Tumor necrosis factor-stimulated gene-6 ameliorates early brain injury after subarachnoid hemorrhage by suppressing NLRC4 inflammasome-mediated astrocyte pyroptosis

Subarachnoid hemorrhage is associated with high morbidity and mortality and lacks effective treatment.Pyroptosis is a crucial mechanism underlying early brain injury after subarachnoid hemorrhage.Previous studies have confirmed that tumor necrosis factor-stimulated gene-6(TSG-6)can exert a neuroprotective effect by suppressing oxidative stress and apoptosis.However,no study to date has explored whether TSG-6 can alleviate pyroptosis in early brain injury after subarachnoid hemorrhage.In this study,a C57BL/6J mouse model of subarachnoid hemorrhage was established using the endovascular perforation method.Our results indicated that TSG-6 expression was predominantly detected in astrocytes,along with NLRC4 and gasdermin-D(GSDMD).The expression of NLRC4,GSDMD and its N-terminal domain(GSDMD-N),and cleaved caspase-1 was significantly enhanced after subarachnoid hemorrhage and accompanied by brain edema and neurological impairment.To explore how TSG-6 affects pyroptosis during early brain injury after subarachnoid hemorrhage,recombinant human TSG-6 or a siRNA targeting TSG-6 was injected into the cerebral ventricles.Exogenous TSG-6 administration downregulated the expression of NLRC4 and pyroptosis-associated proteins and alleviated brain edema and neurological deficits.Moreover,TSG-6 knockdown further increased the expression of NLRC4,which was accompanied by more severe astrocyte pyroptosis.In summary,our study revealed that TSG-6 provides neuroprotection against early brain injury after subarachnoid hemorrhage by suppressing NLRC4 inflammasome activation-induced astrocyte pyroptosis.

Evaluation of the updated definition of early allograft dysfunction in donation after brain death and donation after cardiac death liver allografts

BACKGROUND:An updated definition of early allograft dysfunction(EAD) was recently validated in a multicenter study of 300 deceased donor liver transplant recipients.This analysis did not differentiate between donation after brain death(DBD) and donation after cardiac death(DCD) allograft recipients.METHODS:We reviewed our prospectively entered database for all DBD(n=377) and DCD(n=38) liver transplantations between January 1,2006 and October 30,2011.The incidence of EAD as well as its ability to predict graft failure and survival was compared between DBD and DCD groups.RESULTS:EAD was a valid predictor of both graft and patient survival at six months in DBD allograft recipients,but in DCD allograft recipients there was no significant difference in the rate of graft failure in those with EAD(11.5%) compared with those without EAD(16.7%)(P=0.664) or in the rate of death in recipients with EAD(3.8%) compared with those without EAD(8.3%)(P=0.565).The graft failure rate in the first 6 months in those with international normalized ratio ≥1.6 on day 7 who received a DCD allograft was 37.5% compared with 6.7% for those with international normalized ratio <1.6 on day 7(P=0.022).CONCLUSIONS:The recently validated definition of EAD is a valid predictor of patient and graft survival in recipients of DBD allografts.On initial assessment,it does not appear to be a useful predictor of patient and graft survival in recipients of DCD allografts,however a study with a larger sample size of DCD allografts is needed to confirm these findings.The high ALT/AST levels in most recipients of DCD livers as well as the predisposition to biliary complications and early cholestasis make these parameters as poor predictors of graft failure.An alternative definition of EAD that gives greater weight to the INR on day 7 may be more relevant in this population.

Partial improvement in performance of patients with severe Alzheimer's disease at an early stage of fornix deep brain stimulation

Deep brain stimulation is a therapy for Alzheimer＇s disease（AD） that has previously been used for mainly mild to moderate cases. This study provides the first evidence of early alterations in performance induced by stimulation targeted at the fornix in severe AD patients. The performance of the five cases enrolled in this study was scored with specialized assessments including the Mini-Mental State Examination and Clinical Dementia Rating, both before and at an early stage after deep brain stimulation. The burden of caregivers was also evaluated using the Zarit Caregiver Burden Interview. As a whole, the cognitive performance of patients remained stable or improved to varying degrees, and caregiver burden was decreased. Individually, an improved mental state or social performance was observed in three patients, and one of these three patients showed remarkable improvement in long-term memory. The conditions of another patient deteriorated because of inappropriate antipsychotic medications that were administered by his caregivers. Taken together, deep brain stimulation was capable of improving some cognitive aspects in patients with severe AD, and of ameliorating their emotional and social performance, at least at an early stage. However, long-term effects induced by deep brain stimulation in patients with severe AD need to be further validated. More research should focus on clarifying the mechanism of deep brain stimulation. This study was registered with ClinicalTrials.gov（NCT03115814） on April 14, 2017.

Matricellular proteins as possible biomarkers for early brain injury after aneurysmal subarachnoid hemorrhage

Aneurysmal subarachnoid hemorrhage remains devastating,and the most important determinant of poor outcome is early brain injury（EBI）.In clinical settings,as a surrogate marker of EBI,loss of consciousness at ictus,poor initial clinical grades,and some radiographic findings are used,but these markers are somewhat subjective.Thus,it is imperative to find biomarkers of EBI that have beneficial prognostic and therapeutic implications.In our opinion,an ideal biomarker is a molecule that is implicated in the pathogenesis of both EBI and subsequently developing delayed cerebral ischemia（DCI）,being a therapeutic target,and can be measured easily in the peripheral blood in an acute stage.A good candidate of such a biomarker is a matricellular protein,which is a secreted,inducible and multifunctional extracellular matrix protein.There are many kinds of matricellular proteins reported,but only tenascin-C,osteopontin,galectin-3 and periostin are reported relevant to EBI and DCI.Reliable biomarkers of EBI may stratify aneurysmal subarachnoid hemorrhage patients into categories of risk to develop DCI,and allow objective monitoring of the response to treatment for EBI and earlier diagnosis of DCI.This review emphasizes that further investigation of matricellular proteins as an avenue for biomarker discovery is warranted.

Neuroprotection mediated by the Wnt/Frizzled signaling pathway in early brain injury induced by subarachnoid hemorrhage

The Wnt/Frizzled signaling pathway participates in many inflammation-linked diseases. However, the inflammatory response mediated by the Wnt/Frizzled signaling pathway in experimental subarachnoid hemorrhage has not been thoroughly investigated. Consequently, in this study, we examined the potential role of the Wnt/Frizzled signaling pathway in early brain injury in rat models of subarachnoid hemorrhage.Simultaneously, possible neuroprotective mechanisms were also investigated. Experimental subarachnoid hemorrhage rat models were induced by injecting autologous blood into the prechiasmatic cistern. Experiment 1 was designed to examine expression of the Wnt/Frizzled signaling pathway in early brain injury induced by subarachnoid hemorrhage. In total, 42 adult rats were divided into sham(injection of equivalent volume of saline), 6-, 12-, 24-, 48-, 72-hour, and 1-week subarachnoid hemorrhage groups. Experiment 2 was designed to examine neuroprotective mechanisms of the Wnt/Frizzled signaling pathway in early brain injury induced by subarachnoid hemorrhage. Rats were treated with recombinant human Wnt1(rhwnt1), small interfering Wnt1(siwnt1) RNA, and monoclonal antibody of Frizzled1(anti-Frizzled1) at 48 hours after subarachnoid hemorrhage. Expression levels of Wnt1, Frizzled1, β-catenin, peroxisome proliferator-activated receptor-γ, CD36, and active nuclear factor-κB were examined by western blot assay and immunofluorescence staining. Microglia type conversion and inflammatory cytokine levels in brain tissue were examined by immunofluorescence staining and enzyme-linked immunosorbent assay. Our results show that compared with the sham group, expression levels of Wnt1, Frizzled1, and β-catenin were low and reduced to a minimum at 48 hours, gradually returning to baseline at 1 week after subarachnoid hemorrhage. rhwnt1 treatment markedly increased Wnt1 expression and alleviated subarachnoid hemorrhage-induced early brain injury(within 72 hours), including cortical cell apoptosis, brain edema, and neurobehavioral deficits, accompanied by increasing protein levels of β-catenin, CD36, and peroxisome proliferator-activated receptor-γ and decreasing protein levels of nuclear factor-κB. Of note, rhwnt1 promoted M2-type microglia conversion and inhibited release of inflammatory cytokines(interleukin-1β, interleukin-6, and tumor necrosis factor-α). In contrast, siwnt1 RNA and anti-Frizzled1 treatment both resulted in an opposite effect. In conclusion, the Wnt/Frizzled1 signaling pathway may participate in subarachnoid hemorrhage-induced early brain injury via inhibiting the inflammatory response, including regulating microglia type conversion and decreasing inflammatory cytokine release. The study was approved by the Animal Ethics Committee of Anhui Medical University and First Affiliated Hospital of USTC,Division of Life Sciences and Medicine, University of Science and Technology of China(approval No. LLSC-20180202) in May 2017.

Role of Glucose-regulated Protein 78 in Early Brain Injury after Experimental Subarachnoid Hemorrhage in Rats

Early brain injury（EBI） plays a key role in the pathogenesis of subarachnoid hemorrhage（SAH）. This study investigated the role of glucose-regulated protein 78（GRP78） in EBI after SAH. Male Sprague-Dawley rats（n=108） weighing 260±40 g were divided into control, sham-operated, and operated groups. Blood was injected into the prechiasmatic cistern of rats in the operated group. Neurological scores, ultrastructures of neurons, apoptosis, and GRP78 expression in the hippocampus were examined using Garcia scoring system, transmission electron microscopy, terminal deoxynucleotidyl transferase-mediated d UTP nick-end labelling, and Western blotting at 1, 6, 12, 24, 48, and 72 h after SAH, respectively. The results showed that neurological scores were significantly decreased in the operated group as compared with those in control and sham-operated groups at 12, 24, 48, and 72 h. Metachromatin, chromatin pyknosis at the edge, endoplasmic reticulum swelling, and invagination of nuclear membrane were observed at 24 h in the operated group, indicating the early morphological changes of apoptosis. The number of apoptotic cells was significantly increased in the operated group as compared with that in control and sham-operated groups at 6, 12, 24, 48, and 72 h. The GRP78 protein expression levels in the operated group were significantly elevated at all time points and reached the peak at 12 h. GRP78 expression was positively associated with apoptosis cells and negatively with neurological scores. In conclusion, EBI was demonstrated to occur after SAH and GRP78 was involved in the development of EBI after SAH.

Elevated NKCC1 transporter expression facilitates early post-traumatic brain injury seizures

As a leading cause for morbidity and mortality in young adults,traumatic brain injury（TBI）,along with the poorly understood TBI-related seizures inducing their predispositions,pose a major health and socioeconomic problem in the world（Huang,2013）.

Obstructive sleep apnea aggravates neuroinflammation and pyroptosis in early brain injury following subarachnoid hemorrhage via ASC/HIF-1α pathway

Obstructive sleep apnea can worsen the prognosis of subarachnoid hemorrhage.Howeve r,the underlying mechanism remains unclear.In this study,we established a mouse model of subarachnoid hemorrhage using the endovascular perforation method and exposed the mice to intermittent hypoxia for 8 hours daily for 2 consecutive days to simulate sleep apnea.We found that sleep apnea aggravated brain edema,increased hippocampal neuron apoptosis,and worsened neurological function in this mouse model of subarachnoid hemorrhage.Then,we established an in vitro HT-22 cell model of hemin-induced subarachnoid hemorrhage/intermittent hypoxia and found that the cells died,and lactate dehydrogenase release increased,after 48 hours.We further investigated the underlying mechanism and found that sleep apnea increased the expression of hippocampal neuroinflammatory factors interleukin-1β,interleukin-18,inte rleukin-6,nuclear factorκB,pyro ptosis-related protein caspase-1,pro-caspase-1,and NLRP3,promoted the prolife ration of astrocytes,and increased the expression of hypoxia-inducible factor 1αand apoptosis-associated speck-like protein containing a CARD,which are the key proteins in the hypoxia-inducible factor 1α/apoptosis-associated speck-like protein containing a CARD signaling pathway.We also found that knockdown of hypoxia-inducible factor 1αexpression in vitro greatly reduced the damage to HY22 cells.These findings suggest that sleep apnea aggravates early brain injury after subarachnoid hemorrhage by aggravating neuroinflammation and pyroptosis,at least in part through the hypoxia-inducible factor 1α/apoptosis-associated speck-like protein containing a CARD signaling pathway.

Sarcopenia diagnosed using masseter muscle area predictive of early mortality following severe traumatic brain injury

Traumatic brain injury（TBI）represents a global pandemic and is currently a leading cause of injury related death worldwide.Unfortunately,those who survive initial injury often suffer devastating functional,social,and economic consequences.

Effect of Early Controlled Hypotension on Patients with Traumatic Brain Injury

Objective:To investigate the clinical effect of early controlled hypotensive therapy in patients with traumatic braininjury(TBI).Methods:68 patients with acute 1Bl in our hospital were selected for this investigation.They were evenly divided into a control group and an observation group according to the difference of blood pressure and basic level,whose lesion area after treatment,postoperative intracranial pressure after 2 d and 7d,and Gcs score of prognostic quality before and after treatment were made comparison.Results:The post-treatment lesion area of the observation group was lower than that in the control group(P<0.05);the postoperative intracranial pressure after 2d and 7d of the control group was better than the observation group(P<0.05),and the same with GCS score,which has statistical sigmificance(P< 0.05).Conclusion:Early controlled hypotensive therapy has a significant clinical effect on patients with brain trauuma,it can reduce the lesion area after treatment and postoperative intracranial pressure as well.

Brain networks in newborns and infants with and without sensorineural hearing loss:A functional near-infrared spectroscopy study

BACKGROUND Understanding the impact of early sensory deficits on brain development is essential for understanding developmental processes and developing potential interventions.While previous studies have looked into the impact of prenatal experiences on language development,there is a lack of research on how these experiences affect early language and brain function development in individuals with sensorineural hearing loss(SNHL).AIM To investigate SNHL effects on early brain development and connectivity in 4-month-olds vs healthy newborns and controls.METHODS The research involved analyzing the functional brain networks of 65 infants,categorized into three groups:28 healthy newborns,224-month-old participants with SNHL,and 15 age-matched healthy participants.The resting-state functional connectivity was measured and compared between the groups using functional near-infrared spectroscopy and graph theory to assess the brain network properties.RESULTS Significant differences were found in resting-state functional connectivity between participants with SNHL and age-matched controls,indicating a developmental lag in brain connectivity for those with SNHL.Surprisingly,SNHL participants showed better connectivity development compared to healthy newborns,with connectivity strengths of 0.13±0.04 for SNHL,0.16±0.08 for controls,and 0.098±0.04 for newborns.Graph theory analysis revealed enhanced global brain network properties for the SNHL group,suggesting higher communication efficiency at 4 months.No significant differences were noted in network properties between 4-month-old SNHL participants and neonates.A unique pattern of central hubs was observed in the SNHL group,with 2 hubs in the left hemisphere compared to 6 in controls.CONCLUSION 4-month-old infants with SNHL have a distinct brain network pattern with efficient long-distance information transmission but less effective local communication compared to age-matched controls.

Brain abscess caused by Streptococcus anginosus group:Three case reports

BACKGROUND This case series investigated the clinical manifestations,diagnoses,and treatment of cerebral abscesses caused by Streptococcus anginosus.We retrospectively analyzed the clinical characteristics and outcomes of three cases of cerebral abscesses caused by Streptococcus anginosus and conducted a comprehensive review of relevant literature.CASE SUMMARY Case 1 presented with a history of left otitis media and exhibited high fever,confusion,and vomiting as primary symptoms.Postoperative pus culture indicated a brain abscess caused by Streptococcus constellatus infection.Case 2 experienced dizziness for two days as the primary symptom.Postoperative pus culture suggested an intermediate streptococcal brain abscess.Case 3:Enhanced head magnetic resonance imaging(MRI)and diffusion-weighted imaging revealed occupancy of the left temporal lobe,initially suspected to be a metastatic tumor.However,a postoperative pus culture confirmed the presence of a brain abscess caused by Streptococcus anginosus infection.The three cases presented in this case series were all patients with community-acquired brain abscesses resulting from angina caused by Streptococcus group infection.All three patients demonstrated sensitivity to penicillin,ceftriaxone,vancomycin,linezolid,chloramphenicol,and levofloxacin.Successful treatment was achieved through stereotaxic puncture,drainage,and ceftriaxone administration with a six-week course of antibiotics.CONCLUSION Preoperative enhanced head MRI plays a critical role in distinguishing brain tumors from abscesses.Selecting the correct early diagnostic methods for brain abscesses and providing timely intervention are very important.This case series was in accordance with the CARE guidelines.

星形胶质细胞在蛛网膜下腔出血中的作用研究进展

蛛网膜下腔出血(subarachnoid hemorrhage,SAH)是具有高致残率和高死亡率的一种脑血管疾病。星形胶质细胞在SAH后的脑损伤和恢复中起着至关重要的作用。文章对SAH基本概念、SAH后星形胶质细胞的活化和极化、星形胶质细胞参与和介导SAH后的早期脑损伤及迟发性脑缺血等环节以及星形胶质细胞在SAH后与其他脑细胞(如神经元、小胶质细胞和血管内皮细胞)进行大量串扰的情况进行了综述。此外,文章还总结了SAH后关于调节星形胶质细胞功能的相关靶点及治疗方法,为减轻SAH的严重后果及未来的转化疗法提供了一些新的策略。

Therapeutic potential of stem cells in subarachnoid hemorrhage

Aneurysm rupture can result in subarachnoid hemorrhage,a condition with potentially severe consequences,such as disability and death.In the acute stage,early brain injury manifests as intracranial pressure elevation,global cerebral ischemia,acute hydrocephalus,and direct blood–brain contact due to aneurysm rupture.This may subsequently cause delayed cerebral infarction,often with cerebral vasospasm,significantly affecting patient outcomes.Chronic complications such as brain volume loss and chronic hydrocephalus can further impact outcomes.Investigating the mechanisms of subarachnoid hemorrhage-induced brain injury is paramount for identifying effective treatments.Stem cell therapy,with its multipotent differentiation capacity and anti-inflammatory effects,has emerged as a promising approach for treating previously deemed incurable conditions.This review focuses on the potential application of stem cells in subarachnoid hemorrhage pathology and explores their role in neurogenesis and as a therapeutic intervention in preclinical and clinical subarachnoid hemorrhage studies.

超早期面体针疗法结合生物波综合康复治疗重症颅脑损伤昏迷患者的促醒效果分析

目的 探析超早期面体针结合生物波疗法对重症颅脑损伤(s TBI)昏迷患者的促醒效果。方法 选择80例sTBI昏迷患者,随机数字表法分为两组各40例。两组均给予早期综合康复治疗,对照组给予生物波疗法,观察组在对照组基础上联合面体针疗法。对比两组治疗前后GCS、CRS-R、脑血流灌注参数(病灶侧CBF、对侧镜面区CBF、CBF相对值)、治疗1月苏醒率及并发症风险。结果 治疗前后两组对侧镜面区CBF均值组间对比差异无统计学意义(P> 0.05),而治疗1周、1月后,两组GCS、CRS-R评分、病灶侧CBF、CBF相对值较治疗前升高,且观察组上述指标均明显高于对照组(P<0.05)。观察组1月苏醒率高于对照组,而并发症发生率低于对照组(P<0.05)。结论 超早期面体针结合生物波疗法应用于sTBI昏迷患者效果显著,可有效改善昏迷评分及脑血流灌注情况,减少并发症发生,促使患者苏醒。

Potential therapeutic molecular targets for blood-brain barrier disruption after subarachnoid hemorrhage

Aneurysmal subarachnoid hemorrhage remains serious hemorrhagic stroke with high morbidities and mortalities.Aneurysm rupture causes arterial bleeding-induced mechanical brain tissue injuries and elevated intracranial pressure,followed by global cerebral ischemia.Post-subarachnoid hemorrhage ischemia,tissue injuries as well as extravasated blood components and the breakdown products activate microglia,astrocytes and Toll-like receptor 4,and disrupt blood-brain barrier associated with the induction of many inflammatory and other cascades.Once blood-brain barrier is disrupted,brain tissues are directly exposed to harmful blood contents and immune cells,which aggravate brain injuries furthermore.Blood-brain barrier disruption after subarachnoid hemorrhage may be developed by a variety of mechanisms including endothelial cell apoptosis and disruption of tight junction proteins.Many molecules and pathways have been reported to disrupt the blood-brain barrier after subarachnoid hemorrhage,but the exact mechanisms remain unclear.Multiple independent and/or interconnected signaling pathways may be involved in blood-brain barrier disruption after subarachnoid hemorrhage.This review provides recent understandings of the mechanisms and the potential therapeutic targets of blood-brain barrier disruption after subarachnoid hemorrhage.

An early neuroprotective effect of atorvastatin against subarachnoid hemorrhage

Atorvastatin has been shown to reduce early brain edema and neuronal death after subarachnoid hemorrhage,but its mechanism is not clear.In this study,rat models of subarachnoid hemorrhage were established by autologous blood injection in the cisterna magna.Rat models were intragastrically administered 20 mg/kg atorvastatin 24 hours before subarachnoid hemorrhage,12 and 36 hours after subarachnoid hemorrhage.Compared with the controls,atorvastatin treatment demonstrated that at 72 hours after subarachnoid hemorrhage,neurological function had clearly improved;brain edema was remarkably relieved;cell apoptosis was markedly reduced in the cerebral cortex of rats;the number of autophagy-related protein Beclin-1-positive cells and the expression levels of Beclin-1 and LC3 were increased compared with subarachnoid hemorrhage only.The ultrastructural damage of neurons in the temporal lobe was also noticeably alleviated.The similarities between the effects of atorvastatin and rapamycin were seen in all the measured outcomes of subarachnoid hemorrhage.However,these were contrary to the results of 3-methyladenine injection,which inhibits the signaling pathway of autophagy.These findings indicate that atorvastatin plays an early neuroprotective role in subarachnoid hemorrhage by activating autophagy.The experimental protocol was approved by the Animal Ethics Committee of Anhui Medical University,China(904 Hospital of Joint Logistic Support Force of PLA;approval No.YXLL-2017-09)on February 22,2017.

Aquaporin 4 expression and ultrastructure of the blood-brain barrier following cerebral contusion injury

This study aimed to investigate aquaporin 4 expression and the ultrastructure of the blood-brain barrier at 2-72 hours following cerebral contusion injury, and correlate these changes to the formation of brain edema. Results revealed that at 2 hours after cerebral contusion and laceration injury, aquaporin 4 expression significantly increased, brain water content and blood-brain barrier permeability increased, and the number of pinocytotic vesicles in cerebral microvascular endothelia cells increased. In addition, the mitochondrial accumulation was observed. As contusion and laceration injury became aggravated, aquaporin 4 expression continued to increase, brain water content and blood-brain barrier permeability gradually increased, brain capillary endothelial cells and astrocytes swelled, and capillary basement membrane injury gradually increased. The above changes were most apparent at 12 hours after injury, after which they gradually attenuated. Aquaporin 4 expression positively correlated with brain water content and the blood-brain barrier index. Our experimental findings indicate that increasing aquaporin 4 expression and blood-brain barrier permeability after cerebral contusion and laceration injury in humans is involved in the formation of brain edema.

Gait and Glasgow Coma Scale scores can predict functional recovery in patients with traumatic brain injury

Fifty-one patients with mild （n -- 14）, moderate （n = 10） and severe traumatic brain injury （n = 27） received early rehabilitation. Level of consciousness was evaluated using the Glasgow Coma Score Functional level was determined using the Glasgow Outcome Score, whilst mobility was evaluated using the Mobility Scale for Acute Stroke. Activities of daily living were assessed using the Barthel Index. Following Bobath neurodevelopmental therapy, the level of consciousness was significantly improved in patients with moderate and severe traumatic brain injury, but was not greatly influenced in patients with mild traumatic brain injury. Mobility and functional level were significantly improved in patients with mild, moderate and severe traumatic brain injury. Gait recovery was more obvious in patients with mild traumatic brain injury than in patients with moderate and severe traumatic brain injury. Activities of daily living showed an improvement but this was insignificant except for patients with severe traumatic brain injury. Nevertheless, complete recovery was not acquired at discharge. Multiple regression analysis showed that gait and Glasgow Coma Scale scores can be considered predictors of functional outcomes following traumatic brain injury.

Early Intervention in the Neurodevelopment of Premature Infants during the First Six Months of Life

Objective: Measure the effects of Early Intervention ad modum Katona (EI-K) in high-risk premature infants by means of clinical, neurobehavioral, and neurophysiologic tests. Method: We used the Amiel-Tison neurologic examination, the Bayley Scale of Infant Behavior, and electroencephalography (EEG) recordings at 42 weeks of conceptional age, and after 6 months of treatment EI-K (n = 14) and compared these results with those of a group of infants without early intervention (nEI) (n = 11). Results: We found better performance of infants in EI-K than nEI group after 6 months of treatment in neurologic and behavioral examination measurements, but found no differences in EEG comparisons. Conclusion: Our data suggest significant benefit of the use of EI-K program over n-EI in the neurologic and neurobe-havior examinations of premature infants after 6 months of age.