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PubMed2005

Anterior pituitary hormone abnormalities following traumatic brain injury.

Traumatic brain injury (TBI) leads to approximately 100 hospitalizations per 100,000/year. Whereas diabetes insipidus is a well-known complication of TBI, anterior hypopituitarism as a consequence of TBI has been regarded as rare. More recent studies, however, suggest a prevalence of at least 30% of anterior pituitary dysfunction after TBI. Clinical signs of anterior hypopituitarism are often subtle and may be masked by sequalae of TBI. Therefore, post-traumatic anterior pituitary dysfunction may remain undiagnosed and, possibly, aggravate symptoms of brain injury. Moreover it may, if undiagnosed, lead to potentially fatal endocrine crises. This review updates clinical researchers, physicians, and other healthcare providers on the relationship between TBI and subsequent anterior pituitary insufficiency.

Brain Injuries↗

PubMed1997

Is high extracellular glutamate the key to excitotoxicity in traumatic brain injury?

Traumatic brain injury (TBI) increases extracellular levels of the excitatory amino acid glutamate and aspartate, and N-methyl-D aspartate (NMDA)-receptor antagonists protect against experimental TBI. These two findings have led to the prevalent hypothesis that excitatory amino acid efflux is a major contributor to the development of neuronal damage subsequent to traumatic injury. However, as with stroke, the hypothesis that high extracellular glutamate is the key to excitotoxicity in TBI conflicts with important data. For example, the initial increase in extracellular glutamate is cleared within 5 min after moderate TBI, whereas antagonists of glutamate receptors and the so- called presynaptic glutamate release inhibitors remain effective when administered 30 min after insult. In this article, we argue that the current concept of excitotoxicity in TBI, centered on high extracellular glutamate, does not withstand scientific scrutiny. As alternatives to explain the beneficial actions of glutamate antagonists in experimental TBI, we propose abnormalities of glutamatergic neurotransmission, such as deficient Mg2+ block of NMDA-receptor ionophore complexes, and phenomena such as spreading depression, which requires activation of glutamate receptors and is detrimental to neurons in damaged/vulnerable brain regions. Finally, we introduce the notion that beneficial effects of glutamate receptor antagonists in experimental models of neurological disorders do not necessarily imply the occurrence of excitotoxic processes. Indeed, glutamate-receptor blockade may be protective by reducing the energy demand required to counterbalance Na+ influx associated with glutamatergic synaptic transmission. In other words, glutamate receptor antagonists (and blockers of voltage-gated Na+-channels) may help nervous tissue to cope with increased permeability of the cellular membrane to ions and reduced efficacy of Na+ extrusion, and thus prevent the decay of transmembrane ionic concentrations gradients.

Animals↗

PubMed2005

Hypopituitarism after traumatic brain injury.

Traumatic brain injury (TBI) is one of the main causes of death and disability in young adults, with consequences ranging from physical disabilities to long-term cognitive, behavioural, psychological and social defects. Post-traumatic hypopituitarism (PTHP) was recognized more than 80 years ago, but it was thought to be a rare occurrence. Recently, clinical evidence has demonstrated that TBI may frequently cause hypothalamic-pituitary dysfunction, probably contributing to a delayed or hampered recovery from TBI. Changes in pituitary hormone secretion may be observed during the acute phase post-TBI, representing part of the acute adaptive response to the injury. Moreover, diminished pituitary hormone secretion, caused by damage to the pituitary and/or hypothalamus, may occur at any time after TBI. PTHP is observed in about 40% of patients with a history of TBI, presenting as an isolated deficiency in most cases, and more rarely as complete pituitary failure. The most common alterations appear to be gonadotropin and somatotropin deficiency, followed by corticotropin and thyrotropin deficiency. Hyper- or hypoprolactinemia may also be present. Diabetes insipidus may be frequent in the early, acute phase post-TBI, but it is rarely permanent. Severity of TBI seems to be an important risk factor for developing PTHP; however, PTHP can also manifest after mild TBI. Accurate evaluation and long-term follow-up of all TBI patients are necessary in order to detect the occurrence of PTHP, regardless of clinical evidence for pituitary dysfunction. In order to improve outcome and quality of life of TBI patients, an adequate replacement therapy is of paramount importance.

Brain Injuries↗

PubMed2006

Mechanisms underlying the inability to induce area CA1 LTP in the mouse after traumatic brain injury.

Traumatic brain injury (TBI) is a significant health issue that often causes enduring cognitive deficits, in particular memory dysfunction. The hippocampus, a structure crucial in learning and memory, is frequently damaged during TBI. Since long-term potentiation (LTP) is the leading cellular model underlying learning and memory, this study was undertaken to examine how injury affects area CA1 LTP in mice using lateral fluid percussion injury (FPI). Brain slices derived from FPI animals demonstrated an inability to induce LTP in area CA1 7 days postinjury. However, area CA1 long-term depression could be induced in neurons 7 days postinjury, demonstrating that some forms of synaptic plasticity can still be elicited. Using a multi-disciplined approach, potential mechanisms underlying the inability to induce and maintain area CA1 LTP were investigated. This study demonstrates that injury leads to significantly smaller N-methyl-D-aspartate potentials and glutamate-induced excitatory currents, increased dendritic spine size, and decreased expression of alpha-calcium calmodulin kinase II. These findings may underlie the injury-induced lack of LTP and thus, contribute to cognitive impairments often associated with TBI. Furthermore, these results provide attractive sites for potential therapeutic intervention directed toward alleviating the devastating consequences of human TBI.

Animals↗

PubMed2000

Continuous infusion of cyclosporin A postinjury significantly ameliorates cortical damage following traumatic brain injury.

Traumatic brain injury (TBI) results in the rapid necrosis of cortical tissue at the site of injury. In the ensuing hours and days, secondary injury exacerbates the original damage resulting in significant neurological dysfunction. Recent reports from our lab demonstrate that a bolus injection of the immunosuppressant cyclosporin A (CsA) is neuroprotective following TBI. CsA transiently inhibits the opening of the mitochondrial permeability transition pore and maintains calcium homeostasis in isolated mitochondria. The present study utilized a unilateral controlled cortical impact model of TBI to assess whether the neuroprotective effects of CsA could be extended by chronic infusion. Adult rats were subjected to a moderate (2 mm) cortical deformation and the extent of cortical damage was assessed using modern stereological techniques. Animals were administrated a 20 mg/kg intraperitoneal bolus of CsA or vehicle 15 min postinjury and osmotic minipumps were implanted subcutaneously to deliver CsA (4.5 or 10 mg/kg/day) or vehicle. All animals receiving CsA demonstrated a significant reduction in lesion volume, with the highest dose offering the most neuroprotection (74% reduction in lesion volume). These results extend our previous findings and demonstrate that chronic infusion of CsA is neuroprotective following TBI. These findings also suggest that the mechanisms responsible for tissue necrosis following TBI are amenable to manipulation.

Animals↗

PubMed2005

[Evidence-based intensive care treatment of intracranial hypertension after traumatic brain injury].

Traumatic brain injury (TBI) occurs frequently and is associated with a poor prognosis. Severe TBI results in substantial disability or death in more than 40% of cases. The major aim of treatment of these patients is to minimize secondary brain injury and in this respect, the prevention of intracranial hypertension plays a key role. In addition to surgical approaches, various conservative treatment options exist, such as the use of osmodiuretics, barbiturates, or corticosteroids, hyperventilation as well as induced therapeutic hypothermia. This review analyzes these treatment options and the therapeutic goals of lowering intracranial pressure (ICP) in patients after TBI using evidence-based criteria, and provides recommendations for clinical practice.

Adrenal Cortex Hormones↗

PubMed2006

Perivascular nerve damage in the cerebral circulation following traumatic brain injury.

Traumatic brain injury (TBI) causes cerebral vascular dysfunction. Most have assumed that it was the result of endothelial and/or smooth muscle alteration. No consideration, however, has been given to the possibility that the forces of injury may also damage the perivascular nerve network, thereby contributing to the observed abnormalities. To test this premise, we subjected rats to impact acceleration. At 6 h, 24 h and 7 days post-TBI, cerebral basal arteries were removed and processed with antibody targeting protein gene product 9.5 (PGP-9.5), with parallel assessments of 5-hydroxytryptamine (5-HT) accumulation in the perivascular nerves. Additionally, Fluoro-Jade was also used as a marker of axonal degeneration. The perivascular nerve network revealed no abnormality in sham animals. However, by 6 h post injury, Fluoro-Jade reactivity appeared in the perivascular regions, with the number of fibers increasing with time. By 24 h post injury, a significant reduction in the perivascular 5-HT accumulation occurred, together with a reduction in PGP-9.5 fiber staining. At 7 days, a recovery of the PGP-9.5 immunoreactivity occurred, however, it did not reach a control-like distribution. These studies suggest that neurogenic damage occurs following TBI and may be a contributor to some of the associated vascular abnormalities.

Animals↗

PubMed2005

N-acetylcysteine attenuates early induction of heme oxygenase-1 following traumatic brain injury.

Traumatic brain injury (TBI) results in a cascade of events that includes the production of reactive oxygen species. Heme oxygenase-1 (HO-1) is induced in glial cells following head trauma, suggestive of oxidative stress. We have studied the temporal and spatial effects of the antioxidant N-acetylcysteine (NAC) on HO-1 levels following lateral fluid-percussion injury by immunoblotting and immunohistochemistry. In the injured cerebral cortex, maximal HO-1 induction was seen 6 h post-TBI and was maintained for up to 24 h following the insult, while the ipsilateral hippocampus and thalamus showed marked induction at 24 h postinjury. In all three brain regions, little or no HO-1 immunoreactivity was observed on the contralateral side. Astrocytes exhibited positive immunoreactivity for HO-1 in the injured cerebral cortex, hippocampus, and thalamus, while some neurons and microglia were also immunoreactive in the injured cortex. The administration of NAC 5 min following TBI resulted in a marked reduction in this widespread induction of HO-1, concomitant with a decrease in the volume of injury in all three brain regions. Together, these findings indicate that HO-1 induction is related to both oxidative and injury characteristics of the affected tissue, suggesting that protein expression of this gene is a credible marker of oxidative damage in this model of TBI.

Acetylcysteine↗

PubMed2005

Morris water maze search strategy analysis in PDAPP mice before and after experimental traumatic brain injury.

Traumatic brain injury (TBI) is a common cause of cognitive dysfunction and a major risk factor for Alzheimer's disease (AD). PDAPP mice, a transgenic line overexpressing a mutant human amyloid precursor protein (APP) implicated in familial AD, have markedly impaired behavioral performance in the Morris water maze relative to wild-type (WT) littermates. Performance further deteriorates following experimental TBI in both PDAPP and WT mice. However, the aspects of cognitive function involved are not well understood. Here, we have analyzed search strategies used in the water maze by 3-4 month old PDAPP and WT C57Bl6 littermates both before and after moderate controlled cortical impact TBI. Prior to TBI, PDAPP mice used less spatial strategies and more nonspatial systematic strategies and strategies involving repetitive looping than WT mice. With training, PDAPP mice used more spatial strategies and less repetitive looping. After TBI, PDAPP mice lost use of spatial strategies and relied more on repetitive looping. TBI in WT mice also reduced their use of spatial strategies but instead caused a switch to nonspatial systematic strategies. We also analyzed changes in the efficiency with which mice used each individual strategy, but found that differences in which strategies were used quantitatively accounted for most of the differences in performance between groups. These results demonstrate that suboptimal search strategy use in addition to effects on spatial learning and memory underlies the impaired performance of PDAPP mice and further deterioration following TBI. Human TBI patients may have analogous poor use of problem solving strategies.

Amyloid beta-Protein Precursor↗

PubMed2006

Transplantation of primed human fetal neural stem cells improves cognitive function in rats after traumatic brain injury.

Traumatic brain injury (TBI) often produces cognitive impairments by primary or secondary neuronal loss. Stem cells are a potential tool to treat TBI. However, most previous studies using rodent stem or progenitor cells failed to correlate cell grafting and cognitive improvement. Furthermore, the efficacy of fetal human neural stem cells (hNSCs) for ameliorating TBI cognitive dysfunction is undetermined. This study therefore characterized phenotypic differentiation, neurotrophic factor expression and release and functional outcome of grafting hNSCs into TBI rat brains. Adult Sprague-Dawley rats underwent a moderate parasagittal fluid percussion TBI followed by ipsilateral hippocampal transplantation of hNSCs or vehicle 1 day post-injury. Prior to grafting, hNSCs were treated in vitro for 7 days with our previously developed priming procedure. Significant spatial learning and memory improvements were detected by the Morris water maze (MWM) test in rats 10 days after receiving hNSC grafts. Morphological analyses revealed that hNSCs survived and differentiated mainly into neurons in the injured hippocampus at 2 weeks after grafting. Furthermore, hNSCs expressed and released glial-cell-line-derived neurotrophic factor (GDNF) in vitro and when grafted in vivo, as detected by RT-PCR, immunostaining, microdialysis and ELISA. This is the first direct demonstration of the release of a neurotrophic factor in conjunction with stem cell grafting. In conclusion, human fetal neural stem cell grafts improved cognitive function of rats with acute TBI. Grafted cells survived and differentiated into neurons and expressed and released GNDF in vivo, which may help protect host cells from secondary damage and aid host regeneration.

Animals↗

PubMed2004

Rehabilitation and hypopituitarism after traumatic brain injury.

Traumatic brain injury (TBI) is a leading cause of death and disability in the United States (US). The severity of a TBI is difficult to assess, and therefore, accurate determination of the prognosis is difficult. The symptoms of a TBI involve most major medical systems, and share many similarities with the symptoms of hypopituitarism. Although more than two-thirds of patients with severe head injuries who die have structural abnormalities in the hypothalamus and the pituitary, pituitary function is not routinely assessed after head trauma. Thus, studies have shown that anterior pituitary hormone deficiencies are common following brain injury [Endocrinologist 11 (2001) 275; J. Clin. Endocrinol. Metab. 86 (2001) 2752]. Survivors of brain injury should be screened for such deficiencies so that replacement therapy can be initiated to optimize rehabilitation and outcome.

Brain Injuries↗

PubMed2004

Motor and cognitive function evaluation following experimental traumatic brain injury.

Traumatic brain injury (TBI) in humans may cause extensive sensorimotor and cognitive dysfunction. As a result, many TBI researchers are beginning to assess behavioral correlates of histologically determined damage in animal models. Although this is an important step in TBI research, there is a need for standardization between laboratories. The ability to reliably test treatments across laboratories and multiple injury models will close the gap between treatment success in the lab and success in the clinic. The goal of this review is to describe and evaluate the tests employed to assess functional outcome after TBI and to overview aspects of cognitive, sensory, and motor function that may be suitable targets for therapeutic intervention.

Animals↗

PubMed2005

Extracellular signal-regulated kinase-mediated IL-1-induced cortical neuron damage during traumatic brain injury.

Traumatic brain injury (TBI) is one of the most prevalent causes of morbidity and mortality in youth. Interleukin-1 (IL-1) has many roles in the brain in addition to mediating glial inflammatory response; it has also been implicated in neurodegenerative diseases. We demonstrated the signal transduction pathway of IL-1 overproduction-induced cortical neuron loss during TBI. A calibrated weight-drop device (450 g weight and 2m height) was used to induce TBI in adult male Sprague-Dawley rats under general anesthesia (sodium pentobarbital: 40 mg/kg, i.p.). Expression of interleukin-1alpha (IL-1alpha), interleukin-1beta (IL-1beta), extracellular signal-regulated kinase (ERK), Jun, and p-38 were determined by Western blotting and RT-PCR. Neuronal damage was evaluated by microscopic examination. We found both mRNA and proteins of cortical IL-1alpha and IL-1beta increased three hours after TBI. Phosphorylation of ERK significantly increased but there were no significant effects on cortical expression of ERK, Jun and p-38. Administration of ERK inhibitor, PD98059, IL-1alpha antibody and IL-1beta antibody protected animals from TBI-induced neuronal damage. Our results suggest that TBI-induced cortical neuron death was mediated by the IL-1 receptor through ERK phosphorylation.

Animals↗

PubMed2005

Hippocampal head atrophy after traumatic brain injury.

Traumatic brain injury (TBI) causes hippocampal damage. The hippocampus can be macroscopically divided into the head, body and tail, which differ in terms of their sensitivity to excitability and also in terms of their cortical connections. We investigated whether damage also varies according to the hippocampal area involved, and studied the relationship of hippocampal reductions with memory performance. Twenty TBI patients and matched controls were examined. MRI measurements were performed separately for the hippocampal head, body and tail. Memory outcome was measured by Rey's auditory verbal learning test, Rey's complex figure test and a modified version of Warrington's facial recognition memory test. Group comparison showed that patients had bilateral hippocampal atrophy, mainly involving the hippocampal head. Moreover, TBI subjects showed verbal memory deficits which presented slight correlations with left hippocampal head atrophy.

Adolescent↗

PubMed2003

Chronic nicotine treatment attenuates alpha 7 nicotinic receptor deficits following traumatic brain injury.

Traumatic brain injury (TBI) often causes a persistent and debilitating impairment of cognitive function. Although the neurochemical basis for TBI-induced cognitive dysfunction is not well characterized, some studies suggest prominent involvement of the CNS cholinergic system. Previous studies from our laboratories have shown that alpha 7* nicotinic cholinergic receptors (nAChrs) are especially vulnerable to the pathophysiological effects of TBI. Hippocampal and cortical alpha-[(125)I]-bungarotoxin (BTX) expression of alpha 7* nAChrs is significantly decreased in many brain regions following TBI and this reduction persists for at least 3 weeks following injury. In the present study we evaluated whether chronic nicotine infusion could attenuate TBI-induced deficits in alpha 7* nAChr expression. Male Sprague-Dawley rats were sham-operated, or subjected to mild or moderate unilateral cortical contusion injury. Immediately following brain injury, osmotic mini-pumps that delivered chronic saline or nicotine (0.125 or 0.25 mg/kg/h) were implanted. The animals were euthanatized and the brains prepared for nAChr quantitative autoradiography, 7 days following surgery. Brain injury caused significant decreases in BTX binding in several regions of the hippocampus. TBI-induced deficits in alpha 7* nAChr density were reversed in four of the six hippocampal brain regions evaluated following chronic nicotine administration. If TBI-induced deficits in alpha 7* nAChr expression play a role in post-injury cognitive impairment, pharmacological treatments which restore nAChr binding to control levels may be therapeutically useful.

Animals↗

PubMed1997

Phasic arousal in response to auditory warnings after traumatic brain injury.

Traumatic brain injury (TBI) is believed to have adverse effects on attention, but because of the multifaceted nature of the arousal and attentional network, the precise impact of TBI on various subcomponents of this network remains controversial. As part of a larger program of research on attention in TBI, we studied the effects of auditory warning signals on accuracy, reaction time, and response bias, as indices of phasic arousal in a visual go/no-go task. Warnings were presented randomly at various pre-stimulus intervals to a sample of recently injured patients and control subjects. For each subject and performance index, we examined the time interval required to reach maximal phasic arousal, the degree of performance change occurring at this maximal point, and the ability to maintain this state of increased arousal over longer warning intervals. After adjustment for baseline differences, there were no significant differences between patients and controls in any aspect of performance. Examination of effect sizes suggested that this was not due to limited statistical power, but that any differences between groups, if present, must have been small. In contrast, in our prior research on sustained attention and observable behaviors related to attention, large group differences have been found. These data suggest that mechanisms responsible for auditorily-induced phasic arousal responses are largely preserved in severe TBI.

Adult↗

PubMed2002

The role of extracellular signal-regulated kinase in cognitive and motor deficits following experimental traumatic brain injury.

Traumatic brain injury (TBI) causes neuronal death and alters the plasticity (e.g. morphology) of surviving neurons. Both of these events contribute to TBI-associated neurological deficits, such as memory dysfunction. Although a majority of current research is directed towards identifying biochemical cascades responsible for cell death, little is known about mechanisms of altered neuronal plasticity following TBI. Extracellular signal-regulated kinases (Erk1 and 2) play a critical role in growth and have been implicated in long-lasting neuronal plasticity and memory storage. The activation of Erk following TBI was investigated utilizing an antibody that specifically binds to dually phosphorylated Erk. Using this antibody, we report that lateral cortical impact injury in rats increases Erk phosphorylation both in the cortex and the hippocampus as early as 10 min post-injury. Double immunostaining experiments using either a neuron-specific or an astroglial-specific marker show that the active Erk is localized almost exclusively in neuronal cells. Furthermore, the increase in phospho-Erk immunoreactivity was initially localized to axons and at later time points was observed to be predominantly in the cell soma. This suggests that Erk redistributed over time and may play a role in retrograde signaling. Administration of inhibitors of the Erk cascade worsened retrograde amnesia, impaired performances in hippocampus- and amygdala-dependent memory tasks, and exacerbated motor deficits following TBI. Furthermore, inhibition of this cascade did not have any overt effects on cell survival, but altered neuronal morphology as detected by a dendritic-specific marker. These findings suggest that the Erk cascade plays an essential role for the maintenance of neuronal function and plasticity following TBI.

Animals↗

PubMed2003

Magnetization transfer and T2 quantitation in normal appearing cortical gray matter and white matter adjacent to focal abnormality in patients with traumatic brain injury.

Traumatic brain injury (TBI) is one of the commonest causes of morbidity and mortality in the developed countries with posttraumatic epilepsy and functional disability being its major sequelae. The purpose of this study was to test the hypothesis whether the normal appearing adjacent gray and white matter regions on T2 and T1 weighted magnetization transfer (MT) weighted images show any abnormality on quantitative imaging in patients with TBI. A total of 51 patients with TBI and 10 normal subjects were included in this study. There were significant differences in T2 and MT ratio values of T2 weighted and T1 weighted MT normal appearing gray matter regions adjacent to focal image abnormality compared to normal gray matter regions in the normal individuals as corresponding contralateral regions of the TBI patient's group (p < 0.05). However the adjoining normal appearing white matter quantitative values did not show any significant change compared to the corresponding contralateral normal white matter values. We conclude that quantitative T2 and MT ratio values provide additional abnormality in patients with TBI that is not discernable on conventional T2 weighted and T1 weighted MT imaging especially in gray matter. This additional information may be of value in overall management of these patients with TBI.

Adolescent↗