The brain nebula: minimally invasive brain-computer interface by endovascular neural recording and stimulation.

A brain-computer interface (BCI) serves as a direct communication channel between brain activity and external devices, typically a computer or robotic limb. Advances in technology have led to the increasing use of intracranial electrical recording or stimulation in the treatment of conditions such as epilepsy, depression, and movement disorders. This indicates that BCIs can offer clinical neurological rehabilitation for patients with disabilities and functional impairments. They also provide a means to restore consciousness and functionality for patients with sequelae from major brain diseases. Whether invasive or non-invasive, the collected cortical or deep signals can be decoded and translated for communication. This review aims to provide an overview of the advantages of endovascular BCIs compared with conventional BCIs, along with insights into the specific anatomical regions under study. Given the rapid progress, we also provide updates on ongoing clinical trials and the prospects for current research involving endovascular electrodes.

Zabramski classification in predicting the occurrence of symptomatic intracerebral hemorrhage in sporadic cerebral cavernous malformations.

OBJECTIVE: The authors aimed to investigate the evolutionary characteristics of the Zabramski classification of cerebral cavernous malformations (CCMs) and the value of the Zabramski classification in predicting clinical outcome in patients with sporadic CCM. METHODS: This retrospective study consecutively included cases of sporadic CCM that had been untreated from January 2001 through December 2021. Baseline and follow-up patient information was recorded. The evolution of the Zabramski classification of a sporadic CCM was defined as the initial lesion type changing into another type for the first time on MRI follow-up. The primary outcome was the occurrence of a hemorrhage event, which was defined as a symptomatic event with radiological evidence of overt intracerebral hemorrhage. RESULTS: Among the 255 included cases, 55 (21.6%) were classified as type I CCM, 129 (50.6%) as type II CCM, and 71 (27.8%) as type III CCM, based on initial MRI. During a mean follow-up of 58.8 ± 33.6 months, 51 (20.0%) patients had lesion classification transformation, whereas 204 (80.0%) patients maintained their initial type. Among the 51 transformed lesions, 29 (56.9%) were type I, 11 (21.6%) were type II, and 11 (21.6%) were type III. Based on all follow-up imaging, of the initial 55 type I lesions, 26 (47.3%) remained type I and 27 (49.1%) regressed to type III because of hematoma absorption; 91.5% of type II and 84.5% of type III lesions maintained their initial type during MRI follow-up. The classification change rate of type I lesions was statistically significantly higher than those of type II and III lesions. After a total follow-up of 1157.7 patient-years, new clinical hemorrhage events occurred in 40 (15.7%) patients. The annual cumulative incidence rate for symptomatic hemorrhage in all patients was 3.4 (95% CI 2.5-4.7) per 100 person-years. Kaplan-Meier survival analysis showed that the annual cumulative incidence rate for symptomatic hemorrhage of type I CCM (15.3 per 100 patient-years) was significantly higher than those of type II (0.6 per 100 patient-years) and type III (2.3 per 100 patient-years). CONCLUSIONS: This study suggests that the Zabramski classification is helpful in estimating clinical outcome and can assist with surgical decision-making in patients with sporadic CCM.

Association between systemic immune-inflammatory markers and the risk of moyamoya disease: a case-control study.

Background:Systemic immune-inflammatory markers such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR) and systemic immune-inflammatory index (SII) are associated with the prognosis of many cardiovascular and neoplastic diseases. Moyamoya disease (MMD) is associated with inflammation, but the relationship between systemic immune-inflammatory markers between MMD is unclear. The aim of our study was to analyse the association between systemic immune-inflammatory markers and the risk of MMD and its subtypes.Methods:We consecutively recruited 360 patients with MMD and 89 healthy control subjects in a case-control study to calculate and analyse the association of systemic immune-inflammatory markers with the risk of MMD and its subtypes.Results:The risk of MMD increased with higher levels of NLR (OR 1.237, 95% CI [1.008, 1.520], p = .042). When NLR and SII were assessed as quartile-spaced subgroups, the third quartile grouping of NLR and SII had a higher risk of MMD than the first quartile grouping (NLR: OR 3.206, 95% CI [1.271, 8.088], p = .014; SII: OR 3.074,95% CI [1.232,7.672], p = .016). When NLR was combined with SII, the highest subgroup had a higher risk of MMD than the lowest subgroup (OR2.643, 95% CI [1.340, 5.212], p = .005). The risk of subtypes also increased with higher levels of NLR and SII. The association between the levels of NLR and SII with the staging of the Suzuki stage follows an inverted U-shape. The highest levels of NLR and SII were found in patients with MMD at Suzuki stages 3-4.Conclusion:The risk of MMD increases with elevated systemic immune-inflammatory markers. This study analysed the association of systemic immune-inflammatory markers with the risk of developing MMD and its subtypes, and identified novel inflammatory markers for MMD.

Systemic immune-inflammatory markers such as neutrophil­lymphocyte ratio and systemic immune-inflammatory index were higher in moyamoya disease (MMD) patients than in normal people.Systemic immune-inflammatory markers may be an independent risk factor for the onset of MMD.Systemic immune-inflammatory markers were associated with the progression of MMD, and their levels showed an inverted U shape with imaging stages.

Identification of heterogeneous subtypes and a prognostic model for gliomas based on mitochondrial dysfunction and oxidative stress-related genes.

Objective: Mitochondrial dysfunction and oxidative stress are known to involved in tumor occurrence and progression. This study aimed to explore the molecular subtypes of lower-grade gliomas (LGGs) based on oxidative stress-related and mitochondrial-related genes (OMRGs) and construct a prognostic model for predicting prognosis and therapeutic response in LGG patients. Methods: A total of 223 OMRGs were identified by the overlap of oxidative stress-related genes (ORGs) and mitochondrial-related genes (MRGs). Using consensus clustering analysis, we identified molecular subtypes of LGG samples from TCGA database and confirmed the differentially expressed genes (DEGs) between clusters. We constructed a risk score model using LASSO regression and analyzed the immune-related profiles and drug sensitivity of different risk groups. The prognostic role of the risk score was confirmed using Cox regression and Kaplan-Meier curves, and a nomogram model was constructed to predict OS rates. We validated the prognostic role of OMRG-related risk score in three external datasets. Quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC) staining confirmed the expression of selected genes. Furthermore, wound healing and transwell assays were performed to confirm the gene function in glioma. Results: We identified two OMRG-related clusters and cluster 1 was significantly associated with poor outcomes (P<0.001). The mutant frequencies of IDH were significantly lower in cluster 1 (P<0.05). We found that the OMRG-related risk scores were significantly correlated to the levels of immune infiltration and immune checkpoint expression. High-risk samples were more sensitive to most chemotherapeutic agents. We identified the prognostic role of OMRG-related risk score in LGG patients (HR=2.665, 95%CI=1.626-4.369, P<0.001) and observed that patients with high-risk scores were significantly associated with poor prognosis (P<0.001). We validated our findings in three external datasets. The results of qRT-PCR and IHC staining verified the expression levels of the selected genes. The functional experiments showed a significant decrease in the migration of glioma after knockdown of SCNN1B. Conclusion: We identified two molecular subtypes and constructed a prognostic model, which provided a novel insight into the potential biological function and prognostic significance of mitochondrial dysfunction and oxidative stress in LGG. Our study might help in the development of more precise treatments for gliomas.

High ECM2 Expression Predicts Poor Clinical Outcome and Promotes the Proliferation, Migration, and Invasiveness of Glioma.

OBJECTIVE: Glioma is the most prevalent and fatal intracranial malignant tumor. Extracellular matrix protein 2 (ECM2) has rarely been studied in gliomas. Therefore, we explored the role of ECM2 in lower-grade gliomas (LGGs). METHODS: The RNA-seq and clinicopathology data were obtained from the TCGA database. The immunohistochemical (IHC) staining was used to verify the expression of ECM2. Functional enrichment analyses, immune-related analyses, drug sensitivity, and mutation profile analyses were further conducted. Cox regression and Kaplan-Meier curves were utilized for survival analyses, while four external datasets were used to validate the prognostic role of ECM2. Furthermore, qRT-PCR, CCK-8, wound healing, and transwell assays were performed to confirm the function of ECM2 in gliomas. RESULTS: The study found a significant upregulation of ECM2 expression with increasing glioma grades and a significant association between ECM2 expression and tumor immune infiltration. Cox regression verified the prognostic role of ECM2 in LGG patients (HR = 1.656, 95%CI = 1.055-2.600, p = 0.028). High ECM2 expression was significantly associated with poor outcome (p < 0.001). Four external datasets validated its prognostic value. After the knockdown of ECM2, the functional experiments showed a significant decrease in proliferation, migration, and invasion in glioma cell lines. CONCLUSION: The study suggested the potential of ECM2 as a novel immune-associated prognostic biomarker and therapeutic target for glioma patients.

Somatic GJA4 mutation in intracranial extra-axial cavernous hemangiomas.

OBJECTIVE: Extra-axial cavernous hemangiomas (ECHs) are sporadic and rare intracranial occupational lesions that usually occur within the cavernous sinus. The aetiology of ECHs remains unknown. METHODS: Whole-exome sequencing was performed on ECH lesions from 12 patients (discovery cohort) and droplet digital polymerase-chain-reaction (ddPCR) was used to confirm the identified mutation in 46 additional cases (validation cohort). Laser capture microdissection (LCM) was carried out to capture and characterise subgroups of tissue cells. Mechanistic and functional investigations were carried out in human umbilical vein endothelial cells and a newly established mouse model. RESULTS: We detected somatic GJA4 mutation (c.121G>T, p.G41C) in 5/12 patients with ECH in the discovery cohort and confirmed the finding in the validation cohort (16/46). LCM followed by ddPCR revealed that the mutation was enriched in lesional endothelium. In vitro experiments in endothelial cells demonstrated that the GJA4 mutation activated SGK-1 signalling that in turn upregulated key genes involved in cell hyperproliferation and the loss of arterial specification. Compared with wild-type littermates, mice overexpressing the GJA4 mutation developed ECH-like pathological morphological characteristics (dilated venous lumen and elevated vascular density) in the retinal superficial vascular plexus at the postnatal 3 weeks, which were reversed by an SGK1 inhibitor, EMD638683. CONCLUSIONS: We identified a somatic GJA4 mutation that presents in over one-third of ECH lesions and proposed that ECHs are vascular malformations due to GJA4-induced activation of the SGK1 signalling pathway in brain endothelial cells.

Endothelial hyperactivation of mutant MAP3K3 induces cerebral cavernous malformation enhanced by PIK3CA GOF mutation.

Cerebral cavernous malformations (CCMs) refer to a common vascular abnormality that affects up to 0.5% of the population. A somatic gain-of-function mutation in MAP3K3 (p.I441M) was recently reported in sporadic CCMs, frequently accompanied by somatic activating PIK3CA mutations in diseased endothelium. However, the molecular mechanisms of these driver genes remain elusive. In this study, we performed whole-exome sequencing and droplet digital polymerase chain reaction to analyze CCM lesions and the matched blood from sporadic patients. 44 of 94 cases harbored mutations in KRIT1/CCM2 or MAP3K3, of which 75% were accompanied by PIK3CA mutations (P = 0.006). AAV-BR1-mediated brain endothelial-specific MAP3K3I441M overexpression induced CCM-like lesions throughout the brain and spinal cord in adolescent mice. Interestingly, over half of lesions disappeared at adulthood. Single-cell RNA sequencing found significant enrichment of the apoptosis pathway in a subset of brain endothelial cells in MAP3K3I441M mice compared to controls. We then demonstrated that MAP3K3I441M overexpression activated p38 signaling that is associated with the apoptosis of endothelial cells in vitro and in vivo. In contrast, the mice simultaneously overexpressing PIK3CA and MAP3K3 mutations had an increased number of CCM-like lesions and maintained these lesions for a longer time compared to those with only MAP3K3I441M. Further in vitro and in vivo experiments showed that activating PI3K signaling increased proliferation and alleviated apoptosis of endothelial cells. By using AAV-BR1, we found that MAP3K3I441M mutation can provoke CCM-like lesions in mice and the activation of PI3K signaling significantly enhances and maintains these lesions, providing a preclinical model for the further mechanistic and therapeutic study of CCMs.

Exosomal miR-3131 derived from endothelial cells with KRAS mutation promotes EndMT by targeting PICK1 in brain arteriovenous malformations.

AIMS: To explore the underlying mechanism by which low-frequency KRAS mutations result in extensive EndMT occurrence. METHODS: Exosomes derived from primarily cultured brain arteriovenous malformation (bAVMs) and human umbilical vein endothelial cells (HUVECs) transfected with KRASG12D , KRASWT , or KRASNC lentiviruses were isolated, and their effects on HUVECs were identified by western blotting and immunofluorescence staining. The expression levels of exosomal microRNAs (miRNAs) were evaluated by miRNA microarray, followed by functional experiments on miR-3131 and detection of its downstream target, and miR-3131 inhibitor in reversing the EndMT process induced by KRASG12D -transfected HUVECs and bAVM endothelial cells (ECs) were explored. RESULTS: Exosomes derived from KRASG12D bAVM ECs and KRASG12D -transfected HUVECs promoted EndMT in HUVECs. MiR-3131 levels were highest in the exosomes of KRASG12D -transfected HUVECs, and HUVECs transfected with the miR-3131 mimic acquired mesenchymal phenotypes. RNA-seq and dual-luciferase reporter assays revealed that PICK1 is the direct downstream target of miR-3131. Exosomal miR-3131 was highly expressed in KRASG12D bAVMexos compared with non-KRAS-mutant bAVMexos or HUVECexos . Finally, a miR-3131 inhibitor reversed EndMT in HUVECs treated with exosomes or the supernatant of KRASG12D -transfected HUVECs and KRASG12D bAVM ECs. CONCLUSION: Exosomal miR-3131 promotes EndMT in KRAS-mutant bAVMs, and miR-3131 might be a potential biomarker and therapeutic target in KRASG12D -mutant bAVMs.

KRAS mutation-induced EndMT of brain arteriovenous malformation is mediated through the TGF-ß/BMP-SMAD4 pathway.

OBJECTIVE: Somatic KRAS mutations have been identified in the majority of brain arteriovenous malformations (bAVMs), and subsequent in vivo experiments have confirmed that KRAS mutation in endothelial cells (ECs) causes AVMs in mouse and zebrafish models. Our previous study demonstrated that the KRASG12D mutant independently induced the endothelial-mesenchymal transition (EndMT), which was reversed by treatment with the lipid-lowering drug lovastatin. However, the underlying mechanisms of action were unclear. METHODS: We used human umbilical vein ECs (HUVECs) overexpressing the KRASG12D mutant for Western blotting, quantitative real-time PCR, and immunofluorescence and wound healing assays to evaluate the EndMT and determine the activation of downstream pathways. Knockdown of SMAD4 by RNA interference was performed to explore the role of SMAD4 in regulating the EndMT. BAVM ECs expressing the KRASG12D mutant were obtained to verify the SMAD4 function. Finally, we performed a coimmunoprecipitation assay to probe the mechanism by which lovastatin affects SMAD4. RESULTS: HUVECs infected with KRASG12D adenovirus underwent the EndMT. Transforming growth factor beta (TGF-ß) and bone morphogenetic protein (BMP) signalling pathways were activated in the KRASG12D-mutant HUVECs and ECs in bAVM tissue. Knocking down SMAD4 expression in both KRASG12D-mutant HUVECs and ECs in bAVM tissues inhibited the EndMT. Lovastatin attenuated the EndMT by downregulating p-SMAD2/3, p-SMAD1/5 and acetylated SMAD4 expression in KRASG12D-mutant HUVECs. CONCLUSIONS: Our findings suggest that the KRASG12D mutant induces the EndMT by activating the ERK-TGF-ß/BMP-SMAD4 signalling pathway and that lovastatin inhibits the EndMT by suppressing TGF-ß/BMP pathway activation and SMAD4 acetylation.

Preoperative nomogram predicting ventriculoperitoneal shunt longevity after initial shunt failure.

Background and objectives: Initial shunt failure following ventriculoperitoneal (VP) shunt surgery has a significant impact on the working time of the shunt. However, there are few studies regarding factors affecting VP shunt longevity. Hence, in this study, we aimed to build a nomogram to predict the longevity of the replacement VP shunt in patients with initial shunt failure. Methods: From 2011 to 2021, 142 patients with initial VP failure who underwent VP shunt revision were enrolled and relevant clinical and demographic factors were analyzed. Univariate and multivariate Cox proportional hazard regression models were used to choose predictors, and a nomogram was constructed using nine independent prognostic variables: sex, age, hydrocephalus type, intensive care unit admission, tracheostomy, decompressive craniectomy, craniotomy, lumbar cisterna drainage, and ventricular drainage. The prediction models' discrimination, accuracy, calibration, and clinical value were evaluated using Harrell's C-index, a calibration plot, and decision curve analysis. Results: At 1 month, 3 months, and 5 years, the nomogram's C-index was 0.680, 0.708, and 0.694, respectively. The nomogram's calibration plot provided a good fit for the overall prediction over the course of 1 year. Decision curve analysis predicted that 1-3 months after surgery will yield good net benefits between 30 and 50% probability thresholds. Conclusion: A preoperative nomogram may be an effective tool for assessing VP shunt longevity after initial VP shunt placement.

Short-term spinal cord stimulation in treating disorders of consciousness monitored by resting-state fMRI and qEEG: The first case report.

Disorders of consciousness (DOC) are one of the most frequent complications in patients after severe brain injury, mainly caused by trauma, stroke, and anoxia. With the development of neuromodulation techniques, novel therapies including deep brain stimulation (DBS) and spinal cord stimulation (SCS) have been employed to treat DOC. Here, we report the case of a DOC patient receiving short-term SCS (st-SCS) treatment and showing improvement monitored by resting-state fMRI (rs-fMRI) and quantitative EEG (qEEG). A 35-year-old male with severe traumatic brain injury remained comatose for 3 months. The patient was evaluated using JFK coma recovery scale-revised (CRS-R) and showed no improvement within 1 month. He received st-SCS surgery 93 days after the injury and the stimulation was applied the day after surgery. He regained communication according to instructions on day 21 after surgery and improved from a vegetative state/unwakefulness syndrome to an emergence from a minimally conscious state. To our knowledge, this report is the first published case of st-SCS in a patient with DOC. These results shed light that st-SCS may be effective in treating certain patients with DOC, which may reduce patients' suffering during treatment and lessen financial burden.

Single-cell atlas reveals different immune environments between stable and vulnerable atherosclerotic plaques.

Introduction: Regardless of the degree of stenosis, vulnerable plaque is an important cause of ischemic stroke and thrombotic complications. The changes of the immune microenvironment within plaques seem to be an important factor affecting the characteristics of the plaque. However, the differences of immune microenvironment between stable and vulnerable plaques were remained unknown. Methods: In this study, RNA-sequencing was performed on superficial temporal arteries from 5 traumatic patients and plaques from 3 atherosclerotic patients to preliminary identify the key immune response processes in plaques. Mass cytometry (CyTOF) technology was used to explore differences in immune composition between 9 vulnerable plaques and 12 stable plaques. Finally, immunofluorescence technique was used to validate our findings in the previous analysis. Results: Our results showed that more CD86+CD68+ M1 pro-inflammatory macrophages were found in vulnerable plaques, while CD4+T memory cells were mainly found in stable plaques. In addition, a CD11c+ subset of CD4+T cells with higher IFN-r secretion was found within the vulnerable plaque. In two subsets of B cells, CD19+CD20-B cells in vulnerable plaques secreted more TNF-a and IL-6, while CD19-CD20+B cells expressed more PD-1 molecules. Conclusion: In conclusion, our study suggested that M1-like macrophages are the major cell subset affecting plaque stability, while functional B cells may also contribute to plaque stability.

Integrative analysis of TP73 profile prognostic significance in WHO grade II/III glioma.

Due to the extremely intrinsic heterogeneity among glioma patients, the outcomes of these patients are tremendously different. Therefore, the exploitation of novel biomarker classification of glioma is vitally important for deep insight into the essence and predicting the prognosis of glioma. We aim to analyze the correlation between TP73 mRNA expression, DNA methylated alteration and the prognosis of WHO grade II/III glioma, utilizing bioinformatics to evaluate its significance as a risk-factor in predicting the prognosis of these glioma patients. The analysis found that TP73 expression was positively correlated with the grade of glioma, and showed a strong correlation with glioma molecular classification, which revealed significantly higher TP73 expression in IDH-wildtype than in IDH-mutant subtype of WHO grade II/III glioma. Cox regression analysis indicated that high expression of TP73 shared an independent high-risk factor impacting the prognosis of WHO grade II/III glioma. We discovered 8 DNA promoter methylation sites with prognostic significance, which were negatively associated with TP73 expression, and positively associated with beneficial overall survival (OS) and progression-free survival (PFS). Integrating with four independent glioma datasets, subsequent Meta-analysis verified that low expression of TP73 was closely related to favorable OS, especially in IDH-mutant subtype. Moreover, we found that 1p/19qCodel /TP73low subgroup shared the most favorable OS, 1p/19qNon-codel /TP73high subgroup suffered the worst OS. Meanwhile, the enrichment analysis of TP73-related differential mRNAs demonstrated that TP73 aberration in WHO grade II/III glioma might be closely related to cell cycle and P53 signaling pathways. Finally, TP73 expression of 53 glioma specimens was measured by qRT-PCR, which was consistent with the previous analytical result, and TP73 high-expression subgroup suffered worse PFS than TP73 low-expression subgroup. In summary, our funding supports that TP73 gene can perform as a reliable biomarker to evaluate the survival outcome of patients diagnosed with WHO grade II/III glioma.

Clinical characteristics and risk factors of perioperative outcomes in elderly patients with intracranial tumors.

We aimed to study the clinical and radiological characteristics of intracranial tumors and explore the possible predictive value of these characteristics in relation to perioperative outcomes in elderly patients. We retrospectively identified 1535 elderly patients (aged 65 years and older) with intracranial tumors who underwent surgical resection between 2014 and 2018 in Beijing Tiantan Hospital. Factors associated with an increased risk of unfavorable perioperative performance and complications were investigated. Meningiomas were the most common tumors in the cohort (43.26%). The overall risk of perioperative death was 0.59%, and 42.80% of patients were discharged with unfavorable performance (Karnofsky Performance Scale [KPS] score ≤ 70). Of all patients, 39.22% had one or more complications after surgical resection. Aggressive surgery significantly lowered the rate of unfavorable perioperative outcomes (P = 0.000) with no increase in postoperative complications (P = 0.153), but it failed to be an independent predictor for perioperative outcomes in the multivariate analysis. Low performance status at admission (KPS ≤ 70) was independently associated with both unfavorable perioperative performance (P = 0.000) and complications (P = 0.000). In addition to the histopathological patterns of tumors, low performance status at admission is an independent predictor for both unfavorable perioperative performance and the occurrence of complications in elderly patients with intracranial tumors who have undergone surgical resections. However, age is not associated with perioperative outcomes in elderly patients.