The aims of this study were to examine both static functional connectivity (FC) and dynamic FC alterations in motor execution regions after stroke and to investigate whether the altered static or dynamic FC was associated with the clinical behaviors in stroke patients. Seventy-six stroke patients and 55 healthy controls (HC) were recruited. Static FC and dynamic FC maps were computed based on the seeds of six core regions in motor execution network. Correlation analyses were performed between static or dynamic FC and clinical behavioral scores in stroke patients. Compared with the HC, the stroke patients had significantly higher static FC between the seeds and the precentral or postcentral gyrus, frontal gyrus, inferior parietal lobule, thalamus and insula, and lower static FC between the seeds and the cerebellum and middle temporal gyrus. There were significant differences in dynamic FC between the seeds and precuneus, calcarine gyrus, insula, inferior parietal lobule, precentral gyrus, and middle temporal, frontal or occipital gyrus between the stroke patients and HC. Furthermore, a significant negative correlation was found between the Fugl-Meyer assessment scores and dynamic FC of the ipsilesional primary motor cortex and contralesional precentral gyrus in patients. The current study shows that the patterns of both static FC and dynamic FC changed after stroke, and correlation between motor function and temporal variability in the FC of the precentral gyrus was significant in stroke patients. Our findings indicate that dynamic FC might be a potential indicator for evaluating motor function after stroke.
A new steroidal alkaloid ( 1), together with three known steroidal alkaloids ( 2 - 4), has been isolated from the roots and rhizomes of Veratrum japonicum (Baker) Loes. f.., their structures were established as neogermine ( 1), germine ( 2), germerine ( 3), and neogermbudine ( 4) by means of physicochemical properties and spectroscopic analysis. Compounds 1 - 4 exhibited genotoxicity on brain cells in mice by using single-cell gel electrophoresis (Comet assay).
We have identified two novel mouse orexin type-2 receptor (OX2R) splice variants: OX2alphaR and OX2betaR. Here, we have mapped in detail the differential gene expression of OX2alphaR and OX2betaR in the mouse brain. Using RT-PCR and in situ hybridization, we show that OX2alphaR is expressed in various areas of the mouse brain and has low expression in caudal part of cerebellum. OX2betaR is expressed in detectable levels, with the exception of striatum, midbrain and anterior part of cerebellum/pons. Our novel findings demonstrate the differential expression of OX2R splice variants in the mouse brain.
The elderly suffer a decline in immune function that increases their vulnerability to infections. Because antioxidants improve some age-related deficits in immune and cognitive function, our goal was to determine whether dietary alpha-tocopherol (alpha-T) and selenium inhibit LPS-induced sickness behavior in aged mice. Male BALB/c mice were fed modified AIN93-M diets that were low, adequate, or high in both alpha-T (10, 75, or 500 mg/kg) and selenium (0.05, 0.15, or 2 mg/kg) from 18 to 21 mo of age. Sickness was quantified by measuring time in social exploration of a novel juvenile conspecific. The lipopolysaccharide treatment reduced social exploration by 74% at 2 h, regardless of diet. By 4 h, aged mice fed the low diet were 88% less social, whereas mice fed the adequate and high diets displayed only approximately 40% reductions due to LPS treatment. Mice fed the low diet had greater LPS-induced weight loss than mice fed the high diet. Plasma alpha-T concentration and glutathione peroxidase (GPX) activity increased with each increment in alpha-T and selenium 24 h post-LPS treatment. Brain alpha-T concentration and GPX activity were lower in mice fed the low diet than in those fed the adequate or high diet. Regardless of diet, interleukin (IL)-6, IL-1beta, and tumor necrosis factor (TNF)alpha mRNA levels were elevated by LPS approximately 3-fold in cortex, cerebellum, striatum, and hippocampus. Thus, antioxidants inhibit sickness behavior independently of IL-6, IL-1beta, and TNFalpha mRNA levels 2 h post-LPS in the brain regions analyzed. Taken together, these findings suggest that adequate intake of dietary alpha-T and selenium may help promote recovery from gram-negative bacterial infection in the aged.
To observe the effect of scalp acupuncture (SA) on the glucose metabolism in different regions of brain in patients with depression by positron emission computed tomography (PET). Twelve depressive patients were treated by scalp acupuncture on middle line of vertex (MS5), middle line of forehead (MS1) and bilateral lateral line 1 of forehead (MS2), once a day for six days per week, and received PET detection on different region of brain before and after 6 weeks acupuncture treatment. Semiquantitative analysis was used to compare the average values of radioactive count gotten from various brain regions before and after treatment, which could reflect the condition of glucose metabolism at the brain region detected. SA could increase the glucose metabolism at bilateral frontal lobes, bilateral parietal lobes, right occipital lobe, right caudate nucleus, right cingulated gyrus and left cerebellum and decrease that at right temporal lobe and bilateral thalamus. SA on MS5, MS1 and MS2 in depressive patients could influence the glucose metabolism in various brain regions. It primarily illustrated that the mechanism of SA in treating depression is related with its regulation on cortex-limbic circuitry dysfunction and increase the glucose metabolism in various brain regions.
To investigate the protective effect of succinic acid (SA) on the cerebellar Purkinje cells (PCs) of neonatal rats with convulsion. A total of 120 healthy neonatal Sprague-Dawley rats aged 7 days were randomly divided into a neonatal period group and a developmental period group. Each of the two groups were further divided into 6 sub-groups: normal control, convulsion model, low-dose phenobarbital (PB) (30 mg/kg), high-dose PB (120 mg/kg), low-dose SA (30 mg/kg), and high-dose SA (120 mg/kg). Intraperitoneal injection of pentylenetetrazole was performed to establish the convulsion model. The normal control group was treated with normal saline instead. The rats in the neonatal group were sacrificed at 30 minutes after the injection of PB, SA, or normal saline, and the cerebellum was obtained. Those in the developmental group were sacrificed 30 days after the injection of PB, SA, or normal saline, and the cerebellum was obtained. Whole cell patch clamp technique was used to record the action potential (AP) of PCs in the cerebellar slices of neonatal rats; the parallel fibers (PF) were stimulated at a low frequency to induce excitatory postsynaptic current (EPSC). The effect of SA on long-term depression (LTD) of PCs was observed. Compared with the normal control groups, the neonatal and developmental rats with convulsion had a significantly higher AP frequency of PCs (P<0.05), and the developmental rats with convulsion had a significantly decreased threshold stimulus (P<0.01) and a significantly greater inhibition of the amplitude of EPSC in PCs (P<0.05). Compared with the normal control groups, the neonatal and developmental rats with convulsion in the high-dose PB groups had a significantly decreased threshold stimulus (P<0.01), a significantly higher AP frequency of PCs (P<0.05), and a significantly greater inhibition of EPSC in PCs (P<0.05). Compared with the neonatal and developmental rats in the convulsion model groups, those in the high-dose SA groups had a significantly decreased AP frequency of PCs (P<0.05). The developmental rats in the low- and high-dose SA groups had a significantly higher AP threshold than those in the convulsion model group (P<0.05). The high excitability of PCs and the abnormal PF-PC synaptic plasticity caused by convulsion in neonatal rats may last to the developmental period, which can be aggravated by PB, while SA can reduce the excitability of PCs in neonatal rats with convulsion and repair the short- and long-term abnormalities of LTD of PCs caused by convulsion.
To describe the anatomical characteristics and patterns of neurovascular compression (NVC) in patients suffering trigeminal neuralgia (TN) by 3D high-resolution magnetic resonance imaging (MRI) method and image fusion technique. The anatomic structure of trigeminal nerve, brain stem and blood vessel was observed in 100 consecutive TN patients by 3D high resolution MRI (3D SPGR, contrast-enhanced T1 3D MP-RAGE and T2/T1 3D FIESTA). The 3D image sources were fused and visualized using 3D DOCTOR software. One or several NVC sites, which usually appeared 0-9.8 mm away from brain stem, were found on the symptomatic side in 93% of the TN cases. Superior cerebellar artery was involved in 76% (71/93) of these cases. The other vessels including antero-inferior cerebellar artery, vertebral artery, basilar artery and veins also contributed to the occurrence of NVC. The NVC sites were found to be located in the proximal segment in 42% of these cases (39/93) and in the distal segment in 45% (42/93). Nerve dislocation or distortion was observed in 32% (30/93). Various 3D high resolution MRI methods combined with the image fusion technique could provide pathologic anatomic information for the diagnosis and treatment of TN.
We report the case of a 46-year-old man with von Hippel-Lindau (VHL) disease, manifesting disseminated leptomeningeal hemangioblastomatosis. The patient initially presented with a solitary hemangioblastoma in the right cerebellum. Later, he was diagnosed with VHL disease and underwent several surgical procedures in the following 14 years. But the prognosis was poor. Recently, the hemangioblastomatosis disseminated along leptomeninges involving both brain and spine. We aim to analyze the possible reason for the leptomeninges dissemination, discuss the imaging characteristics of this rare disease with ominous manifestation and propose the optimal strategy for treatment. We think the optimal treatment strategy should be surgical biopsy and surgical decompression. A long-term follow-up is inevitable. Antiangiogenic medication might be the hope for remission of this disease.
Slc39a8 encodes ZIP8, a divalent cation/bicarbonate symporter expressed in pluripotent mouse embryonic stem cells, and therefore ubiquitous in adult tissues; ZIP8 influxes Zn, Mn and Fe. Slc39a8(neo/neo) knockdown mice exhibit 10-15% of wild-type ZIP8 mRNA and protein levels, and show pleiotropic phenotype of stunted growth, neonatal lethality, multi-organ dysmorphogenesis, and dysregulated hematopoiesis manifested as severe anemia. Herein we performed RNA-seq analysis of gestational day (GD)13.5 yolk sac and placenta, and GD16.5 liver, kidney, lung, heart and cerebellum, comparing Slc39a8(neo/neo) with Slc39a8(+/+) wild-type. Meta-data analysis of differentially-expressed genes revealed 29 unique genes from all tissues - having enriched GO categories associated with hematopoiesis and hypoxia and KEGG categories of complement, response to infection, and coagulation cascade - consistent with dysregulated hematopoietic stem cell fate. Based on transcription factor (TF) profiles in the JASPAR database, and searching for TF-binding sites enriched by Pscan, we identified numerous genes encoding zinc-finger and other TFs associated with hematopoietic stem cell functions. We conclude that, in this mouse model, deficient ZIP8-mediated divalent cation transport affects zinc-finger (e.g. GATA proteins) and other TFs interacting with GATA proteins (e.g. TAL1), predominantly in yolk sac. These data strongly support the phenotype of dysmorphogenesis and anemia seen in Slc39a8(neo/neo) mice in utero.
To explore common biological pathways for attention deficit hyperactivity disorder (ADHD) and low birth weight (LBW). Thei-Gsea4GwasV2 software was used to analyze the result of genome-wide association analysis (GWAS) for LBW (pathways were derived from Reactome), and nominally significant (P< 0.05, FDR< 0.25) pathways were tested for replication in ADHD.Significant pathways were analyzed with DAPPLE and Reatome FI software to identify genes involved in such pathways, with each cluster enriched with the gene ontology (GO). The Centiscape2.0 software was used to calculate the degree of genetic networks and the betweenness value to explore the core node (gene). Weighed gene co-expression network analysis (WGCNA) was then used to explore the co-expression of genes in these pathways.With gene expression data derived from BrainSpan, GO enrichment was carried out for each gene module. Eleven significant biological pathways was identified in association with LBW, among which two (Selenoamino acid metabolism and Diseases associated with glycosaminoglycan metabolism) were replicated during subsequent ADHD analysis. Network analysis of 130 genes in these pathways revealed that some of the sub-networksare related with morphology of cerebellum, development of hippocampus, and plasticity of synaptic structure. Upon co-expression network analysis, 120 genes passed the quality control and were found to express in 3 gene modules. These modules are mainly related to the regulation of synaptic structure and activity regulation. ADHD and LBW share some biological regulation processes. Anomalies of such proces sesmay predispose to ADHD.
Topoisomerase IIβ (topoIIβ) is a nuclear enzyme specifically expressed in neurons, and plays an important role in the development of the cerebellum. To date, the expression of topoIIβ protein in medulloblastoma (MB) has not been investigated. In this study, 16 MB specimens including 10 classical subtypes of MB and 6 desmoplastic subtypes of MB (DMB), along with 5 normal cerebellum samples, were obtained from clinics. With immunohistochemical staining, prominently expressed topoIIβ was seen in normal cerebellar tissues, while there was no or less pronounced staining in classical MB cells. Interestingly, on comparing topoIIβ expression in different regions of DMB samples, relatively high levels of topoIIβ were revealed within nodules composed of differentiated neurocytic cells, which are known to predict a favorable clinical outcome for MB. We also examined the expression of two epigenetic factors, H3K27me3 and JMJD3 in the different tissues. Very high levels of H3K27me3 were found in all MB samples, except the intranodules of DMB, where JMJD3 expression was more prominent. Furthermore, a negative correlation between topoIIβ and H3K27me3 in MB was revealed in this study. Thus, our data primarily indicate that topoIIβ can be used to estimate neuronal differentiation in MB, and may serve as a target for improving the survival rates for this condition. We speculate that H3K27me3 repression of topoIIβ at the transcriptional level may occur, although this needs to be verified using larger numbers of MB samples in future experiments.
The fruit of Psoralea corylifolia L., Psoraleae fructus (PF), is widely used in traditional Chinese medicine as a well-known herbal tonic. Previous studies have shown that PF and its major constituents may have potential values in the treatment of Parkinson and Alzheimer diseases, though their pharmacokinetics and brain distribution were largely unknown. To develop a liquid chromatographic-tandem mass spectrometry (LC-MS/MS) method for simultaneous studies of the plasma pharmacokinetics and cerebral nuclei (including cerebellum, thalamus, brainstem, hippocampus, corpus striatum and cortex) distribution in rats of eleven known PF compounds following as psoralen, isopsoralen, psoralidin, bavachin, bavachinin, isobavachin, isobavachalcone, bavachalcone, neobavaisoflavone, corylifol A, and corylin. Rats were orally administered via gavage at a single dose of PF extract at 1.2 g/kg. The eleven known PF compounds were extracted from rat plasma and cerebral nuclei at different time points, and then determined by the established LC-MS/MS method. Non-compartmental pharmacokinetic profiles were calculated, and the distribution in rat plasma and cerebral nuclei were compared. The results showed that all the tested compounds were quickly absorbed into rat plasma and distributed almost evenly to the cerebral nuclei. The distribution concentrations at different nuclei varied at one determined time point, but the overall trends were basically similar to the plasma concentration-time results. Psoralen and isopsoralen, the two highest coumarins contained in PF, displayed far higher plasma concentrations (AUC≈53,884∼65,578 ng·h/ml) and central nervous system penetration (AUC ≈44,659∼65,823 ng·h/g) than the prenylflavonoids (other compounds except psoralidin, AUC≈69∼324 ng·h/ml; AUC ≈119∼3662 ng·h/g). However, the total brain-to-plasma ratios of the prenylflavonoids were higher than the coumarins, suggesting the prenylflavonoids can more readily enter the brain than the coumarins. The established LC-MS/MS method is sensitive and specific for the simultaneous quantitation of the eleven PF compounds in rat plasma and cerebral nuclei. The results of plasma pharmacokinetics and cerebral nuclei distribution may reveal the possible substance basis for the CNS activities of PF, and highlight the application possibility of PF and its major constituents in the treatment of Parkinson and Alzheimer diseases.
During the past several years, the rapid development of neuroimaging techniques has contributed greatly in the noninvasive imaging studies of tinnitus. The aim of the present study was to explore the brain anatomical alterations in patients with right-sided unilateral pulsatile tinnitus (PT) in the early stage of PT symptom using voxel-based morphometry (VBM) analysis. Twenty-four patients with right-sided pulsatile tinnitus and 24 age- and gender-matched normal controls were recruited to this study. Structural image data preprocessing was performed using VBM8 toolbox. Tinnitus Handicap Inventory (THI) score was acquired in the tinnitus group to assess the severity of tinnitus and tinnitus-related distress. Two-sample -test and Pearson's correlation analysis were used in statistical analysis. Patients with unilateral pulsatile tinnitus had significantly increased gray matter (GM) volume in bilateral superior temporal gyrus compared with the normal controls. However, the left cerebellum posterior lobe, left frontal superior orbital lobe (gyrus rectus), right middle occipital gyrus (MOG), and bilateral putamen showed significantly decreased brain volumes. This was the first study which demonstrated the features of neuroanatomical changes in patients with unilateral PT during their early stages of the symptom.