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.     

Sleep disorders in patients with traumatic brain injury: a review

Traumatic brain injury (TBI) is a global problem and causes long-term disability in millions of individuals. This is a major problem for both military- and civilian-related populations. The prevalence of sleep disorders in individuals with TBI is very high, yet mostly unrecognized. Approximately 46% of all chronic TBI patients have sleep disorders, which require nocturnal polysomnography and the Multiple Sleep Latency Test for diagnosis. These disorders include sleep apnoea (23% of all TBI patients), post-traumatic hypersomnia (11%), narcolepsy (6%) and periodic limb movements (7%). Over half of all TBI patients will have insomnia complaints, most often with less severe injury and after personal assault, and half of these may be related to a circadian rhythm disorder. Hypothalamic injury with decreased levels of wake-promoting neurotransmitters such as hypocretin (orexin) and histamine may be involved in the pathophysiology of excessive sleepiness associated with TBI. These sleep disorders result in additional neurocognitive deficits and functional impairment, which might be attributed to the original brain injury itself and thus be left without specific treatment. Most standard treatment regimens of sleep disorders appear to be effective in these patients, including continuous positive airway pressure for sleep apnoea, pramipexole for periodic limb movements and cognitive behavioural therapy for insomnia. The role of wake-promoting agents and CNS stimulants for TBI-associated narcolepsy, post-traumatic hypersomnia and excessive daytime sleepiness requires further study with larger numbers of patients to determine effectiveness and benefit in this population. Future research with multiple collaborating centres should attempt to delineate the pathophysiology of TBI-associated sleep disorders, including CNS-derived hypersomnia and circadian rhythm disturbances, and determine definitive, effective treatment for associated sleep disorders.     

Dysfunction of the auditory efferent system in patients with traumatic brain injuries with tinnitus and hyperacusis

OBJECTIVES: Tinnitus, hyperacusis and difficulty listening in background noise are common symptoms reported by patients with traumatic brain injury (TBI). The aim of this study was to explore the function of the auditory system in TBI patients with and without auditory complaints but having normal pure-tone audiograms. METHODS: The study consisted of 24 TBI patients with and 10 TBI patients without auditory complaints. In addition, 15 normal controls were included in the study. The function of the auditory system was tested by recording transient otoacoustic emissions (TEOAE) during the presentation of increasing levels of white noise in the contralateral ear. RESULTS: Most of the TBI patients with auditory complaints (87%) showed absent or significantly reduced effect of the auditory efferent system as compared with the TBI patients without auditory complaints and to normal controls. However, the global amplitude of the TEOAE was significantly higher in TBI patients with auditory complaints compared to those without. CONCLUSIONS: Due to its role in peripheral and central auditory activity, dysfunction of the efferent system may be at least partially responsible for these auditory complaints. This study underscores the importance of testing and evaluating the functional integrity of the medial efferent system by an objective and non-invasive method in patients with TBI.     

颅脑损伤合并脑垂体激素紊乱24例报道

目的探讨创伤性颅脑损伤合并脑垂体激素紊乱的诊断和治疗。方法回顾分析24例创伤性颅脑损伤合并脑垂体激素紊乱的发生、发展和归转。并分析与其相关的因素。结果本组24例脑垂体激素紊乱者中,生长激素型9例(37%),促性腺激素型8例(33%),脑垂体后叶素型5例(20.8%),同时存在两种以上激素下降者5例(20.8%),死亡7例(28%),颅脑损伤3个月内激素恢复正常者6例(35.57%)。CT检查示:颅底骨折和脑挫伤与脑垂体激素障碍间有明确关系。P值分别为0.011和0.014。结论创伤性脑损伤患者约有16%发生脑垂体激素紊乱,主要是发生在伤后6个月内,早期诊断和治疗对患者是有益的。     

右美托咪定对脑外伤所致认知功能和脑组织损伤的保护作用

目的： 研究右美托咪定对脑外伤（traumatic brain injury,TBI）后小鼠认知功能和脑组织损伤的影响,揭示右美托咪定（Dex）治疗脑外伤的可能作用机制。方法： 将60只小鼠随机分为假手术组（Sham组）、模型组（TBI组）和右美托咪定治疗组（Dex+TBI组）。采用神经损伤严重程度评分（NSS）和旋转实验（Rotarod test）评价各组小鼠在TBI后24 d的神经功能;采用行为学实验评估TBI后小鼠运动依赖的学习记忆能力损害;HE染色观察脑组织体积损伤,TUNEL染色分析神经元细胞死亡,蛋白印迹实验分析突触相关蛋白pre-BDNF、BDNF、GAP43、Synaptophysin和Synapsin表达。结果： 与TBI组相比,TBI+Dex组小鼠神经损伤恢复水平和认知能力均提高,差异有统计学意义（P<0.01）;脑组织体积损伤减小（P<0.01）,TUNNEL阳性细胞数量显著增加（P<0.01）;突触相关蛋白表达显著增加（P<0.01）。结论： 右美托咪定对脑外伤后小鼠认知功能和脑组织损伤具有保护作用,其机制可能是增加了突触相关蛋白的表达。     

Cyclosporine A for neuroprotection: establishing dosing guidelines for safe and effective use

Numerous neuroprotective compounds have been investigated to ameliorate secondary changes and the progression of injury after the primary insult in traumatic brain injury (TBI). This cascade of events is complex and difficult to abate once initiated following the primary injury. The clinical consequences of this secondary injury are unpredictable and often permanently incapacitating. Cyclosporine A (CsA) interrupts the endogenous mediators of secondary insult through inhibition of the mitochondrial permeability transition pore and prevention of subsequent mitochondrial dysfunction. This drug may have a role in neuroprotection but has several pharmacologic effects that must be considered when using it in the TBI population. This review discusses the physiologic responses following TBI that may affect CsA efficacy and safety when used for neuroprotective indications. So far, CsA seems to be safe in the TBI population. The role of CsA after acute TBI will be better defined after the completion of upcoming planned clinical trials.     

Moderate traumatic brain injury is linked to acute behaviour deficits and long term mitochondrial alterations

Traumatic brain injury (TBI) remains one of the leading causes of death and disability worldwide. Mild TBI may lead to neuropsychiatric sequelae, including memory loss and motor impairment. Mitochondrial dysfunction and oxidative stress have a contributory role in several neurological disorders; however, their association with mitophagy in mild TBI is unclear. TBI was induced in female Sprague Dawley (SD) rats using a New York University Impactor (10 g, impactor head 2.5 mm diameter, weight drop 50 mm) and compared to sham surgery controls. The novel object recognition and error ladder tests were performed at 24 hours and for 6 weeks post injury, and the brains were examined histologically to confirm the extent of injury. Mitochondria manganese superoxide dismutase (MnSOD) and the oxidative phosphorylation (OXPHOS) complexes I‐V (CI‐CV), as well as mitophagy markers, dynamin related protein 1 (DRP‐1), LC3A/B and PTEN‐induced putative kinase 1 (PINK‐1), were measured in the penumbra by western blot. At 24 hours sham rats performed as expected on a novel object recognition test while TBI rats showed cognitive deficits at the early time points. TBI rats also showed more early motor deficits on a horizontal ladder, compared with the sham rats. MnSOD, OXPHOS CI, CIII and CV protein levels were significantly lower in the TBI group at 24 hours. DRP‐1, LC3A/B I and II, and PINK‐1 were increased at 6 weeks suggesting abnormal mitophagy. Moderate TBI caused immediate cognitive and mild motor functional deficits in the rats that did not persist. Reduced antioxidative capacity and possibly compromised mitochondrial function may affect the long term functional recovery.     

Dopaminergic modulation of the default mode network in Parkinson's disease

Default mode network (DMN) is characterized by a deactivation of several cortical areas (including medial prefrontal cortex and posterior cingulate cortex) during goal-directed experimental tasks. Few findings are reported on DMN and the involvement of dopaminergic medication on this network in Parkinson's disease (PD).To evaluate the effect of levodopa on DMN deactivation, we conducted a randomized, crossover, placebo-controlled experiment consisting of two fMRI assessments in fourteen non-demented, non-depressed PD patients compared to thirteen healthy volunteers. They received either acute doses of levodopa or placebo in two fMRI sessions. Brain deactivation was evaluated during a facial emotion recognition task.While the control subjects showed a classical brain deactivation pattern during the emotional task, the PD patients taking placebo only deactivated the ventral medial prefrontal cortex. Patients failed to deactivate the posterior midline and lateral parts of DMN network. After levodopa administration, this network was restored conjointly with the improvement of motor dysfunction in PD patients.The levodopa effect on DMN is probably the consequence of a beneficial dopamine (DA) medication effect which leads to a fine tuning of the dopamine level in the motor part of striatum, resulting to a global improvement of physical state of PD patients and consequently an increased attentional resource to external stimuli. The absence of medial prefrontal deactivation impairment may suggest a preserved mesocortical DA system in these patients.     

Auditory and vestibular sequelae to traumatic brain injury: a pilot study

AIM: To investigate the incidence of persisting auditory and vestibular sequelae in a group of 30 young adults recovering from Traumatic Brain Injury (TBI). METHODS: 30 participants, aged 21-45 years, with TBI suffered 19 months to 27 years previously, underwent a semi-structured interview and pure-tone hearing test in their home. Participants who failed the hearing screen then undertook a more comprehensive audiological evaluation. RESULTS: A variety of sequelae to TBI were reported. These were interpreted as tinnitus (53%), vestibular dysfunction (83%), abnormal facial sensory symptoms (27%) and intolerance to loud/sudden noises (87%). Ten (33%) participants demonstrated significant sensorineural hearing impairment in addition to speech recognition performance significantly worse than would have been predicted from their hearing impairment. CONCLUSIONS: Findings from this study will be of benefit to health professionals working in this area of rehabilitation as they seek to provide functional assessments and devise programmes to treat the often devastating auditory processing problems of people recovering from TBI.     

Modulation of midbrain dopamine neurotransmission by serotonin, a versatile interaction between neurotransmitters and significance for antipsychotic drug action

Schizophrenia has been associated with a dysfunction of brain dopamine (DA). This, so called, DA hypothesis has been refined as new insights into the pathophysiology of schizophrenia have emerged. Currently, dysfunction of prefrontocortical glutamatergic and GABAergic projections and dysfunction of serotonin (5-HT) systems are also thought to play a role in the pathophysiology of schizophrenia. Refinements of the DA hypothesis have lead to the emergence of new pharmacological targets for antipsychotic drug development. It was shown that effective antipsychotic drugs with a low liability for inducing extra-pyramidal side-effects have affinities for a range of neurotransmitter receptors in addition to DA receptors, suggesting that a combination of neurotransmitter receptor affinities may be favorable for treatment outcome.This review focuses on the interaction between DA and 5-HT, as most antipsychotics display affinity for 5-HT receptors. We will discuss DA/5-HT interactions at the level of receptors and G protein-coupled potassium channels and consequences for induction of depolarization blockade with specific attention to DA neurons in the ventral tegmental area (VTA) and the substantia nigra zona compacta (SN), neurons implicated in treatment efficacy and the side-effects of schizophrenia, respectively. Moreover, it has been reported that electrophysiological interactions between DA and 5-HT show subtle, but important, differences between the SN and the VTA which could explain (in part) the effectiveness and lower propensity to induce side-effects of the newer atypical antipsychotic drugs. In that respect the functional implications of DA/5-HT interactions for schizophrenia will be discussed.     

轻中度创伤性脑损伤患者记忆受损与血清Tau蛋白的关系

目的 探讨轻中度创伤性脑损伤（TBI）患者记忆受损与血清Tau蛋白的关系。方法 选取安徽医科大学第一附属医院2016年6月至2017年6月收治的TBI患者60例为研究对象,依据患者入院时格拉斯哥昏迷评分（GCS）分为轻度TBI组（30例）与中度TBI组（30例）。另选取20名志愿者为健康对照组。在入院时、伤后第72小时、2周、6周和3个月时,采用ELISA法检测受试对象的血清Tau蛋白浓度,同时运用神经心理学测试量表对受试对象记忆认知特点进行评估。结果 入院时,TBI组患者血清Tau蛋白浓度为（574.3±270.1） pg/mL、健康对照组为（79.9±36.3） pg/mL,两组差异有统计学意义（t=13.807,P<0.05）。伤后第72小时,中度TBI组患者血清Tau蛋白浓度为（1 051.2±333.9） pg/mL、轻度TBI组为（805.2±400.2） pg/mL,两组差异有统计学意义（t=2.585,P=0.012）。伤后3个月,TBI组患者血清Tau蛋白浓度为（100.8±35.6） pg/mL,与健康对照组相比,差异无统计学意义（t=2.001,P=0.051）。TBI组患者记忆受损明显,且伤后第72小时患者记忆认知水平处于最低,至伤后6周,TBI组患者记忆受损逐渐恢复至健康对照组水平,两组差异无统计学意义（P>0.05）。伤后第72小时和伤后2周,TBI组患者血清Tau蛋白浓度与神经心理学测试评分呈负相关（P<0.05）。结论 早期检测TBI患者的血清Tau蛋白浓度不仅可以评估患者的受伤程度,而且能够有效地反映患者记忆受损的程度。     

Challenges of Delirium Management in Patients with Traumatic Brain Injury: From Pathophysiology to Clinical Practice

Traumatic brain injury (TBI) can initiate a very complex disease of the central nervous system (CNS), starting with the primary pathology of the inciting trauma and subsequent inflammatory and CNS tissue response. Delirium has long been regarded as an almost inevitable consequence of moderate to severe TBI, but more recently has been recognized as an organ dysfunction syndrome with potentially mitigating interventions. The diagnosis of delirium is independently associated with prolonged hospitalization, increased mortality and worse cognitive outcome across critically ill populations. Investigation of the unique problems and management challenges of TBI patients is needed to reduce the burden of delirium in this population.In this narrative review, possible etiologic mechanisms behind post-traumatic delirium are discussed, including primary injury to structures mediating arousal and attention and secondary injury due to progressive inflammatory destruction of the brain parenchyma. Other potential etiologic contributors include dysregulation of neurotransmission due to intravenous sedatives, seizures, organ failure, sleep cycle disruption or other delirium risk factors. Delirium screening can be accomplished in TBI patients and the presence of delirium portends worse outcomes.There is evidence that multi-component care bundles including an analgesia-prioritized sedation algorithm, regular spontaneous awakening and breathing trials, protocolized delirium assessment, early mobility and family engagement can reduce the burden of ICU delirium. The aim of this review is to summarize the approach to delirium in TBI patients with an emphasis on pathogenesis and management. Emerging CNS-active drug therapies that show promise in preclinical studies are highlighted.     

Rat brain monoamine metabolism and hypobaric hypoxia: a new approach

A chromatographic method with electrochemical detection was used to measure noradrenaline (NA), dopamine (DA), and serotonin (5-HT), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-methoxytyramine (3-MT) and 5-hydroxyindoleacetic acid (5-HIAA) in several brain areas (hypothalamus, hippocampus, striatum and rest of the brain) of rats exposed to a 7000 m simulated altitude for 3 hr. This new direct approach, not using a pharmacological tool, provides further information on the hypobaric hypoxia effects on the main DA and 5-HT metabolic steps. In the hypothalamus, a decreased NA level with increased DA and DOPAC contents was considered as the result of dopamine-beta-hydroxylase activity impairment. The decrease of both 5-HIAA and DOPAC in all brain areas provides further evidence of the hypoxia-induced decrement in MAO activity. Furthermore, in the striatum, it was shown that catechol-O-methyl transferase, up to now considered unaffected by hypoxia, may also be altered by oxygen deficiency.     

Contemporary pharmacologic issues in the management of traumatic brain injury

Traumatic brain injury (TBI) is a major cause of death and disability in the United States. While there are no pharmacotherapeutic options currently available for attenuating the neurologic injury cascade after TBI, numerous pharmacologic issues are encountered in these critically ill patients. Adequate fluid resuscitation, reversal of coagulopathy, maintenance of cerebral perfusion, and treatment of intracranial hypertension are common interventions early in the treatment of TBI. Other deleterious complications such as venous thromboembolism, extremes in glucose concentrations, and stress-related mucosal disease should be anticipated and avoided. Early provision of nutrition and prevention of drug or alcohol withdrawal are also cornerstones of routine care in TBI patients. Prevention of infections and seizures may also be helpful. Clinicians caring for TBI patients should be familiar with the pharmacologic issues typical of this vulnerable population in order to develop optimal strategies of care to anticipate and prevent common complications.     

Effects of tiaspirone (BMY-13859) and a chemical congener (BMY-13980) on A9 and A10 dopamine neurons in the rat

Two new potential antipsychotic drugs, BMY-13980 and BMY-13859 were compared for the ability to influence the electrophysiological activity of dopaminergic neurons in the substantia nigra zona compacta (A9 DA cells) and ventral tegmental area (A10 DA cells) in the brain of the rat. Both drugs reversed the rate-suppressant effects of the DA agonist apomorphine on DA cells in A10 to a greater extent than DA cells in A9; BMY-13980 was particularly selective in this regard. These results indicate that both drugs may exert DA antagonist effects which are suggestive of antipsychotic potential. In other experiments, the effects of chronic (28 days) treatment with BMY-13980 and BMY-13859 on the neuronal activity of DA were evaluated. Both compounds caused a significant decrease in the number of spontaneously active DA neurons in A10 recorded per electrode track, an effect previously demonstrated to be associated with antipsychotic efficacy. The drug BMY-13859, but not BMY-13980, also significantly decreased the number of spontaneously active DA cells/track in A9, an effect which may predict the liability of potential antipsychotic drugs for causing extrapyramidal motor dysfunction, including tardive dyskinesia. Thus, these experiments indicate that both BMY-13980 and BMY-13859 exert effects which may predict potential antipsychotic efficacy in clinical trials and that BMY-13980 may be less likely to cause extrapyramidal side effects.     

Depression following traumatic brain injury: epidemiology, risk factors and management

It is important for clinicians to recognize major depression following traumatic brain injury (TBI) because of its association with poor global and psychosocial outcome, postconcussive symptoms and cognitive deficits. The purpose of this review is to provide an up-to-date selective review of the current understanding of epidemiology, risk factors and management of major depression following TBI. Many studies of prevalence of depression following TBI have not used accepted structured criteria for the diagnoses, but those that did found wide ranges of rates, from 17% to 61%. The risk factors for development of depression following TBI are poorly understood, but past psychiatric history, frontal lesions and atrophy, and family dysfunction have been shown in more than one study to play important roles. There are few controlled trials of the treatment of major depression in patients with TBI using accepted diagnostic criteria for major depression, as well as defined criteria for response and remission. As such, it is important for clinicians to use best practice guidelines for the treatment of major depression in the absence of TBI.     

舒张性心功能不全患者血浆BNP水平的临床研究

目的 探讨舒张性心功能不全患者的血浆脑钠肽（BNP）水平.方法 选择住院70例舒张性心功能不全患者（根据NYHA分级法诊断心功能,将患者分为Ⅰ、Ⅱ、Ⅲ、Ⅳ级;根据超声测定结果将左心室舒张功能障碍分为轻度、中度、重度3组）,40例本院体检中心体检对照者的血浆BNP的水平,比较各组血浆BNP水平的变化情况.结果 舒张性心功能不全患者血浆BNP明显高于健康对照者（P＜0.01）,并且BNP水平随着舒张功能不全分级（Ⅰ～Ⅳ级）升高而梯次升高（P＜0.05）,随着左心室舒张功能障碍（轻-重度）加重而梯次升高（P＜0.05）.结论 血浆BNP可以用于诊断舒张性心功能不全,而且可以反映左室舒张功能障碍的严重程度,可以将BNP作为舒张性心功能不全患者诊断及随访指标.     

Evaluation of pharmacological treatment strategies in traumatic brain injury

Traumatic brain injury (TBI) is a devastating disease, predominately affecting young people. Although the prognosis for TBI victims has improved in recent years, many survivors of TBI suffer from emotional, cognitive and motor disturbances and a decreased quality of life. In recent years, there has been a rapid increase in the number of pharmacological targets evaluated in clinically-relevant experimental TBI models, showing improved cognitive and motor outcome and decreased loss of brain tissue. Despite the completion of several recent clinical trials using compounds showing neuroprotection in preclinical studies, pharmaceutical treatment strategies with proven clinical benefit are still lacking. This paper reviews the preclinical pharmacological treatment studies evaluated to date in experimental models of TBI. Although human TBI is a complex and multifaceted disease, these studies provide encouraging translational data suggesting that pharmacological compounds, delivered in a clinically-relevant time window, may improve the outcome of TBI patients.     

Effects on shock-elicited aggression in mice of preferentially protecting brain monoamines against the depleting action of reserpine

Summary Drug regimes designed to preferentially prevent reserpine-induced depletion of elther catecholamines or 5-hydroxytryptamine (5-HT) in the brain were used to study shock-elicited aggression in mice. With a drug schedule known to maintain dopamine (DA) and noradrenaline (NA) at normal levels but producing a reduction in brain 5-HT, mice displayed an increase in fighting but no change in either locomotor activity or shock threshold. Animals treated with either reserpine or with a drug regimen producing normal levels of 5-HT but reduced DA and NA showed a decrease in aggression and motility but slightly elevated shock thresholds. In view of the motor impairment observed with the latter two regimens, it is suggested that, whereas catecholamines may play an important role in mediating the motor components of aggressive behavior, 5-HT may significantly contribute to the modulation of mood-dependent aspects.     

Cooling the injured brain: how does moderate hypothermia influence the pathophysiology of traumatic brain injury

Neither any neuroprotective drug has been shown to be beneficial in improving the outcome of severe traumatic brain injury (TBI) nor has any prophylactically-induced moderate hypothermia shown any beneficial effect on outcome in severe TBI, despite the optimism generated by preclinical studies. This contrasts with the paradox that hypothermia still is the most powerful neuroprotective method in experimental models because of its ability to influence the multiple biochemical cascades that are set in motion after TBI. The aim of this short review is to highlight the most recent developments concerning the pathophysiology of severe TBI, to review new data on thermoregulation and induced hypothermia, the regulation of core and brain temperature in mammals and the multiplicity of effects of hypothermia in the pathophysiology of TBI. Many experimental studies in the last decade have again confirmed that moderate hypothermia confers protection against ischemic and non-ischemic brain hypoxia, traumatic brain injury, anoxic injury following resuscitation after cardiac arrest and other neurological insults. Many posttraumatic adverse events that occur in the injured brain at a cellular and molecular level are highly temperature-sensitive and are thus a good target for induced hypothermia. The basic mechanisms through which hypothermia protects the brain are clearly multifactorial and include at least the following: reduction in brain metabolic rate, effects on cerebral blood flow, reduction of the critical threshold for oxygen delivery, blockade of excitotoxic mechanisms, calcium antagonism, preservation of protein synthesis, reduction of brain thermopooling, a decrease in edema formation, modulation of the inflammatory response, neuroprotection of the white matter and modulation of apoptotic cell death. The new developments discussed in this review indicate that, by targeting many of the abnormal neurochemical cascades initiated after TBI, induced hypothermia may modulate neurotoxicity and, consequently, may play a unique role in opening up new therapeutic avenues for treating severe TBI and improving its devastating effects. Furthermore, greater understanding of the pathophysiology of TBI, new data from both basic and clinical research, the good clinical results obtained in randomized clinical trials in cardiac arrest and better and more reliable cooling methods have given hypothermia a second chance in treating TBI patients. A critical evaluation of hypothermia is therefore mandatory to elucidate the reasons for previous failures and to design further multicenter randomized clinical trials that would definitively confirm or refute the potential of this therapeutic modality in the management of severe traumatic brain injuries.