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OBJECTIVE Spontaneous basal ganglia hemorrhage is a common type of intracerebral hemorrhage (ICH) with no definitive treatment. Minimally invasive endoscopic evacuation is a promising therapeutic approach for ICH. In this study the authors examined prognostic factors associated with long-term functional dependence (modified Rankin Scale [mRS] score ≥ 4) in patients who had undergone endoscopic evacuation of basal ganglia hemorrhage. METHODS In total, 222 consecutive patients who underwent endoscopic evacuation between July 2019 and April 2022 at four neurosurgical centers were enrolled prospectively. Patients were dichotomized into functionally independent (mRS score ≤ 3) and functionally dependent (mRS score ≥ 4) groups. Hematoma and perihematomal edema (PHE) volumes were calculated using 3D Slicer software. Predictors of functional dependence were assessed using logistic regression models. RESULTS Among the enrolled patients, the functional dependence rate was 45.50%. Factors independently associated with long-term functional dependence included female sex, older age (≥ 60 years), Glasgow Coma Scale score ≤ 8, larger preoperative hematoma volume (OR 1.02), and larger postoperative PHE volume (OR 1.03, 95% CI 1.01–1.05). A subsequent analysis evaluated the effect of stratified postoperative PHE volume on functional dependence. Specifically, patients with large (≥ 50 to < 75 ml) and extra-large (≥ 75 to 100 ml) postoperative PHE volumes had 4.61 (95% CI 0.99–21.53) and 6.75 (95% CI 1.20–37.85) times greater likelihood of long-term dependence, respectively, than patients with a small postoperative PHE volume (≥ 10 to < 25 ml). CONCLUSIONS A large postoperative PHE volume is an independent risk factor for functional dependence among basal ganglia hemorrhage patients after endoscopic evacuation, especially with postoperative PHE volume ≥ 50 ml.

The nucleus accumbens (NAc) is the key area of the reward circuit, but its heterogeneity has been poorly studied. Using single-cell RNA sequencing, we revealed a subcluster of GABAergic neurons characterized by cell division cycle 20 (Cdc20) mRNA expression in the NAc of adult rats. We studied the coexpression of Cdc20 and Gad1 mRNA in the NAc neurons of adult rats and assessed Cdc20 protein expression in the NAc during rat development. Moreover, we microinjected AAV2/9-hSyn-Cdc20 with or without the dual-AAV system into the bilateral NAc for sparse labeling to observe changes in the synaptic morphology of mature neurons and assessed rat behaviors in open field and elevated plus maze tests. Furthermore, we performed the experiments with a Cdc20 inhibitor, Cdc20 over-expression AAV vector, and Cdc20 conditional knockout primary striatal neurons to understand the ubiquitination-dependent degradation of fragile X mental retardation protein (FMRP) in vitro and in vivo. We confirmed the mRNA expression of Cdc20 in the NAc GABAergic neurons of adult rats, and its protein level was decreased significantly 3 weeks post-birth. Up-regulated Cdc20 expression in the bilateral NAc decreased the dendritic spine density in mature neurons and induced anxiety-like behavior in rats. Cdc20-APC triggered FMRP degradation through K48-linked polyubiquitination in Neuro-2a cells and primary striatal neurons and down-regulated FMRP expression in the NAc of adult rats. These data revealed that up-regulation of Cdc20 in the bilateral NAc reduced dendritic spine density and led to anxiety-like behaviors, possibly by enhancing FMRP degradation via K48-linked polyubiquitination.

Moderate traumatic brain injury (mTBI) is a heterogeneous entity that is poorly defined in the literature. Patients with mTBI have a high rate of neurological deterioration (ND), which is usually accompanied by poor prognosis and no definitive methods to predict. The purpose of this study is to develop and validate a prediction model that estimates the ND risk in patients with mTBI using data collected on admission. Data for 479 patients with mTBI collected retrospectively in our department were analyzed by logistic regression models. Bivariable logistic regression identified variables with a

Objective: patients with moderate traumatic brain injury (TBI) are under the threat of intracranial hypertension(IHT), which is an important cause of death and unfavorable outcome of TBI patients. However, it is unclear which moderate TBI patients will develop IHT and when to receive ICP-lowering treatment or even invasive ICP monitoring after admission. The purpose of the present study was to develop and validate a prediction model that estimates the risk of IHT in moderate TBI patients with lower GCS (9-11) by admission data. Methods: baseline data collected on admission of 296 moderate TBI patients with GCS score of 9-11 were collected and analyzed. Multi-variable logistic regression modeling with backward stepwise elimination was used to develop a prediction model for IHT. The discrimination efficacy, calibration efficacy, and clinical utility of the prediction model were evaluated. Finally, the prediction model was validated in a separate cohort of 74 patients from 3 hospitals. Results: four independent prognostic factors for IHT were identified: GCS score of 9, Marshall diffuse injury type IV and nonevacuated mass lesion, ISS≥18and location of contusion (frontal and temporal contusion). A prediction model was established and shown as a nomogram. The C-statistic of the prediction model in internal validation was 84.30% (95% confidence interval [CI]: 0.794–0.892). External validation was performed in a separate cohort of 85 patients. The area under the curve for the prediction model was 82.70% (95% CI: 0.726~0.928). Conclusions: A prediction model based on patient parameters collected on admission was found to be highly sensitive in distinguishing moderate TBI patients with lower GCS score of 9-11 who would suffer IHT. The high discriminative ability of the prediction model supports its use in identifying moderate TBI patients with lower GCS score of 9-11 who need ICP-lowering therapy or invasive ICP monitoring.

Mitochondrial dysfunction and oxidative stress are important mechanisms for secondary injury after traumatic brain injury (TBI), which result in progressive pathophysiological exacerbation. Although the Fibronectin type III domain-containing 5 (FNDC5) was reported to repress oxidative stress by retaining mitochondrial biogenesis and dynamics, while its possible role in the secondary injury after TBI remain obscure. In the present study, we observed thatthe level of plasma irisin (the cleavage product of FNDC5) significantly correlated with the neurological outcomes ofTBI patients. Knockout of FNDC5increased the lesion volume and exacerbated apoptosis and neurological deficitsafter TBI in mice, whileFNDC5 overexpression yielded a neuroprotective effect. Moreover, FNDC5 deficiency disrupted mitochondrial dynamics and function. Activation of Sirtuin 3 (SIRT3) alleviated FNDC5 deficiency-induced disruption of mitochondrial dynamics and bioenergetics. In neuron-specific SIRT3 knockout mice, FNDC5failed to attenuateTBI-induced mitochondrial damage and brain injuries. Mechanically, FNDC5 deficiency led to reduced SIRT3 expression via enhanced ubiquitin degradation of transcription factor Nuclear factor erythroid 2-related factor 2 (NRF2), which contributed to the hyperacetylation and inactivation of key regulatory proteins of mitochondrial dynamics and function, including OPA1 and SOD2. Finally, engineered RVG29-conjugated nanoparticles were generated to selectively and efficiently deliver irisin to the brain of mice, which yielded a satisfactory curative effect against TBI. In conclusion, FNDC5/irisin exerts a protective role against acute brain injury by promoting SIRT3-dependent mitochondrial quality control and thus represents a potential target for neuroprotection after TBI.

Background Minimally invasive surgery (MIS), including endoscopic evacuation and minimally invasive catheter (MIC) evacuation, has been widely used in spontaneous cerebellar hemorrhage (SCH) patients. However, the long-term prognosis varies widely. Herein, we aimed to explore the prognostic risk factors of neurological outcome, including peri-operative hematoma and perihematomal edema (PHE), in SCH patients after MIS. Methods Eighty consecutive SCH patients, who underwent MIS between July 2019 and Nov. 2021 from 4 neurosurgical centers were enrolled prospectively. Patients were dichotomized into good (modified Rankin Scale (mRS) score ≤ 3) and poor neurological outcome (mRS score ≥ 4) groups. Peri-operative CT scans were assessed by two independent raters. Hematoma and PHE volume were calculated using 3D Slicer software. Predictors of poor neurological outcome were assessed in logistic regression models. Results Among the enrolled patients, 44 underwent endoscopic evacuation and 36 underwent MIC evacuation. The overall poor neurological outcome rate was 23.8%. Older patients, underwent MIC evacuation, large postoperative PHE, and large preoperative PHE (OR = 1.57, 95% CI: 1.20–1.90) were independently associated with poor neurological outcome. According to the restricted cubic splines analysis, patients were divided into large preoperative PHE subgroup (PHE ≥ 10 ml) and small preoperative PHE subgroup (PHE < 10 ml). In small preoperative PHE subgroup, 1 patient (2.4%) had poor neurological outcome. However, in large preoperative PHE subgroup, 18 patients (47.4%) had poor neurological outcome. Conclusion Large preoperative PHE is an independent risk factor for poor neurological outcome among SCH patients after MIS, especially when the preoperative PHE ≥ 10 ml.

Objective: With a mortality rate of 10–30%, a moderate traumatic brain injury (mTBI) is one of the most variable traumas. The indications for intracranial pressure (ICP) monitoring in patients with mTBI and the effects of ICP on patients’ outcomes are uncertain. The purpose of this study was to examine the indications of ICP monitoring (ICPm) and its effects on the long-term functional outcomes of mTBI patients. Methods: Patients with Glasgow Coma Scale (GCS) scores of 9–11 at Tangdu hospital, between January 2015 and December 2021, were enrolled and treated in this retrospective cohort study. We assessed practice variations in ICP interventions using the therapy intensity level (TIL). Six-month mortality and a Glasgow Outcome Scale Extended (GOS-E) score were the main outcomes. The secondary outcome was neurological deterioration (ND) events. The indication and the estimated impact of ICPm on the functional outcome were investigated by using binary regression analyses. Results: Of the 350 patients, 145 underwent ICP monitoring-assisted management, and the other 205 patients received a standard control based on imaging or clinical examinations. A GCS ≤ 10 (OR 1.751 (95% CI 1.216–3.023), p = 0.003), midline shift (mm) ≥ 2.5 (OR 3.916 (95% CI 2.076–7.386) p < 0.001), and SDH (OR 1.772 (95% CI 1.065–2.949) p = 0.028) were predictors of ICP. Patients who had ICPm (14/145 (9.7%)) had a decreased 6-month mortality rate compared to those who were not monitored (40/205 (19.5%), p = 0.011). ICPm was linked to both improved neurological outcomes at 6 months (OR 0.815 (95% CI 0.712–0.933), p = 0.003) and a lower ND rate (2 = 11.375, p = 0.010). A higher mean ICP (17.32 ± 3.52, t = −6.047, p < 0.001) and a more significant number of ICP > 15 mmHg (27 (9–45.5), Z = −5.406, p < 0.001) or ICP > 20 mmHg (5 (0–23), Z = −4.635, p < 0.001) 72 h after injury were associated with unfavorable outcomes. The best unfavorable GOS-E cutoff value of different ICP characteristics showed that the mean ICP was >15.8 mmHg (AUC 0.698; 95% CI, 0.606–0.789, p < 0.001), the number of ICP > 15 mmHg was >25.5 (AUC 0.681; 95% CI, 0.587–0.774, p < 0.001), and the number of ICP > 20 mmHg was >6 (AUC 0.660; 95% CI, 0.561–0.759, p < 0.001). The total TIL score during the first 72 h post-injury in the non-ICP group (9 (8, 11)) was lower than that of the ICP group (13 (9, 17), Z = −8.388, p < 0.001), and was associated with unfavorable outcomes. Conclusion: ICPm-assisted management was associated with better clinical outcomes six months after discharge and lower incidences of ND for seven days post-injury. A mean ICP > 15.8 mmHg, the number of ICP > 15 mmHg > 25.5, or the number of ICP > 20 mmHg > 6 implicate an unfavorable long-term prognosis after 72 h of an mTBI.

Blood-brain barrier (BBB) injury critically exacerbates the poor prognosis of patients with subarachnoid hemorrhage (SAH). The massively increased matrix metalloproteinases 9 (MMP-9) plays a deleterious role in BBB. However, the main source and mechanism of MMP-9 production after SAH remain unclear. We reported that the increased MMP-9 was mainly derived from reactive astrocytes after SAH. Ndrg2 knockout in astrocytes inhibited MMP-9 expression after SAH and attenuated BBB damage. Astrocytic Ndrg2 knockout decreased the phosphorylation of Smad2/3 and the transcription of MMP-9. Notably, cytoplasmic NDRG2 bound to the protein phosphatase PPM1A and restricted the dephosphorylation of Smad2/3. Accordingly, TAT-QFNP12, a novel engineered peptide that could block the NDRG2-PPM1A binding and reduce Smad2/3 dephosphorylation, decreased astrocytic MMP-9 production and BBB disruption after SAH. In conclusion, this study identified NDRG2-PPM1A signaling in reactive astrocytes as a key switch for MMP-9 production and provided a novel therapeutic avenue for BBB protection after SAH.

Gang Zhu,1,* Shirong Yang,2,* Ronglin Wang,3,* Jie Lei,4 Peigang Ji,1 Jiancai Wang,1 Kai Tao,1 Chen Yang,1 Shunnan Ge,1 Liang Wang1 1Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi’an, Shaanxi, People’s Republic of China; 2Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi’an, Shaanxi, People’s Republic of China; 3Department of Oncology, Tangdu Hospital, The Fourth Military Medical University, Xi’an, Shaanxi, People’s Republic of China; 4Department of Neurosurgery, Wuhan General Hospital of PLA, Wuhan, Hubei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Liang Wang; Shunnan GeDepartment of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xinsi Road, Xi’an, 710038, People’s Republic of ChinaTel +86-29-84717851; Tel +86-29-84717824Email drwangliang@126.com; gesn8561@163.comPurpose: Glioblastoma multiforme (GBM) is an aggressive brain tumor with a rather short survival time. Mutation of p53 has been observed and reported to play critical roles in the progression of GBM. However, the pathological mechanisms are still unclear. This study was designed to identify the role of miR-154 in mediating the biological functions of p53 in glioblastoma multiforme.Methods: In the current study, the expression of miR-154 in GBM tissue samples and cell lines with wt-p53 or mutant p53 was evaluated. The functions of miR-154 in tumor migration, invasion and epithelial-mesenchymal transition were analyzed in vitro. A luciferase reporter assay was used to identify the target of miR-154.Results: We found that expression of miR-154 was much lower in patient tissues with mutant p53. Further study revealed that p53 was a transcription factor of miR-154 and that the R273H mutation led to its inactivation. In addition, overexpression of miR-154 remarkably suppressed cell migration, invasion and EMT in vitro and tumor growth in vivo. Moreover, TCF12 was proven to be a direct target of miR-154, and the tumor suppressive effect of miR-154 was reversed by TCF12.Conclusion: Overall, miR-154, which was regulated by wt-p53, inhibited migration, invasion and EMT of GBM cells by targeting TCF12, indicating that miR-154 may act as a biomarker and that the p53/miR-154/TCF12 pathway could be a potential therapeutic target for GBM.Keywords: glioblastoma, p53, microRNA, EMT, TCF12

Glioblastoma (GBM) is the most common primary malignant intracranial tumor and the median age at diagnosis is 65 years. However, elderly patients are usually excluded from clinical studies and age is considered as an independent negative prognostic factor for patients with GBM. Therefore, the best treatment method for GBM in elderly patients has remained controversial. Elderly GBM patients (≥ 60 years old) treated between January 2015 and December 2019 were enrolled in this study. Medical records were reviewed retrospectively, and clinicopathological characteristics, treatments, and outcomes were analyzed. A total of 68 patients were included, with a median age of 65.5 years (range: 60–79). The median preoperative Karnofsky performance scale (KPS) score was 90 (range 40–100) and median postoperative KPS score was 80 (range 0–90). Univariate analysis results showed that age, gender, comorbidities, preoperative KPS < 90 and MGMT promoter methylation were not significantly associated with PFS and OS. On the other hand, total resection, postoperative KPS ≥ 80, Ki67 > 25%, and Stupp-protocol treatment were significantly associated with prolonged PFS and OS. Moreover, multivariate analysis found that postoperative KPS ≥ 80, total resection, and Stupp-protocol treatment were prognostic factors for PFS and OS. The findings of this study have suggested that, on the premise of protecting function as much as possible, the more aggressive treatment regimens may prolong survival for elderly patients with GBM. However, further studies, particularly prospective randomized clinical trials, should be conducted to provide more definitive data on the appropriate management of elderly patients, especially for patients with MGMT promoter methylation.

Rationale: Neuroadaptations in the medial prefrontal cortex (mPFC) and Nucleus Accumbens (NAc) play a role in the disruption of control-reward circuits in opioid addiction. Small Conductance Calcium-Activated Potassium (SK) channels in the mPFC have been implicated in neuronal excitability changes during morphine withdrawal. However, the mechanism that modulates SK channels during withdrawal is still unknown. Methods: Rats were exposed for one week to daily morphine injections (10 mg·kg-1 s.c.) followed by conditional place preference (CPP) assessment. One week after withdrawal, electrophysiological, morphological and molecular biological methods were applied to investigate the effects of morphine on SK channels in mPFC, including infralimbic (IL), prelimbic (PrL) cortices and NAc (core and shell). We verified the hypothesis that Rac1, a member of Rho family of small GTPases, implicated in SK channel regulation, modulate SK channel neuroadaptations during opiate withdrawal. Results: One week after morphine withdrawal, the neuronal excitability of layer 5 pyramidal neurons in IL was decreased, but not in PrL. Whereas, the excitability was increased in NAc-shell, but not in NAc-core. In mPFC, the expression of the SK3 subunit was enhanced after one-week of withdrawal compared to controls. In the IL, Rac1 signaling was increased during withdrawal, and the Rac1 inhibitor NSC23766 disrupted SK current, which increased neuronal firing. Suppression of Rac1 inhibited morphine-induced CPP and expression of SK channels in IL. Conclusions: These findings highlight the potential value of SK channels and the upstream molecule Rac1, which may throw light on the therapeutic mechanism of neuromodulation treatment for opioid dependence.

We reported a case of awake surgery for the left frontal low-grade glioma and reviewed the literature on the strategy of awake surgical resection for glioma. The eloquent cerebral areas that are involved in motor, language, memory, and visuospatial functions, which have to be preserved during surgery, is identified through intraoperative use of brain mapping techniques. This technique of combining intraoperative ultrasound and neuronavigation enabled extension of the surgical indications and improved the extent of resection, while minimizing postoperative morbidity and safeguarding the patient's quality of life. This work was approved by the Institutional Review Board of Tangdu Hospital, Fourth Military Medical University, China.

Background and Purpose: As a rare lesion secondary to brain trauma, traumatic intracranial aneurysms (TICAs) lead to high mortality and morbidity, and multiple treatment modalities have been applied for TICAs. All patients diagnosed with TICAs in our institution from 2010 to 2020 were included in the report, and their clinical features, treatment, and outcomes are described in detail. The purpose of this study is to illustrate the characteristic of different therapeutic methods of TICAs, and focus on the endovascular treatment.Methods: A total of 20 patients were included in this study. The 3 patients who declined treatment all died. Five of the other 17 patients were treated surgically, including clipping, wrapping, and trapping with or without EC-IC high-flow bypass, with only 1 case of parent artery preservation. Twelve patients underwent endovascular treatment, including bare coil embolization (1 case), stent-assisted coiling (2 cases), balloon-assisted coils/Onyx glue embolization (1 case) and covered stents (8 cases), with only 1 case of parent artery sacrifice.Results: 20 patients were included in the present study with 17 males, and the mean of age on 27 years (IQR: 22, 44 years). Eight patients presented with epistaxis, followed by 5 patients with coma, 3 patients with visual defects and 2 patients with CSF leakage. There were 18 TICAs located at the internal carotid artery (ICA); The other 2 TICAs located at pericallosal artery and A1 segment anterior cerebral artery (ACA). One case of diplopia occurred due to sacrifice of the ICA. Occlusion of the ophthalmic artery occurred in 3 patients after placement of a covered stent, with 1 patient suffering an irreversible vision decrease. None of the other patients who underwent the treatment have experienced an aggravation of their symptoms since the treatment; During the imaging follow-up, 1 case of recurrence and 1 case of endoleak occurred in this case series.Conclusions: TICAs are associated with significant morbidity and mortality, and endovascular treatment has emerged as a valuable option, which may be promising to improve the clinical outcomes due to their advantages of preserving the parent artery if occlusion of the side branch artery can be avoided.

Objective: To assess the association between immediate postoperative coagulopathy and the long-term survival of traumatic brain injury (TBI) patients undergoing surgery, as well as to explore predisposing risk factors of immediate postoperative coagulopathy.Methods: This retrospective study included 352 TBI patients from January 1, 2015, to April 25, 2019. The log-rank test and a Cox proportional hazard model were conducted to assess the relationship between immediate postoperative coagulopathy and the long-term survival of TBI patients. Furthermore, a multivariate logistic regression model was performed to identify the underlying risk factors for postoperative coagulopathy.Results: Of the 352 patients analyzed, the median age was 50 (41,60) years, and 82 (23%) patients were female. By May 26, 2019, 117 (33.24%) patients had died, 195 (55.40%) had survived, and 40 (11.36%) had been lost to follow-up. The median follow-up time was 773 days. In the log-rank test, immediate postoperative coagulopathy was significantly associated with the survival of TBI patients (P = 0.002). A Cox proportional hazard model identified immediate postoperative coagulopathy (HR, 1.471; 95% CI, 1.011-2.141; P = 0.044) as an independent risk factor for survival following TBI. According to multivariate logistic regression analysis, abnormal ALT and RBC at admission, intraoperative infusion of crystalloid solution > 2900 mL, infusion of colloidal solution > 1100 mL and intraoperative bleeding > 950 mL were identified as independent risk factors for immediate postoperative coagulopathy.Conclusions: Those who suffered from immediate postoperative coagulopathy due to TBI were at higher risk of poor prognosis than those who did not.

Backgroud: to investigate secondary glioblastoma (sGBM) patients undergoing resection and evaluate the impact of treatment on survival of malignant progression (PMS) and the prognostic factors of secondary glioblastoma. Method: the prognostic factors of secondary glioblastoma were analyzed retrospectively including gender, age, the interval between first diagnosis and second, the extent of resection, adjuvant treatment, postoperative Karnofsky score (KPS), 06-methylguanine-DNA methytransferase (MGMT) status, IDH1 mutation status, and PMS in patients with sGBM. Result: Thirty-four patients with sGBM were included in this study. Sixteen patients were female and eighteen were male. Median PMS in females was longer than male patients with sGBM (17.38 (95%CI 10.63–24.12) vs 10.06(95%CI 5.32–14.79), p = 0.032). 22(64.7%) patients achieved gross total resection (GTR),12(35.3%) patients achieved subtotal resection (STR). Kaplan-Meier analysis showed that GTR significantly improved survival after malignant progression (PMS) compared with STR (17.18(95%CI 10.97–23.40) vs 7.17(95%CI 4.97–9.36), p = 0.004). Adjuvant treatment after resection was executed in 17 (50.0%) patients, radiotherapy in one (2.9%) patient, chemotherapy in seven (20.6%) patients, and radio-chemotherapy in nine (26.5%) patients. Median preoperative KPS was 80(range 30–100), and 85(range 30–100) after surgery. The difference in PMS probability was significant between patients having a good postoperative clinical status (KPS༞70)versus poor (KPS ≤ 70). Long term survival could be achieved in patients with a good clinical status (16.57(95%CI 10.54–22.60) vs 9.00(95%CI 3.66–14.34), p = 0.02). Patients with a greater interval after initial diagnosis had longer survival than those with intervals less than 26.5 months (18.62(95%CI 10.81–26.43) vs 9.22(95%CI 5.61–12.83), p = 0.025). Conclusion: GTR and any adjuvant treatment significantly improved PMS in patients with secondary glioblastoma. Gender, postoperative KPS, time interval since the first diagnosis are associated with prognosis.

Background: Traumatic intracerebellar hematoma (TICH) is a very rare entity but with high morbidity and mortality rate, and there is no consensus on its optimal surgical management. In particular, whether and when to place external ventricle drainage in TICH patients without acute hydrocephalus pre-operation is still controversial.Methods: A single-institutional, retrospective analysis of total 47 TICH patients with craniectomy hematoma evacuation in a tertiary medical center from January 2009 to October 2020 was performed. Primary outcomes were mortality in hospital and neurological function evaluated by GOS at discharge and 6 months after the ictus. The special attention was paid to the significance of external ventricular drainage (EVD) in TICH patients without acute hydrocephalus on admission.Results: Analysis of the clinical characteristics of the TICH patients revealed that the odds use of EVD was seen in patients with IVH (p=0.03), fourth ventricle compression (p=0.02), and acute hydrocephalus (pConclusion: For TICH patients, EVD is safe and can significantly improve neurological prognosis. Especially for patients whose GCS dropped by more than 2 points before operation, EVD can significantly improve the patient's GCS score, reduce the risk of herniation, and gain more time for surgical preparation. Even for TICH patients without acute hydrocephalus on admission CT scan, EVD placement still has positive clinical significance. However, future studies with larger sample size are warranted to confirm whether EVD can reduce in-hospital mortality and the risk of delayed hydrocephalus in TICH.

Objectives 20‐hydroxyeicosatetraenoic acid (20‐HETE) is a metabolite of arachidonic acid catalysed by cytochrome P450 enzymes and plays an important role in cell death and proliferation. We hypothesized that 20‐HETE synthesis inhibition may have protective effects in traumatic brain injury (TBI) and investigated possible underlying molecular mechanisms. Materials and methods Neurologic deficits, and lesion volume, reactive oxygen species (ROS) levels and cell death as assessed using immunofluorescence staining, transmission electron microscopy and Western blotting were used to determine post‐TBI effects of HET0016, an inhibitor of 20‐HETE synthesis, and their underlying mechanisms. Results The level of 20‐HETE was found to be increased significantly after TBI in mice. 20‐HETE synthesis inhibition reduced neuronal apoptosis, ROS production and damage to mitochondrial structures after TBI. Mechanistically, HET0016 decreased the Drp1 level and increased the expression of Mfn1 and Mfn2 after TBI, indicating a reversal of the abnormal post‐TBI mitochondrial dynamics. HET0016 also promoted the restoration of SIRT1 and PGC‐1α in vivo, and a SIRT1 activator (SRT1720) reversed the downregulation of SIRT1 and PGC‐1α and the abnormal mitochondrial dynamics induced by 20‐HETE in vitro. Furthermore, plasma 20‐HETE levels were found to be higher in TBI patients with unfavourable neurological outcomes and were correlated with the GOS score. Conclusions The inhibition of 20‐HETE synthesis represents a novel strategy to mitigate TBI‐induced mitochondrial dysfunction and neuronal apoptosis by regulating the SIRT1/PGC‐1α pathway., The mechanism on 20‐HETE–induced alterations of mitochondrial dynamics in neurons. 20‐HETE is synthesized from AA by CYP4A, which is inhibited by HET0016. The alterations of mitochondrial dynamics induced by 20‐HETE activate oxidative stress and subsequently result in neuronal apoptosis mediated by inhibition of the Sirt1/PGC‐1α signalling pathway.

The imbalanced hemostatic equilibrium caused by brain tissue or vessel damage underlies the pathophysiology of traumatic brain injury (TBI)-induced coagulopathy, and cranial computed tomography (CT) is the gold standard for evaluating brain injury. The present study aimed to explore the correlation between quantitative cranial CT parameters and coagulopathy after TBI.We retrospectively collected the medical records of TBI patients with extracranial abbreviated injury scale (AIS) scores3 who were admitted to our institution. The quantitative cranial CT parameters of patients with and without coagulopathy were compared, and univariate correlation analysis between CT parameters and coagulation subtest values and platelet counts was performed. The predictors for each subtest of coagulation function were probed by multivariate regression.TBI patients with coagulopathy had a larger intracerebral haematoma/contusion (ICH/C) volume (ICH/C volume was a main quantitative cranial CT parameter for predicting coagulopathy, suggesting that parenchymal brain damage and vessel injury were closely associated with coagulopathy after TBI.

Traumatic brain injury (TBI)-induced coagulopathy has increasingly been recognized as a significant risk factor for poor outcomes, but the pathogenesis remains poorly understood. In this study, we aimed to investigate the causal role of acrolein, a typical lipid peroxidation product, in TBI-induced coagulopathy, and further explore the underlying molecular mechanisms. We found that the level of plasma acrolein in TBI patients suffering from coagulopathy was higher than that in those without coagulopathy. Using a controlled cortical impact mouse model, we demonstrated that the acrolein scavenger phenelzine prevented TBI-induced coagulopathy and recombinant ADAMTS-13 prevented acrolein-induced coagulopathy by cleaving von Willebrand factor (VWF). Our results showed that acrolein may contribute to an early hypercoagulable state after TBI by regulating VWF secretion. mRNA sequencing (mRNA-seq) and transcriptome analysis indicated that acrolein over-activated autophagy, and subsequent experiments revealed that acrolein activated autophagy partly by regulating the Akt/mTOR pathway. In addition, we demonstrated that acrolein was produced in the perilesional cortex, affected endothelial cell integrity, and disrupted the blood-brain barrier. In conclusion, in this study we uncovered a novel pro-coagulant effect of acrolein that may contribute to TBI-induced coagulopathy and vascular leakage, providing an alternative therapeutic target. Supplementary Information The online version contains supplementary material available at 10.1007/s12264-021-00681-0.

Background Despite advances in decompressive craniectomy (DC) for the treatment of traumatic brain injury (TBI), these patients are at risk of having a poor long-term prognosis. The aim of this study was to predict 1-year mortality in TBI patients undergoing DC using logistic regression and random tree models. Methods This was a retrospective analysis of TBI patients undergoing DC from January 1, 2015, to April 25, 2019. Patient demographic characteristics, biochemical tests, and intraoperative factors were collected. One-year mortality prognostic models were developed using multivariate logistic regression and random tree algorithms. The overall accuracy, sensitivity, specificity, and area under the receiver operating characteristic curves (AUCs) were used to evaluate model performance. Results Of the 230 patients, 70 (30.4%) died within 1 year. Older age (OR, 1.066; 95% CI, 1.045–1.087; P < 0.001), higher Glasgow Coma Score (GCS) (OR, 0.737; 95% CI, 0.660–0.824; P < 0.001), higher d-dimer (OR, 1.005; 95% CI, 1.001–1.009; P = 0.015), coagulopathy (OR, 2.965; 95% CI, 1.808–4.864; P < 0.001), hypotension (OR, 3.862; 95% CI, 2.176–6.855; P < 0.001), and completely effaced basal cisterns (OR, 3.766; 95% CI, 2.255–6.290; P < 0.001) were independent predictors of 1-year mortality. Random forest demonstrated better performance for 1-year mortality prediction, which achieved an overall accuracy of 0.810, sensitivity of 0.833, specificity of 0.800, and AUC of 0.830 on the testing data compared to the logistic regression model. Conclusions The random forest model showed relatively good predictive performance for 1-year mortality in TBI patients undergoing DC. Further external tests are required to verify our prognostic model.

Background: Although operative indications for traumatic brain injury (TBI) have been evaluated, neurosurgeons often face a dilemma of whether or not to remove the bone flap after mass lesion evacuation, and a useful predictive scoring model for which patients should be decompressive craniectomy (DC) has yet to be developed. The aim of this study was firstly to compare the outcomes of craniotomy and DC, and secondly to determine independent predictors and develop a multivariate logistic regression equation to determine whom should perform primary DC in TBI patients with mass lesions.Methods: A total of nine different variables were evaluated. All 245 patients with severe TBI in this study were retrospectively evaluated between June 2015 and May 2019 and all underwent decompressive craniectomy (DC) or craniotomy for mass lesion removal. The 6-month mortality and Extended Glasgow Outcome Scale (GOSE) were compared between DC and craniotomy. By using univariate, multiple logistic regression and prognostic regression scoring equations it was possible to draw Receiver Operating Characteristic curves (ROC) to predict the decision for DC.Results: The overall 6-month mortality in the entire cohort was 11.43% (28/245). DC patients had a lower mean preoperative Glasgow Coma Scale (GCS) (p = 0.01); more patients with GCS of 6 (p=0.007);more unresponsive pupillary light reflex (p< 0.001); more closed basal cisterns (p< 0.001); and more patients with diffuse injury (p=0.025) than craniotomy patients. Given the greater severity, patients undergoing primary DC had higher 6-month mortality than the remainder of the cohort. However, in the surviving patients, the favorable GOSE rate was similar in two groups. We found that pupillary light reflex and basal cisterns were independent predictors for DC decision. Using ROC curve to predict the probability of DC, the sensitivity was 81.6% and the specificity was 84.9%.Conclusion: Our preliminary findings showed that the primary DC may benefit subgroups of sTBI with mass lesions, and unresponsive pre-op pupil reaction, and closed basal cistern to predict the DC decision were useful. These sensitive variables can be used as a referential guideline in our daily practice to decide to perform or avoid primary DC.

PurposeGlioma is one of the most common tumors of the central nervous system, and many patients suffer from recurrence even after standard comprehensive treatment. However, little is known about the molecular markers that predict the recurrence patterns of glioma. This study aimed to demonstrate the correlations between molecular markers and glioma recurrence patterns, which included local/nonlocal recurrence and paraventricular/nonparaventricular recurrence.MethodsImmunohistochemical techniques were used to assess the molecular markers of 88 glioma tissues following surgical resection. The recurrence patterns were divided into local recurrence, marginal recurrence, distant recurrence, multirecurrence, and subarachniod recurrence, with the last four recurrence patterns being collectively called nonlocal recurrence. According to whether the recurrence invaded ventricles, the nonlocal recurrence patterns were divided into paraventricular and nonparaventricular recurrence. Then, we compared the different recurrence patterns and their clinical characteristics, focusing on the expression of molecular markers.ResultsMore patients in the nonlocal recurrence group received combined radiotherapy and chemotherapy than patients in the local recurrence group (p=0.019). Sex, age, extent of surgery, time to recurrence, tumor location, size, and WHO grade were not different in the defined groups (P>0.05). Recurrent tumor volume and WHO grade were significantly different between the paraventricular and nonparaventricular recurrence groups (p=0.046 and 0.033). The expression of Ki-67, P53, and PCNA in the nonlocal recurrence group was significantly higher than that in the local recurrence group (p=0.015, 0.009, and 0.037), while the expression of S-100 in the nonlocal recurrence group was significantly lower than that in the local recurrence group (p=0.015). Cox regression indicated hazard ratio (HR) for high expression level of PCNA associated with non-local recurrence was 3.43 (95% CI, 1.15, 10.24), and HR for high expression level of MGMT associated with paraventricular recurrence was 2.64 (95% CI, 1.15,6.08).ConclusionsKi-67, P53, PCNA, and MGMT might be important clinical markers for nonlocal recurrence and paraventricular recurrence.

Background: Deep brain stimulation (DBS) is currently used to treat addiction, with the nucleus accumbens (NAc) as one promising target. The anterior limb of the internal capsule (ALIC) is also a potential target, as it carries fiber tracts connecting the mesocorticolimbic circuits that are crucially involved in several psychiatric disorders, including addiction. Stimulating the NAc and ALIC simultaneously may have a synergistic effect against addiction. Methods: Eight patients with a long history of heroin use and multiple relapses, despite optimal conventional treatments, were enrolled. Customized electrodes were implanted through the ALIC into the NAc, and deep brain stimulation (DBS) treatment began two weeks after surgery. The patients were followed for at least 24 months. The duration of drug-free time, severity of drug cravings, psychometric evaluations, and PET studies of glucose metabolism before and after DBS were conducted. All adverse events were recorded. Results: With DBS, five patients were abstinent for more than three years, two relapsed after abstaining for six months, and one was lost of follow-up at three months. The degree of cravings for drug use after DBS was reduced if the patients remained abstinent (p

To evaluate the clinical effect of the position of stimulation contacts relative to the hyperdirect pathway (HDP) on the alleviation of motor symptoms in patients with Parkinson disease (PD).A group of 11 patients diagnosed with idiopathic PD were included in this study, and all selected targets were in the subthalamic nucleus (STN). In 1 patient, a single side electrode was implanted because of unilateral symptoms; in all other patients, bilateral electrodes each containing 4 discrete contacts were implanted. Nine contacts were excluded due to adverse reactions caused by stimulation, and thus a total of 75 active contacts were evaluated using the same stimulus parameters. Fiber tractography results were individually processed using StealthViz software before all data were subjected to statistical analysis.Under the same stimulus parameters, the shortest distance of each contact to the HDP was smaller in group I (n = 45;50% improvement rate) compared with group II (n = 30; ≤50% improvement rate) (mean, 1.18 ± 0.86 mm vs. 2.14 ± 1.20 mm; t = 3.78; P0.05), and the shortest distance had a negative correlation with the improvement of motor symptoms (r = -0.48; P0.05).Stimulation of the HDP coincided with the improvement of motor symptoms in patients with PD. We propose an improvement of the direct visualization method based on diffusion tensor imaging fiber tractography of the HDP to select the motor part of the STN. Further rigorous clinical trials are needed to verify the value of this method for achieving precise target location and individualized treatment.

Objectives Bevacizumab (BEV) plus daily temozolomide (TMZ) as a salvage therapy have been recommended to recurrent glioma. The objective of this retrospective study was to evaluate the effect of the combined regimen on health related quality of life (HRQL) and treatment response in patients with recurrent glioma. Patients and Methods Twenty patients with recurrent glioma were treated with BEV (5–10 mg/kg, i.v. every 2 weeks) plus daily TMZ (daily, 50 mg/m2). The treatment response was evaluated via the RANO criteria. HRQL were measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire core 30 (QLQ-C30) and Brain Module (QLQ-BN20). Results Twenty patients received a total of 85 cycles of BEV with a median number of 4 cycles (range: 2–10). No patients showed complete response (CR) to treatment. Twelve patients had partial response (PR), stable disease (SD) in 5 patients with, and 3 patients showed progressive disease (PD). In the functioning domains of QLQ-C30, physical functioning, cognitive functioning and emotional functioning significantly improved after the second cycle of BEV compared to baseline, with the mean score of 45.0 vs. 64.0 (p = 0.020), 55.8 vs. 71.7 (p = 0.020) and 48.3 vs. 67.5 (p = 0.015), respectively. In the symptom scales, the scores of pain and nausea/vomiting significantly decreased compared to baseline from the mean score of 39.1 to 20.0 (p = 0.020) and 29.2 to 16.7 (p = 0.049), respectively. Score of global health status also increased from 47.5 to 63.3 (p = 0.001). As determined with the QLQ-BN20, motor dysfunction (43.3 vs. 25.0, p = 0.021), weakness of legs (36.7 vs. 18.3, p = 0.049), headache (38.3 vs. 20.0, p = 0.040), and drowsiness (50.0 vs. 30.0, p = 0.026) after the second cycle of BEV also significantly improved compared to baseline. Conclusion BEV plus daily TMZ as a salvage therapy improved HRQL in patients with recurrent glioma.

Objective: The purpose of this study was to identify the relationship between coagulopathy during the perioperative period (before the operation and on the first day after the operation) and the long-term survival of TBI patients undergoing surgery, as well as to explore the predisposing risk factors that may cause perioperative coagulopathy.Methods: This retrospective study included 447 TBI patients who underwent surgery from January 1, 2015 to April 25, 2019. Clinical parameters, including patient demographic characteristics, biochemical tests, perioperative coagulation function tests (before the operation and on the first day after the operation) and intraoperative factors were collected. Log-rank univariate analysis and Cox regression models were conducted to assess the relationship between perioperative coagulopathy and the long-term survival of TBI patients. Furthermore, univariate and multivariate analyses were performed to identify the underlying risk factors for perioperative coagulopathy.Results: Multivariate Cox regression analysis identified age, AIS(head) = 5, GCS ≤ 8, systolic pressure at admission < 90 mmHg and postoperative coagulopathy (all P < 0.05) as independent risk factors for survival following TBI; we were the first to identify postoperative coagulopathy as an independent risk factor. According to multivariate logistic regression analysis, for the first time, abnormal ALT and RBC at admission, preoperative coagulopathy, infusion of colloidal solution > 1100 mL and intraoperative bleeding > 950 mL (all P < 0.005) were identified as independent risk factors for postoperative coagulation following surgery after TBI.Conclusions: Those who suffered from postoperative coagulopathy due to TBI had a higher hazard for poor prognosis than those who did not. Closer attention should be paid to postoperative coagulopathy and more emphasis should be placed on managing the underlying risk factors.

Synchronization and desynchronization of neuronal oscillatory activities between different brain areas play an important role in effective information communication. The hippocampus-mPFC circuit is well recognized as an important neural circuit pathway involved in drug addiction. We aimed to examine cocaine-related changes in oscillation synchronization in the hippocampus-mPFC circuit and to explore the role of the NAc in oscillation synchronization between the hippocampus and the mPFC during intravenous cocaine administration. In our experiment, adult male Sprague-Dawley rats were divided into the Saline group, Cocaine group and Lesion group by the random number table method. Using an electrophysiological method, we continuously recorded the local field potentials (LFPs) of the hippocampus and the mPFC after pulse intravenous cocaine or saline. Our results showed that theta coherence occurred in the hippocampus-mPFC circuit during intravenous cocaine administration (Coherenceθ, Pre-drug = 0.2212 ± 0.0126, Coherenceθ, Post-drug = 0.3118 ± 0.0149, t = 4.894, P

Secretory carrier membrane proteins (SCAMPs) play an important role in exocytosis in animals, but the precise function of SCAMPs in human disease is unknown. In this study, we identified a homozygous mutation, SCAMP5 R91W, in a Chinese consanguineous family with pediatric epilepsy and juvenile Parkinson's disease. Scamp5 R91W mutant knock-in mice showed typical early-onset epilepsy similar to that in humans. Single-neuron electrophysiological recordings showed that the R91W mutation significantly increased the frequency of miniature excitatory postsynaptic currents (mEPSCs) at a resting state and also increased the amplitude of evoked EPSCs. The R91W mutation affected the interaction between SCAMP5 and synaptotagmin 1 and may affect the function of the SNARE complex, the machinery required for vesicular trafficking and neurotransmitter release. Our work shows that dysfunction of SCAMP5 shifted the excitation/inhibition balance of the neuronal network in the brain, and the deficiency of SCAMP5 leads to pediatric epilepsy.

Vesicular glutamate transporter (VGLUT) 1 and VGLUT2 have been reported to distribute complementally in most brain regions and have been assumed to define distinct functional elements. Previous studies have shown the expression of VGLUT1 mRNA and VGLUT2 mRNA in the lateral reticular nucleus (LRN), a key precerebellar nucleus sending mossy fibers to the cerebellum. In the present study, we firstly examined the coexpression of VGLUT1 and VGLUT2 mRNA in the LRN of the rat by dual-fluorescence in situ hybridization. About 81.89 % of glutamatergic LRN neurons coexpressed VGLUT1 and VGLUT2 mRNA, and the others expressed either VGLUT1 or VGLUT2 mRNA. We then injected the retrograde tracer Fluogold (FG) into the vermal cortex of cerebellum, and observed that 95.01 % and 86.80 % of FG-labeled LRN neurons expressed VGLUT1 or VGLUT2 mRNA respectively. We further injected the anterograde tracer biotinylated dextran amine (BDA) into the LRN, and found about 82.6 % of BDA labeled axon terminals in the granular layer of cerebellar cortex showed both VGLUT1- and VGLUT2-immunoreactivities. Afterwards, we observed under electron microscopy that anterogradely labeled axon terminals showing immunoreactivity for VGLUT1 or VGLUT2 made asymmetric synapses with dendritic profiles of cerebellar neurons. Finally, we selectively down-regulated the expression of VGLUT1 mRNA or VGLUT2 mRNA by using viral vector mediated siRNA transfection and detected that the fine movements of the forelimb of rats were disturbed. These results indicated that LRN neurons coexpressing VGLUT1 and VGLUT2 project to the cerebellar cortex and these neurons might be critical in mediating the forelimb movements.

Cerebral venous infarction (CVI) caused by the injury of cortical bridging veins (CBVs), is one of the most serious complications following neurosurgical craniotomy. Different from cerebral artery infarction, this CVI pathological process is more complicated, accompanied by acute venous hypertension, brain edema, cerebral ischemia and hemorrhage in the veins bridged brain area. Therefore, a reliable and stable small animal model is particularly important for the pathological study of CVI induced by surgical CBV interruption (CBVi). A mouse model established by cutting off the right CBVs from bregma to lambda with microsurgical technique is used for the assessment of the pathological process. Adult male mice underwent craniotomy after transection of the parietal skin under anesthesia. The right CBVs were exposed by removing the right skull along the right lateral edge of the sagittal sinus (forming a 4 mm × 3 mm bone window from bregma to lambda) with a drill under the operating microscope. Following the final inspection of the cerebral veins, the CBVs (30% one, 60% two, 10% none) were sacrificed using bipolar coagulation technique. Intracranial pressure (ICP) monitoring, motor function examination, brain edema assessment and brain histopathological observation after perfusion were performed at different time points (6 h, 12 h, 24 h, and 48 h) in the postoperative mice. Cerebral hemisphere swelling, midline shift and subcortical petechial hemorrhage were found on histological sections 6 h after CBVs dissection. The change of ICP was consistent with cerebral edema and peaked at 12 h after surgery, as well as the disruption of the blood–brain barrier assessed by Evans Blue staining. Tissue necrosis, nerve cell loss and monocytes infiltration were also dynamically increased in the postoperative hemispheric cortex. Behavioral tests showed obvious somato- and forelimb-motor dysfunction, and severe somatosensory disorder on the operative mice at 12 h, which were substantially recovered at 48 h. Our study provided a novel mouse model of CVI caused by surgical CBVi that was close to clinical practice, and preliminarily confirmed its pathological process. This model might become an important tool to study the clinical pathology and the molecular mechanism of nerve injury following CVI.

IntroductionDeep brain stimulation (DBS) is a new potential surgical treatment for opioid dependence. However, the implement of DBS treatment in addicted patients is currently controversial due to the significant associated risks. The aim of this study was mainly to investigate the therapeutic efficacy and safety of bilateral DBS of nucleus accumbens and the anterior limb of the internal capsule (NAc/ALIC-DBS) in patients with refractory opioid dependence (ROD).Methods and analysis60 patients with ROD will be enrolled in this multicentre, prospective, double-blinded study, and will be followed up for 25 weeks (6 months) after surgery. Patients with ROD (semisynthetic opioids) who meet the criteria for NAc/ALIC-DBS surgery will be allocated to either the early stimulation group or the late stimulation group (control group) based on the randomised ID number. The primary outcome was defined as the abstinence rate at 25 weeks after DBS stimulation on, which will be confirmed by an opiate urine tests. The secondary outcomes include changes in the Visual Analogue Scale (VAS) score for craving for opioid drugs, body weight, as well as psychological evaluation measured using the 17-item Hamilton Depression Rating Scale, the Hamilton Anxiety Rating Scale, the Pittsburgh Sleep Quality Index, Fagerstrom test for nicotine dependence assessment, social disability screening schedule, the Activity of Daily Living Scale, the 36-item Short Form-Health Survey and safety profiles of both groups.Ethics and disseminationThe study received ethical approval from the medical ethical committee of Tangdu Hospital, The Fourth Military Medical University, Xi’an, China. The results of this study will be published in a peer-reviewed journal and presented at international conferences.Trial registration numberNCT03424616; Pre-results.

Drug addiction can be viewed as a chronic psychiatric disorder that is related to dysfunction of neural circuits, including reward deficits, stress surfeits, craving changes, and compromised executive function. The nucleus accumbens (NAc) plays a crucial role in regulating craving and relapse, while the medial prefrontal cortex (mPFC) represents a higher cortex projecting into the NAc that is active in the management of executive function. In this study, we investigated the role of the small conductance calcium-activated potassium channels (SK channels) in NAc and mPFC after morphine withdrawal. Action potential (AP) firing of neurons in the NAc shell was enhanced via the downregulations of the SK channels after morphine withdrawal. Furthermore, the expression of SK2 and SK3 subunits in the NAc was significantly reduced after 3 weeks of morphine withdrawal, but was not altered in the dorsal striatum. In mPFC, the SK channel subunits were differentially expressed. To be specific, the expression of SK3 was upregulated, while the expression of SK2 was unchanged. Furthermore, the AP firing in layer 5 pyramidal neurons of the infralimbic (IL) cortex was decreased via the upregulations of the SK channel-related tail current after 3 weeks of morphine withdrawal. These results suggest that the SK channel plays a specific role in reward circuits following morphine exposure and a period of drug withdrawal, making it a potential target for the prevention of relapse.