Multivariate analysis of seizure outcomes after resective surgery for focal epilepsy: a single-center study on 833 patients.

The predictors of seizure outcomes after resective surgery for focal epilepsy, for an update on the features of good and poor outcomes, are investigated. A retrospective study of patients with focal epilepsy undergoing resective surgery from March 2011 to April 2019 was performed. There were 3 groups according to the seizure outcomes: seizure freedom, seizure improvement, and no improvement. Predictors of seizure outcomes were identified by multivariate logistic regression analysis. Of all 833 patients, 561 (67.3%) patients remained seizure-free at the last follow-up, 203 (24.4%) patients had seizure improvement, and 69 (8.3%) had no improvement. The mean follow-up duration was 5.2 years (range: 2.7 to 9.6). Predictors of better outcomes included epilepsy duration < 5 years, localized discharge, no. of antiepileptic drugs at surgery < 3, and temporal lobe resection. However, predictors of worse outcomes included intracranial hemorrhage in infancy, interictal abnormal discharge, intracranial electrode monitoring, and acute postoperative seizure. Our study suggests that resective surgery for focal epilepsy has satisfactory outcomes. Short epilepsy duration, localized discharge, and temporal lobe resection are positive predictors of seizure freedom. Patients with these predictors are intensively recommended for surgery.

Stereotactic Surgery for Treating Intractable Tourette Syndrome: A Single-Center Pilot Study.

To evaluate the potential effect of radiofrequency ablation and deep brain stimulation in patients with treatment-refractory Tourette syndrome (TS), this study enrolled thirteen patients with TS who were admitted to our hospital between August 2002 and September 2018. Four patients received a single- or multi-target radiofrequency ablation after local, potentiated, or general anesthesia; eight patients underwent deep brain stimulation (DBS) surgery; and one patient underwent both ablation and DBS surgery. The severity of tics and obsessive compulsive disorder symptoms and the quality of life were evaluated using the Yale Global Tic Severity Scale (YGTSS), Yale−Brown Obsessive Compulsive Scale (YBOCS), and Gilles de la Tourette Syndrome Quality of Life scale (GTS-QOL), respectively, before surgery, one month after surgery, and at the final follow-up after surgery, which was conducted in December 2018. A paired-sample t test and a multiple linear regression analysis were performed to analyze the data. All patients underwent the operation successfully without any severe complications. Overall, the YGTSS total scores at one month post-surgery (44.1 ± 22.3) and at the final visit (35.1 ± 23.7) were significantly decreased compared with those at baseline (75.1 ± 6.2; both p < 0.05). Additionally, the YBOCS scores at one month post-surgery (16.5 ± 10.1) and at the final visit (12.0 ± 9.5) were significantly decreased compared with those at baseline (22.5 ± 13.1; both p < 0.05). Furthermore, the GTS-QOL scores at one month post-surgery (44.0 ± 12.8) and at the final visit (31.0 ± 17.8) were significantly decreased compared with those at baseline (58.4 ± 14.2; both p < 0.05). Results from a multiple linear regression analysis revealed that the improvement in the YGTSS total score was independently associated with the improvement in the GTS-QOL score at one month post-surgery (standardized ß = 0.716, p = 0.023) and at the final visit (standardized ß = 1.064, p = 0.000). Conversely, changes in YBOCS scores did not correlate with changes in GTS-QOL scores (p > 0.05). Our results demonstrate that tics, psychiatric symptoms, and the quality of life in patients with intractable TS may be relieved by stereotactic ablation surgery and deep brain stimulation. Furthermore, it appears that the improvement in tics contributes more to the post-operative quality of life of patients than does the improvement in obsessive compulsive symptoms.

Optimized Deep Brain Stimulation Surgery to Avoid Vascular Damage: A Single-Center Retrospective Analysis of Path Planning for Various Deep Targets by MRI Image Fusion.

Co-registration of stereotactic and preoperative magnetic resonance imaging (MRI) images can serve as an alternative for trajectory planning. However, the role of this strategy has not yet been proven by any control studies, and the trajectories of commonly used targets have not been systematically studied. The purpose of this study was to analyze the trajectories for various targets, and to assess the role of trajectories realized on fused images in preventing intracranial hemorrhage (ICH). Data from 1019 patients who underwent electrode placement for deep brain stimulation were acquired. Electrode trajectories were not planned for 396 patients, whereas trajectories were planned for 623 patients. Preoperative various MRI sequences and frame-placed MRI images were fused for trajectory planning. The patients' clinical characteristics, the stereotactic systems, intracranial hemorrhage cases, and trajectory angles were recorded and analyzed. No statistically significant differences in the proportions of male patients, patients receiving local anesthesia, and diseases or target distributions (p > 0.05) were found between the trajectory planning group and the non-trajectory planning group, but statistically significant differences were observed in the numbers of both patients and leads associated with symptomatic ICH (p < 0.05). Regarding the ring and arc angle values, statistically significant differences were found among various target groups (p < 0.05). The anatomic structures through which leads passed were found to be diverse. Trajectory planning based on MRI fusion is a safe technique for lead placement. The electrode for each given target has its own relatively constant trajectory.

Circ_RPPH1 regulates glioma cell malignancy by binding to miR-627-5p/miR-663a to induce SDC1 expression.

BACKGROUND: Recent studies revealed the key role of circular RNA (circRNA) in glioma progression. However, the effect of circ_0000520, also named as circRNA ribonuclease P RNA component H1 (circ_RPPH1), in glioma development was unknown. The study aimed to reveal the role of circ_RPPH1 in glioma cell malignancy. METHODS: Human astrocytes (NHA) and glioma cell lines (A172 and U251) were employed in this study. Quantitative real-time polymerase chain reaction and western blot were used to check the expression of circ_RPPH1, microRNA-627-5p (miR-627-5p), miR-663a and syndecan 1 (SDC1). Immunohistochemistry assay was conducted to assess the protein expression of nuclear proliferation marker ki67 and matrix metalloprotein 9 (MMP9). Cell viability was assessed by 3-(4,5-Dimethylthazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell proliferation and apoptosis were investigated by flow cytometry analysis, 5-Ethynyl-29-deoxyuridine, or cell colony formation assay. Cell migration and invasion were evaluated by transwell assays. The interaction between miRNAs (miR-627-5p and miR-663a) and circ_RPPH1 or SDC1 was identified by a dual-luciferase reporter assay. A mouse model assay was performed to reveal the impact of circ_RPPH1 knockdown on glioma cell malignancy in vivo by analyzing neoplasm volume and weight. RESULTS: Circ_RPPH1 and SDC1 expression were significantly increased, whereas miR-627-5p and miR-663a expression were decreased in glioma tissues and cells in comparison with healthy brain tissues or human astrocytes. Circ_RPPH1 depletion led to the decreased cell proliferation, migration and invasion, and the increased cell apoptosis. Additionally, circ_RPPH1 bound to miR-627-5p/miR-663a and mediated glioma cell processes by interacting with them. SDC1 overexpression attenuated miR-627-5p/miR-663a-mediated actions. Moreover, circ_RPPH1 regulated SDC1 expression through interaction with miR-627-5p and/or miR-663a. Furthermore, circ_RPPH1 knockdown inhibited glioma cell malignancy in vivo, accompanied by the decreases of ki67 and MMP9 expression. CONCLUSION: Circ_RPPH1 knockdown inhibited glioma tumorigenesis by downregulating SDC1 by binding to miR-627-5p/miR-663a, showing that circ_RPPH1 might be an effective therapeutic target for glioma.

Downregulation of hsa_circ_0001836 Induces Pyroptosis Cell Death in Glioma Cells via Epigenetically Upregulating NLRP1.

BACKGROUND: It has been shown that circular RNAs (circRNAs) play a vital role in the progression of glioma. Recently, hsa_circ_0001836 was found to be upregulated in glioma tissues, but the role of hsa_circ_0001836 in glioma remains unclear. METHODS: EdU staining and flow cytometry assays were used to measure the viability and death of glioma cells. In addition, scanning electron microscopy (SEM) was used to observe the morphology of cells undergoing cell death. RESULTS: Hsa_circ_0001836 expression was upregulated in U251MG and SHG-44 cells. In addition, hsa_circ_0001836 knockdown significantly reduced the viability and proliferation of U251MG and SHG-44 cells. Moreover, hsa_circ_0001836 knockdown markedly induced the pyroptosis of U251MG and SHG-44 cells, evidenced by the increased expressions of NLRP1, cleaved caspase 1 and GSDMD-N. Meanwhile, methylation specific PCR (MSP) results indicated that hsa_circ_0001836 knockdown epigenetically increased NLRP1 expression via mediating DNA demethylation of NLRP1 promoter region. Furthermore, downregulation of hsa_circ_0001836 notably induced pyroptosis and inhibited tumor growth in a mouse xenograft model of glioma. CONCLUSION: Collectively, hsa_circ_0001836 knockdown could induce pyroptosis cell death in glioma cells in vitro and in vivo via epigenetically upregulating NLRP1 expression. These findings suggested that hsa_circ_0001836 may serve as a potential therapeutic target for the treatment of glioma.

Identification of a three-long non-coding RNA signature for predicting survival of temozolomide-treated isocitrate dehydrogenase mutant low-grade gliomas.

Temozolomide (TMZ) is the major chemotherapy agent in glioma, and isocitrate dehydrogenase (IDH) is a well-known prognostic marker in glioma. O6-methylguanine-DNA methyltransferase promoter methylation (MGMTmethyl) is a predictive biomarker in overall gliomas rather than in IDH mutant gliomas. To discover effective biomarkers that could predict TMZ efficacy in IDH mutant low-grade gliomas (LGGs), we retrieved data of IDH mutant LGGs from TMZ arm of the EORTC22033-26033 trial as the training-set (n = 83), analyzed correlations between long non-coding RNAs (lncRNAs) and progression-free survival (PFS) using Lasso-Cox regression, and created a risk score (RS) to stratify patients. We identified a three-lncRNA signature in TMZ-treated IDH mutant LGGs. All of the three lncRNAs, as well as the RS derived, were significantly correlated with PFS. Patients were classified into high-risk and low-risk groups according to RS. PFS of the high-risk group was significantly worse than that of the low-risk group (P < 0.001). AUCs of the three-, four-, and five-year survival probability predicted by RS were 0.73, 0.79, and 0.76, respectively. The predictive role of the three-lncRNA signature was further validated in an independent testing-set, the TCGA-LGGs, which resulted in a significantly worse PFS (P < 0.001) in the high-risk group. Three-, four-, and five-year survival probabilities predicted by RS were 0.65, 0.69, and 0.84, respectively. Functions of these three lncRNAs involve cell proliferation and differentiation, predicted by their targeting cancer genes. Conclusively, we created a scoring model based on the expression of three lncRNAs, which can effectively predict the survival of IDH mutant LGGs treated with TMZ.

Integrated Genetics and Micronutrient Data to Inform the Causal Association Between Serum Calcium Levels and Ischemic Stroke.

There has been an increased interest for observational studies or randomized controlled trials exploring the impact of calcium intake on cardiovascular diseases (CVD) including coronary artery disease (CAD) and ischemic stroke (IS). However, a direct relationship between total calcium intake and CVD has not been well established and remains controversial. Mendelian randomization (MR) studies have been performed to evaluate the causal association between serum calcium levels and CAD risk and found that increased serum calcium levels could increase the risk of CAD. However, MR analysis found no significant association between genetically higher serum calcium levels and IS as well as its subtypes. Hence, three MR studies reported inconsistent effects of serum calcium levels on CAD and IS. Here, we performed an updated MR study to investigate the association of serum calcium levels with the risk of IS using large-scale genome-wide association study (GWAS) datasets. We selected 14 independent genetic variants as the potential instrumental variables from a large-scale serum calcium GWAS dataset and extracted summary statistics corresponding to the 14 serum calcium genetic variants from the MEGASTROKE Consortium IS GWAS dataset. Interestingly, we found a significant association between serum calcium levels and IS risk using the robust inverse-variance weighted (IVW) and penalized robust IVW methods, with ß = 0.243 and P = 0.002. Importantly, the MR results from the robust MR-Egger and penalized robust MR-Egger methods further supported the causal association between serum calcium levels and IS risk, with ß = 0.256 and P = 0.005. Meanwhile, the estimates from other MR methods are also consistent with the above findings.

Corrigendum: Integrated Genetics and Micronutrient Data to Inform the Causal Association Between Serum Calcium Levels and Ischemic Stroke.

[This corrects the article DOI: 10.3389/fcell.2020.590903.].

Altered Activity of SK Channel Underpins Morphine Withdrawal Relevant Psychiatric Deficiency in Infralimbic to Accumbens Shell Pathway.

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.

Deep Brain Stimulation of Nucleus Accumbens for Methamphetamine Addiction: Two Case Reports.

BACKGROUND: Methamphetamine (MA) addiction is one of the most prevalent socioeconomic and health problems worldwide. In recent years, deep brain stimulation (DBS) has increasingly been used for the treatment of addiction. CASE DESCRIPTION: This study reports on 2 MA-dependent patients who received DBS of the nucleus accumbens (NAc). During the approximately 2-year follow-up period, one patient (A) remained abstinent and presented with positive emotional experiences, whereas the other (B) had no significant psychobehavioral changes during stimulation at low-to-moderate voltages and subsequently relapsed. Through coregistration of preoperative magnetic resonance imaging with postoperative computed tomography/magnetic resonance imaging, the DBS electrode of patient A was confirmed to be accurately implanted in the NAc, whereas one side of the electrode of patient B deviated from the target. CONCLUSIONS: These case reports demonstrate that NAc-DBS maybe a possible treatment option for MA addiction.

Long-term results after deep brain stimulation of nucleus accumbens and the anterior limb of the internal capsule for preventing heroin relapse: An open-label pilot study.

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 < 0.001). Simultaneous DBS of the NAc and ALIC also improved the quality of life, alleviated psychiatric symptoms, and increased glucose metabolism in addiction-related brain regions. Moreover, stimulation-related adverse events were few and reversible. CONCLUSIONS: Simultaneous DBS of the NAc and ALIC appears to be safe, with few side effects, and may prevent long-term heroin relapse after detoxification in certain patients. (This trial was registered at ClinicalTrials.gov, NCT01274988).

Role of the Cortico-Subthalamic Hyperdirect Pathway in Deep Brain Stimulation for the Treatment of Parkinson Disease: A Diffusion Tensor Imaging Study.

OBJECTIVE: 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). METHODS: 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. RESULTS: 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; P < 0.05), and the shortest distance had a negative correlation with the improvement of motor symptoms (r = -0.48; P < 0.05). CONCLUSIONS: 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.

Clinical analysis and treatment of symptomatic intracranial hemorrhage after deep brain stimulation surgery.

BACKGROUND: Symptomatic intracranial hemorrhage (ICH) may lead to permanent neurological disability of patients and has impeded the extensive clinical application of deep brain stimulation (DBS). The present study was conducted to discuss the incidence, prevention, and treatment of symptomatic ICH after DBS surgery. METHODS: From January 2009 to December 2014, 396 patients underwent DBS with a total of 691 implanted leads. In all, 10 patients had symptomatic ICH. We analyzed these cases' clinical characteristics, including comorbid diagnoses and coagulation profile. We described the onset of ICH, imaging features, clinical manifestations, treatment, neurological impairment, and outcome of DBS. RESULTS: Of the 10 patients with symptomatic ICH, 2 had hypertension. Three cases of ICH occurred within 12 h of the procedure; four cases within 24 h. Five experienced grand mal seizures concurrently with hemorrhage. Unilateral frontal lobe hemorrhage occurred in all cases. In seven cases, hematomas occurred around the electrodes. Some hematomas were not well-circumscribed and had perihematomal edema. Conservative therapy was administered to 8 patients, and 2 patients underwent craniotomy and hematoma evacuation. All electrodes were successfully preserved. Neurological dysfunction in all patients gradually improved. Nine patients ultimately experienced effective symptom relief of Parkinson's disease with DBS. CONCLUSIONS: Symptomatic ICH should be identified as soon as possible after implantation surgery and treated effectively to limit neurological deficit and preserve DBS leads.