Autonomic and neural correlates of dysregulated arousal in severe traumatic brain injury

Severe traumatic brain injury (TBI) in adults is associated with abnormalities in arousal and emotional responsivity, which are observed physiologically, behaviourally and via self-report measures. While an accurate measure of physiological arousal is debated, ,  and  have consistently shown an inverse relationship between skin conductance level (SCL), and mean alpha power (alpha) during an eyes-closed resting condition (EC), accompanied by an increase in SCL and corresponding decrease in alpha during eyes-open (EO). Thus, alpha may provide a novel index of autonomic arousal. This study aimed to elucidate the neural and autonomic correlates of arousal disturbances in TBI.     

局限性脑外伤患者的心理推理能力和执行功能缺陷

目的:观察额叶、颞叶、额颞叶脑外伤患者的心理推理能力和执行功能的缺陷,并分析两者之间的相关性。方法:本研究为横断面研究。研究组为110名在本所进行司法鉴定的局限性颅脑外伤患者,包括额叶损伤组29例,颞叶损伤组33例,额颞叶损伤组48例。选取正常对照50例。所有被试接受3个心理推理能力测试(错误信念、解释性任务、失言任务),以及3个执行功能测试(河内塔测验、Stroop测验和威斯康星卡片分类测验)。比较各组间的心理推理能力和执行功能差异,并对心理推理能力和执行功能进行相关性分析和多元逐步回归分析。结果:3个研究组心理推理能力和执行功能的成绩均差于正常对照组,其中额叶组的错误信念和Stroop卡B正确数最低;颞叶组的失言任务得分最低,河内塔测验步数最多;额颞叶组的解释性任务和威斯康星完成分类数最低(均P<0.01)。研究组的错误信念与河内塔步数(r=-0.30)、Stroop测验卡B耗时(r=-0.43)和威斯康星完成首次分类所用卡数(r=-0.30)均呈负相关(均P<0.01);解释性任务与河内塔耗时(r=-0.36)和Stroop卡AB时差(r=-0.36)呈负相关,与威斯康星测验完成分类数呈正相关(r=0.66);失言任务与河内塔耗时(r=-0.69)、Stroop卡B耗时(r=-0.46)和威斯康星完成首次分类所用卡数(r=-0.52)均呈负相关(均P<0.01)。对照组各项心理推理能力任务和执行功能之间无明显线性相关。多元逐步回归分析显示,三组脑外伤患者各个心理推理能力的相关因素基本相似,其中,Stroop卡B耗时越少,其错误信念得分越高;威斯康星完成首次分类越快,其解释性任务得分越高;河内塔测验耗时越少,其失言任务得分越高。结论:脑外伤患者存在心理推理能力的下降,这种下降与其同时存在的执行功能低下存在正相关,其中,错误信念成绩与Stroop测验成绩、解释性任务与威斯康星卡片测验、失言任务与河内塔测验的相关关系较为突出。     

Possible roles of COX-1 in learning and memory impairment induced by traumatic brain injury in mice

People who suffer from traumatic brain injury (TBI) often experience cognitive deficits in spatial reference and working memory. The possible roles of cyclooxygenase-1 (COX-1) in learning and memory impairment in mice with TBI are far from well known. Adult mice subjected to TBI were treated with the COX-1 selective inhibitor SC560. Performance in the open field and on the beam walk was then used to assess motor and behavioral function 1, 3, 7, 14, and 21 days following injury. Acquisition of spatial learning and memory retention was assessed using the Morris water maze on day 15 post-TBI. The expressions of COX-1, prostaglandin E2 (PGE2), interleukin (IL)-6, brain-derived neurotrophic factor (BDNF), platelet-derived growth factor BB (PDGF-BB), synapsin-I, and synaptophysin were detected in TBI mice. Administration of SC560 improved performance of beam walk tasks as well as spatial learning and memory after TBI. SC560 also reduced expressions of inflammatory markers IL-6 and PGE2, and reversed the expressions of COX-1, BDNF, PDGF-BB, synapsin-I, and synaptophysin in TBI mice. The present findings demonstrated that COX-1 might play an important role in cognitive deficits after TBI and that selective COX-1 inhibition should be further investigated as a potential therapeutic approach for TBI.     

Impaired emotional contagion following severe traumatic brain injury

Empathy deficits are widely-documented in individuals after severe traumatic brain injury (TBI). This study examined the relationship between empathy deficits and psychophysiological responsivity in adults with TBI to determine if impaired responsivity is ameliorated through repeated emotional stimulus presentations. Nineteen TBI participants (13 males; 41 years) and 25 control participants (14 males; 31 years) viewed five repetitions of six 2-min film clip segments containing pleasant, unpleasant, and neutral content. Facial muscle responses (zygomaticus and corrugator), tonic heart rate (HR) and skin conductance level (SCL) were recorded. Mean responses for each viewing period were compared to a pre-experiment 2-min resting baseline period. Self-reported emotional empathy was also assessed. TBI participants demonstrated identical EMG response patterns to controls, i.e. an initial large facial response to both pleasant and unpleasant films, followed by habituation over repetitions for pleasant films, and sustained response to unpleasant films. Additionally, an increase in both arousal and HR deceleration to stimulus repetitions was found, which was larger for TBI participants. Compared to controls, TBI participants self-reported lower emotional empathy, and had lower resting arousal, and these measures were positively correlated. Results are consistent with TBI producing impairments in emotional empathy and responsivity. While some normalisation of physiological arousal appeared with repeated stimulus presentations, this came at the cost of greater attentional effort.     

Effect of APOE polymorphisms on early responses to traumatic brain injury

To investigate the relationship between apolipoprotein E (APOE) polymorphisms and the severity of traumatic brain injury (TBI) in acute stage in the cohort of mainland Chinese patients. We prospectively identified admissions to the two neurosurgical departments for head injury. A total of 110 subjects with TBI (80 males and 30 females, with mean age of 43.87 years) were enrolled from December 2003 to May 2004, and demographic and clinical data were collected. Venous blood was collected from patients with TBI on admission to determine the APOE genotype polymorphisms. The APOE genotyping was performed by means of PCR-RFLP. The deterioration of patients’ condition in acute stage (<7 days after TBI) was judged by either of following criteria: decrease of GCS, increase in hematoma volume or delayed hematoma both detected by repeated CT scanning. χ²-test and logistic regression analyses were done by SPSS. The distributions of APOE genotypes and alleles matched Hardy–Weinberg law. In 110 Chinese patients, 19 subjects presented with deteriorated clinical condition after hospitalization, and seven of 17 patients with APOE ?4 (41.2%) had a deteriorated condition which was significantly different from those without APOE ?4 (12 of 93 patients, 12.9%, P = 0.01). However, neither the presence of ?2 nor of ?3 was significantly different from those absent of it (P > 0.05). Logistic regression analyses showed that APOE ?4 was a risk factor (OR = 4.836, P = 0.011, 95% CI 1.443–16.208) to predispose to clinical deterioration after adjusting for patient age, sex, smoking or not, alcohol-drinking or not, injury severity, injury mechanisms, treatments, and pattern of TBI. This finding suggests that the patients with APOE ?4 predispose to clinical deterioration in acute phase after TBI and APOE polymorphisms play a role in early responses to TBI.     

Long-term potentiation deficits and excitability changes following traumatic brain injury

The effects of traumatic brain injury (TBI) on hippocampal long-term potentiation (LTP) and cellular excitability were assessed at postinjury days 2, 7, and 15. TBI was induced using a well-characterized central fluid-percussion model. LTP of the Schaffer collateral/commissural system was assessed in vivo in urethane-anesthetized rats. Significant LTP of the population excitatory postsynaptic potential (EPSP) slope was found only in controls, and no recovery to control levels was observed for any postinjury time point. Four measurement parameters reflecting pyramidal cell discharges (population spike) indicated that TBI significantly increased cellular excitability at postinjury day 2: (1) pretetanus baseline recording showed that TBI reduced population spike threshold and latency; (2) tetanic stimulation (400 Hz) increased population spike amplitudes to a greater degree in injured animals than in control animals; (3) tetanus-induced population spike latency shifts were greater in injured cases; and (4) tetanic stimulation elevated EPSP to spike ratios (E-S potentiation) to a greater degree in injured animals. These parameters returned to control levels, as measured on postinjury days 7 and 15. These results suggest that TBI-induced excitability changes persist at least through 2 days postinjury and involve a differential impairment of mechanisms subserving LTP of synaptic efficacy and mechanisms related to action potential generation     

Sleep and wake disturbances following traumatic brain injury

Traumatic brain injury (TBI) is a major health concern in industrialised countries. Sleep and wake disturbances are among the most persistent and disabling sequelae after TBI. Yet, despite the widespread complaints of post-TBI sleep and wake disturbances, studies on their etiology, pathophysiology, and treatments remain inconclusive. This narrative review aims to summarise the current state of knowledge regarding the nature of sleep and wake disturbances following TBI, both subjective and objective, spanning all levels of severity and phases post-injury. A second goal is to outline the various causes of post-TBI sleep-wake disturbances. Globally, although sleep-wake complaints are reported in all studies and across all levels of severity, consensus regarding the objective nature of these disturbances is not unanimous and varies widely across studies. In order to optimise recovery in TBI survivors, further studies are required to shed light on the complexity and heterogeneity of post-TBI sleep and wake disturbances, and to fully grasp the best timing and approach for intervention.     

Neuroprotective effects of resveratrol against traumatic brain injury in immature rats

Childhood trauma resulting in traumatic brain injury (TBI) due to accidents and abuse is the major cause of death and dysfunction in the young. Since there are no approved specific pharmacological agents that block the progression of the secondary injury, the current management of TBI is mainly supportive. We aimed to determine the effect of resveratrol on hippocampal damage and behavioral deficits in 7-day-old rat pups subjected to contusion injury. Resveratrol was injected intraperitoneally at the doses of 100 mg/kg of body weight immediately after induction of traumatic injury. Hippocampal damage was examined by cresyl violet staining and behavioral alterations were evaluated using open field and novel object recognition tests 2 weeks after trauma. Histopathological evaluation showed that treatment with a single dose of 100 mg/kg resveratrol (i.p.) after the trauma significantly ameliorated the trauma induced hippocampal neuron loss at ipsilateral and contralateral hippocampal brain regions of rats. Additionally, treatment with resveratrol decreased anxiety and increased cortex/hippocampus dependent memory of animals subjected to blunt head trauma. These results show that acute treatment of resveratrol has a neuroprotective role against trauma induced hippocampal neuron loss and associated cognitive impairment in rats.     

创伤性脑损伤后大鼠外周血CD8的变化

目的:探讨外周血CD8在创伤性脑损伤后的变化特点。方法:改良Feeney's自由落体打击法制备创伤性脑损伤模型;ELISA检测大鼠血清中神经元特异性烯醇化酶(NSE)和CD8的含量,双变量分析两者的相关性;Western blot法检测大鼠血液淋巴细胞FasL蛋白的表达。结果:颅脑外伤后大鼠血清CD8升高滞后于NSE。大鼠伤后1 d血清NSE水平即显著升高,伤后3 d达到峰值,随后逐渐下降;大鼠血清CD8在伤后3 d开始升高,峰值出现在伤后7 d,随后逐渐下降。统计分析显示伤后1 d、3 d、7 d的血清的NSE与伤后3 d、7 d、14 d的血清CD8含量变化呈现正相关。但伤后不同时间大鼠血液淋巴细胞FasL蛋白表达的差异均无统计学显著性。结论:创伤性脑损伤后释放入血的NSE刺激机体免疫应答,引起外周血CD8增多,推测其可能与创伤性脑损伤后继发性损伤的免疫应答有关。     

Sex differences in XIAP cleavage after traumatic brain injury in the rat

Sex influences histological and behavioral outcomes following traumatic brain injury (TBI), but the underlying sex-dependent pathomechanisms regulating outcome measures remain poorly defined. Here, we investigated the TBI-induced regulation of the X-linked inhibitor of apoptosis protein (XIAP) that, in addition to suppressing cell death by inhibition of caspases, is involved in signaling cascades, including immune regulation and cell migration. Since estrogen has been shown to have anti-apoptotic properties, we specifically examined sex differences and the influence of estrogen on XIAP processing after TBI. Sprague–Dawley male (TBI-M), female (TBI-F), ovariectomized female (TBI-OVX) and ovariectomized females supplemented with estrogen (TBI-OVX + EST) were subjected to moderate (1.7–2.2 atm) fluid percussion (FP) injury. Animals were sacrificed 24 h after FP injury; cortical tissue (ipsilateral and contralateral) was dissected and analyzed for XIAP processing by immunoblot analysis (n = 6–7/group) or confocal microscopy (n = 2–3/group). Significant differences in XIAP cleavage products in the ipsilateral cortex were found between groups (p < 0.03). Post hoc analysis showed an increase in XIAP processing in both TBI-F and TBI-OVX + EST compared to TBI-M and TBI-OVX (p < 0.05), indicating that more XIAP is cleaved following injury in intact females and TBI-OVX + EST than in TBI-M and TBI-OVX groups. Co-localization of XIAP within neurons also demonstrated sex-dependent changes. Based on these data, it appears that the processing of XIAP after injury is different between males and females and may be influenced by exogenous estrogen treatment.     

Electrophysiological markers of cognitive deficits in traumatic brain injury: A review

Event-related potentials (ERPs) and oscillatory activity from the human electroencephalogram (EEG) provides a rich source of data that helps elucidate specific processing impairments in TBI patients. This review will focus on some of the central and disabling cognitive deficits in TBI and how broadband ERP markers and the spectral content of the EEG can help explain abnormalities in brain function that impact upon processing speed, sustained attention, performance monitoring, inhibitory control and cognitive flexibility. Physiological signals also provide useful outcome markers in cognitive intervention studies in conjunction with behavioural endpoints. Potential rehabilitation approaches utilising electrophysiological markers of recovery are also discussed. Progress has been made in recent years in defining key pathophysiological mechanisms in the context of sensitive laboratory paradigms. However, aberrant physiological signals need to be understood more clearly in future studies in terms of the neuroanatomical impact of injury, particularly in relation to the most common type of damage in TBI, disrupting extended white matter fibres.     

Treadmill exercise inhibits traumatic brain injury-induced hippocampal apoptosis

Traumatic brain injury (TBI) occurs when an outside force impacts the brain. The main problem associated with TBI is neuronal cell death of the brain, and the outcome of TBI ranges from complete recovery to permanent disability, and sometimes death. Physical exercise is known to ameliorate neurologic impairment induced by various brain insults. In the present study, we investigated the effects of treadmill exercise on short-term memory and apoptosis in the hippocampus following TBI in rats. TBI was induced by an electromagnetic-controlled cortical impact. The rats in the exercise group were forced to run on a treadmill for 30 min once daily for 10 consecutive days, beginning 2 days after induction of TBI. For the current study, a step-down avoidance task, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay, Western blot for Bcl-2 and Bax, and immunohistochemistry for caspase-3 were conducted. The present results revealed that TBI impaired short-term memory, and increased DNA fragmentation and caspase-3 expression in the hippocampus. Induction of TBI also enhanced expression of pro-apoptotic factor Bax protein and suppressed expression of anti-apoptotic factor Bcl-2 protein in the hippocampus. Treadmill exercise alleviated short-term memory impairment, and decreased DNA fragmentation and caspase-3 expression in the hippocampus. In addition, treadmill exercise remarkably suppressed expression of Bax protein and slightly increased expression of Bcl-2 protein in TBI-induced rats. The present study showed that treadmill exercise might overcome TBI-induced apoptotic neuronal cell death, thus facilitating recovery following TBI.     

脑外伤小鼠海马水通道蛋白-9表达的变化

目的探讨脑外伤小鼠海马水通道蛋白-9(aquaporin 9,AQP9)表达的变化。方法40只Balb/c小鼠随机分为假手术组(10只)和脑外伤组(30只)。脑外伤组依据脑外伤的不同时间点再分6 h、1 d、3 d三个小组,每组10只。免疫组化和Western blot检测各组小鼠海马AQP9蛋白的表达。RT-PCR方法检测各组小鼠海马AQP9 mRNA的表达变化。结果免疫组化和Western blot结果发现,脑外伤组小鼠海马AQP9蛋白表达量明显高于假手术组(P<0.05);RT-PCR结果也发现,脑外伤组小鼠海马AQP9 mRNA表达量明显高于假手术组(P<0.05)。结论脑外伤小鼠海马AQP9表达明显升高。     

The influence of attention and arousal on emotion perception in adults with severe traumatic brain injury

Many people with traumatic brain injury (TBI) have poor emotion recognition, with negative emotions more frequently impaired. They can also display abnormal affective responses to emotionally charged material, however, the mechanisms underpinning such deficits are unclear. This study examined whether affective responsivity can be improved by focusing attention and whether responsivity is associated with perception accuracy. Eighteen adults with moderate-to-severe TBI and 18 control participants viewed facial expressions while skin conductance (SCR) and evoked cardiac deceleration (ECD) (used as indices of orientation) and skin conductance levels (SCL) (used as an index of phasic arousal) were monitored. They viewed two blocks of faces (8 angry and 8 happy per block), passively in the first block and with the instruction to identify the emotional expression in the second. No differences between conditions, emotions or groups were found using SCR. Both groups demonstrated increasing ECD for the attend condition relative to the passive condition. For the passive task the control group showed increasing SCL (sensitisation) over trials when viewing angry faces and decreasing SCL (habituation) to happy faces. No differences between emotions were shown for the TBI group who rapidly habituated to both expressions. For the attend task, there was no evidence of habituation for either expression for either the control or TBI participants. Physiological measures did not correlate to accuracy in recognising emotions. The results suggest that increasing attentional demands improves orientation and emotional engagement (arousal) to emotional faces following TBI. However, the relationship to this and emotion perception accuracy remains unclear.     

Chelation of neurotoxic zinc levels does not improve neurobehavioral outcome after traumatic brain injury

Increases of synaptically released zinc and intracellular accumulation of zinc in hippocampal neurons after traumatic or ischemic brain injury is neurotoxic and chelation of zinc has been shown to reduce neurodegeneration. Although our previous studies showed that zinc chelation in traumatically brain-injured rats correlated with an increase in whole-brain expression of several neuroprotective genes and reduced numbers of apoptotic neurons, the effect on functional outcome has not been determined, and the question of whether this treatment may actually be clinically relevant has not been answered. In the present study, we show that treatment of TBI rats with the zinc chelator calcium EDTA reduces the numbers of injured, Fluoro-Jade-positive neurons in the rat hippocampus 24 h after injury but does not improve neurobehavioral outcome (spatial memory deficits) 2 weeks post-injury. Our data suggest that zinc chelation, despite providing short-term histological neuroprotection, fails to improve long-term functional outcome, perhaps because long-term disruptions in homeostatic levels of zinc adversely influence hippocampus-dependent spatial memory.     

Alpha-2 adrenergic challenge with guanfacine one month after mild traumatic brain injury: Altered working memory and BOLD response

Alterations in working memory (WM) are common after traumatic brain injury (TBI). Frontal catecholaminergic systems, including the alpha-2 adrenergic system, modulate WM function and may be affected in TBI. We hypothesized that administration of an alpha-2 adrenergic agonist might improve WM after mild TBI (MTBI). Thirteen individuals with MTBI 1 month after injury and 14 healthy controls (HC) were challenged with guanfacine and placebo prior to administration of a verbal WM functional MRI task. Guanfacine was associated with improved WM performance in the MTBI but not the HC group. On guanfacine the MTBI group showed increased activation within a WM task-specific region of interest. Findings are consistent with the hypothesis that alterations in WM after MTBI may be improved with the alpha-2 agonist guanfacine.     

Performance discrepancies on the California Verbal Learning Test: Second Edition (CVLT-II) after traumatic brain injury.

One hundred fourteen patients with traumatic brain injury (TBI), selected from a 5-year series of consecutive rehabilitation referrals, completed the California Verbal Learning Test -- Second Edition (CVLT-II) within 1 year after injury. Various performance contrasts (i.e., proactive interference, retroactive interference, rapid forgetting, and retrieval problems) were evaluated. Initial analyses revealed higher rates of rapid forgetting in the TBI group as compared to the standardization sample. Follow-up analyses between those patients with and without unusual degrees of rapid forgetting did not reveal any significant differences between these groups on demographic or neurological variables (p>0.10 for all variables). It is concluded that performance discrepancies on the CVLT-II should never be used in isolation to determine the presence or absence of acquired cerebral or memory impairment. However, regardless of the cause, such discrepancies may still be relevant for clinical treatment recommendations.     

Characterising error-awareness of attentional lapses and inhibitory control failures in patients with traumatic brain injury

Awareness deficits are a significant problem following traumatic brain injury (TBI). This study examined error processing as candidate marker of awareness and compared the performance of 18 TBI participants and 18 controls using an online error-monitoring task while participants performed simple go/no-go tasks. Error-monitoring performance was compared where the no-go target was part of (a) a predictive sequence, (b) predictive sequence plus a dual-task element and (c) a random sequence. Results showed that the TBI participants, in contrast to control participants, were significantly impaired at monitoring their errors during both predictive sequence tasks but were not impaired on the random sequence task. These findings suggest that following TBI, when an error is more impulsive it may be more easily monitored, whereas when an error is characterised by attentional drift, subsequent error-processing mechanisms may fail to engage. Higher levels of online error-awareness were also associated with lower levels of anxiety, fewer symptoms of frontal dysfunction and greater competence in everyday functioning.     

The synthetic NCAM-derived peptide, FGL, modulates the transcriptional response to traumatic brain injury

Cerebral responses to traumatic brain injury (TBI) include up- and downregulation of a vast number of proteins involved in endogenous inflammatory responses and defense mechanisms developing postinjury. The present study analyzed the global gene expression profile in response to cryo-induced TBI by means of microarray analysis. Adolescent rats were subjected to TBI and treated with either placebo or a neural cell adhesion molecule (NCAM)-derived fibroblast growth factor receptor (FGFR) agonist, FGL peptide, which has been demonstrated to have neuroprotective effects. mRNA levels were measured at various time-points postlesion (6 h, 1 day and 4 days). The effects of injury, treatment, and injury-treatment interaction were observed. TBI alone rendered a large number of genes affected. Analysis of lesion and treatment interactions resulted in a clear effect of the interaction between injury and FGL-treatment compared to injury and placebo-treatment. Genes affected by TBI alone included inflammation markers, protein kinases, ion channel members and growth factors. Genes encoding regulators of apoptosis, signal transduction and metabolism were altered by the interaction between FGL-treatment and TBI. FGL-treatment in non-injured animals rendered genes regulating signaling, transport and cytoskeleton maintenance significantly increased. Thus, the hypothesis of a putative neuroprotective role of FGL was supported by our findings.