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C E Dixon

Publications and source records attributed to C E Dixon.

16 recordsLinked to original sources
PubMed1992

Cognitive deficits following traumatic brain injury produced by controlled cortical impact.

Traumatic brain injury produces significant cognitive deficits in humans. This experiment used a controlled cortical impact model of experimental brain injury to examine the effects of brain injury on spatial learning and memory using the Morris water maze task. Rats (n = 8) were injured at a moderate level of cortical impact injury (6 m/sec, 1.5-2.0 mm deformation). Eight additional rats served as a sham-injured control group. Morris water maze performance was assessed on days 11-15 and 30-34 following injury. Results revealed that brain-injured rats exhibited significant deficits (p less than 0.05) in maze performance at both testing intervals. Since the Morris water maze task is particularly sensitive to hippocampal dysfunction, the results of the present experiment support the hypothesis that the hippocampus is preferentially vulnerable to damage following traumatic brain injury. These results demonstrate that controlled cortical impact brain injury produces enduring cognitive deficits analogous to those observed after human brain injury.

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PubMed1992

Microtubule-associated protein 2 levels decrease in hippocampus following traumatic brain injury.

We examined microtubule-associated protein 2 (MAP2) levels in hippocampal and cortical tissue 3 h following moderate traumatic brain injury (TBI) in the rat. MAP2 levels were assayed by quantitative immunoreactivity in tissue fractions obtained from naive, sham-injured, or fluid percussion-injured animals. Tissues were homogenized in the presence of protease inhibitors (0.3 mM phenylmethylsulfonyl fluoride, PMSF), a specific calpain inhibitors (0.1 mM leupeptin), and chelators (2 mM ethylene glycol-bis-tetraacetic acid, EGTA; 1 mM ethylenedinitrilo-tetraacetic acid, EDTA) to eliminate in vitro MAP2 proteolysis during tissue processing. Compared to naive rats, sham injury had no effect on soluble MAP2 levels in either cortex (105.0 +/- 4.4% of naive value) or hippocampus (106.6 +/- 5.2% of naive value). However, TBI caused a significant (p < 0.005) decrease in hippocampal MAP2 levels (55.7 +/- 5.9% of sham-injured controls). The effect appeared to be regionally selective, since the MAP2 decrease did not occur in cortex (89.1 +/- 1.4%). The degree of MAP2 decrease in hippocampus was similar in both membrane (57.8%) and cytosolic (55.7%) fractions, ruling out the possibility of partitioning artifacts. The data suggest that sublethal alterations of neuronal structure and function caused by MAP2 degradation may play an important role in the development of TBI-induced functional deficits. Since MAP2 is exclusively associated with the cytoskeleton in somal and dendritic compartments of neurons, the pathophysiology of sublethal magnitudes of TBI may also involve dendritic and somal dysfunction.

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PubMed1991

A controlled cortical impact model of traumatic brain injury in the rat.

Controlled cortical impact models produce brain injury by using a pneumatic impactor to impact exposed brain. This study systematically examined the effects of varying magnitudes of controlled cortical impact to the rat brain on neurological, cardiovascular, and histopathological variables. As the magnitude of injury increased, the duration of suppression of somatomotor reflexes and the duration of chronic vestibular motor deficits increased. The blood pressure response was observed to depend on injury levels; a moderate injury level produced a hypotensive response while a high injury level produced an immediate brief hypertensive response followed by hypotension. Low injury levels produced no significant macroscopic or microscopic change, but higher injury levels produced cortical contusion and intraparenchymal hemorrhage which, with increasing survival time, evolved into necrotic changes and cavitation underlying the injury site. Also with high levels of injury, axonal injury was found throughout the brain-stem with the greatest concentration of injured axons occurring in the cerebellar peduncles and pontomedullary junction. These data demonstrate that controlled cortical impact in the rat reproduces many of the features observed in other experimental animal models. This model allows independent control of many mechanical loading parameters associated with traumatic brain injury. The controlled cortical impact rat model should be an effective experimental tool to investigators of traumatic brain injury.

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PubMed1990

Prolonged memory impairment in the absence of hippocampal cell death following traumatic brain injury in the rat.

Prolonged neurological dysfunction that results from an insult to the brain is often attributed to irreversible structural damage such as loss of neurons or axonal degeneration. For example, following cerebral ischemia even partial hippocampal CA1 neuronal loss has been proposed to be sufficient to result in deficits in hippocampal dependent spatial memory. This study examined if hippocampal CA1 neuronal loss and/or axonal injury was necessary to produce prolonged spatial memory deficits resulting from traumatic brain injury (TBI). Prior to TBI Sprague-Dawley rats were trained on an 8-arm radial maze, a task sensitive to detecting specific lesions of the hippocampus or its extrinsic connections. Following a mild, moderate, or sham injury, rats were tested for working and reference memory for 25 days. After 25 days of maze testing, histological cell counts were made from consistent coronal sections of the mid-dorsal hippocampus. Rats subjected to mild or moderate TBI manifested working memory deficits for 5 and 15 days, respectively, after injury in the absence of overt (all brain regions) or quantitative (CA1 only) evidence of neuronal death. The number of CA1 pyramidal neurons of representative sections of the mid-dorsal hippocampi for injured maze-deficit rats and sham control rats were: 1626 (S.E.M. = +/- 66) and 1693 (S.E.M. = +/- 69) per 10(6) micron2, respectively. Additionally, no overt evidence of axonal injury was observed in any forebrain structure including major intrinsic or extrinsic connecting hippocampal pathways. These data strongly suggest that mild to moderate TBI is capable of producing prolonged spatial memory deficits in the rat without evidence of either neuronal cell death in the intrinsic hippocampus or overt axonal injury in hippocampal pathways.

Animals↗
PubMed1990

Excitatory amino acid receptor subtype binding following traumatic brain injury.

Sprague-Dawley rats were subjected to a moderate level (2.2 atm) of traumatic brain injury (TBI) using fluid percussion. Injured animals were allowed post-trauma survival periods of 5 min, 3 and 24 h. Regional glutamate receptor subtype binding was assessed with quantitative autoradiography in each group for N-methyl-D-aspartate (NMDA), quisqualate and kainate receptor subpopulations at approximately the -3.8 bregma level and compared to a sham control group. [3H]glutamate binding to the NMDA receptor was significantly (P less than 0.05) decreased at 3 h post-TBI in the hippocampal CA1 stratum radiatum, the molecular layers of the dentate gyri and the outer (layers 1-3) and inner (layers 5 and 6) overlying neocortex. NMDA receptor binding was significantly reduced in layers 5 and 6 of the neocortex at all post-trauma survival times but no further differences were seen in the hippocampi. No significant changes were observed with [3H]AMPA binding to quisqualate receptors and [3H]KA binding was significantly reduced only in layers 5 and 6 of the neocortex at 24 h after TBI. These data further confirm the pathological involvement of the NMDA receptor complex in brain regions selectively vulnerable to moderate levels of TBI in this model.

Animals↗
PubMed1989

Increased vulnerability of the mildly traumatized rat brain to cerebral ischemia: the use of controlled secondary ischemia as a research tool to identify common or different mechanisms contributing to mechanical and ischemic brain injury.

Fasted Wistar rats were subjected to either a mild mechanical injury, 6 min of transient forebrain ischemia, or a mild mechanical injury followed 1 h later by 6 min of forebrain ischemia. EEG and evoked potentials were assessed intermittently and morphological analyses were performed after 7 days postinjury survival. In all groups complete qualitative recovery of electrical activity and general behavior was observed with 7-day survival. However, rats subjected to combined concussion and ischemia displayed EEG spike activity and a delayed return of EEG and evoked potentials during acute recovery not evident in other groups. No overt neuronal cell loss was seen in trauma alone and was minimal or absent in ischemia alone. However, extensive bilateral CA1 and subicular pyramidal cell loss was found in the septal and mid-dorsal hippocampi in the combined trauma and ischemia group. In contrast, no overt axonal injury was found in any group. We conclude that even mild mechanical injury can potentiate selective ischemic hippocampal neuronal necrosis in the absence of overt axonal injury. This potentiation also occurs in conjunction with more generalized electrophysiological disturbances such as EEG evidence of postischemic neuronal hyperactivity suggesting that mild concussion may also decrease the threshold for post-ischemic neuronal excitation. These results suggest the potential of this model for examining common or different injury mechanisms in mechanical and ischemic brain injury.

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PubMed1989

Experimental models of brain injury.

General categories of experimental brain injury models are reviewed regarding their clinical significance, and two new models are presented that use different methodology to produce injury. This report describes and characterizes the pathophysiologic changes produced by a novel fluid percussion (FP) method and a controlled cortical impact (CI) technique, both developed at the General Motors Research Laboratories (GMRL). The new models are compared to prior experimental brain injury techniques in relation to ongoing physical and analytical modeling used in automotive safety research by GMRL. Experimental results from our laboratory indicate that although the FP technique, currently the most widely used method for producing brain injury, is useful for producing graded injury responses systemically and centrally, it is not well-suited for detailed biomechanical analyses. This conclusion is based on high-speed cineradiographic studies where the physiologic saline in the FP cannula was substituted with a radiopaque contrast medium (Conray 1:1 dilution/saline). High speed x-ray movies (1000 fps) were taken of the fluid percussion pulse (1.5-3.4 atm/20 msec) in sagittal, dorsal, and frontal planes of orientation. When viewed together, the cineradiography revealed a complex, dynamic interaction between the injected fluid and the skull/cranial contents. Rapid lateral and anterior/posterior epidural fluid flow suggest that the pathology and dysfunction following FP brain injury reflects diffuse mechanical loading of the brain. Because fluid is used to transfer mechanical energy to brain tissue, and because fluid flow characteristics (i.e., direction, velocity, and displacement) are dependent on the brain geometry and species used, accurate analytical and biomechanical analyses of the resultant injury would be difficult at best. In contrast, the cortical impact model of experimental brain injury uses a known impact interface and a measurable, controllable impact velocity and cortical compression. These controlled variables enable the amount of deformation and the change in deformation over time to be accurately determined. In addition, the CI model produces graded, reproducible cortical contusion, prolonged functional coma, and extensive axonal injury, unlike the FP technique. The quantifiable nature of the single mechanical input used to produce the injury allows correlations to be made between the amount of deformation and the resultant pathology and functional changes.(ABSTRACT TRUNCATED AT 400 WORDS)

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PubMed1988

Effects of scopolamine treatment on long-term behavioral deficits following concussive brain injury to the rat.

Scopolamine (0.1, 1.0, or 10.0 mg/kg) or saline was systemically (i.p.) administered to rats 15 min prior to concussive fluid percussion brain injury. Animals pretreated with the 1.0 mg/kg dose exhibited significantly (P less than 0.05) less motor deficits and less body weight loss and recovered to baseline performance sooner than saline-treated rats. Mortality and associated convulsions were significantly lower in rats pretreated with the 1.0 mg/kg dose of scopolamine. A 1.0 mg/kg dose of scopolamine administered (i.p.) 30 s after injury also significantly reduced behavioral deficits. No differences were observed between saline- and scopolamine-treated animals in either the incidence or duration of transient apnea following injury. A 1.0 mg/kg dose of scopolamine administered (i.p.) 15 min prior to epidural clip compression of the spinal cord had no effect on the severity of motor function deficits assessed by an inclined plane test. The data from these experiments suggest muscarinic cholinergic involvement in at least some of the long-term behavioral deficits following mild and moderate levels of brain injury. These results suggest that muscarinic cholinergic antagonists may prove beneficial in the treatment of human head injury.

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PubMed1988

The effect of concussive head injury on central cholinergic neurons.

This study examined the effect of fluid percussion head injury on the activity of cholinergic neurons in specific brain areas of the rat 12 min, 4 h and 24 h following injury. Acetylcholine (ACh) turnover, used as an index of cholinergic neuronal activity, was determined using a gas chromatographic-mass spectrometric technique. The most striking changes in cholinergic activity were observed in the dorsal pontine tegmentum, where concussive head injury produced an increase in ACh turnover 12 min and 4 h following injury. This area has been previously associated with behavioral changes observed following concussive injury. ACh turnover in the thalamus, a region to which pontine cholinergic neurons project, also tended to increase 4 h following injury. On the other hand, ACh turnover tended to decrease in the amygdala 4 h following injury. Although there were no significant changes in hippocampal ACh content or turnover following injury. ACh content did tend to increase in that brain region 12 min following injury. There were no significant effects of injury on cholinergic neurons in the cingulate/frontal cortex. These changes in cholinergic neuronal activity may contribute to the neurological deficits following concussive injury. In particular, activation of cholinergic neurons in the pontine region may contribute to components of behavioral suppression associated with reversible traumatic unconsciousness. More generalized changes in cholinergic function may lead to the production of more chronic deficits.

Acetylcholine↗
PubMed1988

Effects of anticholinergic treatment on transient behavioral suppression and physiological responses following concussive brain injury to the rat.

Increasing doses (0.1, 1.0, 10.0 mg/kg) of scopolamine were systemically (i.p.) administered to rats subjected to moderate fluid percussion brain injury. Scopolamine treatment (1.0 mg/kg, i.p.) 15 min prior to trauma significantly reduced mortality and the duration of transient behavioral suppression assessed by a variety of measures. No differences were observed between saline- and scopolamine-treated animals in either the incidence or duration of transient apnea associated with injury. Preinjury treatment with methylscopolamine (1.04 mg/kg) or mecamylamine (1.0 mg/kg) had no effect on transient behavioral suppression. Except for increased heart rate, preinjury treatment with scopolamine (1.0 mg/kg) did not significantly alter systemic physiological responses to injury. Rats treated with scopolamine (1.0 mg/kg, i.p.) 30 s after injury tended to have shorter durations of reflex and response suppression. These experiments suggest that antimuscarinics can attenuate components of transient behavioral suppression associated with concussive brain injury. These findings are consistent with previous experimental and clinical observations and lend further support to the hypothesis that activation of a muscarinic system within the CNS mediates components of reversible traumatic unconsciousness following cerebral concussion.

Animals↗
PubMed1988

The effects of scopolamine and traumatic brain injury on central cholinergic neurons.

This study examined the effects of scopolamine and fluid percussion traumatic brain injury (TBI) on the activity of cholinergic neurons in specific areas of the rat brain 12 min, 4 h, and 24 h after injury. Acetylcholine (ACh) turnover, used as an index of cholinergic neuronal activity, was determined using gas chromatography-mass fragmentography. Scopolamine pretreatment prevented significant increases in dorsal pontine ACh turnover at 12 min and 4 h after TBI, suggesting that the drug's protective actions against the neurologic deficits following TBI may involve blockade of cholinergic neuronal activation as well as postsynaptic muscarinic blockade. The responses of thalamic, hippocampal, and amygdaloid cholinergic neurons to TBI did not differ substantially in scopolamine-pretreated rats from those studied previously in untreated fluid-percussion-injured rats. However, cholinergic neurons in the cingulate-frontal cortex of rats receiving TBI did respond in a different manner to scopolamine than those of rats receiving sham injury, suggesting a disruption of regulation of cortical cholinergic neurons following this model of TBI.

Acetylcholine↗
PubMed1988

Changes in regional brain acetylcholine content in rats following unilateral and bilateral brainstem lesions.

Previous research (Adametz, 1959) has shown that two-step bilateral lesions of the reticular formation in cats produce minimal behavioral disruption compared to one-step bilateral lesions, which produce profound behavioral suppression. We systematically examined alterations in forebrain acetylcholine (ACh) content and neurologic tolerance to one-step and two-step bilateral and unilateral lesions of the pontomesencephalic reticular formation (PMRF) in rats. One-step and two-step bilateral lesions separated by 1 or 5 days produced irreversible bilateral motor dysfunction. Survival after lesioning was 10%, 20%, and 0%, respectively. Unilateral lesion or two-step bilateral lesions separated by 15 or 30 days produced transient (less than 3 days) contralateral motor dysfunction. Survival after lesioning was 90%, 90%, and 100%, respectively. Within 24 h after one-step bilateral lesions, ACh content was significantly decreased bilaterally in thalamus, frontal cortex, amygdala, hippocampus, and basal forebrain. Within 5 days after unilateral lesioning, ACh content was significantly decreased ipsilaterally in the thalamus, amygdala, and hippocampus and had returned to control values by day 10 in the thalamus and hippocampus. The increased neurologic tolerance and recovery of ACh content in two-step bilateral PMRF lesions demonstrate important functional and neurochemical plasticity to brain injury. Although not directly addressing mechanisms of neural plasticity, this research examined possible associations between neurologic tolerance to PMRF lesions and neurochemical markers of forebrain ACh activity.

Acetylcholine↗
PubMed1988

Physiologic, histopathologic, and cineradiographic characterization of a new fluid-percussion model of experimental brain injury in the rat.

The fluid-percussion technique produces experimental brain injury by rapid injection of a fluid volume into the closed cranial cavity. The experiments reported here characterize a new, more controlled technique for fluid-percussion brain injury in the rat and systematically examine systemic physiologic, histopathologic, and electroencephalographic responses in the rat at two levels of injury severity. The new technique was developed to permit independent variation of the fluid pressure pulse parameters and, thus, more accurately define the brain loading conditions associated with fluid-percussion injury. The new technique produced changes in mean arterial blood pressure similar to previous techniques; however, bradycardia was not observed. Significant increases in heart rate were produced by both injury levels and were more prolonged at the high level of injury severity. Both magnitudes of injury produced significant decreases in EEG amplitude immediately postinjury, but high severity injury produced a greater decrease in delta frequency band (1-4 Hz) activity than did low severity injury. Both levels produced hemorrhage at the site of injury, thalamus, corpus callosum, hippocampus, and fimbria hippocampus similar to previous techniques. Higher levels of injury produced more extensive cerebral hemorrhage and greater spinal involvement. In a separate group of animals, cineradiographic images were made at coronal, sagittal, and dorsal orientations during the fluid pressure pulse. Intracranial fluid movement was characterized by rapid radial movement within the epidural space. The data suggest that the distributed nature of fluid-percussion induces pathology, and dysfunction may reflect a diffuse mechanical loading of the brain surface. The model appears to give repeatable effects useful in the study of closed head injury.

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PubMed1986

Metabolic and neurophysiologic sequelae of brain injury: a cholinergic hypothesis.

This paper reviews a number of lines of evidence developed in our laboratories indicating that at least some components of neurologic disturbances following concussion may be attributable to increased functional activity of cholinergic systems located within specific brain regions. These lines of evidence include EEG studies indicating that disruption of the reticular activating system is not necessary for production of a reversible, flaccid, comatose state following low levels of concussion, systematic transection studies indicating that regions bounded by collicular and midpontine transections may contribute to at least motor components of the behavioral suppression associated with concussion, local rates of glucose utilization following fluid percussion injury increase in restricted areas bounded by collicular and midpontine transections; microinjection of carbachol (but not tetracaine) into these hypermetabolic regions produced behavioral suppression and electroencephalographic changes resembling those following concussion, systemic administration or microinjections of atropine, but not mecamylamine, antagonized the behavioral effects of carbachol, and data indicating that pharmacologic blockage of muscarinic cholinergic systems can attenuate neurologic deficits. Taken in conjunction with data from earlier clinical and laboratory studies, our research also indicates that anticholinergic therapy may potentially benefit head-injured patients.

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PubMed1975

Silent aneurysm.

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