Widespread and lateralized effects of acute traumatic brain injury on norepinephrine turnover in the rat brain

Norepinephrine (NE) has been implicated in recovery of function following traumatic brain injury (TBI). While bilateral decreases in brain NE turnover occur at 6–24 h after TBI, it is unknown what effects unilateral TBI might have on brain NE turnover over the first few minutes after injury. Here male Sprague-Dawley rats had unilateral contusions of either the right or left somatosensory cortex produced by an air driven piston. At 30min after TBI, brain NE turnover was assessed by measuring the ratio of 3-methoxy-4-hydroxyphenylglycol (MHPG) to NE levels in various brain regions. Both right and left TBI produced 32–103% increases in NE turnover at the injury site and in the ipsilateral cerebral cortex surrounding, rostral and caudal to the injury as compared to the contralateral, uninjured site or to the homologous sites in uninjured controls. NE turnover was also altered selectively in some brain areas not affected by right TBI. Left TBI decreased NE turnover by 29% in the frontal cortex contralateral to the injury and by 24% bilaterally in the hypothalamus while increasing locus coeruleus NE turnover by 72% compared to uninjured controls. Thus, unilateral cortical TBI produced predominantly ipsilateral increases in cortical NE turnover but variable, bilateral changes in NE turnover in subcortical areas which were dependent upon the side of injury. These subcortical differences may explain some of the lateralized effects of cortical injury on post-injury behavior.     

Norepinephrine and traumatic brain injury: a possible role in post-traumatic edema

Unilateral cerebral contusion is associated with an early (30 min) increase in norepinephrine (NE) turnover followed by a later (6–24 h) depression of turnover which is bilateral and widespread throughout the brain. Blockade of NE function during the first few hours after traumatic brain injury (TBI) impedes subsequent recovery of function without enlarging the size of the lesion. The current studies were carried out to characterize further the timing of the switch from increased to decreased NE turnover and to investigate the pathogenesis of the delayed recovery of function associated with blocking NE function. Adult male rats had unilateral somatosensory cortex contusions made with a 5 mm diameter impact piston. They were killed after 2 h and their brains analyzed for NE turnover by HPLC with electrochemical detection. In general, NE turnover (the ratio of 3-methoxy-4-hyroxyphenylglycol to NE levels) had returned to sham-lesion control levels in most brain regions by 2 h after either left or right sided contusions. The only exceptions were a persistent 87% increase at the lesion site after right-sided contusions and 22% and 32% increases in the contralateral cerebellum after right- and left-sided contusions, respectively. Blockade of α₁-adrenoceptors by treatment with prazosin (3 mg/ kg, i.p.) 30 min prior to TBI produced edema in the striatum and hippocampus at 24 h which was not seen saline-treated rats nor in rats where NE reuptake was blocked with desmethylimipramine (DMI; 10 mg/kg, i.p.). DMI increased edema at the lesion site at 24 h, however. These data suggest that the early increase in NE release following unilateral cerebral contusion is protective and that this may act to stabilize the blood–brain barrier in areas adjacent to the injury site. Drugs that interfere with this enhanced noradrenergic function might enhance the damage caused by TBI.     

低温对实验型颅脑损伤大鼠免疫功能的影响

目的：研究不同低温状态下实验颅脑损伤大鼠免疫功能的动态变化,方法;采用^3H-TdR掺入法,LDH释放法及流式细胞术分别检测实验型液压颅脑损伤大鼠不同低温处后脾脏T,B淋巴细胞转化功能,NK细胞活性及外周血T细胞亚群的动态变化,结果,与颅脑损伤常温（37℃）组相比,损伤27℃组伤后1天B细胞转化率,NK细胞活性,伤后3天T细胞转化率降低,T细胞亚群CD3细胞伤后1天降低,损伤33℃组伤后1天B细胞转化率降低,伤后3天CD4／CD8升高,结论：（1）27℃低温对实验型颅脑伤大鼠免疫功能有抑制作用,（2）33℃低温不影响实验型颅服损伤大鼠细胞免疫,但对介导体液免疫的B细胞功能有一定的可逆性损害作用。     

Expression of nestin after traumatic brain injury in rat brain

We tested the hypothesis that traumatic brain injury upregulates expression of nestin, an embryonic cell intermediate filament protein. Brain from rats (n=24) subjected to controlled cortical impact injury and sham operated (n=3) and normal (n=3) rats were processed for dual label immunohistochemical study to identify cellular expression of nestin. Our results show that in normal noninjured animals, nestin is expressed slightly and localized only in a few endothelial and subventricular cells. In contrast, at 1–4 weeks postinjury nestin is strongly expressed in astrocytes and microglia. The expression of nestin in astrocytes and microglia after traumatic brain injury support the hypothesis that injured cerebral tissue expresses developmental proteins, and that these proteins may promote recovery after injury.     

Localized in vivo H-MRS of traumatic brain injury

¹H-MRS examinations were carried out on 14 patients, recovering from traumatic brain injury (TBI), who were in a stabilized clinical status and showed a good clinical outcome. Magnetic resonance spectra were recorded in subcortical (SC) and mid-brain (MB) areas where no detectable lesions appeared under magnetic resonance imaging. These two brain areas were selected because they are crucial sites of damage due to the physiopathologic mechanisms of TBI. A significant increase in inositol and choline peaks was found in MB compared to a control group of healthy individuals, whereas lower N-acetyl-aspartate peaks in the same area were detected. Reduced levels in the latter metabolite were also evident in the SC area. A significant correlation emerged between the inositol concentration in MB and the Glasgow Coma Scale Score measured just after the trauma. No correlation was found between the Glasgow Outcome Scale (GOS) at the time of the ¹H-MRS examination and the peaks of all the metabolites. Our study demonstrated that ¹H-MRS is a sensitive tool to evidentiate brain metabolic damage after TBI even in areas with lesions that are not detectable with current imaging techniques. The present research also shows an association between the alteration in one of the brain metabolites and the clinical parameters of TBI severity, but does not provide a clinical index of the patient's recovery. Further longitudinal studies on more conspicuous groups of patients with TBI could help to clarify whether metabolite modifications revealed by ¹H-MRS could be predictive of clinical outcome.     

Educational skills: Long-term outcome and predictors following paediatric traumatic brain injury

Given that reading, spelling and arithmetic skills are acquired through childhood, their development may be compromised following a childhood traumatic brain injury (TBI). The present study examined educational skills (reading accuracy, spelling and arithmetic) at a mean follow-up interval of 6.8 years post-injury in children who had sustained a mild, moderate, or severe TBI at two ages: ‘Young’ (age at injury: 3–7 years, n = 48) and ‘Old’: (age at injury: 8–12 years, n = 36). Comparisons between the young and old TBI groups resulted in inconsistent findings. While a dose-response relationship for severity was evident for the young group, this was not always the case for the old group. Significant predictors of outcome included both severity and acute intellectual function.     

Myelinated and unmyelinated axons of the corpus callosum differ in vulnerability and functional recovery following traumatic brain injury

Traumatic axonal injury (TAI), a common feature of traumatic brain injury, is associated with postinjury morbidity and mortality. However, TAI is not uniformly expressed in all axonal populations, with fiber caliber and anatomical location influencing specific TAI pathology. To study differential axonal vulnerability to brain injury, axonal excitability and integrity were assessed in the corpus callosum following fluid percussion injury in the rat. In brain slice electrophysiological recordings, compound action potentials (CAPs) were evoked in the corpus callosum, and injury effects were quantified separately for CAP waveform components generated by myelinated axons (N1 wave) and by unmyelinated axons (N2 wave). Ultrastructural analyses were also conducted of TAI-induced morphological changes in these axonal populations. The two populations of axons differed in response to brain injury, and in their functional recovery, during the first week postinjury. Amplitudes of N1 and N2 were significantly depressed at 3 h, 1 day, and 3 days survival. N1 amplitudes exhibited a recovery to control levels by 7 days postinjury. In contrast, N2 amplitudes were persistently suppressed through 7 days postinjury. Strength-duration properties of evoked CAPs further differentiated the effects of injury in these axonal populations, with N2 exhibiting an elevated strength-duration time constant postinjury. Ultrastructural observations revealed degeneration of myelinated axons consistent with diffuse injury sequelae, as well as previously undocumented pathology within the unmyelinated fiber population. Collectively, these findings demonstrate differential vulnerabilities of axons to brain injury and suggest that damage to unmyelinated fibers may play a significant role in morbidity associated with brain injury.     

Antipyretic treatment of noninfectious fever in children with severe traumatic brain injury

Objective The purpose of this study was to describe the treatment of noninfectious fever in children with severe traumatic brain injury (TBI). Materials and methods We conducted a retrospective study to compare type of and response to antipyretic treatment strategies in children less than or equal to 17 years and Glasgow Coma Scale (GCS) score less than 9. Results The average admission GCS score was 4. Forty children (35 boys, 5 girls), age 7.8 ± 5.2 years, had noninfectious fever. Seventy percent (28 of 40) received acetaminophen only, and 30% (12 of 40) received acetaminophen plus either ibuprofen or physical cooling. Time to next febrile episode was longer in patients receiving combination therapy than those receiving monotherapy (p = 0.03). Fever refractory to treatment dose or strategy occurred in more than 40% of the patients. Conclusions Early combination antipyretic therapy may be needed to effectively maintain normothermia in children with severe TBI.     

Persistent cognitive dysfunction after traumatic brain injury: A dopamine hypothesis

Traumatic brain injury (TBI) represents a significant cause of death and disability in industrialized countries. Of particular importance to patients the chronic effect that TBI has on cognitive function. Therapeutic strategies have been difficult to evaluate because of the complexity of injuries and variety of patient presentations within a TBI population. However, pharmacotherapies targeting dopamine (DA) have consistently shown benefits in attention, behavioral outcome, executive function, and memory. Still it remains unclear what aspect of TBI pathology is targeted by DA therapies and what time-course of treatment is most beneficial for patient outcomes. Fortunately, ongoing research in animal models has begun to elucidate the pathophysiology of DA alterations after TBI. The purpose of this review is to discuss clinical and experimental research examining DAergic therapies after TBI, which will in turn elucidate the importance of DA for cognitive function/dysfunction after TBI as well as highlight the areas that require further study.     

Administration of raloxifene reduces sensorimotor and working memory deficits following traumatic brain injury

Hormonal differences between males and females have surfaced as a crucial component in the search for effective treatments after experimental models of traumatic brain injury (TBI). Recent findings have shown that selective estrogen receptor modulators (SERMs) may have therapeutic benefit. The present study examined the effects of raloxifene, a SERM, on functional recovery after bilateral cortical contusion injury (bCCI) or sham procedure. Male rats received injections of raloxifene (3.0 mg/kg, i.p.) or vehicle (1.0 ml/kg, i.p.) 15 min, 24, 48, 72, and 96 h after bCCI or sham procedure. Rats were tested on both sensorimotor (bilateral tactile removal and locomotor placing tests) and cognitive tests (reference and working memory in the Morris water maze). Raloxifene-treated animals showed a significant reduction in the initial magnitude of the deficit and facilitated the rate of recovery for the bilateral tactile removal test, compared to vehicle-treated animals. The raloxifene-treated animals also showed a significant improvement in the acquisition of working memory compared to vehicle-treated animals. However, raloxifene did not significantly improve the acquisition of reference memory or locomotor placing ability. Raloxifene treatment also did not result in a significant reduction in the size of the lesion cavity. Thus, the task-dependent improvements seen following raloxifene treatment do not appear to be the result of cortical neuroprotection. However, these results suggest that raloxifene improves functional outcome following bCCI and may present an interesting avenue for future research.     

Pancreatitis associated with remote traumatic brain injury in children

Vomitting, abdominal distension, and feeding intolerance are common findings following brain injury in children, and are usually attributed to the brain injury or to delayed gastric emptying: a specific cause is usually not sought. We report six children who developed mild to moderate pancreatitis at least 7 days following apparently isolated brain injury, a previously unreported association. Five of the six patients received drugs that are known or suspected pancreatotoxins; all recovered without changes in the medications. When children develop feeding intolerance or upper gastrointestinal symptoms following traumatic brain injury, pancreatitis should be suspected.     

Evidence that synaptically-released zinc contributes to neuronal injury after traumatic brain injury

Prior evidence indicates that synaptically-released zinc enters postsynaptic neurons in toxic excess during ischemia and seizures. In addition, prevention of this zinc translocation has been shown to be neuroprotective in both ischemia and seizures. Here we show evidence that the same translocation of zinc from presynaptic boutons into postsynaptic neurons occurs after mechanical injury to the brain. Specifically, using a rat model of traumatic brain injury, we show that trauma is associated with (i) loss of zinc from presynaptic boutons (ii) appearance of zinc in injured neurons, and (iii) neuroprotection by intraventricular administration of a zinc chelator just prior to brain impact. The possible use of zinc chelators for neuroprotection after head trauma is considered.     

Enduring suppression of hippocampal long-term potentiation following traumatic brain injury in rat

This study investigated changes in synaptic responses (population spike and population EPSP) of CA1 pyramidal cells of the rat hippocampus to stimulation of the Schaffer collateral/commissural pathways 2-3 h after traumatic brain injury (TBI). TBI was induced by a fluid percussion pulse delivered to the parietal epidural space resulting in loss of righting responses for 4.90-8.98 min. Prior to tetanic stimulation, changes observed after the injury included: (1) decreases in population spikes threshold but not EPSP thresholds; (2) decreases in maximal amplitude of population spikes as well as EPSPs. TBI also suppressed long-term potentiation (LTP), as evidenced by reductions in post-tetanic increases in population spikes as well as EPSPs. Since LTP may reflect processes involved in memory formation, the observed suppression of LTP may be an electrophysiological correlate of enduring memory deficits previously demonstrated in the same injury model.     

Exploring theory of mind after severe traumatic brain injury

Previous studies have reported a dissociation between social behavioral impairments after severe traumatic brain injury (TBI) and relatively preserved performances in traditional tasks that investigate cognitive abilities. Theory of mind (ToM) refers to the ability to make inferences about other's mental states and use them to understand and predict others' behavior. We tested a group of 15 patients with severe TBI and 15 matched controls on a series of four verbal and non-verbal ToM tasks: the faux pas test, the first-order and second-order false belief task, the character intention task and the Reading the Mind in the Eyes Test. Participants with severe TBI were also compared to controls on non-ToM inference tasks of indirect speech act from the Montreal Evaluation of Communication (M.E.C.) Protocol and empathy (Davis Interpersonal Reactivity Index - I.R.I.) and tests for executive functions. Subjects with TBI performed worse than control subjects on all ToM tasks, except the first-order false belief task. The findings converge with previous evidence for ToM deficit in TBI and dissociation between ToM and executive functions. We show that ToM deficit is probably distinct from other aspects of social cognition like empathy and pragmatic communication skills.     

Axonal damage in severe traumatic brain injury: an experimental study in cat

Summary Based upon recent clinical findings, evidence exists that severe traumatic brain injury causes widespread axonal damage. In the clinical setting, it has been assumed that such axonal damage is the immediate consequence of traumatically induced tearing. However, in laboratory studies of minor head injury, evidence for primary traumatically induced axonal tearing has not been found. Rather the traumatic event has been linked to the onset of subtle axonal abnormalities, which become progressively severe over time (i.e., 12–24 h). In the light of these discrepant findings, we investigated, in the present study, whether progressive axonal change other than immediate tearing occurs with severe traumatic brain injury. Anesthetized cats were subjected to high intensity fluid-percussion brain injury. Prior to injury all animals received cortical implants of horseradish peroxidase (HRP) conjugated to what germ agglutinin to anterogradely label the major motor efferent pathways. Such an approach provided a sensitive probe for detecting traumatically induced axonal abnormality via both light microscopy (LM) and transmission electron microscopy (TEM). The animals were followed over a 1- to 6-h posttraumatic course, and processed for the LM and TEM visualization of HRP. Through such an approach no evidence of frank traumatically induced tearing was found. Rather, with LM, an initial intra-axonal peroxidase pooling was observed. With time, unilobular HRP-containing pools increased in size and progressed to bi- or multilobulated profiles. Ultimately, these lobulated configurations separated. Ultrastructurally, the initial unilobular pool was associated with organelle accumulation and focal axolemmal distention without frank disruption. Over time, such organelle accumulations increased in size and sequestered into multiple pools reminiscent of the bi- and multilobulated structures seen with LM. Ultimately, these organelle accumulations became detached, resulting in physically separated proximal and distal organelle-laden swellings surrounded by a distended axolemma and thinned myelin sheath. The findings reject the hypothesis that axons are immediately torn upon impact.Supported by NIH grants NS-20193, NS-12587 and NS-07288     

Time course of increased vulnerability of cholinergic neurotransmission following traumatic brain injury in the rat

We have previously shown that spatial memory changes following experimental traumatic brain injury (TBI) include long-term changes that are (1) ‘overt’: detected by routine behavioral assessments, or (2) ‘covert’: undetected in the absence of a secondary pharmacological challenge, such as by the cholinergic antagonist, scopolamine. Our objective in this study was to extend this finding by characterizing the time course of recovery of overt and covert spatial memory performance following two magnitudes of experimental TBI. The Morris water maze was used to assess cognitive performance. Rats received either moderate magnitude (6 m/s, 1.7 mm deformation) or low magnitude (6 m/s, 1 mm deformation) impacts through a lateral craniectomy under isoflurane anesthesia. Sham rats underwent identical surgical procedures but were not injured. To avoid motor deficits, water maze testing started two weeks post-injury. Rats were given four trials per day for seven consecutive days. For each trial, latency to find a hidden platform was timed. On the sixth, rats were injected (i.p.) with scopolamine (1 mg/kg) 15 min prior to maze testing. The next day, rats were retested. This testing regimen was repeated, beginning 4, 6, and 10 weeks post-TBI. Results showed that, while the low-magnitude injury produced no overt spatial memory deficits, the moderate-magnitude group exhibited overt deficits during the first test regimen. Also, while both injury magnitudes produced an enhanced sensitivity to spatial memory impairment by scopolamine at two weeks post-TBI, this covert deficit persisted only in the severe group at 4, 6, and 10 weeks post-TBI. Qualitative light microscopy showed that both injury groups had graded cortical necrosis. However, underlying subcortical structures such as the hippocampus appeared intact, with no overt cellular or parenchymal damage to the neuropil. These data suggest three distinct stages of functional recovery: (1) the initial period when overt deficits are present, (2) a period following recovery from overt deficits within which covert deficits can be reinstated by a pharmacological challenge, and (3) a period following recovery from both overt and covert deficits. Covert deficits can persist long after the recovery of overt deficits and, like other neurological deficits, the rate of recovery is dependent on the magnitude of TBI. Finally, spatial memory deficits can occur in the absence of light microscopic evidence of cell death in the hippocampus.     

依达拉奉对颅脑损伤病人脑水肿及预后的影响

目的探讨依达拉奉对颅脑损伤病人脑水肿及预后的影响。方法采用随机双盲平行对照试验,98例急性颅脑损伤的病人随机分成治疗组50例和对照组48例,对照组按照急性脑损伤常规治疗,治疗组在常规治疗的基础上给予依达拉奉注射液30mg加入生理盐水注射液100ml中静滴,bid,共14d。2组在治疗后3、7、14、28d做头部CT检查,根据脑CT显示脑水肿最大层面的长×宽测算脑水肿面积表示脑水肿的程度,观察脑水肿的变化。于治疗前和治疗后28d分别进行格拉斯哥昏迷评分(GCS)。结果2组病人伤后脑水肿均逐渐加重而至第7d达高峰期,在第7d前2组脑水肿变化比较无统计学意义(P>0.05)。从第14～28d2组病人均明显减轻,但治疗组脑水肿减轻程度明显优于对照组(P<0.01);2组在第28dGCS评分均有提高,但治疗组GCS评分明显高于对照组(P<0.05)。依达拉奉治疗期间未发现明显不良反应。结论依达拉奉可以减轻颅脑损伤病人脑水肿,并能改善预后,无明显不良反应。     

颅脑损伤后男性勃起功能障碍的临床调查

目的探讨影响颅脑损伤后男性患者性功能的因素。方法对126例颅脑损伤后男性患者的勃起功能进行回顾性调查,采用SPSS统计分析软件对男性功能障碍进行统计学分析。结果本组颅脑损伤男性患者126例,发生勃起功能障碍者18例,发生率为14.3%。颅脑损伤后综合征、GCS、脑损伤部位和应用抗癫痫药物的OR估计值分别为17.020,3.035,11.153和6.141。血清睾酮水平低于正常的8例中,发生勃起功能障碍5例(62.5%);血清睾酮水平正常的118例中,发生勃起功能障碍13例(11.0%),两组相比较,勃起功能障碍发生率差异非常显著(P0.01)。结论颅脑损伤后综合征、脑损伤的部位、受伤的严重程度、抗癫痫药物的应用和激素水平等因素影响男性颅脑损伤患者的性功能水平,其中以颅脑损伤后综合征的影响最为显著。     

Muscarinic cholinergic receptor binding in rat brain following traumatic brain injury

Recent evidence suggests that excessive activation of muscarinic cholinergic receptors (mAChRs) contributes significantly to the pathophysiological consequences of traumatic brain injury (TBI). To examine possible alterations in mAChRs after TBI, the affinity (K_d) and maximum number of binding sites (B_max) of mAChRs in hippocampus, neocortex, brain stem and cerebellum were determined by [³H]QNB binding. Three groups of rats were examined: 1 h post-TBI (n = 21), 24 h post-TBI (n = 21) and sham-injured rats (n = 21). K_d values were significantly higher in hippocampus and brain stem at 1 but not 24 h post-TBI compared with sham-injured controls (P < 0.05). K_d values did not significantly differ in neocortex and cerebellum at 1 or 24 h post-TBI compared with sham-injured controls. B_max values did not significantly differ in any brain areas at 1 or 24 h post-TBI compared with sham-injured controls These results show that TBI significantly decreases the affinity of mAChRs in hippocampus and brain stem at an early stage post-TBI, which may contribute to desensitization of mAChRs after TBI. The findings of no change in B_max values are consistent with a transient elevation in ACh concentrations after TBI.