerous studies have demonstrated that the rat fluid percussion model reproduces a wide range of pathological features associated with human TBI.

NAAG peptidase inhibitor reduces acute neuronal degeneration and astrocyte damage following lateral fluid percussion TBI in rats.

Traumatic brain injury (TBI) produces a rapid and excessive elevation in extracellular glutamate associated with excitotoxicity and secondary brain pathology. The peptide neurotransmitter Nacetylaspartylglutamate (NAAG) suppresses glutamate transmission through selective activation of presynaptic Group II metabotropic glutamate receptor subtype 3 (mGluR3). Thus, inhibition of NAAG peptidase activity and the prolong presence of synaptic NAAG were hypothesized to have significant potential for cellular protection following TBI. In the present study, a novel NAAG peptidase inhibitor, ZJ-43, was used in four different doses (0, 50, 100, or 150 mg/kg). Each dose was repeatedly administered i.p. (n=5/group) by multiple injections at three times (0 time, 8 h, 16 h) after moderate lateral fluid percussion TBI in the rat. An additional group was co-administered ZJ-43 (150 mg/kg) and the Group II mGluR antagonist, LY341495 (1 mg/kg), which was predicted to abolish any protective effects of ZJ-43. Rats were euthanized at 24 h after TBI, and brains were processed with a selective marker for degenerating neurons (Fluoro-Jade B) and a marker for astrocytes (GFAP). Ipsilateral neuronal degeneration and bilateral astrocyte loss in the CA2/3 regions of the hippocampus were quantified using stereological techniques. Compared with vehicle, ZJ-43 significantly reduced the number of the ipsilateral degenerating neurons (p<0.01) with the greatest neuroprotection at the 50 mg/kg dose. Moreover, LY341495 successfully abolished the protective effects of ZJ-43. 50 mg/kg of ZJ-43 also significantly reduced the ipsilateral astrocyte loss (p<0.05). We conclude that the NAAG peptidase inhibitor ZJ-43 is a potential novel strategy to reduce both neuronal and astrocyte damage associated with the glutamate excitotoxicity after TBI.

Fluid percussion injury device for the precise control of injury parameters.

BACKGROUND: Injury to the brain can occur from a variety of physical insults and the degree of disability can greatly vary from person to person. It is likely that injury outcome is related to the biomechanical parameters of the traumatic event such as magnitude, direction and speed of the forces acting on the head. NEW METHOD: To model variations in the biomechanical injury parameters, a voice coil driven fluid percussion injury (FPI) system was designed and built to generate fluid percussion waveforms with adjustable rise times, peak pressures, and durations. Using this system, pathophysiological outcomes in the rat were investigated and compared to animals injured with the same biomechanical parameters using the pendulum based FPI system. RESULTS IN COMPARISON WITH EXISTING METHODS: Immediate post-injury behavior shows similar rates of seizures and mortality in adolescent rats and similar righting times, toe pinch responses and mortality rates in adult rats. Interestingly, post injury mortality in adult rats was sensitive to changes in injury rate. Fluoro-Jade labeling of degenerating neurons in the hilus and CA2-3 hippocampus were consistent between injuries produced with the voice coil and pendulum operated systems. Granule cell population spike amplitude to afferent activation, a measure of dentate network excitability, also showed consistent enhancement 1 week after injury using either system. CONCLUSIONS: Overall our results suggest that this new FPI device produces injury outcomes consistent with the commonly used pendulum FPI system and has the added capability to investigate pathophysiology associated with varying rates and durations of injury.

Acute Temporal Profiles of Serum Levels of UCH-L1 and GFAP and Relationships to Neuronal and Astroglial Pathology following Traumatic Brain Injury in Rats.

A number of potential traumatic brain injury (TBI) biomarkers have been proposed and evaluated in the laboratory and clinic. This study investigated the temporal profile of circulating biomarkers of astrocytic and neuronal injury over the first 24 h and relevant histopathological changes after experimental moderate TBI. Twenty male rats were randomly assigned to either moderate parasagittal fluid percussion or sham injury. Blood serum samples were collected 2 d prior to TBI (baseline) and at 3, 6, and 24 h after TBI. A single cerebrospinal fluid (CSF) sample was collected from the cisterna magna 24 h after TBI, followed by euthanasia and brain harvesting for histology. Serum and CSF samples were analyzed for neuronal (ubiquitin carboxy-terminal hydrolase L1 [UCH-L1]) and astroglial (glial fibrillary acidic protein [GFAP]) protein levels using enzyme-linked immunosorbent assay. Brain histology included GFAP immunostaining and Fluoro-Jade histofluorescence. Serum and CSF levels of GFAP were near zero in sham animals. Serum GFAP levels were significantly elevated at 3 and 6 h post-TBI, compared with baseline and time-matched sham values, while UCH-L1 was significantly elevated only at 3 h post-TBI. Both CSF GFAP and UCH-L1 at 24 h post-TBI were significantly elevated, compared with sham. GFAP immunohistochemistry and FJ histofluorescence of degenerating neurons were performed in the same animals after 24 h survival. Histology revealed characteristic acute neuronal degeneration in the ipsilateral hippocampus and parietal cortex and reduction in GFAP immunostaining in areas of neuronal cell loss. The data provide evidence of a causal relationship between TBI-induced acute brain pathology and circulating neuronal and glial markers, further demonstrating their role as candidate markers for TBI. Studies of relative changes in biomarker levels in CSF and serum suggest that different mechanisms may underlie the transport and/or clearance of UCH-L1 and GFAP in these two compartments.

Septohippocampal Neuromodulation Improves Cognition after Traumatic Brain Injury.

Traumatic brain injury (TBI) often results in persistent attention and memory deficits that are associated with hippocampal dysfunction. Although deep brain stimulation (DBS) is used to treat neurological disorders related to motor dysfunction, the effectiveness of stimulation to treat cognition remains largely unknown. In this study, adult male Harlan Sprague-Dawley rats underwent a lateral fluid percussion or sham injury followed by implantation of bipolar electrodes in the medial septal nucleus (MSN) and ipsilateral hippocampus. In the first week after injury, there was a significant decrease in hippocampal theta oscillations that correlated with decreased object exploration and impaired performance in the Barnes maze spatial learning task. Continuous 7.7 Hz theta stimulation of the medial septum significantly increased hippocampal theta oscillations, restored normal object exploration, and improved spatial learning in injured animals. There were no benefits with 100 Hz gamma stimulation, and stimulation of sham animals at either frequency did not enhance performance. We conclude, therefore, that there was a theta frequency-specific benefit of DBS that restored cognitive function in brain-injured rats. These data suggest that septal theta stimulation may be an effective and novel neuromodulatory therapy for treatment of persistent cognitive deficits following TBI.

Craniectomy position affects morris water maze performance and hippocampal cell loss after parasagittal fluid percussion.

Valid and reliable animal models are essential for mechanistic and therapeutic studies of traumatic brain injury (TBI). Therefore, model characterization is a continual and reciprocal process between the experimental laboratory and the clinic. Several excellent experimental models of TBI, including the lateral fluid percussion rat model, are currently in wide use in many neurotrauma laboratories. However, small differences in the position of lateral fluid percussion craniectomy are reported between labs. Additionally, differences in hippocampal cell death have also been reported. Therefore, we hypothesized that small changes in craniectomy position could affect commonly used outcome measures such as vestibulomotor function, Morris water maze (MWM) performance, hippocampal cell loss, and glial fibrillary acidic protein (GFAP) immunoreactivity. Four placements were systematically manipulated: rostral, caudal, medial, and lateral. The medial and caudal placements produced significantly greater impairments in the MWM acquisition task over the lateral and rostral placements. The rostral placement produced diffuse cortical damage but little hippocampal cell loss. In contrast, the medial, lateral, and caudal placements produced more mid-dorsally localized cortical damage and significant cell loss in the CA2/CA3 and hilus ipsilateral to the injury site. Furthermore, reactive astrocytosis was more pronounced in the medial, lateral, and caudal placements than in the rostral placement. All craniectomy position groups had similar durations of traumatic unconsciousness and similar impairment on motor tasks. We conclude that small alterations in craniectomy position produce differences in cognitive performance, hippocampal cell loss, and reactive astrocytosis but not in motor performance nor transient unconsciousness.