A triphosphate tunnel metalloenzyme from pear (PbrTTM1) moonlights as an adenylate cyclase.

Adenylyl cyclase (AC) is the vital enzyme for generating 3',5'-cyclic adenosine monophosphate, an important signaling molecule with profound nutritional and medicinal values. However, merely, a dozen of AC proteins have been reported in plants so far. Here, a protein annotated as triphosphate tunnel metalloenzyme (PbrTTM1) in pear, the important worldwide fruit plant, was firstly identified to possess AC activity with both in vivo and in vitro methods. It exhibited a relatively low AC activity but was capable of complementing AC functional deficiencies in the E. coli SP850 strain. Its protein conformation and potential catalytic mechanism were analyzed by means of biocomputing. The active site of PbrTTM1 is a closed tunnel constructed by nine antiparallel ß-folds surrounded with seven helices. Inside the tunnel, the charged residues were possibly involved in the catalytic process by coordinating with divalent cation and ligand. The hydrolysis activity of PbrTTM1 was tested as well. Compared to the much higher capacity of hydrolyzing, the AC activity of PbrTTM1 tends to be a moonlight function. Through a comparison of protein structures in various plant TTMs, it is reasonable to speculate that many plant TTMs might possess AC activity as a form of moonlighting enzyme function.

Combined LC-MS-based metabolomics and GC-IMS analysis reveal changes in chemical components and aroma components of Jujube leaf tea during processing.

Making tea from jujube leaves changed the chemical composition and aroma composition of jujube leaves. Here, Through LC-MS, GC-IMS, and GC-MS technology, we have revealed the effect of jujube leaf processing changes on metabolites. LC-MS identified 468 non-volatile metabolites, while GC-IMS and GC-MS detected 52 and 24 volatile metabolites, respectively. 109 non-volatile metabolites exhibiting more pronounced differences were screened. Most lipids and lipid-like molecules, organic acids, amino acids, and flavonoids increased significantly after processing. GC-IMS and GC-MS analysis revealed that the contents of aldehydes and ketones were significantly increased, while esters and partial alcohols were decreased after processing into jujube leaf tea. The main flavor substances of fresh jujube leaf and jujube leaf tea were eugenol and (E) - 2-Hexenal, respectively. Furthermore, amino acids and lipids were closely linked to the formation of volatile metabolites. Our study provided new insights into the changes in metabolites of jujube leaves processed into jujube leaf tea, and had great potential for industrial application. It laid a foundation for further research on fruit tree leaf tea.

Fronto-parieto-subthalamic activity decodes motor status in Parkinson's disease.

AIMS: Patients with Parkinson's disease (PD) have various motor difficulties, including standing up, gait initiation and freezing of gait. These abnormalities are associated with cortico-subthalamic dysfunction. We aimed to reveal the characteristics of cortico-subthalamic activity in PD patients during different motor statuses. METHODS: Potentials were recorded in the superior parietal lobule (SPL), the primary motor cortex (M1), premotor cortex (PMC), and the bilateral subthalamic nucleus (STN) in 18 freely walking patients while sitting, standing, walking, dual-task walking, and freezing in medication "off" (Moff) and "on" (Mon) states. Different motor status activities were compared in band power, and a machine learning classifier was used to differentiate the motor statuses. RESULTS: SPL beta power was specifically inhibited from standing to walking, and negatively correlated with walking speed; M1 beta power reflected the degree of rigidity and was reversed by medication; XGBoost algorithm classified the five motor statuses with acceptable accuracy (68.77% in Moff, 60.58% in Mon). SPL beta power ranked highest in feature importance in both Moff and Mon states. CONCLUSION: SPL beta power plays an essential role in walking status classification and could be a physiological biomarker for walking speed, which would aid the development of adaptive DBS.

Fluoride exposure disrupts the cytoskeletal arrangement and ATP synthesis of HT-22 cell by activating the RhoA/ROCK signaling pathway.

BACKGROUND: Fluoride, an environmental contaminant, is ubiquitously present in air, water, and soil. It usually enters the body through drinking water and may cause structural and functional disorders in the central nervous system in humans and animals. Fluoride exposure affects cytoskeleton and neural function, but the mechanism is not clear. METHODS: The specific neurotoxic mechanism of fluoride was explored in HT-22 cells. Cellular proliferation and toxicity detection were investigated by CCK-8, CCK-F, and cytotoxicity detection kits. The development morphology of HT-22 cells was observed under a light microscope. Cell membrane permeability and neurotransmitter content were determined using lactate dehydrogenase (LDH) and glutamate content determination kits, respectively. The ultrastructural changes were detected by transmission electron microscopy, and actin homeostasis was observed by laser confocal microscopy. ATP enzyme and ATP activity were determined using the ATP content kit and ultramicro-total ATP enzyme content kit, respectively. The expression levels of GLUT1 and 3 were assessed by Western Blot assays and qRT-PCR. RESULTS: Our results showed that fluoride reduced the proliferation and survival rates of HT-22 cells. Cytomorphology showed that dendritic spines became shorter, cellular bodies became rounder, and adhesion decreased gradually after fluoride exposure. LDH results showed that fluoride exposure increased the membrane permeability of HT-22 cells. Transmission electron microscopy results showed that fluoride caused cells to swell, microvilli content decreased, cellular membrane integrity was damaged, chromatin was sparse, mitochondria ridge gap became wide, and microfilament and microtubule density decreased. Western Blot and qRT-PCR analyses showed that RhoA/ROCK/LIMK/Cofilin signaling pathway was activated by fluoride. F-actin/G-actin fluorescence intensity ratio remarkably increased in 0.125 and 0.5 mM NaF, and the mRNA expression of MAP2 was significantly decreased. Further studies showed that GLUT3 significantly increased in all fluoride groups, while GLUT1 decreased (p < 0.05). ATP contents remarkably increased, and ATP enzyme activity substantially decreased after NaF treatment with the control. CONCLUSION: Fluoride activates the RhoA/ROCK/LIMK/Cofilin signaling pathway, impairs the ultrastructure, and depresses the connection of synapses in HT-22 cells. Moreover, fluoride exposure affects the expression of glucose transporters (GLUT1 and 3) and ATP synthesis. Sum up fluoride exposure disrupts actin homeostasis, ultimately affecting structure, and function in HT-22 cells. These findings support our previous hypothesis and provide a new perspective on the neurotoxic mechanism of fluorosis.

Deep brain stimulation of the nucleus basalis of Meynert modulates hippocampal-frontoparietal networks in patients with advanced Alzheimer's disease.

BACKGROUND: Deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM) has shown potential for the treatment of mild-to-moderate Alzheimer's disease (AD). However, there is little evidence of whether NBM-DBS can improve cognitive functioning in patients with advanced AD. In addition, the mechanisms underlying the modulation of brain networks remain unclear. This study was aimed to assess the cognitive function and the resting-state connectivity following NBM-DBS in patients with advanced AD. METHODS: Eight patients with advanced AD underwent bilateral NBM-DBS and were followed up for 12 months. Clinical outcomes were assessed by neuropsychological examinations using the Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale. Resting-state functional magnetic resonance imaging and positron emission tomography data were also collected. RESULTS: The cognitive functioning of AD patients did not change from baseline to the 12-month follow-up. Interestingly, the MMSE score indicated clinical efficacy at 1 month of follow-up. At this time point, the connectivity between the hippocampal network and frontoparietal network tended to increase in the DBS-on state compared to the DBS-off state. Additionally, the increased functional connectivity between the parahippocampal gyrus (PHG) and the parietal cortex was associated with cognitive improvement. Further dynamic functional network analysis showed that NBM-DBS increased the proportion of the PHG-related connections, which was related to improved cognitive performance. CONCLUSION: The results indicated that NBM-DBS improves short-term cognitive performance in patients with advanced AD, which may be related to the modulation of multi-network connectivity patterns, and the hippocampus plays an important role within these networks. TRIAL REGISTRATION: ChiCTR, ChiCTR1900022324. Registered 5 April 2019-Prospective registration. https://www.chictr.org.cn/showproj.aspx?proj=37712.

Altered Structural Brain Network Topology in Patients With Primary Craniocervical Dystonia.

Purpose: Regional cortical thickness or volume analyses based upon structural MRI scans have been employed to study the pathophysiology of primary craniocervical dystonia (CCD). In the present study, brain connectivity network analyses based upon morphological distribution similarities among different brain areas were used to study the network disruption in individuals affected by CCD. Methods: The T1 MRI scans were completed for 37 patients with CCD and 30 healthy controls, with individual brain structural networks being constructed based upon gray matter (GM) similarities in 90 regions within the brain. Area under the curve (AUC) values for each network parameter were determined, and the GRETNA program was used to conduct a graph theory-based measurement of nodal and global network properties. These properties were then compared between healthy controls and those with CCD. In addition, relationships between nodal properties and the severity of clinical dystonia were assessed through Spearman's correlation analyses. Results: Relative to individuals in the control group, patients with CCD exhibited decreased local nodal properties in the right globus pallidus, right middle frontal gyrus, and right superior temporal pole. The degree of centrality as well as the node efficiency of the right globus pallidus were found to be significantly correlated with ocular dystonic symptom. The node efficiency of right middle frontal gyrus was significantly related to the total motor severity. No nodal properties were significantly correlated with oral dystonic motor scores. Among CCD patients, the right hemisphere exhibited more widespread decreases in connectivity associated with the motor related brain areas, associative cortex, and limbic system, particularly in the middle frontal gyrus, globus pallidus, and cingulate gyrus. Conclusions: The assessment of morphological correlations between different areas in the brain may represent a sensitive approach for detecting alterations in brain structures and to understand the mechanistic basis for CCD at the network level. Based on the nodal properties identified in this study, the right middle frontal gyrus and globus pallidus were the most severely affected in patients with CCD. The widespread alterations in morphological connectivity, such as the cortico-cortical and cortico-subcortical networks, further support the network mechanism as a basis for CCD.

Cortical phase-amplitude coupling is key to the occurrence and treatment of freezing of gait.

Freezing of gait is a debilitating symptom in advanced Parkinson's disease and responds heterogeneously to treatments such as deep brain stimulation. Recent studies indicated that cortical dysfunction is involved in the development of freezing, while evidence depicting the specific role of the primary motor cortex in the multi-circuit pathology of freezing is lacking. Since abnormal beta-gamma phase-amplitude coupling recorded from the primary motor cortex in patients with Parkinson's disease indicates parkinsonian state and responses to therapeutic deep brain stimulation, we hypothesized this metric might reveal unique information on understanding and improving therapy for freezing of gait. Here, we directly recorded potentials in the primary motor cortex using subdural electrocorticography and synchronously captured gait freezing using optoelectronic motion-tracking systems in 16 freely-walking patients with Parkinson's disease who received subthalamic nucleus deep brain stimulation surgery. Overall, we recorded 451 timed up-and-go walking trials and quantified 7073 s of stable walking and 3384 s of gait freezing in conditions of on/off-stimulation and with/without dual-tasking. We found that (i) high beta-gamma phase-amplitude coupling in the primary motor cortex was detected in freezing trials (i.e. walking trials that contained freezing), but not non-freezing trials, and the high coupling in freezing trials was not caused by dual-tasking or the lack of movement; (ii) non-freezing episodes within freezing trials also demonstrated abnormally high couplings, which predicted freezing severity; (iii) deep brain stimulation of subthalamic nucleus reduced these abnormal couplings and simultaneously improved freezing; and (iv) in trials that were at similar coupling levels, stimulation trials still demonstrated lower freezing severity than no-stimulation trials. These findings suggest that elevated phase-amplitude coupling in the primary motor cortex indicates higher probabilities of freezing. Therapeutic deep brain stimulation alleviates freezing by both decoupling cortical oscillations and enhancing cortical resistance to abnormal coupling. We formalized these findings to a novel 'bandwidth model,' which specifies the role of cortical dysfunction, cognitive burden and therapeutic stimulation on the emergence of freezing. By targeting key elements in the model, we may develop next-generation deep brain stimulation approaches for freezing of gait.

Acute lead acetate induces neurotoxicity through decreased synaptic plasticity-related protein expression and disordered dendritic formation in nerve cells.

Lead (Pb) is a widespread environmental heavy metal that can damage the cerebral cortex and hippocampus, and reduce the learning and memory ability in humans and animals. In vivo and in vitro models of acute lead acetate exposure were established to further study the mechanism of neurons injury. In this study, 4-week-old female Kunming mice were randomly divided into four groups. Each group was treated with distilled water with different Pb concentrations (0, 2.4, 4.8 and 9.6 mM). Mice were killed, and brain tissues were collected to detect the changes in synaptic plasticity-related protein expression. Furthermore, Neuro-2A cells were treated with 0, 5, 25 and 50 µM lead acetate for 24 h to observe the changes in cell morphology and function. In in vivo experiment, results showed that the expression levels of cytoskeleton-associated and neural function-related proteins decreased in a dose-dependent manner in the mouse brain tissue. In in vitro experiment, compared with the control group, Pb treatment groups were observed with smaller and round cells, decreased cell density and number of synapses. In the Pb exposure group, the survival rate of nerve cells decreased evidently, and the permeability of the cell membrane was increased. Western blot results showed that the expression of cytoskeleton-associated and function-related proteins decreased gradually with increased Pb exposure dose. Confocal laser scanning microscopy results revealed the morphological and volumetric changes in Neuro-2A cells, and a dose-dependent reduction in the number of axon and dendrites. These results suggested that abnormal neural structures and inhibiting expression of synaptic plasticity-related proteins might be the possible mechanisms of Pb-induced mental retardation in human and animals, thereby laying a foundation for the molecular mechanism of Pb neurotoxicity.

Seed-Based Connectivity Prediction of Initial Outcome of Subthalamic Nuclei Deep Brain Stimulation.

Subthalamic nuclei deep brain stimulation (STN-DBS) is a well-established treatment for Parkinson's disease (PD). Some studies have confirmed the long-term efficacy is associated with brain connectivity; however, whether the initial outcome is associated with brain connectivity and efficacy of prediction based on these factors has not been well investigated. In the present study, a total of 98 patients were divided into a training set (n = 78) and a test set (n = 20). The stimulation and medication responses were calculated based on the motor performance. The functional and structural connectomes were established based on a public database and used to measure the association between stimulation response and brain connectivity. The prediction of initial outcome was achieved via a machine learning algorithm-support vector machine based on the model established with the training set. It was found that the initial outcome of STN-DBS was associated with functional/structural connectivities between the volume of tissue activated and multiple brain regions, including the supplementary motor area, precentral and frontal areas, cingulum, temporal cortex, and striatum. These factors could be used to predict the initial outcome, with an r value of 0.4978 (P = 0.0255). Our study demonstrates a correlation between a specific connectivity pattern and initial outcome of STN-DBS, which could be used to predict the initial outcome of DBS.

Synchronized Intracranial Electrical Activity and Gait Recording in Parkinson's Disease Patients With Freezing of Gait.

Background: This study aimed to describe a synchronized intracranial electroencephalogram (EEG) recording and motion capture system, which was designed to explore the neural dynamics during walking of Parkinson's disease (PD) patients with freezing of gait (FOG). Preliminary analysis was performed to test the reliability of this system. Methods: A total of 8 patients were enrolled in the study. All patients underwent bilateral STN-DBS surgery and were implanted with a right subdural electrode covering premotor and motor area. Synchronized electrophysiological and gait data were collected using the Nihon Kohden EEG amplifier and Codamotion system when subjects performed the Timed Up and Go (TUG) test. To verify the reliability of the acquisition system and data quality, we calculated and compared the FOG index between freezing and non-freezing periods during walking. For electrophysiological data, we first manually reviewed the scaled (five levels) quality during waking. Spectra comprising broadband electrocorticography (ECoG) and local field potential (LFP) were also compared between the FOG and non-FOG states. Lastly, connectivity analysis using coherence between cortical and STN electrodes were conducted. In addition, we also use machine learning approaches to classified FOG and non-FOG. Results: A total of 8 patients completed 41 walking tests, 30 of which had frozen episodes, and 21 of the 30 raw data were level 1 or 2 in quality (70%). The mean ± SD walking time for the TUG test was 85.94 ± 47.68 s (range: 38 to 190.14 s); the mean ± SD freezing duration was 12.25 ± 7.35 s (range: 1.71 to 27.50 s). The FOG index significantly increased during the manually labeled FOG period (P < 0.05). The beta power of STN LFP in the FOG period was significantly higher than that in the non-FOG period (P < 0.05), while the band power of ECoG did not exhibit a significant difference between walking states. The coherence between the ECoG and STN LFP was significantly greater in high beta and gamma bands during the FOG period compared with the shuffled surrogates (P < 0.05). Lastly, STN-LFP band power features showed above-chance performance (p < 0.01, permutation test) in identifying FOG epochs. Conclusion: In this study, we established and verified the synchronized ECoG/LFP and gait recording system in PD patients with FOG. Further neural substrates underlying FOG could be explored using the current system.

Predict initial subthalamic nucleus stimulation outcome in Parkinson's disease with brain morphology.

AIM: Subthalamic nucleus deep brain stimulation (STN-DBS) has been reported to be effective in treating motor symptoms in Parkinson's disease (PD), which may be attributed to changes in the brain network. However, the association between brain morphology and initial STN-DBS efficacy, as well as the performance of prediction using neuroimaging, has not been well illustrated. Therefore, we aim to investigate these issues. METHODS: In the present study, 94 PD patients underwent bilateral STN-DBS, and the initial stimulation efficacy was evaluated. Brain morphology was examined by magnetic resonance imaging (MRI). The volume of tissue activated in the motor STN was measured with MRI and computed tomography. The prediction of stimulation efficacy was achieved with a support vector machine, using brain morphology and other features, after feature selection and hyperparameter optimization. RESULTS: A higher stimulation efficacy was correlated with a thicker right precentral cortex. No association with subcortical gray or white matter volumes was observed. These morphological features could estimate the individual stimulation response with an r value of 0.5678, an R2 of 0.3224, and an average error of 11.4%. The permutation test suggested these predictions were not based on chance. CONCLUSION: Our results indicate that changes in morphology are associated with the initial stimulation motor response and could be used to predict individual initial stimulation-related motor responses.

A Metabolic Reprogramming Amino Acid Polymer as an Immunosurveillance Activator and Leukemia Targeting Drug Carrier for T-Cell Acute Lymphoblastic Leukemia.

Compromised immunosurveillance leads to chemotherapy resistance and disease relapse of hematological malignancies. Amino acid metabolism regulates immune responses and cancer; however, a druggable amino acid metabolite to enhance antitumor immunosurveillance and improve leukemia targeting-therapy efficacy remains unexplored. Here, an L-phenylalanine polymer, Metabolic Reprogramming Immunosurveillance Activation Nanomedicine (MRIAN), is invented to effectively target bone marrow (BM) and activate the immune surveillance in T-cell acute lymphoblastic leukemia (T-ALL) by inhibiting myeloid-derived suppressor cells (MDSCs) in T-ALL murine model. Stable-isotope tracer and in vivo drug distribution experiments show that T-ALL cells and MDSCs have enhanced cellular uptake of L-phenylalanine and MRIANs than normal hematopoietic cells and progenitors. Therefore, MRIAN assembled Doxorubicin (MRIAN-Dox) specifically targets T-ALL cells and MDSCs but spare normal hematopoietic cells and hematopoietic stem and progenitor cells with enhanced leukemic elimination efficiency. Consequently, MRIAN-Dox has reduced cardiotoxicity and myeloablation side effects in treating T-ALL mice. Mechanistically, MRIAN degrades into L-phenylalanine, which inhibits PKM2 activity and reduces ROS levels in MDSCs to disturb their immunosuppressive function and increase their differentiation toward normal myeloid cells. Overall, a novel amino acid metabolite nanomedicine is invented to treat T-ALL through the combination of leukemic cell targeting and immunosurveillance stimulation.

A lysosome-targeted dextran-doxorubicin nanodrug overcomes doxorubicin-induced chemoresistance of myeloid leukemia.

The hypoxic microenvironment is presumed to be a sanctuary for myeloid leukemia cells that causes relapse following chemotherapy, but the underlying mechanism remains elusive. Using a zebrafish xenograft model, we observed that the hypoxic hematopoietic tissue preserved most of the chemoresistant leukemic cells following the doxorubicin (Dox) treatment. And hypoxia upregulated TFEB, a master regulator of lysosomal biogenesis, and increased lysosomes in leukemic cells. Specimens from relapsed myeloid leukemia patients also harbored excessive lysosomes, which trapped Dox and prevented drug nuclear influx leading to leukemia chemoresistance. Pharmaceutical inhibition of lysosomes enhanced Dox-induced cytotoxicity against leukemic cells under hypoxia circumstance. To overcome lysosome associated chemoresistance, we developed a pH-sensitive dextran-doxorubicin nanomedicine (Dex-Dox) that efficiently released Dox from lysosomes and increased drug nuclear influx. More importantly, Dex-Dox treatment significantly improved the chemotherapy outcome in the zebrafish xenografts transplanted with cultured leukemic cells or relapsed patient specimens. Overall, we developed a novel lysosome targeting nanomedicine that is promising to overcome the myeloid leukemia chemoresistance.

A Bulk Retrospective Study of Robot-Assisted Stereotactic Biopsies of Intracranial Lesions Guided by Videometric Tracker.

Background: Biopsies play an important role in the diagnosis of intracranial lesions, and robot-assisted procedures are increasingly common in neurosurgery centers. This research investigates the diagnoses, complications, and technology yield of 700 robotic frameless intracranial stereotactic biopsies conducted with the Remebot system. Method: This research considered 700 robotic biopsies performed between 2016 and 2020 by surgeons from the Department of Functional Neurosurgery in Beijing's Tiantan Hospital. The data collected included histological diagnoses, postoperative complications, operation times, and the accuracy of robotic manipulation. Results: Among the 700 surgeries, the positive rate of the biopsies was 98.2%. The most common histological diagnoses were gliomas, which accounted for 62.7% of cases (439/700), followed by lymphoma and germinoma, which accounted for 18.7% (131/700) and 7.6% (53/700). Bleeding was found in 14 patients (2%) by post-operation computed tomography scans. A total of 29 (4.14%) patients had clinical impairments after the operation, and 9 (1.29%) experienced epilepsy during the operation. The post-biopsy mortality rate was 0.43%. Operation time-from marking the cranial point to suturing the skin-was 16.78 ± 3.31 min (range 12-26 min). The target error was 1.13 ± 0.30 mm, and the entry point error was 0.99 ± 0.24 mm. Conclusion: A robot-assisted frameless intracranial stereotactic biopsy guided by a videometric tracker is an efficient, safe, and accurate method for biopsies.

Anterior thalamic nuclei deep brain stimulation inhibits mossy fiber sprouting via 3',5'-cyclic adenosine monophosphate/protein kinase A signaling pathway in a chronic epileptic monkey model.

BACKGROUND: Anterior thalamic nuclei (ATN) deep brain stimulation (DBS) is an effective method of controlling epilepsy, especially temporal lobe epilepsy. Mossy fiber sprouting (MFS) plays an indispensable role in the pathogenesis and progression of epilepsy, but the effect of ATN-DBS on MFS in the chronic stage of epilepsy and the potential underlying mechanisms are unknown. This study aimed to investigate the effect of ATN-DBS on MFS, as well as potential signaling pathways by a kainic acid (KA)-induced epileptic model. METHODS: Twenty-four rhesus monkeys were randomly assigned to control, epilepsy (EP), EP-sham-DBS, and EP-DBS groups. KA was injected to establish the chronic epileptic model. The left ATN was implanted with a DBS lead and stimulated for 8 weeks. Enzyme-linked immunosorbent assay, Western blotting, and immunofluorescence staining were used to evaluate MFS and levels of potential molecular mediators in the hippocampus. One-way analysis of variance, followed by the Tukey post hoc correction, was used to analyze the statistical significance of differences among multiple groups. RESULTS: ATN-DBS is found to significantly reduce seizure frequency in the chronic stage of epilepsy. The number of ectopic granule cells was reduced in monkeys that received ATN stimulation (P < 0.0001). Levels of 3',5'-cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) in the hippocampus, together with Akt phosphorylation, were noticeably reduced in monkeys that received ATN stimulation (P = 0.0030 and P = 0.0001, respectively). ATN-DBS also significantly reduced MFS scores in the hippocampal dentate gyrus and CA3 sub-regions (all P < 0.0001). CONCLUSION: ATN-DBS is shown to down-regulate the cAMP/PKA signaling pathway and Akt phosphorylation and to reduce the number of ectopic granule cells, which may be associated with the reduced MFS in chronic epilepsy. The study provides further insights into the mechanism by which ATN-DBS reduces epileptic seizures.

The Epidemiology, Cause, and Prognosis of Painful Tic Convulsif Syndrome: An Individual Patient Data Analysis of 192 Cases.

BACKGROUND: Characterized by the coexistence of trigeminal neuralgia and ipsilateral hemifacial spasm (HFS), painful tic convulsif (PTC) is a rare entity that has not yet been systematically studied. OBJECTIVE: To systematically explore the epidemiology, cause, prognosis, and prognosis predictors of PTC. METHODS: We searched PubMed, Web of Science, and the Cochrane Library for relevant studies published between establishment of the library and July 1, 2020. Information on demographics, causes, specific interventions, and intervention outcomes was extracted. We first performed descriptive analysis of demographics, causes, and surgical outcomes of PTC. Univariate and multivariate regression methods were used to explore potential prognosis predictors. Further, a 2-step meta-analysis method was used to validate the identified factors. RESULTS: Overall, 57 reports including 192 cases with PTC were included in the analysis. The median age of patients with PTC is 54 years (range, 44-62 years), with more patients being female (P < 0.001), initiated as HFS (P = 0.005), and being affected with left side (P = 0.045). The vertebrobasilar artery contributes to >65% of the causes of single vascular compression for PTC. Anterior inferior cerebellar artery/posterior inferior cerebellar artery involvement (odds ratio, 4.050; 95% confidence interval, 1.091-15.031) and older age (P = 0.008) predict freedom from symptoms and recurrence after microvascular decompression, respectively. CONCLUSIONS: PTC occurs more in middle-aged women between 40 and 60 years old, initiates as HFS, and affects the left side. Vertebrobasilar artery compression is the most common single cause of PTC. Microvascular decompression effectively treated PTC, with a cure rate >80%. Anterior inferior cerebellar artery/posterior inferior cerebellar artery involvement predicts successful surgery and older age predicts recurrence.

Deep brain stimulation of the anterior nuclei of the thalamus relieves basal ganglia dysfunction in monkeys with temporal lobe epilepsy.

AIMS: Deep brain stimulation of the anterior nuclei of the thalamus (ANT-DBS) is effective in temporal lobe epilepsy (TLE). Previous studies have shown that the basal ganglia are involved in seizure propagation in TLE, but the effects of ANT-DBS on the basal ganglia have not been clarified. METHODS: ANT-DBS was applied to monkeys with kainic acid-induced TLE using a robot-assisted system. Behavior was monitored continuously. Immunofluorescence analysis and Western blotting were used to estimate protein expression levels in the basal ganglia and the effects of ANT stimulation. RESULTS: The seizure frequency decreased after ANT-DBS. D1 and D2 receptor levels in the putamen and caudate were significantly higher in the ANT-DBS group than in the epilepsy (EP) model. Neuronal loss and apoptosis were less severe in the ANT-DBS group. Glutamate receptor 1 (GluR1) in the nucleus accumbens (NAc) shell and globus pallidus internus (GPi) increased in the EP group but decreased after ANT-DBS. γ-Aminobutyric acid receptor A (GABAA -R) decreased and glutamate decarboxylase 67 (GAD67) increased in the GPi of the EP group, whereas the reverse tendencies were observed after ANT-DBS. CONCLUSION: ANT-DBS exerts neuroprotective effects on the caudate and putamen, enhances D1 and D2 receptor expression, and downregulates GPi overactivation, which enhanced the antiepileptic function of the basal ganglia.

Subthalamic nucleus deep brain stimulation suppresses neuroinflammation by Fractalkine pathway in Parkinson's disease rat model.

Subthalamic nucleus deep brain stimulation (STN-DBS) is widely used to treat patients with Parkinson's disease (PD), and recent studies have shown that it is more beneficial for early stages, suggesting a potential neuroprotective effect. And the neuroinflammation plays an indispensable role in progress of PD. However, the underlying mechanisms are not well understood. The aim of this study was to investigate the effect of STN-DBS on neuroinflammation and the potential pathway. To address this question, we established a rat PD model by unilateral 6-hydroxydopamine injection into the left striatum and implanted stimulation leads into the ipsilateral STN to deliver electrical stimulation for a week. The neuroprotective effects of STN-DBS were examined by molecular biology techniques, including western blotting, immunohistochemistry and so on. We found that motor deficits were alleviated by STN-DBS, with increased survival of dopaminergic neurons in the substantia nigra (SN). Furthermore, STN-DBS decreased Fractalkine (CX3CL1) and its receptor (CX3CR1) expression. Meanwhile, the suppressed microglia activation and nuclear factor-κB expression, decrease in the levels of pro-inflammatory cytokine interleukin (IL)-1ß and IL-6 and increase in anti-inflammatory cytokine IL-4, downregulated IL-1 receptor, extracellular signal-regulated kinase (ERK) and cleaved-caspase3 were also observed in SN of PD models received STN-DBS. In conclusion, we observed a significant association between the suppressed neuroinflammation and STN-DBS, which may be attributed to CX3CL1/CX3CR1 signaling. These results provide novel insight into the mechanistic basis of STN-DBS therapy for PD.

Yap-lin28a axis targets let7-Wnt pathway to restore progenitors for initiating regeneration.

The sox2 expressing (sox2+) progenitors in adult mammalian inner ear lose the capacity to regenerate while progenitors in the zebrafish lateral line are able to proliferate and regenerate damaged HCs throughout lifetime. To mimic the HC damage in mammals, we have established a zebrafish severe injury model to eliminate both progenitors and HCs. The atoh1a expressing (atoh1a+) HC precursors were the main population that survived post severe injury, and gained sox2 expression to initiate progenitor regeneration. In response to severe injury, yap was activated to upregulate lin28a transcription. Severe-injury-induced progenitor regeneration was disabled in lin28a or yap mutants. In contrary, overexpression of lin28a initiated the recovery of sox2+ progenitors. Mechanistically, microRNA let7 acted downstream of lin28a to activate Wnt pathway for promoting regeneration. Our findings that lin28a is necessary and sufficient to regenerate the exhausted sox2+ progenitors shed light on restoration of progenitors to initiate HC regeneration in mammals.

Characteristics of globus pallidus internus local field potentials in generalized dystonia patients with TWNK mutation.

OBJECTIVE: We focused on a rare gene mutation causing dystonia in two siblings who received globus pallidus internus deep brain stimulation (GPi-DBS). The aim was to characterize the relationship between neuronal activity patterns and clinical syndromes. METHODS: Whole exome sequencing was applied to identify the TWNK (previous symbol C10orf2) mutation; Two siblings with TWNK mutation presented as generalized dystonia with rigidity and bradykinesia; four other sporadic generalized dystonia patients underwent GPi-DBS and local field potentials (LFPs) were recorded. Oscillatory activities were illustrated with power spectra and temporal dynamics measured by the Lempel-Ziv complexity (LZC). RESULTS: Normalized power spectra of GPi LFPs differed between patients with TWNK mutation and dystonia over the low beta bands. Patients with TWNK mutation had higher low beta power (15-27 Hz, unpaired t-test, corrected P < 0.0022) and lower LZC (15-27 Hz, unpaired t-test, P < 0.01) than other patients with generalized dystonia. On the other hand, the TWNK mutation patients showed decreased low frequency and beta oscillation in the GPi after DBS, as well as improved movement performance. CONCLUSION: The LFPs were different in TWNK mutation dystonia siblings than other patients with generalized dystonia, which indicate the abnormal LFPs were related to symptoms rather than specific disease. In addition, the inhibited effect on oscillations also provided a potential evidence for DBS treatment on rare movement disorders. SIGNIFICANCE: This study could potentially aid in the future development of adaptive DBS via rare disease LFPs comparison.