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All phase III trials evaluating medical treatments for traumatic brain injury (TBI), performed to date, have failed. To facilitate future success there is a need for novel outcome metrics that can bridge pre-clinical studies to clinical proof of concept trials. Our objective was to assess diffusion tensor imaging (DTI) and biofluid-based biomarkers as efficacy outcome metrics in a large animal study evaluating the efficacy of cyclosporine in TBI. This work builds on our previously published study that demonstrated a reduced volume of injury by 35% with cyclosporine treatment based on magnetic resonance imaging (MRI) results. A focal contusion injury was induced in piglets using a controlled cortical impact (CCI) device. Cyclosporine in a novel Cremophor/Kolliphor EL-free lipid emulsion, NeuroSTAT, was administered by continuous intravenous infusion for 5 days. The animals underwent DTI on day 5. Glial fibrillary acidic protein (GFAP), as a measure of astroglia injury, and neurofilament light (NF-L), as a measure of axonal injury, were measured in blood on days 1, 2, and 5, and in cerebrospinal fluid (CSF) on day 5 post-injury. Normalized fractional anisotropy (FA) was significantly (

Objective To evaluate the effects of electric cortical stimulation (ECS) and transcranial direct current stimulation (tDCS) on motor and cognitive function recovery and brain plasticity in focal traumatic brain injury (TBI) of rats model. Methods Forty rats were pre-trained to perform a single pellet reaching task (SPRT), rotarod test (RRT), and Y-maze test for 14 days, then a focal TBI was induced by a weight drop model on the motor cortex. All rats were randomly assigned to one of the three groups: anodal ECS (50 Hz and 194 μs) (ECS group), tDCS (0.1 mA, 50 Hz and 200 μs) (tDCS group), and no stimulation as a control group. Four-week stimulation, including rehabilitation, was started 3 days after the operation. SPRT, RRT, and Y-maze were measured from day 1 to day 28 after the TBI was induced. Histopathological and immunohistochemistry staining evaluations were performed at 4 weeks. Results SPRT was improved from day 7 to day 26 in ECS, and from day 8 to day 26 in tDCS compared to the control group (p

The aim of this review is to discuss the research presented in a symposium entitled “Current progress in characterizing therapeutic strategies and challenges in experimental CNS injury” which was presented at the 2016 International Behavioral Neuroscience Society annual meeting. Herein we discuss diffuse and focal traumatic brain injury (TBI) and ensuing chronic behavioral deficits as well as potential rehabilitative approaches. We also discuss the effects of stress on executive function after TBI as well as the response of the endocrine system and regulatory feedback mechanisms. The role of the endocannabinoids after CNS injury is also discussed. Finally, we conclude with a discussion of antipsychotic and antiepileptic drugs, which are provided to control TBI-induced agitation and seizures, respectively. The review consists predominantly of published data.

This research focuses on describing the differences between mild traumatic brain injury (mTBI) and focal traumatic brain injury (fTBI). The purpose of this research was to compare clinical mTBI and fTBI groups who incurred brain injury from falls to hard surfaces to identify clinical and biomechanical factors that may delineate between these two outcomes. Reconstructions of mTBI (n = 11) and fTBI (n = 20) cases that resulted from falls presented themselves at the hospital were conducted using computational and physical models. The cases were compared using peak and component dynamic response, brain injury criterion (BrIC), Gadd severity index and head injury criterion. Peak resultant rotational acceleration had the best percentage correct classification with 50% risk of severe TBI was found to be 21 krad/s2. The BrIC and component acceleration and rotational velocity of impact were also found to have significant predictions of risk between the two groups. This data provides information to improve ...

Recovery is limited following traumatic brain injury (TBI) since injured axons regenerate poorly and replacement of lost cells is minimal. Behavioral improvements could instead be due to plasticity of uninjured brain regions. We hypothesized that plasticity of the uninjured hemisphere occurs contralateral to a focal TBI in the adult rat. Thus, we performed cortical mapping of the cortex contralateral to the TBI using intracortical microstimulation (ICMS).A focal TBI was induced using the weight-drop technique (n = 5) and sham-injured animals were used as controls (n = 4). At five weeks post-injury, ICMS was used to map the motor area contralateral to the injury. Motor responses were detected by visual inspection and electromyography (EMG).In sham- and brain-injured animals, numerous fore- and hindlimb motor responses contralateral to the stimulation (ipsilateral to the injury) were obtained. Compared to sham-injured controls, there was a markedly increased (p0.05) number of fore- and hindlimb responses ipsilateral to the stimulation after TBI.Following focal TBI in the rat, our data suggest reorganization of cortical and/or subcortical regions in the uninjured hemisphere contralateral to a focal TBI leading to an altered responsiveness to ICMS. Although we cannot exclude that these changes are maladaptive, it is plausible that this plasticity process positively influences motor recovery after TBI.

OBJECTIVE: To evaluate the effects of electric cortical stimulation in the experimentally induced focal traumatic brain injury (TBI) rat model on motor recovery and plasticity of the injured brain. METHOD: Twenty male Sprague-Dawley rats were pre-trained on a single pellet reaching task (SPRT) and on a Rotarod task (RRT) for 14 days. Then, the TBI model was induced by a weight drop device (40 g in weight, 25 cm in height) on the dominant motor cortex, and the electrode was implanted over the perilesional cortical surface. All rats were divided into two groups as follows: Electrical stimulation (ES) group with anodal continuous stimulation (50 Hz and 194 µs duration) or Sham-operated control (SOC) group with no electrical stimulation. The rats were trained SPRT and RRT for 14 days for rehabilitation and measured Garcia's neurologic examination. Histopathological and immunostaining evaluations were performed after the experiment. RESULTS: There were no differences in the slice number in the histological analysis. Garcia's neurologic scores & SPRT were significantly increased in the ES group (p

Quantitation of lesions in large gyrencephalic brains presents a variety of technical challenges. Specific techniques are required when comparing lesions in subjects of different ages in order to assess maturational effects. We have modified existing techniques to attain reliable, consistent and reproducible paraffin-embedded histological sections for volumetric lesion analysis and correlation with magnetic resonance imaging (MRI) in piglets of different ages following focal traumatic brain injury. Twenty-four Yorkshire domestic piglets at three different ages (5 days, 1 month, and 4 months old) underwent scaled cortical impact injury to the fronto-parietal cortex. This contusion model utilizes a rapid volume of indentation scaled proportionally to the growth of the brain, allowing for examination of maturational influences on the brain's response to focal mechanical trauma. To overcome problems with differential processing and embedding of brains ranging from 43 to 107 g, we developed a piglet parallel brain slicing apparatus. Along with specific methods for processing, embedding, mounting, and slide preparation, these techniques enabled excellent quality 10-μm serial coronal sections to be obtained for histology and immunohistochemical analysis. Accurate co-registration of histologic, immunohistochemical and radiologic images at different ages was possible, which may enhance understanding of developmental aspects of brain injury pathophysiology.

Serum biomarkers could indicate the pathological changes during the secondary injury process after traumatic brain injury (TBI). Furthermore, they could reflect specific pathological processes following different types of TBI. Here we analyzed time-dependent changes of select protein biomarkers in serum samples collected from a rodent model of penetrating type of injury (pen-TBI). The model is a controlled penetration of a 2 mm thick needle-shaped object, which is accelerated into the brain tissue with a bullet from an air gun. The results obtained in the current study were compared to previously reported results of levels of serum biomarker following a rotational acceleration injury that mimics mild TBI. A total of 24 animals were used, grouped in normal controls, sham-operated and injured animals. The rats were sacrificed at day 1, day 3 and day 14 post-injury and serum samples were analyzed for Tau, neurofilament heavy chain (NF-H), myelin basic protein (MBP), N-cadherin and S100B. We found that all markers but MBP showing a bi-phasic response to injury. Their serum levels significantly increased at day 1, dropped at 3 and increased again at day 14 post-injury. This was in contrast to rotational TBI model where the peak of biomarkers was found at day 3. Our study suggests that pen-TBI results in both acute axonal and neuronal damages as well as delayed changes likely part of the ongoing secondary injury process. These findings illustrate the dynamics of the injury process in pen-TBI and underline the importance of monitoring changes in serum biomarker levels for more accurate assessment of injury severity and outcome. In addition, comparison to rotational TBI model revealed distinctive temporal pattern of serum biomarker expression dependent on the type of injury.

Vibro-acoustography (VA) uses two or more beams of confocal ultrasound to generate local vibrations within their target tissue through induction of a time-dependent radiation force whose frequency equals that of the difference of the applied frequencies. While VA has proven effective for assaying the mechanical properties of clinically relevant tissue such as breast lesions and tissue calcifications, its application to brain remains unexplored. Here we investigate the ability of VA to detect acute and focal traumatic brain injury (TBI) in-vivo through the use of transcranially delivered high-frequency (2 MHz) diagnostic focused ultrasound to rat brain capable of generating measurable low-frequency (200–270 kHz) acoustic emissions from outside of the brain. We applied VA to acute sham-control and TBI model rats (sham N = 6; TBI N = 6) and observed that acoustic emissions, captured away from the site of TBI, had lower amplitudes for TBI as compared to sham-TBI animals. The sensitivity of VA to acute brain damage at frequencies currently transmittable across human skulls, as demonstrated in this preliminary study, supports the possibility that the VA methodology may one day serve as a technique for detecting TBI.

SUMMARY Significant declines in brain intracellular free magnesium concentration (Mgf) have been reported following focal traumatic brain injury but not following diffuse axonal brain injury. Since diffuse axonal brain injury is a common feature of clinical trauma, we have used 31P magnetic resonance spectroscopy to determine whether Mgf decline is also a feature of a nonfocal traumatic brain injury model that primarily induces widespread axonal injury. Impact acceleration-induced injury resulted in a highly significant decline in Mgf with an associated decline in cytosolic phosphorylation ratio. There were no significant changes in either ATP concentration or brain pH. We propose that decline in brain Mgf may be a common feature of both focal and diffuse forms of traumatic brain injury and therefore a possible target for therapeutic intervention.

Lien vers l'éditeur :http://www.scirp.org/journal/jbise/; International audience; Experimental models of traumatic brain injury (TBI) provide a useful tool for understanding the cerebral metabolic changes induced by this pathological con-dition. Here, we report on the time course of changes in cerebral metabolites after TBI using high-resolution proton magnetic resonance spectros-copy (NMR). Extracts from adult male Spra-gue-Dawley rats were subjected to fluid lateral per-cussion were examined by NMR at 3, 24 and 48h af-ter the injury. A metabolomic approach was carried out to identify the cerebral metabolites impacted by the TBI and their quantitative temporal changes. Lactate, valine and ascorbate were the three first metabolites to be significantly modified after TBI. The quantitative elevation for these compounds last for the entire experimental time explored. Within 24hours post-TBI, a significant elevation in cho-line-derivates, alanine and glucose were also meas-ured. On the other hand, N-acetyl aspartate, a neu-ronal marker, and myo-inositol, an important organic osmolyte in the mammalian brain, were not signifi-cantly impacted in the chronic phase of TBI.

Contains fulltext : 87476.pdf (Publisher’s version ) (Open Access) Traumatic brain injury (TBI) is a frequent and clinically highly heterogeneous neurological disorder with large socioeconomic consequences. TBI severity classification, based on the hospital admission Glasgow Coma Scale (GCS) score, ranges from mild (GCS 13-15) and moderate (GCS 9-12) to severe (GCS

Introduction: The goal of the present study was to determine whether age-related differences in the acute physiologic response to scaled cortical impact injury contribute to differences in vulnerability to traumatic brain injury (TBI). Methods: Heart rate (HR), mean arterial pressure (MAP), brain temperature (BrT) and cerebral blood flow (CBF) were measured in 22 piglets (7 of age 5 days, 8 of age 1 month, 7 of age 4 months) at baseline and for 3 h following scaled cortical impact injury. Results: There were no age-dependent variations from baseline in HR, MAP or BrT following injury. CBF increased in the 5-day-old animals following injury while CBF in the 1- and 4-month-old animals decreased following injury (p = 0.0049). Conclusion: CBF was shown to have a significant age-dependent response to TBI with the youngest animals exhibiting increased CBF following injury.