Maturation-Dependent Response of the Piglet Brain to Scaled Cortical Impact

Object. The goal of this study was to investigate the relationship between maturational stage and the brain\u27s response to mechanical trauma in a gyrencephalic model of focal brain injury. Age-dependent differences in injury response might explain certain unique clinical syndromes seen in infants and young children and would determine whether specific therapies might be particularly effective or even counterproductive at different ages. Methods. To deliver proportionally identical injury inputs to animals of different ages, the authors have developed a piglet model of focal contusion injury by using specific volumes of rapid cortical displacement that are precisely scaled to changes in size and dimensions of the growing brain. Using this model, the histological response to a scaled focal cortical impact was compared at 7 days after injury in piglets that were 5 days, 1 month, and 4 months of age at the time of trauma. Despite comparable injury inputs and stable physiological parameters, the percentage of hemisphere injured differed significantly among ages, with the youngest animals sustaining the smallest lesions (0.8%, 8.4%, and 21.5%, for 5-day-, 1-month-, and 4-month-old animals, respectively, p = 0.0018). Conclusions. These results demonstrate that, for this particular focal injury type and severity, vulnerability to mechanical trauma increases progressively during maturation. Because of its developmental and morphological similarity to the human brain, the piglet brain provides distinct advantages in modeling age-specific responses to mechanical trauma. Differences in pathways leading to cell death or repair may be relevant to designing therapies appropriate for patients of different ages

Repetitive Mild Traumatic Brain Injury Impairs Performance in a Rodent Assay of Cognitive Flexibility

Mild traumatic brain injury (mTBI) occurs in almost 80% of the 3 million reported cases of TBI-related emergency department visits each year in the United States. The majority of mTBIs, sometimes classified as concussions, are due to sports-related activities and typically occur repeatedly over the course of an athlete’s career. mTBI symptoms are generally classified as either somatic or neuropsychiatric/cognitive in nature and include impairments in prefrontal cortex mediated functions, including attention, memory, processing speed, reaction times, problem solving, and cognitive flexibility. To date, there remains a major gap in our understanding of the behavioral manifestations, underlying neurobiology, and treatment of mTBI. An even greater gap exists in our understanding of the consequences of repeated mTBI incidents. The goal of the present study was to examine the effects of repetitive mTBI within a rodent assay of cognitive flexibility. Rats were exposed to a series of three closed head injuries (controlled cortical impact model) within a week prior to performing an automated strategy shifting task, which required rats to learn and shift strategies according to changing task demands. Rats initially acquired a visual cue strategy in which a light illuminated above one of two possible levers (left or right) indicated the correct response for reward. Twenty-four hours after initial acquisition, rats again performed the task using the visual cue strategy followed by a series of strategy shifting and reversal learning challenges. Repetitive mTBI reduced throughput scores, a performance index that blends accuracy and response speed, and increased reaction times within the task. These results indicate that performance and task efficiency in an operant test of cognitive flexibility are impaired after repetitive mTBI. As such, this model presents a useful approach for further investigating the behavioral deficits and potential treatment strategies for patients who have experienced multiple mTBI insults

Trajectory of long-term outcome in severe pediatric diffuse axonal injury: An exploratory study

Introduction: Pediatric severe traumatic brain injury (TBI) is one of the leading causes of disability and death. One of the classic pathoanatomic brain injury lesions following severe pediatric TBI is diffuse (multifocal) axonal injury (DAI). In this single institution study, our overarching goal was to describe the clinical characteristics and long-term outcome trajectory of severe pediatric TBI patients with DAI.Methods: Pediatric patients (<18 years of age) with severe TBI who had DAI were retrospectively reviewed. We evaluated the effect of age, sex, Glasgow Coma Scale (GCS) score, early fever ≥ 38.5°C during the first day post-injury, the extent of ICP-directed therapy needed with the Pediatric Intensity Level of Therapy (PILOT) score, and MRI within the first week following trauma and analyzed their association with outcome using the Glasgow Outcome Score—Extended (GOS-E) scale at discharge, 6 months, 1, 5, and 10 years following injury.Results: Fifty-six pediatric patients with severe traumatic DAI were analyzed. The majority of the patients were >5 years of age and male. There were 2 mortalities. At discharge, 56% (30/54) of the surviving patients had unfavorable outcome. Sixty five percent (35/54) of surviving children were followed up to 10 years post-injury, and 71% (25/35) of them made a favorable recovery. Early fever and extensive DAI on MRI were associated with worse long-term outcomes.Conclusion: We describe the long-term trajectory outcome of severe pediatric TBI patients with pure DAI. While this was a single institution study with a small sample size, the majority of the children survived. Over one-third of our surviving children were lost to follow-up. Of the surviving children who had follow-up for 10 years after injury, the majority of these children made a favorable recovery

Deletion of the p53 tumor suppressor gene improves neuromotor function but does not attenuate regional neuronal cell loss following experimental brain trauma in mice.

Deletion of the tumor suppressor gene p53 has been shown to improve the outcome in experimental models of focal cerebral ischemia and kainate-induced seizures. To evaluate the potential role of p53 in traumatic brain injury, genetically modified mice lacking a functional p53 gene (p53(-/-), n = 9) and their wild-type littermates (p53(+/+), n = 9) were anesthetized and subjected to controlled cortical impact (CCI) experimental brain trauma. After brain injury, neuromotor function was assessed by using composite neuroscore and rotarod tests. By 7 days posttrauma, p53(-/-) mice exhibited significantly improved neuromotor function, in the composite neuroscore (P = 0.002) as well as in two of three individual tests, when compared with brain-injured p53(+/+) animals. CCI resulted in the formation of a cortical cavity (mean volume = 6.1 mm(3)) 7 days postinjury in p53(+/+) as well as p53(-/-) mice. No difference in lesion volume was detected between the two genotypes (P = 0.95). Although significant cell loss was detected in the ipsilateral hippocampus and thalamus of brain-injured animals, no differences between p53(+/+) and p53(-/-) mice were detected. Although our results suggest that lack of the p53 gene results in augmented recovery of neuromotor function following experimental brain trauma, they do not support a role for p53 acting as a mediator of neuronal death in this context, underscoring the complexity of its role in the injured brain

Experimental brain injury induces regionally distinct apoptosis during the acute and delayed post-traumatic period

The temporal pattern of apoptosis in the adult rat brain after lateral fluid-percussion (FP) brain injury was characterized using terminal deoxynucleotidyl-transferase-mediated biotindUTP nick end labeling (TUNEL) histochemistry and agarose gel electrophoresis. Male Sprague Dawley rats were subjected to brain injury and killed for histological analysis at intervals from 12 hr to 2 months after injury (n � 3/time point). Sham (uninjured) controls were subjected to anesthesia with (n � 3) or without (n � 3) surgery. Apoptotic TUNEL-positive cells were defined using stringent morphological criteria including nuclear shrinkage and fragmentation and condensation of chromatin and cytoplasm. Double-labeled immunocytochemistry was performed to identify TUNEL-positive neurons (anti-neurofilament monoclonal antibody RM044), astrocytes (anti-glial fibrillary acidic protein polyclonal antibody), and oligodendrocytes (anticycli

Sedation and Analgesia in Children with Developmental Disabilities and Neurologic Disorders

Sedation and analgesia performed by the pediatrician and pediatric subspecialists are becoming increasingly common for diagnostic and therapeutic purposes in children with developmental disabilities and neurologic disorders (autism, epilepsy, stroke, obstructive hydrocephalus, traumatic brain injury, intracranial hemorrhage, and hypoxic-ischemic encephalopathy). The overall objectives of this paper are (1) to provide an overview on recent studies that highlight the increased risk for respiratory complications following sedation and analgesia in children with developmental disabilities and neurologic disorders, (2) to provide a better understanding of sedatives and analgesic medications which are commonly used in children with developmental disabilities and neurologic disorders on the central nervous system