Functional connectivity of the language area in migraine: a preliminary classification model.

BACKGROUND: Migraine is a complex disorder characterized by debilitating headaches. Despite its prevalence, its pathophysiology remains unknown, with subsequent gaps in diagnosis and treatment. We combined machine learning with connectivity analysis and applied a whole-brain network approach to identify potential targets for migraine diagnosis and treatment. METHODS: Baseline anatomical T1 magnetic resonance imaging (MRI), resting-state functional MRI(rfMRI), and diffusion weighted scans were obtained from 31 patients with migraine, and 17 controls. A recently developed machine learning technique, Hollow Tree Super (HoTS) was used to classify subjects into diagnostic groups based on functional connectivity (FC) and derive networks and parcels contributing to the model. PageRank centrality analysis was also performed on the structural connectome to identify changes in hubness. RESULTS: Our model attained an area under the receiver operating characteristic curve (AUC-ROC) of 0.68, which rose to 0.86 following hyperparameter tuning. FC of the language network was most predictive of the model's classification, though patients with migraine also demonstrated differences in the accessory language, visual and medial temporal regions. Several analogous regions in the right hemisphere demonstrated changes in PageRank centrality, suggesting possible compensation. CONCLUSIONS: Although our small sample size demands caution, our preliminary findings demonstrate the utility of our method in providing a network-based perspective to diagnosis and treatment of migraine.

Brain alterations in patients with intractable tinnitus before and after rTMS: A resting-state functional magnetic resonance imaging study.

OBJECTIVE: To observe abnormal tinnitus activity by evaluating the amplitude of low-frequency fluctuation (ALFF) changes in the brain was which detected by resting-state functional magnetic resonance imaging (rs-fMRI) in patients with intractable tinnitus before and after repetitive transcranial magnetic stimulation (rTMS). We hypothesized that rTMS could progressively revert local brain function back to a relatively normal range. METHODS: This prospective observational research study recruited 25 patients with intractable tinnitus, with 28 healthy controls matched by age, sex, and education level. Participants' Tinnitus Handicap Inventory (THI) scores and the visual analog scale (VAS) were used to determine the severity of their tinnitus before and after treatment. We processed the brain spontaneous neural activity of intractable tinnitus patients by ALFF, then, we determined its association with clinically evaluated indicators of intractable tinnitus. RESULTS: The total and the three sub-modules (functional [F], emotional [E], and catastrophic [C]) score of the THI and VAS in patients with intractable tinnitus decreased after treatment (P < 0.001). The effective rate of tinnitus patients was 66.9%. A few patients had a slight left facial muscle tremor or temporary mild scalp pain during treatment. Compared with healthy controls, participants with tinnitus significantly reduced ALFF within the left and right medial superior frontal gyrus (P < 0.005). After rTMS treatment, the left fusiform gyrus and right superior cerebellar lobe increased ALFF in those with tinnitus (P < 0.005). The changes in THI, VAS, and ALFF were positively correlated (P < 0.05). CONCLUSION: RTMS is effective in the treatment of tinnitus. It significantly reduces the THI/VAS score and improves the symptoms of tinnitus. No serious adverse reaction during rTMS were reported. The changes in the left fusiform gyrus and right superior part of the cerebellum may explain the mechanism of rTMS treatment in intractable tinnitus.

A novel effect of PDLIM5 in α7 nicotinic acetylcholine receptor upregulation and surface expression.

Nicotinic acetylcholine receptors (nAChRs) are widespread throughout the central nervous system. Signaling through nAChRs contributes to numerous higher-order functions, including memory and cognition, as well as abnormalities such as nicotine addiction and neurodegenerative disorders. Although recent studies indicate that the PDZ-containing proteins comprising PSD-95 family co-localize with nicotinic acetylcholine receptors and mediate downstream signaling in the neurons, the mechanisms by which α7nAChRs are regulated remain unclear. Here, we show that the PDZ-LIM domain family protein PDLIM5 binds to α7nAChRs and plays a role in nicotine-induced α7nAChRs upregulation and surface expression. We find that chronic exposure to 1 µM nicotine upregulated α7, ß2-contained nAChRs and PDLIM5 in cultured hippocampal neurons, and the upregulation of α7nAChRs and PDLIM5 is increased more on the cell membrane than the cytoplasm. Interestingly, in primary hippocampal neurons, α7nAChRs and ß2nAChRs display distinct patterns of expression, with α7nAChRs colocalized more with PDLIM5. Furthermore, PDLIM5 interacts with α7nAChRs, but not ß2nAChRs in native brain neurons. Knocking down of PDLIM5 in SH-SY5Y abolishes nicotine-induced upregulation of α7nAChRs. In primary hippocampal neurons, using shRNA against PDLIM5 decreased both surface clustering of α7nAChRs and α7nAChRs-mediated currents. Proteomics analysis and isothermal titration calorimetry (ITC) results show that PDLIM5 interacts with α7nAChRs through the PDZ domain, and the interaction between PDLIM5 and α7nAChRs can be promoted by nicotine. Collectively, our data suggest a novel cellular role of PDLIM5 in the regulation of α7nAChRs, which may be relevant to plastic changes in the nervous system.

The Regulation of Lipid Binding and Kinase Activities of EphA2 Kinase Domain by Its Adjacent SAM Domain / 中国生物化学与分子生物学报

The erythropoietin-producing hepatocellular receptor (Eph receptor) family is the largest subfamily in the receptor tyrosine kinase (RTK) families which mediates cell morphology, adhesion, movement, proliferation, survival, and differentiation by its bidirectional signals coupled with Ephrin ligands. EphA2 receptor is an important isoform which is involved in the pathological changes in cataract, breast cancer, etc. Previous studies found that the kinase domain of the EphA2 receptor binds to the plasma membrane, and its kinase activity is regulated by the plasma membrane. However, it is still unclear that the impact of the adjacent SAM domain on the membrane binding and kinase activities of kinase domain. In this study we purified the cytoplasmic kinase-SAM tandem of the EphA2 receptor by co-expression with the phosphatase PTP1B 1-301 fragment. Our results showed that the SAM domain of EphA2 receptor can further enhance the interaction between the kinase domain and liposomes (4 mg/mL) by 6 folds (P<0. 001). And the phosphorylation of kinase-SAM tandem can enhance its lipid (4 mg/mL) binding ability by 2. 5 folds (P < 0. 05). In addition, the lipid binding ability and tyrosine phosphorylation activities of kinase domain are mutual promoted, which creating a positive feedback loop in the two biological processes. In conclusion, our studies indicate that the kinase domain and the adjacent SAM domain can function as an intact unit, whose lipid binding ability and kinase activity are quite different from the individual kinase domain. Therefore, our results provide a biochemical basis for better understanding of the regulation mechanism of other Eph receptors in its kinase domain.

Altered expression of DENND5B in patients with epilepsy and its regulation of seizures in mice.

Epilepsy is a high incidence neurological disease, and its repeated attacks cause serious physical and psychological damage to the patient. Differentially expressed in normal and neoplastic cells (DENN) domain containing 5B (DENND5B) is a lipoprotein binding protein that mediates synaptic vesicle transport and regulates neuroplasticity and lipid metabolism. Nevertheless, the effect of DENND5B on seizures remains unclear. We aimed to investigate the association of DENND5B with epilepsy, detect its expression and distribution in the nervous system, and explore its role in epileptogenesis through western blot, immunofluorescence staining, and behavioral studies. In this experiment, two C57BL/6 mice models, which induced seizures by pentylenetetrazole and kainic acid, were established. We observed that the expression of DENND5B was reduced in the brains of patients with temporal lobe epilepsy, and its expression was also similarly decreased in both chronic epileptic mice. The findings strongly suggest that DENND5B may be associated with epileptic seizures. Results of immunofluorescence showed that DENND5B was mainly expressed in the hippocampal region and co-located with neurons but not with astrocytes. Next, we used lentivirus to induce both lentiviral vector-mediated overexpression and knockdown of DENND5B in mice to test the change of susceptibility and severity of seizures in the two chronic seizure models. Knockdown of DENND5B was found to promote epileptic seizures, increase chronic spontaneous recurrent epileptic seizures and epileptic discharge, and reduce the incubation period. However, overexpression of DENND5B showed the opposite effect. These results suggest that DENND5B overexpression decreased the behavioral phenotype of epileptic seizures, but DENND5B downregulation had the opposite effect. In summary, our findings suggest that DENND5B can regulate epileptic seizures and may provide a new target for antiepileptic therapy.

Prenatal diagnosis of Meier-Gorlin syndrome 7: a case presentation.

BACKGROUND: Meier-Gorlin syndrome 7 (MGS7) is a rare autosomal recessive condition. We reported a fetus diagnosed with Meier-Gorlin syndrome 7. The antenatal sonographic images were presented, and compound heterozygous mutations of CDC45 on chromosome 22 were identified by whole-exome sequencing (WES). CASE PRESENTATION: Fetal growth restriction (FGR), craniosynostosis, and brachydactyly of right thumb were found in a fetus of 28th gestational weeks. The fetus was diagnosed as MGS7 clinically. After extensive counseling, the couple opted for prenatal diagnosis by cordocentesis and termination of pregnancy. Karyotype analysis and WES were performed. Chromosomal karyotyping showed that the fetus was 46, XY. There were 2 mutations of CDC45, the causal gene of MGS7 on chromosome 22, which were inherited from the couple respectively were identified by WES. Facial dysmorphism, brachydactyly of right thumb, and genitalia abnormally were proved by postpartum autopsy, and craniosynostosis was confirmed by three-dimensional computed tomography (3D-CT) reconstruction. CONCLUSIONS: It is possible to detect multiple clinical features of Meier-Gorlin syndrome in prenatal sonography. Deteriorative FGR complicated with craniosynostosis indicates MGS7. Combination of 2D and 3D ultrasonography helps to detect craniosynostosis. The affected fetus was confirmed a compound heterozygote of CDC45 related MGS by whole-exome sequencing, which is critical in identifying rare genetic diseases.

Comparative Study of Brain fMRI of Olfactory Stimulation in Neuromyelitis Optica Spectrum Disease and Multiple Sclerosis.

Objective: To observe the characteristics of brain fMRI during olfactory stimulation in patients with neuromyelitis optica spectrum disease (NMOSD) and multiple sclerosis (MS), compare the differences of brain functional activation areas between patients with NMOSD and MS, and explore the characteristics of olfactory-related brain networks of NMOSD and MS. Methods: Nineteen patients with NMOSD and 16 patients with MS who met the diagnostic criteria were recruited, and 19 healthy controls matched by sex and age were recruited. The olfactory function of all participants was assessed using the visual analog scale (VAS). Olfactory stimulation was alternately performed using a volatile body (lavender and rose solution) and the difference in brain activation was evaluated by task-taste fMRI scanning simultaneously. Results: Activation intensity was weaker in the NMOSD group than in the healthy controls, including the left rectus, right superior temporal gyrus, and left cuneus. The activation intensity was stronger for the NMOSD than the controls in the left insula and left middle frontal gyrus (P < 0.05). Activation intensity was weaker in the MS group than the healthy controls in the bilateral hippocampus, right parahippocampal gyrus, right insula, left rectus gyrus, and right precentral gyrus, and stronger in the left paracentral lobule among the MS than the controls (P < 0.05). Compared with the MS group, activation intensity in the NMOSD group was weaker in the right superior temporal gyrus and left paracentral lobule, while it was stronger among the NMOSD group in the bilateral insula, bilateral hippocampus, bilateral parahippocampal gyrus, left inferior orbital gyrus, left superior temporal gyrus, left putamen, and left middle frontal gyrus (P < 0.05). Conclusion: Olfactory-related brain networks are altered in both patients, and there are differences between their olfactory-related brain networks. It may provide a new reference index for the clinical differentiation and disease evaluation of NMOSD and MS. Moreover, further studies are needed.

[Retrospective Analysis of Neurological Symptoms of Severe/Critical COVID-19 Patients in Sichuan Province].

OBJECTIVE: To retrospectively analyze the symptoms and characteristics of nervous system damage in severe/critically severe patients with coronavirus disease 2019 (COVID-19) in Sichuan province, with a view to providing basic references for the prevention and treatment of COVID-19. METHODS: A total of 90 patients with severe/critically severe COVID-19 were included, who were diagnosed and treated in COVID-19 designated hospital of Sichuan province from 11 January 2020 to 20 March 2020. Clinical features, test results, treatment options and clinical outcomes were analyzed retrospectively. RESULTS: Of 90 patients, there were 54 males and 36 females, with an average age of (53.90±16.92) years. In addition to the classic symptoms such as fever and/or respiratory symptoms, 53 patients also had various degrees of neurologic manifestations, including 33 cases of fatigue, 21 muscle soreness, 12 dizziness, 8 headaches, 3 mental disorders, and 1 consciousness disorders and 1 case of neck pain. Compared with the patients without neurologic manifestations, those with neurologic manifestations took a longer time from admission to diagnosis of COVID-19 ( P<0.05), and received more antifungal treatment ( P<0.05). CONCLUSIONS: Neurological symptoms are not uncommon in severe/critically severe patients with COVID-19, and it's relatively difficult in the treatment. It should be paid attention in order to avoid misdiagnosis.

Nicotine recruits glutamate receptors to postsynaptic sites.

Cholinergic neurons project throughout the nervous system and activate nicotinic receptors to modulate synaptic function in ways that shape higher order brain function. The acute effects of nicotinic signaling on long-term synaptic plasticity have been well-characterized. Less well understood is how chronic exposure to low levels of nicotine, such as those encountered by habitual smokers, can alter neural connections to promote addiction and other lasting behavioral effects. We show here that chronic exposure of hippocampal neurons in culture to low levels of nicotine recruits AMPA and NMDA receptors to the cell surface and sequesters them at postsynaptic sites. The receptors include GluA2-containing AMPA receptors, which are responsible for most of the excitatory postsynaptic current mediated by AMPA receptors on the neurons, and include NMDA receptors containing GluN1 and GluN2B subunits. Moreover, we find that the nicotine treatment also increases expression of the presynaptic component synapsin 1 and arranges it in puncta juxtaposed to the additional AMPA and NMDA receptor puncta, suggestive of increases in synaptic contacts. Consistent with increased synaptic input, we find that the nicotine treatment leads to an increase in the excitatory postsynaptic currents mediated by AMPA and NMDA receptors. Further, the increases skew the ratio of excitatory-to-inhibitory input that the cell receives, and this holds both for pyramidal neurons and inhibitory neurons in the hippocampal CA1 region. The GluN2B-containing NMDA receptor redistribution at synapses is associated with a significant increase in GluN2B phosphorylation at Tyr1472, a site known to prevent GluN2B endocytosis. These results suggest that chronic exposure to low levels of nicotine not only alters functional connections but also is likely to change excitability levels across networks. Further, it may increase the propensity for synaptic plasticity, given the increase in synaptic NMDA receptors.

[Expression of aquaporins 1, 3, 8, 9 mRNA in human fetal membranes].

OBJECTIVE: To investigate the expression of aquaporin (AQP)-1, 3, 8, 9 in human fetal membrane and their role in the human amniotic fluid circulation. METHODS: RT-PCR was employed for detection of the expressions of AQP-1, 3, 8, 9 mRNA in human amnion and chorion from 20 women with normal term pregnancy. RESULTS: AQP-1, 3, 8, 9 mRNA expression was detected in both human amnion and chorion, and no significant difference was found in their expression levels or between the amnion and chorion (P>0.05). CONCLUSION: AQP-1, 3, 8, 9 can be associated with intramembranous transport and volume regulation of amniotic fluid.