Interaction between Dietary Lactoferrin and Gut Microbiota in Host Health.

The gut microbiota are known to play an important role in host health and disease. Alterations in the gut microbiota composition can disrupt the stability of the gut ecosystem, which may result in noncommunicable chronic diseases (NCCDs). Remodeling the gut microbiota through personalized nutrition is a novel therapeutic avenue for both disease control and prevention. However, whether there are commonly used gut microbiota-targeted diets and how gut microbiota-diet interactions combat NCCDs and improve health remain questions to be addressed. Lactoferrin (LF), which is broadly used in dietary supplements, acts not only as an antimicrobial in the defense against enteropathogenic bacteria but also as a prebiotic to propagate certain probiotics. Thus, LF-induced gut microbiota alterations can be harnessed to induce changes in host physiology, and the underpinnings of their relationships and mechanisms are beginning to unravel in studies involving humans and animal models.

Selection signatures and landscape genomics analysis to reveal climate adaptation of goat breeds.

Goats have achieved global prominence as essential livestock since their initial domestication, primarily owing to their remarkable adaptability to diverse environmental and production systems. Differential selection pressures influenced by climate have led to variations in their physical attributes, leaving genetic imprints within the genomes of goat breeds raised in diverse agroecological settings. In light of this, our study pursued a comprehensive analysis, merging environmental data with single nucleotide polymorphism (SNP) variations, to unearth indications of selection shaped by climate-mediated forces in goats. Through the examination of 43,300 SNPs from 51 indigenous goat breeds adapting to different climatic conditions using four analytical methods: latent factor mixed models (LFMM), F-statistics (Fst), Extended haplotype homozygosity across populations (XPEHH), and spatial analysis method (SAM), A total of 74 genes were revealed to display clear signs of selection, which are believed to be influenced by climatic conditions. Among these genes, 32 were consistently identified by at least two of the applied methods, and three genes (DENND1A, PLCB1, and ITPR2) were confirmed by all four approaches. Moreover, our investigation yielded 148 Gene Ontology (GO) terms based on these 74 genes, underlining pivotal biological pathways crucial for environmental adaptation. These pathways encompass functions like vascular smooth muscle contraction, cellular response to heat, GTPase regulator activity, rhythmic processes, and responses to temperature stimuli. Of significance, GO terms about endocrine regulation and energy metabolic responses, key for local adaptation were also uncovered, including biological processes, such as cell differentiation, regulation of peptide hormone secretion, and lipid metabolism. These findings contribute to our knowledge of the genetic structure of climate-triggered adaptation across the goat genome and have practical implications for marker-assisted breeding in goats.

Surface-enhanced photoluminescence and Raman spectroscopy of single molecule confined in coupled Au bowtie nanoantenna.

Optical nanoantennas possess broad applications in the fields of photodetection, environmental science, biosensing and nonlinear optics, owing to their remarkable ability to enhance and confine the optical field at the nanoscale. In this article, we present a theoretical investigation of surface-enhanced photoluminescence spectroscopy for single molecules confined within novel Au bowtie nanoantenna, covering a wavelength range from the visible to near-infrared spectral regions. We employ the finite element method to quantitatively study the optical enhancement properties of the plasmonic field, quantum yield, Raman scattering and fluorescence. Additionally, we systematically examine the contribution of nonlocal dielectric response in the gap mode to the quantum yield, aiming to gain a better understanding of the fluorescence enhancement mechanism. Our results demonstrate that altering the configuration of the nanoantenna has a significant impact on plasmonic sensitivity. The nonlocal dielectric response plays a crucial role in reducing the quantum yield and corresponding fluorescence intensity when the gap distance is less than 3 nm. However, a substantial excitation field can effectively overcome fluorescence quenching and enhance the fluorescence intensity. By optimizing nanoantenna configuration, the maximum enhancement of surface-enhanced Raman can be turned to 9 and 10 magnitude orders in the visible and near-infrared regions, and 3 and 4 magnitude orders for fluorescence enhancement, respectively. The maximum spatial resolutions of 0.8 nm and 1.5 nm for Raman and fluorescence are also achieved, respectively. Our calculated results not only provide theoretical guidance for the design and application of new nanoantennas, but also contribute to expanding the range of surface-enhanced Raman and fluorescence technology from the visible to the near-infrared region.

Enhancement and quenching of plasmon-enhanced spectroscopy of single molecule confined in metallic nanoparticle dimers.

We present a theoretical analysis of plasmon-enhanced fluorescence (PEF) and Raman scattering (PERS) spectroscopy of a single molecule confined in the laser-irradiated metallic nanoparticles (NPs) dimer, focusing on the origin of the spectral enhancement and quenching effects. The theoretical method ofD-parameters has been used to calculate the dimer distance-dependent nonlocal dielectric effect in Ag and Au NPs. Meanwhile, other damping rates and electric field enhancements are quantitatively computed by finite element method. Moreover, PEF and PERS spectra of rhodamine 6G are obtained within the density-functional theory. Our calculated results show that the PERS mainly depend on the excitation and emission field enhancements, and thus it occurs at the narrower dimer gap due to the stronger localized plasmon coupling. The PEF is related to fluorescence rate caused by the competition between excitation electric field and quantum efficiency, and the increase of former may enhance the fluorescence intensity while the lower latter lead to reduce the intensity as decreasing the dimer distance. The contribution of nonlocal dielectric effect can significantly reduce the quantum efficiency at smaller distance so that it overcomes the excitation field enhancement, leading to the fluorescence quenching for Au NPs dimer. Furthermore, by optimizing the dimer distance and NPs size, the maximum PERS and PEF cross sections reach 10-14and 10-15under 2.45 eV laser excitation for Ag NPs dimer, and 10-18for Au NPs. Our study finely explains the experiment results showed either fluorescence enhancement or quenching with the change of molecule-NPs distance, and better guidance for optimizing the experiments.

Inhibitory Neurons in Nucleus Tractus Solitarius Are Involved in Decrease of Heart Rate Variability and Development of Depression-Like Behaviors in Temporal Lobe Epilepsy.

BACKGROUND: Diminished heart rate variability (HRV) has been observed in epilepsy, especially in epilepsy with depressive disorders. However, the underlying mechanism remains elusive. METHODS: We studied HRV, spontaneous recurrent seizures, and depression-like behaviors in different phases of pilocarpine-induced temporal lobe epilepsy (TLE) in mice. Single-cell RNA sequencing analysis was used to identify various nerve cell subsets in TLE mice with and without depression. Differentially expressed gene (DEG) analysis was performed in epilepsy, depression, and HRV central control-related brain areas. RESULTS: We found decreased HRV parameters in TLE mice, and alterations were positively correlated with the severity of depression-like behaviors. The severity of depression-like behaviors was correlated with the frequency of spontaneous recurrent seizure. Characteristic expression of mitochondria-related genes was significantly elevated in mice with depression in glial cells, and the enrichment analysis of those DEGs showed an enriched GABAergic synapse pathway in the HRV central control-related brain area. Furthermore, inhibitory neurons in the nucleus tractus solitarius, which is an HRV central control-related brain area, were specifically expressed in TLE mice combined with depression compared with those in mice without depression. A significantly enriched long-term depression pathway in DEGs from inhibitory neurons was found. CONCLUSIONS: Our study reported correlations between HRV and epilepsy-depression comorbidity in different phases of TLE. More importantly, we found that HRV central control-related inhibitory neurons are involved in the development of depression in TLE, providing new insights into epilepsy comorbid with depression.

Complexed Crystal Structure of the Dihydroorotase Domain of Human CAD Protein with the Anticancer Drug 5-Fluorouracil.

Dihydroorotase (DHOase) is the third enzyme in the pathway used for the biosynthesis of pyrimidine nucleotides. In mammals, DHOase is active in a trifunctional enzyme, CAD, which also carries out the activities of carbamoyl phosphate synthetase and aspartate transcarbamoylase. Prior to this study, it was unknown whether the FDA-approved clinical drug 5-fluorouracil (5-FU), which is used as an anticancer therapy, could bind to the DHOase domain of human CAD (huDHOase). Here, we identified huDHOase as a new 5-FU binding protein, thereby extending the 5-FU interactome to this human enzyme. In order to investigate where 5-FU binds to huDHOase, we solved the complexed crystal structure at 1.97 Å (PDB ID 8GVZ). The structure of huDHOase complexed with malate was also determined for the sake of comparison (PDB ID 8GW0). These two nonsubstrate ligands were bound at the active site of huDHOase. It was previously established that the substrate N-carbamoyl-L-aspartate is either bound to or moves away from the active site, but it is the loop that is extended towards (loop-in mode) or moved away (loop-out mode) from the active site. DHOase also binds to nonsubstrate ligands via the loop-out mode. In contrast to the Escherichia coli DHOase model, our complexed structures revealed that huDHOase binds to either 5-FU or malate via the loop-in mode. We further characterized the binding of 5-FU to huDHOase using site-directed mutagenesis and the fluorescence quenching method. Considering the loop-in mode, the dynamic loop in huDHOase should be a suitable drug-targeting site for further designing inhibitors and clinical chemotherapies to suppress pyrimidine biosynthesis in cancer cell lines.

Crystal Structure of Allantoinase from Escherichia coli BL21: A Molecular Insight into a Role of the Active Site Loops in Catalysis

Allantoinase (ALLase; EC 3.5.2.5) possesses a binuclear metal center in which two metal ions are bridged by a posttranslationally carbamylated lysine. ALLase acts as a key enzyme for the biogenesis and degradation of ureides by catalyzing the conversion of allantoin into allantoate. Biochemically, ALLase belongs to the cyclic amidohydrolase family, which also includes dihydropyrimidinase, dihydroorotase, hydantoinase (HYDase), and imidase. Previously, the crystal structure of ALLase from Escherichia coli K-12 (EcALLase-K12) was reported; however, the two active site loops crucial for substrate binding were not determined. This situation would limit further docking and protein engineering experiments. Here, we solved the crystal structure of E. coli BL21 ALLase (EcALLase-BL21) at a resolution of 2.07 Å (PDB ID 8HFD) to obtain more information for structural analyses. The structure has a classic TIM barrel fold. As compared with the previous work, the two missed active site loops in EcALLase-K12 were clearly determined in our structure of EcALLase-BL21. EcALLase-BL21 shared active site similarity with HYDase, an important biocatalyst for industrial production of semisynthetic penicillin and cephalosporins. Based on this structural comparison, we discussed the functional role of the two active site loops in EcALLase-BL21 to better understand the substrate/inhibitor binding mechanism for further biotechnological and pharmaceutical applications.

Frontotemporal phase lag index correlates with seizure severity in patients with temporal lobe epilepsy.

Objectives: To find the brain network indicators correlated with the seizure severity in temporal lobe epilepsy (TLE) by graph theory analysis. Methods: We enrolled 151 patients with TLE and 36 age- and sex-matched controls with video-EEG monitoring. The 90-s interictal EEG data were acquired. We adopted a network analyzing pipeline based on graph theory to quantify and localize their functional networks, including weighted classical network, minimum spanning tree, community structure, and LORETA. The seizure severities were evaluated using the seizure frequency, drug-resistant epilepsy (DRE), and VA-2 scores. Results: Our network analysis pipeline showed ipsilateral frontotemporal activation in patients with TLE. The frontotemporal phase lag index (PLI) values increased in the theta band (4-7 Hz), which were elevated in patients with higher seizure severities (P < 0.05). Multivariate linear regression analysis showed that the VA-2 scores were independently correlated with frontotemporal PLI values in the theta band (ß = 0.259, P = 0.001) and age of onset (ß = -0.215, P = 0.007). Significance: This study illustrated that the frontotemporal PLI in the theta band independently correlated with seizure severity in patients with TLE. Our network analysis provided an accessible approach to guide the treatment strategy in routine clinical practice.

Timing matters: there are significant differences in short-term outcomes between two time points of status epilepticus.

BACKGROUND: In 2015, the International League Against Epilepsy proposed a new conceptual definition of status epilepticus (SE) with two operational dimensions (t1 and t2) to guide emergency treatment. The purpose of this study was to compare clinical characteristics and prognoses of patients at these two different time points. METHODS: We conducted a prospective observational cohort study of consecutive adults diagnosed with SE. In case of convulsive SE, t1 is 5 min and t2 is 30 min, whereas in case of focal SE with impaired consciousness, t1 is 10 min, t2 is 60 min. Data on clinical characteristics, including age, gender, history of prior seizures, neuroimaging, semiology, duration, and etiology of SE, were collected. The primary outcome was mortality, with seizure recurrence as a secondary measure, and functional status as tertiary outcome of enrolled patients at 3 months after SE onset. RESULTS: We screened one hundred patients with SE, with a median age of 66 years and 61% were male. Fifty-six (56.0%) patients reached t1 of SE, while 44 (44.0%) reached t2 of SE. Convulsive SE (52.0%, n = 52) was more common than focal SE with impaired consciousness (48.0%, n = 48). Status epilepticus secondary to an acute symptomatic process was the most common (50%, n = 50). Patients meeting t2 of SE demonstrated a remarkably increased risk of mortality (unadjusted analysis-RR 3.606, 95%CI 1.552-8.376, p = 0.003; adjusted analysis-RR 2.924, 95%CI 1.221-7.003, p = 0.016) and unfavorable functional status (unadjusted analysis-RR 1.803, 95%CI 1.280-2.539, p = 0.001; adjusted analysis-RR 1.664, 95%CI 1.184-2.340, p = 0.003) at 3 months compared to those who only reached t1 of SE. Patients reaching t2 of SE were more likely to experience seizure recurrence, however, there was no significant difference between the two cohorts. CONCLUSIONS: Our study provides strong support for the new definition of SE. Patients meeting t2 of SE tend to have a remarkably increased risk of mortality and unfavorable functional outcomes compared to those who only reached t1 of SE. Furthermore, patients were likely to experience seizure recurrence after undergoing an episode of SE. Physicians must be educated about prompt recognition and appropriate management of SE.

Analysis of World-Scale Mitochondrial DNA Reveals the Origin and Migration Route of East Asia Goats.

Despite much attention on the history of goat evolution, information on origin, demographic history, and expansion route remains controversial. To address these questions, we collected 4,189 published goat DNA sequences including 1,228 sequences from 57 breeds in China and 2,961 sequences including 193 goat breeds from 71 other countries and carried out an integrated analysis. We found goat breeds from South China had the highest genetic diversity of lineage B, and subclades B2 only were found in Southwest China, suggesting that lineage B (particularly, subclade B2) probably originated from Southwest China and its surrounding areas. In addition, in this study, we found that lineage A from South China also presented higher genetic diversity and earlier expansion time (10, 606 years ago), even earlier than breeds from the Middle East. Hence, we speculated that South China and surrounding areas were the origin of lineage B and also the transportation hub for lineage A spreading to North China and Southwest Asia. Furthermore, according to the analysis of correlation between genetic differentiation value λ1 and λ2 and geographical distance, we further confirmed two phases of migration in goat breeds of North China. These results will contribute to a better understanding of the origin and migration history of domestic goat.

Felt Stigma and Its Underlying Contributors in Epilepsy Patients.

Objective: To explore the correlated clinical and psychological factors of stigmatization and investigate the relationship between stigma and white matter abnormalities in epilepsy patients. Methods: Stigmatization was obtained by a three-item stigma scale in 256 epilepsy patients with genetic or unknown etiology. Personality and quality of life (QOL) were assessed by Eysenck Personality Questionnaire (EPQ) and QOL-31 questionnaire respectively. One hundred and fourteen of them were performed Hamilton Depression Scale-17 (HAMD) and scanned with diffusion tensor imaging in 3T MRI. Fractional anisotropy (FA) values of frontotemporal contact fibers were calculated. Results: There were about 39.8% patients felt stigma, with the highest score (Score 3) in 8.2% (21/256). Stigma scores were significantly negatively correlated with education (P < 0.01), age of onset (P < 0.05), extraversion score of EPQ (P < 0.01), total and all the subscale QOL scores (P < 0.001), and positively correlated with duration (P < 0.01), HAMD score (P < 0.001), neuroticism score of EPQ (P < 0.001). We found negative correlation between stigma scores and FA values of right superior longitudinal fasciculus and left cingulum (P < 0.05). Logistic regression results showed that FA value of left cingulum (P = 0.011; OR = 0.000), social function (P = 0.000; OR = 0.935) of QOL, and neuroticism score of EPQ (P = 0.033; OR = 1.123) independently correlated to felt stigma. Conclusion: Felt stigma in epilepsy patients was found to be correlated with neuroticism, depression, and deficient social function of QOL, which might be predisposed by the impairment of the left cingulum. Our results provide preliminary evidence for the underlying neural circuits in stigmatization.

Interictal Heart Rate Variability as a Biomarker for Comorbid Depressive Disorders among People with Epilepsy.

Depressive disorders are common among people with epilepsy (PwE). We here aimed to report an unbiased automatic classification of epilepsy comorbid depressive disorder cases via training a linear support vector machine (SVM) model using the interictal heart rate variability (HRV) data. One hundred and eighty-six subjects participated in this study. Among all participants, we recorded demographic information, epilepsy states and neuropsychiatric features. For each subject, we performed simultaneous electrocardiography and electroencephalography recordings both in wakefulness and non-rapid eye movement (NREM) sleep stage. Using these data, we systematically explored the full parameter space in order to determine the most effective combinations of data to classify the depression status in PwE. PwE with depressive disorders exhibited significant alterations in HRV parameters, including decreased time domain and nonlinear domain values both in wakefulness and NREM sleep stage compared with without depressive disorders and non-epilepsy controls. Interestingly, PwE without depressive disorder showed the same level of HRV values as the non-epilepsy control subjects. The SVM classification model of PwE depression status achieved a higher classification accuracy with the combination of HRV parameters in wakefulness and NREM sleep stage. Furthermore, the receiver operating characteristic (ROC) curve of the SVM classification model showed a satisfying area under the ROC curve (AUC: 0.758). Intriguingly, we found that the HRV measurements during NREM sleep are particularly important for correct classification, suggesting a mechanistic link between the dysregulation of heart rate during sleep and the development of depressive disorders in PwE. Our classification model may provide an objective measurement to assess the depressive status in PwE.

Development of emergent ferroelectric nematic liquid crystals with highly fluorinated and rigid mesogens.

The emerging ferroelectric nematic liquid crystals have been attracting broader interests in new liquid crystal physics and their unique material properties. One big challenge for the ferroelectric nematic research is to enrich the material choice, which is now limited to RM734 and DIO families as representatives, in sharp contrast to the enormously diverse variety of the traditional apolar nematic liquid crystals. Here, we report a design of novel ferroelectric nematic materials with highly fluorinated and rigid mesogens. Noteworthily, they show distinct chemical structural features compared with previous aromatic ester-based molecules. The ferroelectric nematic phase was identified and confirmed through rigorous experiments. The bulk polarization was found to become purely along the long axis director, creating giant dielectric anisotropy. This work demonstrates a great potential for expanding ferroelectric nematic material diversity and will accelerate the corresponding application research and technology innovation.

The effect of lactoferrin in aging: role and potential.

Aging is frequently accompanied by various types of physiological deterioration, which increases the risk of human pathologies. Global public health efforts to increase human lifespan have increasingly focused on lowering the risk of aging-related diseases, such as diabetes, neurodegenerative diseases, cardiovascular disease, and cancers. Dietary intervention is a promising approach to maintaining human health during aging. Lactoferrin (LF) is known for its physiologically pleiotropic properties. Anti-aging interventions of LF have proven to be safe and effective for various pharmacological activities, such as anti-oxidation, anti-cellular senescence, anti-inflammation, and anti-carcinogenic. Moreover, LF has a pivotal role in modulating the major signaling pathways that influence the longevity of organisms. Thus, LF is expected to be able to attenuate the process of aging and greatly ameliorate its effects.

TPPU Pre-Treatment Rescues Dendritic Spine Loss and Alleviates Depressive Behaviours during the Latent Period in the Lithium Chloride-Pilocarpine-Induced Status Epilepticus Rat Model.

Epileptogenesis may be responsible for both of recurrent seizures and comorbid depression in epilepsy. Disease-modifying treatments targeting the latent period before spontaneous recurrent seizures may contribute to the remission of seizures and comorbid depression. We hypothesized that pre-treatment with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), a soluble epoxide hydrolase (sEH) inhibitor, which has anti-inflammatory and neuroprotective effects might rescue status epilepticus (SE)-induced dendritic spine loss and alleviate depressive behaviours. Rats were either pre-treated with TPPU (0.1 mg/kg/d) intragastrically or with vehicle (40% polyethylene glycol 400) from 7 days before to 7 days after SE that was induced with lithium chloride and pilocarpine intraperitoneally. Rats in the Control group were given saline instead. The forced swim test (FST) was performed on the 8th day after SE to evaluate the depression-like behaviours in rats. The results showed that seizures severity during SE was significantly decreased, and the immobility time during FST was significantly increased through TPPU pre-treatment. Moreover, pre-treatment with TPPU attenuated inflammations including microglial gliosis and the level of proinflammatory cytokine IL-1ß in the hippocampus; in addition, neuronal and dendritic spine loss in the subfields of hippocampus was selectively rescued, and the expression of NR1 subunit of N-methyl-D-aspartate (NMDA) receptor, ERK1/2, CREB, and their phosphorylated forms involved in the dendritic spine development were all significantly increased. We concluded that pre-treatment with TPPU attenuated seizures severity during SE and depressive behaviours during the period of epileptogenesis probably by rescuing dendritic spine loss in the hippocampus.

Efficacy of cathodal transcranial direct current stimulation on electroencephalographic functional networks in patients with focal epilepsy: Preliminary findings.

BACKGROUND: Neuromodulation is a promising therapeutic alternative for epilepsy. We aimed to explore the efficacy and safety of cathodal transcranial current direct stimulation (ctDCS) on electroencephalographic functional networks in focal epilepsy. METHODS: A sham-controlled, double-blinded, randomized study was conducted on 25 participants with focal epilepsy who underwent a 5-day, -1.0 mA, 20 min ctDCS, which targeted at the most active interictal epileptiform discharge (IED) region. We examined the electroencephalograms (EEGs) at baseline, immediately and at 4 weeks following ctDCS. The graph theory-based brain networks were established through time-variant partial directed coherence (TVPDC), and were calculated between each pair of EEG signals. The functional networks were characterized using average clustering coefficient, characteristic path length, and small-worldness index. The seizure frequencies, IEDs, graph-theory metrics and cognitive tests were compared. RESULTS: Preliminary findings indicated an IED reduction of 30.2% at the end of 5-day active ctDCS compared to baseline (p < 0.10) and a significant IED reduction of 33.4% 4 weeks later (p < 0.05). In terms of the EEG functional network, the small-worldness index significantly reduced by 3.5% (p < 0.05) and the characteristic path length increased by 1.8% (p < 0.10) at the end of the session compared to the baseline. No obvious change was found in the seizure frequency during follow-up (p > 0.05). The Mini-Mental State Examination (MMSE) showed no difference between the active and sham groups (p > 0.05). No severe adverse reactions were observed. CONCLUSIONS: In focal epilepsy, the 5-day consecutive ctDCS may potentially decrease the IEDs and ameliorate the EEG functional network, proposing a novel personalized therapeutic scenario for epilepsy.

A survey on doctors' cognition of depression in patients with epilepsy.

OBJECTIVE: This survey aimed to assess doctors' cognition on depressive symptoms in patients with epilepsy in Shanghai China. METHODS: Questionnaires were handed out to doctors who have taken part in the epilepsy care, covering those from all third-grade hospitals and several second-grade hospitals in Shanghai China. Respondents were asked to make choices for their demographic profiles, clinical practices, acquired knowledge of, and attitudes toward the comorbidity of epilepsy and depression. RESULTS: A total of 282 questionnaires were collected from 16 hospitals in Shanghai China, of which 280 copies were included in the statistical analysis. Respondents were mainly less than 50 years (260, 92.8%), mostly residents and attendings (206, 73.6%), and mostly master and doctor's degrees (225, 80.3%). The ratio of epileptologists and nonepileptologists was 56 (20.1%):224 (79.9%). Compared to nonepileptologists and residents, epileptologists and doctors with higher professional titles were more likely to answer that they received a higher percentage of patients with the comorbidity of epilepsy and depression (≥30%), and they knew very well about the knowledge, and held the view that depression exacerbated seizures (p < .05). Surprisingly, most doctors including chief doctors and epileptologists answered that they had difficulties in prescribing antidepressants. Quite a few doctors from lower class hospitals even preferred to use tricyclic antidepressants for controlling depressive symptoms in patients with epilepsy. SIGNIFICANCE: Doctors, especially younger doctors and nonepileptologists, need more training to get knowledge of the comorbidity of epilepsy and depression. However, the therapeutic methods for depressive symptoms in patients with epilepsy were still limited and in a challenge.

Functional Network Alterations as Markers for Predicting the Treatment Outcome of Cathodal Transcranial Direct Current Stimulation in Focal Epilepsy.

BACKGROUND AND PURPOSE: Transcranial direct current stimulation (tDCS) is an emerging non-invasive neuromodulation technique for focal epilepsy. Because epilepsy is a disease affecting the brain network, our study was aimed to evaluate and predict the treatment outcome of cathodal tDCS (ctDCS) by analyzing the ctDCS-induced functional network alterations. METHODS: Either the active 5-day, -1.0 mA, 20-min ctDCS or sham ctDCS targeting at the most active interictal epileptiform discharge regions was applied to 27 subjects suffering from focal epilepsy. The functional networks before and after ctDCS were compared employing graph theoretical analysis based on the functional magnetic resonance imaging (fMRI) data. A support vector machine (SVM) prediction model was built to predict the treatment outcome of ctDCS using the graph theoretical measures as markers. RESULTS: Our results revealed that the mean clustering coefficient and the global efficiency decreased significantly, as well as the characteristic path length and the mean shortest path length at the stimulation sites in the fMRI functional networks increased significantly after ctDCS only for the patients with response to the active ctDCS (at least 20% reduction rate of seizure frequency). Our prediction model achieved the mean prediction accuracy of 68.3% (mean sensitivity: 70.0%; mean specificity: 67.5%) after the nested cross validation. The mean area under the receiver operating curve was 0.75, which showed good prediction performance. CONCLUSION: The study demonstrated that the response to ctDCS was related to the topological alterations in the functional networks of epilepsy patients detected by fMRI. The graph theoretical measures were promising for clinical prediction of ctDCS treatment outcome.

The Management and Alternative Therapies for Comorbid Sleep Disorders in Epilepsy.

BACKGROUND: There is a complex and interactive relationship between sleep and epilepsy. Sleep disorders are common in patients with epilepsy, and methods for managing sleep disorders in patients with epilepsy are limited. OBJECTIVE: This review addresses the relationship among sleep, sleep disorders, and epilepsy, focusing on the management of sleep disorders in epilepsy, including some complementary and alternative therapies. METHODS: The terms related to "sleep" and "epilepsy" were searched in "Pubmed" and "Cochrane Library". RESULTS: Sleep stages differently affect both seizures and interictal epileptiform discharges. Seizures disrupt sleep architecture greatly, especially when occurring during sleep in the night. Insomnia and obstructive sleep apnea (OSA) are the most frequent types of comorbid sleep disorders in patients with epilepsy. Pharmacological agents with both anti-convulsant and sedative effects are the priorities for comorbid sleep disorders in epilepsy. Continuous positive airway pressure (CPAP) therapy is the most effective non-pharmacological method to improve OSA and reduce seizures. Complementary and alternative therapies such as Chinese traditional medicine, cognitive behavioral therapy, meditation, yoga, neurofeedback, and acupuncture may have benefits in reducing seizures and improving sleep quality simultaneously by alleviating stress and seizure triggers; however, evidence- based therapies are still deficient. CONCLUSION: Management of sleep disorders in patients with epilepsy is challenging. Large-scale randomized controlled clinical trials are in demand to guide the treatments in the future.

Anti-inflammatory treatment with a soluble epoxide hydrolase inhibitor attenuates seizures and epilepsy-associated depression in the LiCl-pilocarpine post-status epilepticus rat model.

PURPOSE: This study aimed to investigate whether 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), a soluble epoxide hydrolase inhibitor with anti-inflammatory effects, could alleviate spontaneous recurrent seizures (SRS) and epilepsy-associated depressive behaviours in the lithium chloride (LiCl)-pilocarpine-induced post-status epilepticus (SE) rat model. METHODS: The rats were intraperitoneally (IP) injected with LiCl (127 mg/kg) and pilocarpine (40 mg/kg) to induce SE. A video surveillance system was used to monitor SRS in the post-SE model for 6 weeks (from the onset of the 2nd week to the end of the 7th week after SE induction). TPPU (0.1 mg/kg/d) was intragastrically given for 4 weeks from the 21st day after SE induction in the SRS + 0.1 TPPU group. The SRS + PEG 400 group was given the vehicle (40% polyethylene glycol 400) instead, and the control group was given LiCl and PEG 400 but not pilocarpine. The sucrose preference test (SPT) and forced swim test (FST) were conducted to evaluate the depression-like behaviours of rats. Immunofluorescent staining, enzyme-linked immunosorbent assay, and western blot analysis were performed to measure astrocytic and microglial gliosis, neuronal loss, and levels of soluble epoxide hydrolase (sEH), cytokines [tumour necrosis factor alpha (TNF-α), interleukin (IL)-1ß, and IL-6], and cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB). RESULTS: The frequency of SRS was significantly decreased at 6 weeks and 7 weeks after SE induction in the 0.1TPP U group compared with the SRS + PEG 400 group. The immobility time (IMT) evaluated by FST was significantly decreased, whereas the climbing time (CMT) was increased, and the sucrose preference rate (SPR) evaluated by SPT was in an increasing trend. The levels of sEH, TNF-α, IL-1ß, and IL-6 in the hippocampus (Hip) and prefrontal cortex (PFC) were all significantly increased in the SRS + PEG 400 group compared with the control group; neuronal loss, astrogliosis, and microglial activation were also observed. The astrocytic and microglial activation and levels of the pro-inflammatory cytokines in the Hip and PFC were significantly attenuated in the TPPU group compared with the SRS + PEG 400 group; moreover, neuronal loss and the decreased CREB expression were significantly alleviated as well. CONCLUSION: TPPU treatment after SE attenuates SRS and epilepsy-associated depressive behaviours in the LiCl-pilocarpine induced post-SE rat model, and it also exerts anti-inflammatory effects in the brain. Our findings suggest a new therapeutic approach for epilepsy and its comorbidities, especially depression.