Effective DBS treatment improves neural information transmission of patients with disorders of consciousness: an fNIRS study.

Objective.Deep brain stimulation (DBS) is a potential treatment that promotes the recovery of patients with disorders of consciousness (DOC). This study quantified the changes in consciousness and the neuromodulation effect of DBS on patients with DOC.Approach.Eleven patients were recruited for this study which consists of three conditions: 'Pre' (two days before DBS surgery), 'Post-On' (one month after surgery with stimulation), and 'Post-Off' (one month after surgery without stimulation). Functional near-infrared spectroscopy (fNIRS) was recorded from the frontal lobe, parietal lobe, and occipital lobe of patients during the experiment of auditory stimuli paradigm, in parallel with the coma recovery scale-revised (CRS-R) assessment. The brain hemodynamic states were defined and state transition acceleration was taken to quantify the information transmission strength of the brain network. Linear regression analysis was conducted between the changes in regional and global indicators and the changes in the CRS-R index.Main results.Significant correlation was observed between the changes in the global transition acceleration indicator and the changes in the CRS-R index (slope = 55.910,p< 0.001,R2= 0.732). For the regional indicators, similar correlations were found between the changes in the frontal lobe and parietal lobe indicators and the changes in the CRS-R index (slope = 46.612,p< 0.01,R2= 0.694; slope = 47.491,p< 0.01,R2= 0.676).Significance.Our study suggests that fNIRS-based brain hemodynamics transition analysis can signify the neuromodulation effect of DBS treatment on patients with DOC, and the transition acceleration indicator is a promising brain functional marker for DOC.

fNIRS-based functional connectivity signifies recovery in patients with disorders of consciousness after DBS treatment.

OBJECTIVE: While deep brain stimulation (DBS) has proved effective for certain patients with disorders of consciousness (DOC), the working neural mechanism is not clear, the response varies for patients, and the assessment is inadequate. This paper aims to quantify the DBS-induced changes of consciousness in DOC patients at the neural functional level. METHODS: Ten DOC patients were included for DBS surgery. The DBS target was the right centromedian-parafascicular (CM-pf) nuclei for four patients and the bilateral CM-pf nuclei for six patients. Functional near-infrared spectroscopy (fNIRS) was taken to measure the neural activation of patients, in parallel with Coma Recovery Scale-Revised (CRS-R), before the DBS surgery and one month after. The fNIRS signals were recorded from the frontal, parietal, and occipital lobes. Functional connectivity analysis quantified the communication between brain regions, area communication strength, and global communication efficiency. Linear regression analysis was conducted between the changes of indices based on functional connectivity analysis and the changes of the CRS-R index. RESULTS: Patients with trauma (n = 4) exhibited a greater increase of CRS-R scores after DBS treatment compared with patients with hemorrhage (n = 4) and brainstem infarction (n = 2). Global communication efficiency changed consistently with the CRS-R index (slope = 57.384, p < 0.05, R2=0.483). No significant relationship was found between the changes of area communication strength of six brain lobes and the changes of the CRS-R index. CONCLUSIONS: The cause of DOC is essential for the outcome of DBS treatment, and brain communication efficiency is a promising functional marker for DOC recovery. SIGNIFICANCE: fNIRS-based functional connectivity analysis on brain network signifies changes of consciousness in DOC patients after DBS treatment.

A non-contact system for intraoperative quantitative assessment of bradykinesia in deep brain stimulation surgery.

BACKGROUND AND OBJECTIVE: Deep brain stimulation (DBS) is an effective treatment for a number of neurological diseases, especially for the advanced stage of Parkinson's disease (PD). Objective assessment of patients' motor symptoms is crucial for accurate electrode targeting and treatment. Existing approaches suffer from subjective variability or interference with voluntary motion. This work is aimed to establish an objective assessment system to quantify bradykinesia in DBS surgery. METHODS: Based on the analysis of the requirements for intraoperative assessment, we developed a system with non-contact measurement, online movement feature extraction, and interactive data analysis and visualization. An optical sensor, Leap Motion Controller (LMC), was taken to detect hand movement in three clinical tasks. A graphic user interface was designed to process, compare and visualize the collected data and assessment results online. Quantified movement features include amplitude, frequency, velocity, their decrement and variability, etc. Technical validation of the system was performed with a motion capture system (Mocap), with respect to data-level and feature-level accuracy and reliability. Clinical validation was conducted with 20 PD patients for intraoperative assessments in DBS surgery. Treatment responses with respect to the bradykinesia movement features were analyzed. Single case analysis and group statistical analysis were performed to examine the differences between preoperative and intraoperative performance, and the correlation between the clinical ratings and the quantified assessment was analyzed. RESULTS: For the movements measured by LMC and Mocap, the average Pearson's correlation coefficient was 0.986, and the mean amplitude difference was 2.11 mm. No significant difference was found for all movement features quantified by LMC and Mocap. For the clinical tests, key movement features showed significant differences between the preoperative baseline and intraoperative performance when the brain stimulation was ON. The assessment results were significantly correlated with the MDS-UPDRS clinical ratings. CONCLUSIONS: The proposed non-contact system has established itself as an objective intraoperative assessment, analysis, and visualization tool for DBS treatment of Parkinson's disease.

Self-assembly of pericentriolar material in interphase cells lacking centrioles.

The major microtubule-organizing center (MTOC) in animal cells, the centrosome, comprises a pair of centrioles surrounded by pericentriolar material (PCM), which nucleates and anchors microtubules. Centrosome assembly depends on PCM binding to centrioles, PCM self-association and dynein-mediated PCM transport, but the self-assembly properties of PCM components in interphase cells are poorly understood. Here, we used experiments and modeling to study centriole-independent features of interphase PCM assembly. We showed that when centrioles are lost due to PLK4 depletion or inhibition, dynein-based transport and self-clustering of PCM proteins are sufficient to form a single compact MTOC, which generates a dense radial microtubule array. Interphase self-assembly of PCM components depends on γ-tubulin, pericentrin, CDK5RAP2 and ninein, but not NEDD1, CEP152, or CEP192. Formation of a compact acentriolar MTOC is inhibited by AKAP450-dependent PCM recruitment to the Golgi or by randomly organized CAMSAP2-stabilized microtubules, which keep PCM mobile and prevent its coalescence. Linking of CAMSAP2 to a minus-end-directed motor leads to the formation of an MTOC, but MTOC compaction requires cooperation with pericentrin-containing self-clustering PCM. Our data reveal that interphase PCM contains a set of components that can self-assemble into a compact structure and organize microtubules, but PCM self-organization is sensitive to motor- and microtubule-based rearrangement.

Plantar pressure-based temporal analysis of gait disturbance in idiopathic normal pressure hydrocephalus: Indications from a pilot longitudinal study.

BACKGROUND AND OBJECTIVE: Idiopathic normal pressure hydrocephalus (iNPH) is a common yet potentially reversible neurodegenerative disease, and gait disturbance is a major symptom. Lots of methodological and clinical work has been conducted on gait disturbance analysis for differential diagnosis, presurgical test, and postsurgery assessment of iNPH. Nevertheless, the verification analysis was mostly lacking for surgery response, and the temporal characteristics of ground reaction force has been rarely investigated. METHODS: In this work, we propose that plantar pressure features fundamentally signifies iNPH gait disturbance and improvement after cerebrospinal fluid (CSF) drainage by lumbar puncture tap test as well as surgical shunt implantation. The plantar pressure signals of six iNPH patients and eight healthy controls were collected, and an online database of sixteen healthy controls were used. For patients, data were collected in five periods, which are the baseline before the tap test, 8, 24, and 72 hours after the tap test, and one month after the shunt implantation surgery, respectively. Fast dynamic time warping (DTW) with an improved DTW barycenter averaging (DBA) method was proposed for temporal analysis with the measured and online plantar pressure data. An plantar-pressure variation index (PPVI) was formulated to characterize the temporal dynamic stability of walking. RESULTS: The PPVI based on temporal analysis of plantar pressure well discriminated the impaired gait (baseline, 24 and 72 hours after tap test) with the improved gait (8 hours after tap test and follow up after surgery) of the patients. Further, the PPVI was close for the improved gait of the patients and the healthy gait measured in our study as well as in the online database. CONCLUSIONS: Plantar pressure-based temporal features are promisingly effective for clinical examination and treatment of iNPH.

A Prognostic Nomogram for Predicting Overall Survival in Pediatric Wilms Tumor Based on an Autophagy-related Gene Signature.

BACKGROUND: Wilms Tumor (WT) is the most common primary renal malignancy in children. Autophagy plays dual roles in the promotion and suppression of various cancers. OBJECTIVE: The goal of our study was to develop a novel autophagy-related gene (ARG) prognostic nomogram for WT. METHODS: The Cancer Genome Atlas (TCGA) database was used. We screened the expression profiles of ARGs in 136 WT patients. The differentially expressed prognostic ARGs were evaluated by multivariate Cox regression analysis and survival analysis. A novel prognostic nomogram based on the ARGs and clinical characteristics was established using multivariate Cox regression analysis. RESULTS: First, 69 differentially expressed ARGs were identified in WT patients. Then, multivariate Cox regression analysis was used to determine 4 key prognostic ARGs (CC3CL1, ERBB2, HIF-α and CXCR4) in WT. According to their ARG expression levels, the patients were clustered into high- and low-risk groups. Next, survival analysis indicated that high-risk patients had significantly poorer overall survival than low-risk patients. The results of functional enrichment analysis suggested that autophagy may play a tumor-suppressive role in the initiation of WT. Finally, a prognostic nomogram with a Harrell's concordance index (C-index) of 0.841 was used to predict the survival probability of WT patients by integrating clinical characteristics and the 4-ARG signature. The calibration curve indicated its excellent predictive performance. CONCLUSION: In summary, the ARG signature could be a promising biomarker for monitoring the outcomes of WT. We established a novel nomogram based on the ARG signature, which accurately predicts the overall survival of WT patients.

Intraoperative Quantitative Measurements for Bradykinesia Evaluation during Deep Brain Stimulation Surgery Using Leap Motion Controller: A Pilot Study.

Deep brain stimulation (DBS) has shown a remarkably high effectiveness for Parkinson's disease (PD). In many PD patients during DBS surgery, the therapeutic effects of the stimulation test are estimated by assessing changes in bradykinesia as the stimulation voltage is increased. In this study, we evaluated the potential of the leap motion controller (LMC) to quantify the motor component of bradykinesia in PD during DBS surgery, as this could make the intraoperative assessment of bradykinesia more accurate. Seven participants with idiopathic PD receiving chronic bilateral subthalamic nucleus deep brain stimulation (DBS) therapy were recruited. The motor tasks of finger tapping (FT), hand opening and closing (OC), and hand pronation and supination (PS) were selected pre- and intraoperatively in accordance with the Movement Disorder Society revision of the Unified Parkinson's Disease Rating Scale. During the test, participants performed these tasks in sequence while being simultaneously monitored by the LMC and two professional clinicians. Key kinematic parameters differed between the preoperative and intraoperative conditions. We suggest that the average velocity ( V ¯ ) and average amplitude ( A ¯ ) of PS isolate the bradykinetic feature from that movement to provide a measure of the intraoperative state of the motor system. The LMC achieved promising results in evaluating PD patients' hand and finger bradykinesia during DBS surgery.

MicroRNA­301a/ZNRF3/wnt/ß­catenin signal regulatory crosstalk mediates glioma progression.

MicroRNA (miR)­mediated mRNA and multiple signaling pathway dysregulations have been extensively implicated in several cancer types, including gliomas. Although previous studies have reported that miR­301a acts as an oncogene, the underlying mechanisms of miR­301a in the initiation and progression of glioma remain unknown. The present study aimed to investigate the involvement of miR­301a­mediated signaling pathway dysregulation in glioma. The results identified that miR­301a was significantly upregulated in gliomas and was associated with a poor prognosis based on The Cancer Genome Atlas and Chinese Glioma Genome Atlas databases. Moreover, zinc and ring finger 3 (ZNRF3) exerted a critical role in the miR­301a­mediated effects on the malignant phenotype, such as by affecting proliferation and apoptosis. Mechanistically, the TOP/FOP luciferase assay, western blotting and immunofluorescence results demonstrated that miR­301a knockdown inhibited the wnt/ß­catenin signaling pathway, at least partially via ZNRF3, while ZNRF3 was a direct functional target of miR­301a, as indicated by luciferase reporter assay and western blot analysis. Furthermore, ZNRF3 could in turn repress miR­301a expression, which was dependent on the wnt pathway. Collectively, the present study identified a novel miR­301a/ZNRF3/wnt/ß­catenin signaling feedback loop that serves critical roles in glioma tumorigenesis, and that may represent a potential therapeutic target.

Blocking the bFGF/STAT3 interaction through specific signaling pathways induces apoptosis in glioblastoma cells.

We have reported that basic fibroblast growth factor (bFGF) demonstrates an intimate connection with signal transducer and activator of transcription 3 (STAT3) in malignant brain tumor cells. However, its mechanisms are still unclear. In this study, we used inhibitors to block specific signaling pathways, including JAK, PI3K/Akt, and Src pathways, to explore how bFGF mediates crosstalk with STAT3 in two glioblastoma(GBM) cell lines: U251 (mutant p53) and U87 (wild-type p53). Furthermore, we explored how the bFGF/STAT3 pathway affects GBM cell apoptosis. Our results suggest that bFGF can induce the activation of STAT3 mainly through the JAK and PI3K/Akt pathways, and that siRNA-mediated knockdown of STAT3 markedly reduces the bFGF levels in U251 cells. Our results also suggest that STAT3 knockdown increases the expression of pro-apoptotic genes and decreases the expression of anti-apoptotic genes, subsequently collapsing the mitochondrial membrane potentials in vitro and impairs tumor growth in vivo.

[A preliminary study about the interaction between basic fibroblast growth factor and signal transducer and activator of transcription 3 in glioma apoptosis].

OBJECTIVE: To study the relationship of basic fibroblast growth factor (bFGF) and signal transducer and activator of transcription 3(STAT3) in glioma apoptosis and possible mechanisms of its interaction. METHODS: Two glioblastomamultiforme (GBM) cell lines: U87 (wild-type p53) and U251 (mutant p53) were used in this study and divided into normal control group, mock group and experiment group.Small interfering RNA-carried recombinant lentivirus, LV-bFGFsiRNA and LV-STAT3siRNA, targeting bFGF and STAT3 were constructed respectively. After 48 hours of lentivirus transfection, small molecular inhibitors were used to block specific signaling pathways, AG490 20 µmol/L blocking JAK, LY294002 20 µmol/L blocking PI3K/Akt pathways for 24 hours, 48 hours and 72 hours, respectively. Then, apoptosis, changes in apoptosis-related proteins and mitochondrial membrane potential were detected through the methods of flow cytometry, protein chip and confocal microscopy, respectively.Groups were compared using single factor analysis of variance (One-way ANOVA). RESULTS: Western blot results revealed the levels of Tyr705 and Ser727 phosphorylationin reduced in a time dependent manner by blocking JAK and PI3K/Akt pathway respectively. The results of flow cytometry showed that the apoptosis rate in normal control group, mock group, experiment group were 17.97% ± 0.24%, 18.26% ± 0.88%, 46.57% ± 1.63% in U87 cells and 15.94% ± 1.18%, 16.88% ± 0.17%, 39.34% ± 0.87% in U251 cells, respectively. There was no statistically significant change between the normal control group and the mock group (P > 0.05) , while when compared with the experiment group, both group showed statistically significant difference (F = 697.41, 729.58, both P < 0.05). The results of protein chip demonstrated that protein expression of Bad, Caspase3, Cytochrome C, p27 were higher and XIAP was lower in the experiment group compared with the normal control group and mock group. Also, confocal microscopy could detect apoptosis and mitochondrial membrane potential reduced significantly in the experimental group compared with the normal control group and the mock group. CONCLUSIONS: bFGF mainly interacts with STAT3 tyrosine site-pSTAT3(Tyr705) to influence the level of STAT3 phosphorylation;blocking bFGF/STAT3 signaling pathway can induce glioma cell apoptosis through mitochondrial pathway.

CFEOM1-associated kinesin KIF21A is a cortical microtubule growth inhibitor.

Mechanisms controlling microtubule dynamics at the cell cortex play a crucial role in cell morphogenesis and neuronal development. Here, we identified kinesin-4 KIF21A as an inhibitor of microtubule growth at the cell cortex. In vitro, KIF21A suppresses microtubule growth and inhibits catastrophes. In cells, KIF21A restricts microtubule growth and participates in organizing microtubule arrays at the cell edge. KIF21A is recruited to the cortex by KANK1, which coclusters with liprin-α1/ß1 and the components of the LL5ß-containing cortical microtubule attachment complexes. Mutations in KIF21A have been linked to congenital fibrosis of the extraocular muscles type 1 (CFEOM1), a dominant disorder associated with neurodevelopmental defects. CFEOM1-associated mutations relieve autoinhibition of the KIF21A motor, and this results in enhanced KIF21A accumulation in axonal growth cones, aberrant axon morphology, and reduced responsiveness to inhibitory cues. Our study provides mechanistic insight into cortical microtubule regulation and suggests that altered microtubule dynamics contribute to CFEOM1 pathogenesis.

[A preliminary study about the apoptostic mechanism of RNA targeting basic fibroblast growth factor in glioma U251 cells].

OBJECTIVE: To preliminarily investigate the mechanism of small interfering RNA (siRNA) induced apoptosis in glioma U251 cells by silencing basic fibroblast growth factor (bFGF). METHODS: U251 cells were divided into the normal control group, the mock group and experiment group, the mock and experiment group were transfected with mock vector (Ad-null) and the recombinant adenovirus carrying bFGF-siRNA (Ad-bFGF-siRNA) respectively at a multiplicity of infection (MOI) of 100. After 72 hours, the expression of related proteins was revealed by the method of Western blot. Mitochondrial transmembrane potential (ΔΨm) was measured with flow cytometry and confocal microscopy, Groups were compared using single factor analysis of variance (One-way ANOVA). RESULTS: After U251 cells were transfected with bFGF-siRNA, the results of Western blot showed that after 72 hours of transfection the bFGF protein in the experiment group decreased obviously, meanwhile Cytochrome C, Caspase-3 and Bax showed increased expression while in the Bcl-xl and Bcl-2 proteins decreased expression. The proportion of high mitochondrial membrane potential of cells by flow cytometry, the experimental group was 74.4% ± 4.7% decreased significantly compared with the control group 92.1% ± 2.5%, the mock group 90.9% ± 1.8% (F = 28.805, P < 0.05); laser scanning confocal microscopy results showed that the red fluorescence and green fluorescence ratio of the experimental group was 0.83 ± 0.12 decreased significantly compared with 1.36 ± 0.40 of the control group and 1.32 ± 0.35 of the mock group(F = 7.920, P < 0.05). CONCLUSION: siRNA targeting bFGF induced U251 cell apoptosis may be achieved through the mitochondrial pathway.