Dynamic functional connectivity and gene expression correlates in temporal lobe epilepsy: insights from hidden markov models.

BACKGROUD: Temporal lobe epilepsy (TLE) is associated with abnormal dynamic functional connectivity patterns, but the dynamic changes in brain activity at each time point remain unclear, as does the potential molecular mechanisms associated with the dynamic temporal characteristics of TLE. METHODS: Resting-state functional magnetic resonance imaging (rs-fMRI) was acquired for 84 TLE patients and 35 healthy controls (HCs). The data was then used to conduct HMM analysis on rs-fMRI data from TLE patients and an HC group in order to explore the intricate temporal dynamics of brain activity in TLE patients with cognitive impairment (TLE-CI). Additionally, we aim to examine the gene expression profiles associated with the dynamic modular characteristics in TLE patients using the Allen Human Brain Atlas (AHBA) database. RESULTS: Five HMM states were identified in this study. Compared with HCs, TLE and TLE-CI patients exhibited distinct changes in dynamics, including fractional occupancy, lifetimes, mean dwell time and switch rate. Furthermore, transition probability across HMM states were significantly different between TLE and TLE-CI patients (p < 0.05). The temporal reconfiguration of states in TLE and TLE-CI patients was associated with several brain networks (including the high-order default mode network (DMN), subcortical network (SCN), and cerebellum network (CN). Furthermore, a total of 1580 genes were revealed to be significantly associated with dynamic brain states of TLE, mainly enriched in neuronal signaling and synaptic function. CONCLUSIONS: This study provides new insights into characterizing dynamic neural activity in TLE. The brain network dynamics defined by HMM analysis may deepen our understanding of the neurobiological underpinnings of TLE and TLE-CI, indicating a linkage between neural configuration and gene expression in TLE.

Abnormalities of regional brain activity and executive function in patients with temporal lobe epilepsy: A cross-sectional and longitudinal resting-state functional MRI study.

PURPOSE: We decided to track changes in regional brain activity and executive function in temporal lobe epilepsy (TLE) patients based on cross-sectional and longitudinal designs and sought potential imaging features for follow-up observation. METHODS: Thirty-two TLE patients and thirty-three healthy controls (HCs) were recruited to detect changes in fractional amplitude of low-frequency fluctuation (fALFF) and regional homogeneity (ReHo) and to evaluate executive function both at baseline and at two-year (23.3 ± 8.3 months) follow-up. Moreover, multivariate pattern analysis (MVPA) was used for follow-up observation. RESULTS: TLE patients displayed lower fALFF values in the right superior frontal gyrus (SFG) and higher ReHo values in the left putamen (PUT) relative to the HCs. Longitudinal analysis revealed that TLE patients at follow-up exhibited higher fALFF values in the left postcentral gyrus (PoCG), higher ReHo values in the left PoCG and the right middle frontal gyrus (MFG), lower ReHo values in the bilateral PUT and the right fusiform gyrus (FFG) compared with these patients at baseline. The executive function was impaired in TLE patients but didn't deteriorate over time. No correlations were discovered between regional brain activity and executive function. The MVPA based on ReHo performed well in differentiating the follow-up group from the baseline group. CONCLUSION: We revealed the abnormalities in regional brain activity and executive function as well as their longitudinal trends in TLE patients. The ReHo might be a good imaging feature for follow-up observation.

Impaired interhemispheric synchrony and effective connectivity in right temporal lobe epilepsy.

BACKGROUND: The brain functional network plays a crucial role in cognitive impairment in temporal lobe epilepsy (TLE). Based on voxel-mirrored homotopic connectivity (VMHC), this study explored how directed functional connectivity changes and is associated with impaired cognition in right TLE (rTLE). METHODS: Twenty-seven patients with rTLE and twenty-seven healthy controls were included to perform VMHC and Granger causality analysis (GCA). Correlation analysis was performed based on GCA and cognitive function. RESULTS: Bilateral middle frontal gyrus (MFG), middle temporal gyrus, dorsolateral superior frontal gyrus (SFGdor), and supramarginal gyrus (SMG) exhibited decreased VMHC values in the rTLE group. Brain regions with altered VMHC had abnormal directed functional connectivity with multiple brain regions, mainly belonging to the default mode network, sensorimotor network, and visual network. Besides, the Montreal Cognitive Assessment (MoCA) score was positively correlated with the connectivity from the left SFGdor to the right cerebellum crus2 and was negatively correlated with the connectivity from the left SMG to the right supplementary motor area (SMA) before correction. Before correction, both phasic and intrinsic alertness reaction time were positively correlated with the connectivity from the left MFG to the left precentral gyrus (PreCG), connectivity from the left SMG to the right PreCG, and the connectivity from the left SMG to the right SMA. The executive control effect reaction time was positively correlated with the connectivity from the left MFG to the left calcarine fissure surrounding cortex before correction. CONCLUSION: The disordered functional network tended to be correlated with cognition impairment in rTLE.

Aberrant functional connectivity of amygdala subregions in temporal lobe epilepsy with ictal panic.

OBJECTIVE: The amygdala joins the model of fear neurocircuitry for its subregional roles in processing and mediating panic. This study aims to explore the underlying neuromechanisms of temporal lobe epilepsy (TLE) patients with ictal panic (IP) by investigating the amygdala subregions functional connectivity (FC) alteration. METHODS: 18 TLE patients with IP (TLE-IP group), 23 TLE patients without IP (TLE-none-IP group) and 22 age- and sex- matched healthy controls (HC) were enrolled and required to take resting-state functional magnetic resonance imaging (rs-fMRI) scanning. The basolateral (BLA), centromedial (CMA), and superficial (SFA) amygdala subregions were extracted from Juelich histological atlas. The amygdala subregions-based FC was computed and compared among three groups. RESULTS: The TLE-IP group demonstrated stronger FC between the left BLA and right middle frontal gyrus (MFG) than the TLE-none-IP group and HC. Compared with the TLE-none-IP group and HC, the TLE-IP group showed increased FC between the right BLA and right postcentral gyrus. The FC between the left BLA/SFA and the orbital part of right MFG increased in the TLE-IP group. Furthermore, the TLE-IP group exhibited decreased FC between the left CMA and pons. Further analysis indicated altered FC between the amygdala subregions and the pons, precuneus and thalamus in the left-sided TLE-IP group, but the MFG, inferior parietal gyrus, supplementary motor area and cerebellum in the right-sided TLE-IP group. CONCLUSIONS: The present study revealed aberrant amygdala subregions-based FC in TLE patients with IP. These findings offer unique insights into the understanding of fear neurocircuitry in TLE patients with IP.

The alterations of spontaneous neural activities and white matter microstructures in anti-N-methyl-D-aspartate receptor encephalitis: a resting-state fMRI and DTI study.

BACKGROUND AND PURPOSE: Limited studies had jointly excavated the structural and functional changes in cognitive deficit in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis patients. We aimed to explore these changes in anti-NMDAR patients and their effect on cognitive function. METHODS: Twenty-three patients and 25 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging, diffusion tensor imaging scanning, and neuroethology tests. The significantly differentiated brain regions via the fractional amplitude of low-frequency fluctuation (fALFF) were defined as regions of interest (ROIs). Granger causal, functional connectivity, and tract-based spatial statistical analyses were applied to explore the functional changes in ROIs and assess the structural changes. RESULTS: HCs outperformed patients in Montreal Cognitive Assessment. The fALFF values of right gyrus rectus (RGR) in patients were significantly reduced. The fractional anisotropy (FA) values of WM in the genu of corpus callosum and right superior corona radiata were significantly decreased and positively associated with neuroethology testing scores. The Granger causal connectivity (GCC) from the left inferior parietal lobule to RGR was significantly decreased and positively associated with inherent vigilance. Indicated by the multiple linear regression result, decreased FA value of the right superior corona radiata might be a reliable marker that reflects the cognitive impairment. CONCLUSIONS: Significant changes in spontaneous neural activities, GCC, and WM structures in anti-NMDAR encephalitis were reported. These findings promote the understanding of underlying relationships between cerebral function, structural network alterations, and cognitive dysfunction.

Identification and effective connections of core networks in patients with temporal lobe epilepsy and cognitive impairment: Granger causality analysis and multivariate pattern analysis.

OBJECTIVE: This study aimed to explore effective connectivity (EC) of the core networks in cognition impairment associated with temporal lobe epilepsy (CI-TLE) by applying resting state and Granger causality analysis (REST-GCA). The specific brain regions that played a critical role in classification were assessed using multivariate pattern analysis (MVPA). METHODS: Thirty-two patients with CI-TLE and 29 healthy controls who were matched based on age and gender underwent functional magnetic resonance imaging (fMRI). RESULTS: REST-GCA revealed that patients with CI-TLE displayed decreased GC values in the following brain areas: from the posterior cingulate cortex (PCC) to the left fusiform gyrus (lFFG) and the right parahippocampal gyrus (rPPG); from the right dorsal prefrontal cortex (rDPFC) to the left superior parietal lobule (lSPL); from the left amygdala (lAG) to the PCC. Inhibitory EC was observed from the rDPFC to the PCC compared to HCs. The GC values increased from the right dorsal prefrontal cingulate cortex (rdACC) to the PCC and from the right dorsal forebrain insula (rDAI) to the right middle temporal gyrus (rMTG) in the CI-TLE patients. MVPA showed that the classification yielded an accuracy of 81.91% (78.12%, specificity =85.71%). CONCLUSION: Our observations indicated that the abnormal EC between the frontal and parietal regions might be associated with the pathophysiological mechanism of CI-TLE. These results also indicated that EC might be play a role as a potential discriminative pattern to detect CI-TLE in patients.

Deep Cerebellar Nuclei Functional Connectivity with Cerebral Cortex in Temporal Lobe Epilepsy With and Without Focal to Bilateral Tonic-Clonic Seizures: a Resting-State fMRI Study.

We aimed to explore the altered functional connectivity patterns within cerebello-cerebral circuits in temporal lobe epilepsy (TLE) patients with and without focal to bilateral tonic-clonic seizures (FBTCS). Forty-two patients with unilateral TLE (21 with and 21 without FBTCS) and 22 healthy controls were recruited. We chose deep cerebellar nuclei as seed regions, calculated static and dynamic functional connectivity (sFC and dFC) in the patients with and without FBTCS and healthy controls, and compared sFC and dFC among the three groups. Correlation analyses were used to assess relationships between the significantly altered imaging features and patient clinical parameters. Compared to the group without FBTCS, the FBTCS group showed decreased sFC between the right dentate nuclei and left hemisphere regions including the middle frontal gyrus, superior temporal gyrus, superior medial frontal gyrus and posterior cingulate gyrus, and significantly increased dFC between the right interposed nuclei and contralateral precuneus. Relative to HCs, the FBTCS group demonstrated prominently decreased sFC between the right dentate nuclei and left middle frontal gyrus. No significant correlations between the altered imaging features and patient clinical parameters were observed. Our results suggest that the disrupted cerebello-cerebral FC might be related to cognitive impairment, epileptogenesis, and propagation of epileptic activities in patients with FBTCS.

Correlation analysis between regional homogeneity and executive dysfunction in anti-N-methyl-D-aspartate receptor encephalitis patients.

BACKGROUND AND PURPOSE: Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is characterized by a range of cognitive impairments, especially in executive function. Our study aims to identify the abnormal regional homogeneity (ReHo) in anti-NMDAR encephalitis patients and its relationship with the executive function. METHODS: Forty patients and 42 healthy volunteers undertook an Attention Network Test and a resting-state functional magnetic resonance imaging scan. ReHo analysis was performed to investigate the neuronal activity synchronization in all subjects. Based on ReHo analysis, a multivariate pattern analysis (MVPA) was carried out to identify the brain regions that differed the most between the two groups. RESULTS: Compared to controls, the patients had higher executive control scores (p < 0.05). The patients presented reduced ReHo values in the bilateral posterior cerebellar lobe, anterior cerebellar lobe, midbrain, bilateral caudate nucleus, right superior frontal gyrus, right middle temporal gyrus, bilateral inferior parietal lobule and the left middle frontal gyrus. The ReHo values of the bilateral inferior parietal lobule in patients were found to be negatively associated with executive control scores. The classification of patients and controls using MVPA had an accuracy of 76.83%, a sensitivity of 82.50%, a specificity of 71.43% and the area under the curve was 0.83. CONCLUSIONS: Our study provides evidence of abnormal cerebral function in anti-NMDAR encephalitis patients, which may contribute to unveiling the neuropathological mechanisms of anti-NMDAR encephalitis and their influences on executive dysfunction. The MVPA classifier, based on ReHo, is helpful in identifying anti-NMDAR encephalitis patients from healthy controls.

A study of brain functional network and alertness changes in temporal lobe epilepsy with and without focal to bilateral tonic-clonic seizures.

BACKGROUND: Temporal lobe epilepsy (TLE) is commonly refractory. Epilepsy surgery is an effective treatment strategy for refractory epilepsy, but patients with a history of focal to bilateral tonic-clonic seizures (FBTCS) have poor outcomes. Previous network studies on epilepsy have found that TLE and idiopathic generalized epilepsy with generalized tonic-clonic seizures (IGE-GTCS) showed altered global and nodal topological properties. Alertness deficits also were found in TLE. However, FBTCS is a common type of seizure in TLE, and the implications for alertness as well as the topological rearrangements associated with this seizure type are not well understood. METHODS: We obtained rs-fMRI data and collected the neuropsychological assessment data from 21 TLE patients with FBTCS (TLE- FBTCS), 18 TLE patients without FBTCS (TLE-non- FBTCS) and 22 controls, and constructed their respective functional brain networks. The topological properties were analyzed using the graph theoretical approach and correlations between altered topological properties and alertness were analyzed. RESULTS: We found that TLE-FBTCS patients showed more serious impairment in alertness effect, intrinsic alertness and phasic alertness than the patients with TLE-non-FBTCS. They also showed significantly higher small-worldness, normalized clustering coefficient (γ) and a trend of higher global network efficiency (gE) compared to TLE-non-FBTCS patients. The gE showed a significant negative correlation with intrinsic alertness for TLE-non-FBTCS patients. CONCLUSION: Our findings show different impairments in brain network information integration, segregation and alertness between the patients with TLE-FBTCS and TLE-non-FBTCS, demonstrating that impairments of the brain network may underlie the disruptions in alertness functions.

The local neural markers of MRI in patients with temporal lobe epilepsy presenting ictal panic: A resting resting-state postictal fMRI study.

OBJECTIVES: Temporal lobe epilepsy (TLE) is one of the most common focal epilepsies. Some patients with TLE have ictal panic (IP), which is often confused with panic attack (PA) in panic disorder (PD). Previous studies have described temporal lobe epilepsy with ictal panic (TLEIP), but the specific mechanisms remain unclear. Here, we used resting-state functional magnetic resonance imaging (rs-fMRI) to investigate local brain abnormalities in patients with TLEIP and tried to find neural markers to explore the mechanism of IP in patients with TLE. METHODS: A total of 40 patients with TLE, including 28 patients with TLE and 12 patients with TLEIP along with 30 age- and gender-matched healthy controls were included. We collected clinical/physiological/neuropsychological and rs-fMRI data. Fractional amplitude of low-frequency fluctuation (fALFF), regional homogeneity (ReHo), and degree centrality (DC) were calculated. ANOVA was used to find different areas and t-tests used to compare differences among fALFF, ReHo, and DC. Correlation analyses explored the relationship between local brain abnormalities and patient characteristics. RESULTS: No significant differences in age and gender were found among the three groups, nor were there differences in education level, Montreal Cognitive Assessment (MOCA) and Hamilton Anxiety Scale (HAMA) between the TLEIP and TLE groups. All the onset sites of patients with TLEIP were on the right. In addition to fear, other symptoms observed included nausea, palpitations, rising epigastric sensation, and dyspnea. There were no correlations between duration of IP and HAMA (p = 0.659). Moreover, all IP durations were <2 min and most <1 min. Compared to the HCs group, the ReHo value of the TLEIP group in the right middle frontal gyrus was significantly decreased (GRF correction, two-tailed, voxel level P < 0.005, cluster level P < 0.05). Compared to the HCs and TLE groups, the DC value of the TLEIP group in the left middle temporal gyrus (MTG) was significantly increased (GRF correction, two-tailed, voxel level P < 0.005, cluster level P < 0.05). No regions showed any significant fALFF difference between HCs and TLE groups (GRF correction, two-tailed, voxel level P < 0.005, cluster level P < 0.05). CONCLUSIONS: This research describes local brain abnormalities in patients with TLE presenting as IP. These results will be preliminarily conducive to understand the seizure mechanism of IP in patients with TLE, find out the MRI neural markers, and to further explore the neurophysiological mechanisms of IP in patients with TLE.

Aberrant resting-state interhemispheric functional connectivity in patients with anti-N-methyl-D-aspartate receptor encephalitis.

PURPOSE: Previous studies have discovered different neuroimaging features in anti-NMDAR encephalitis associated with cognitive dysfunction. However, it is unknown whether there is a correlation between abnormal homotopic connectivity and cognitive impairment in anti-NMDAR encephalitis. We aim to explore the homotopic connectivity patterns of patients with anti-NMDAR encephalitis and their associations with clinical characteristics. METHODS: Resting-state functional magnetic resonance imaging (rs-fMRI) was performed on 29 patients with anti-NMDAR encephalitis and 26 healthy controls (HCs). Voxel-mirrored homotopic connectivity (VMHC) and multivariate pattern analysis (MVPA) were applied to analyze the imaging data. A correlation was also performed between aberrant brain regions and clinical parameters. RESULTS: Compared to HCs, the performance of alertness in the patient group was typically worse (p < 0.05). A significant decrease in VMHC was observed in many regions of the patients in comparison to HCs, including the cerebellar 6, para-hippocampal gyrus, insula, precuneus, and middle frontal gyrus (p < 0.001). The insula and middle frontal gyrus were found to show positive correlations with alertness. The MVPA method achieved a classification accuracy of 74.55% with a sensitivity of 82.76% and a specificity of 65.38% in discriminating patients from HCs. CONCLUSION: Our findings indicate that interhemispheric functional imbalance may play a significant role in the pathophysiology of cognitive dysfunction in anti-NMDAR encephalitis. The MVPA results suggest that abnormal VMHC may play a crucial role in the identification of patients with anti-NMDAR encephalitis from HCs.

Altered static and dynamic functional network connectivity in temporal lobe epilepsy with different disease duration and their relationships with attention.

The brain network alterations associated with temporal lobe epilepsy (TLE) progression are still unclear. The purpose of this study was to investigate altered patterns of static and dynamic functional network connectivity (sFNC and dFNC) in TLE with different durations of disease. In this study, 19 TLE patients with a disease duration of ≤5 years (TLE-SD), 24 TLE patients with a disease duration of >5 years (TLE-LD), and 21 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging and attention network test. We used group independent component analysis to determine the target resting-state networks. Sliding window correlation and k-means clustering analysis methods were used to obtain different dFNC states, temporal properties, and temporal variability. We then compared sFNC and dFNC between groups and found that compared with HCs, TLE-SD patients had increased sFNC between the dorsal attention network and sensorimotor network/visual network (VN), but decreased sFNC between the inferior-posterior default mode network and VN. In the strongly connected dFNC state, TLE-SD patients spent more time, had greater mean dwell time, and showed greater inconsistent abnormal network connectivity. There was a significant negative correlation between the temporal variability of auditory network- left fronto-parietal network connectivity and orienting effect. No significant differences in sFNC and dFNC were detected between TLE-LD and HC groups. These findings suggest that the damage and functional brain network abnormalities gradually occur in TLE patients after the onset of epilepsy, which might lead to functional network reorganization and compensatory remodeling as the disease progresses.

Disturbance of functional and effective connectivity of the salience network involved in attention deficits in right temporal lobe epilepsy.

The salience network (SN) acts as a switch that generates transient control signals to regulate the executive control network (ECN) and the default mode network (DMN) and has been implicated in cognitive processes. Temporal lobe epilepsy (TLE) is usually accompanied by different types of cognitive deficits, but whether it is associated with dysfunctional connectivity of the SN remains unknown. To address this, thirty-six patients with right TLE (rTLE) and thirty-six healthy controls (HCs) were recruited for the present study. All of the participants were subjected to attention network test (ANT) and resting-state functional resonance imaging (rs-fMRI) scanning. The patient group showed deficits in attention performance. Moreover, the functional connectivity (FC) and effective connectivity (EC) were analyzed based on key SN hubs (the anterior cingulate cortex (ACC) and the bilateral anterior insula (AI)). When compared with those in the HC group, the ACC showed increased FC with the left middle frontal gyrus and the left precentral gyrus, and the right AI showed decreased FC with the right precuneus and the right superior occipital gyrus in the patient group. The EC analysis revealed an increased inflow of information from the left middle temporal gyrus to the ACC and the right AI and an increased outflow of information from the bilateral AI to the left middle frontal gyrus. Furthermore, in the correlation analysis, the abnormal EC from the right AI to the left middle temporal gyrus was positively correlated with the executive control effect. These findings demonstrated aberrant modulation of the SN in rTLE, which was particularly characterized by dysfunctional connectivity between the SN and key brain regions in the DMN and ECN. Elucidation of this effect may further contribute to the comprehensive understanding of the neural mechanisms of the SN in regard to attention deficits in patients with TLE.

Altered interhemispheric functional homotopy and connectivity in temporal lobe epilepsy based on fMRI and multivariate pattern analysis.

PURPOSE: This study aimed to investigate how the functional homotopy and further functional connectivity (FC) of whole brain changed in temporal lobe epilepsy (TLE). We also evaluated which brain regions played a decisive role in classification by using functional magnetic resonance imaging (fMRI). METHODS: Patients with TLE and matched healthy controls were included to collect the fMRI data and perform the voxel-mirrored homotopic connectivity (VMHC) and FC analyses. The correlation between the changed functional homotopy and neuropsychology tests was examined. Based on VMHC, the weight of each region in the classification was obtained using multivariate pattern analysis (MVPA). RESULTS: The patients exhibited decreased functional coordination in the bilateral inferior temporal gyrus (ITG) and increased functional homotopy in the bilateral lingual gyrus compared with the control group in the VMHC analysis. Compared with healthy controls, the Montreal Cognitive Assessment score was lower, and the scores of Hamilton Anxiety (HAMA) and Hamilton Depression Scales were higher. The score of the HAMA Scale was positively correlated with the altered bilateral ITG. The FC analysis revealed increased connections between the right lingual gyrus and the left superior temporal gyrus/left insula. The MVPA showed that the accuracy, sensitivity, and specificity of classification were 68.49, 66.67 and 70.27%, respectively, and it confirmed that the temporal lobe, cerebellum, and parietal lobe provided significant contributions. CONCLUSION: These findings demonstrated that the VMHC and FC changed in TLE, and the alterations were correlated with the anxiety state. The MVPA indicated that the abnormal VMHC was a crucial fMRI feature.

Carisbamate add-on therapy for drug-resistant focal epilepsy.

BACKGROUND: Epilepsy is one of the most common neurological disorders. Many people with epilepsy are drug-resistant and require add-on therapy, meaning that they concomitantly take multiple antiepileptic drugs. Carisbamate is a drug which is taken orally and inhibits voltage-gated sodium channels. Carisbamate may be useful for drug-resistant focal epilepsy. OBJECTIVES: To evaluate the efficacy and tolerability of carisbamate when used as an add-on therapy for drug-resistant focal epilepsy. SEARCH METHODS: We searched the following databases on 8 April 2021: Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid) 1946 to April 07, 2021. CRS Web includes randomised or quasi-randomised controlled trials from PubMed, Embase, ClinicalTrials.gov, WHO ICTRP, the Cochrane Central Register of Controlled Trials (CENTRAL), and the specialised registers of Cochrane review groups including Epilepsy. We also searched ongoing trials registers, checked reference lists, and contacted authors of the included trials. SELECTION CRITERIA: Double-blind randomised controlled trials (RCTs) comparing carisbamate versus placebo or another antiepileptic drug, as add-on therapy for drug-resistant focal epilepsy. Trials could have a parallel-group or cross-over design. DATA COLLECTION AND ANALYSIS: Two review authors independently selected the trials for inclusion, assessed trial quality, and extracted data. The primary outcome was 50% or greater reduction in seizure frequency (responder rate). The secondary outcomes were: seizure freedom, treatment withdrawal (for any reason and due to adverse events); adverse events, and quality of life. We analysed data using the Mantel-Haenszel statistical method and according to the intention-to-treat population. We presented results as risk ratios (RRs) with 95% confidence intervals (CIs). MAIN RESULTS: We included four RCTs involving a total of 2211 participants. All four trials compared carisbamate with placebo for drug-resistant focal epilepsy. Participants in all trials were over 16 years of age and received at least one other antiepileptic drug concomitantly. We detected substantial risk of bias across the included trials. All four trials were at high risk of attrition bias due to the incomplete reporting of attrition and the high treatment withdrawal rates noted, especially with higher doses. All four trials also had unclear risk of detection bias, as they did not specify whether outcome assessors were blinded. Meta-analysis suggested that carisbamate produced a higher responder rate compared to placebo (RR 1.36, 95% CI 1.14 to 1.62; 4 studies; moderate-certainty evidence). More participants in the carsibamate group achieved seizure freedom (RR 2.43, 95% CI 0.84 to 7.03; 1 study); withdrew from treatment for any reason (RR 1.32, 95% CI 0.82 to 2.12; 4 studies); and withdrew from treatment due to adverse events (RR 1.80, 95% CI 0.78 to 4.17; 4 studies) than in the placebo group. However, the evidence for the three outcomes was very low-certainty. There was no difference between treatment groups for the proportion of participants experiencing at least one adverse event (RR 1.10, 95% CI 0.93 to 1.30; 2 studies; low-certainty evidence). More participants in the carisbamate group than in the placebo group developed dizziness (RR 2.06, 95% CI 1.23 to 3.44; 4 studies; very low-certainty evidence) and somnolence (RR 1.82, 95% CI 1.28 to 2.58; 4 studies; low-certainty evidence), but not fatigue (RR 1.11, 95% CI 0.73 to 1.68; 3 studies); headache (RR 1.13, 95% CI 0.92 to 1.38; 4 studies); or nausea (RR 1.19, 95% CI 0.81 to 1.75; 3 studies). None of the included trials reported quality of life. AUTHORS' CONCLUSIONS: The results suggest that carisbamate may demonstrate efficacy and tolerability as an add-on therapy for drug-resistant focal epilepsy. Importantly, the evidence for all outcomes except responder rate was of low to very low certainty, therefore we are uncertain of the accuracy of the reported effects. The certainty of the evidence is limited by the significant risk of bias associated with the included studies, as well as the statistical heterogeneity detected for some outcomes. Consequently, it is difficult for these findings to inform clinical practice. The studies were all of short duration and only included adult study populations. There is a need for further RCTs with more clear methodology, long-term follow-up, more clinical outcomes, more seizure types, and a broader range of participants.

Clinical characteristics and long-term prognosis of relapsing anti-N-methyl-D-aspartate receptor encephalitis: a retrospective, multicenter, self-controlled study.

OBJECTIVE: To analyze the clinical profile and long-term prognosis of relapsing anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. METHOD: This is a retrospective, multicenter, self-controlled study of 10 patients with relapsing anti-NMDAR encephalitis. Relapse was defined as new psychiatric or neurologic syndrome unexplainable by other causes that improved after immunotherapy. RESULTS: The main symptoms at first onset and relapse included psychiatric symptoms, cognitive impairment, speech dysfunction, seizures, consciousness disturbance, movement disorders, central hypoventilation, and autonomic dysfunction. There were significantly fewer seizures and consciousness disturbances at relapse. At the first onset, the antibody positivity rate was significantly higher in the cerebrospinal fluid (CSF) than in the serum, and abnormal electroencephalograms results were noted in all patients. The relapse rate was 12.2%. After first-onset discharge, the duration of medication intake was 3.10 ± 2.69 months; the relapse time was 18.3 ± 16.5 months. The Modified Rankin Scale (MRS) score at relapse was significantly lower than that at the first onset. The MRS scores at relapse and first onset after immunotherapy were significantly lower than those before immunotherapy. At follow-up, the average duration of antiepileptic drug (AED) intake was < 1 year; the relapse rate was low. CONCLUSIONS: Patients have fewer symptoms and better quality of life at relapse than at the first onset. Active immunotherapy can significantly improve the quality of life during first onset and relapse. Encephalitis antibody testing in the CSF is preferred at first onset and relapse. Increasing antibody titers suggest clinical relapse. Prematurely stopping immunotherapy may lead to relapse, but prolonged AED intake is unnecessary.

Overexpression of cortistatin alleviates oxygen/glucose-deprivation-induced ER stress and prompts neural stem cell proliferation via SSTR2.

Cerebral infarction (CI), a blood circulatory disorder, causes a high mortality and disability rate worldwide. Intriguingly, a newly discovered neuropeptide, Cortistatin (CST), has been indicated to inhibit the cortical activity. In our research, we aimed to explore the functional relevance of CST in neural stem cells (NSCs) in CI rats. The expression of CST was determined in NSCs induced by oxygen-glucose deprivation (OGD). NSCs isolated from the embryonic rat brain were treated with OGD to establish an in vitro CI model while dithiothreitol (DTT) was introduced to induce endoplasmic reticulum stress (ERS), which were evaluated by assessment of GRP94, caspase-12 and CHOP expression. Then CST expression was restored by transfection of oe-CST, followed by assessment of NSC proliferation ability and cytotoxicity. Finally, the expression of CST and its receptor Somatostatin receptor subtype 2 (SSTR2) was quantified for mechanism exploration. CST was downregulated in CI, which was further confirmed in NSCs under OGD treatment. Overexpressed CST was found to promote cell activity and attenuate OGD-induced cytotoxicity of NSCs. Meanwhile, it was observed that the injured proliferation ability of NSCs was restored by CST overexpression. Besides, lower expression of GRP94, caspase-12 and CHOP was indicative of suppressed occurrence of ERS by CST. Mechanically, CST inhibited ERS through SSTR2. CST could facilitate the proliferation of NSCs in CI induced by OGD, ultimately highlighting a novel therapeutic target for CI treatment.

Disrupted alertness and related functional connectivity in patients with focal impaired awareness seizures in temporal lobe epilepsy.

OBJECTIVE: Focal impaired awareness seizures are common in temporal lobe epilepsy (TLE). The cognitive impairment associated with this type of seizure is unclear. Alertness is a fundamental aspect of cognition. The locus coeruleus (LC) is closely related to alertness. We aimed to assess the impairment in alertness and LC-related alertness network in patients with focal impaired awareness seizures. METHODS: Patients with unilateral TLE were grouped into the only focal impaired awareness seizure group (focal group, n = 19) and the focal impaired awareness seizure with focal to bilateral tonic-clonic seizure (FBTCS) group (FBTCS group, n = 19) and compared with matched healthy controls (HC, n = 19). Alertness was assessed with the attention network test. Functional magnetic resonance imaging (fMRI) was used to construct an alertness-related LC-based functional connectivity (FC) network. RESULTS: The focal group exhibited impaired tonic and phasic alertness and exhibited a decreased trend of LC-based FC to the left superior frontal gyrus (SFG). The FBTCS group exhibited impaired tonic alertness, phasic alertness, and alertness efficiency. No significant difference or trend in LC-based FC was found in the FBTCS group. SIGNIFICANCE: This study reveals disrupted alertness and alertness-related LC-based FC in patients with focal impaired awareness seizures. Our results further demonstrate that the patterns of impaired alertness and of changed LC-based FC were not significantly different between focal impaired awareness seizures and FBTCS.

Longitudinal assessment of resting-state fMRI in temporal lobe epilepsy: A two-year follow-up study.

In this study, we aimed to detect longitudinal alterations in local spontaneous brain activity and functional connectivity (FC) of the default mode network (DMN) in patients with temporal lobe epilepsy (TLE) over a two-year follow-up. We used amplitude of low-frequency fluctuation (ALFF) analysis and independent component analysis (ICA) to explore differences in local spontaneous brain activity and FC strength. In total, 33 participants (16 patients with TLE and 17 age- and gender-matched healthy controls (HCs)) were recruited in this study. All participants performed the Attention Network Test (ANT) for evaluation of the executive control function. Compared with healthy patients at baseline, patients with TLE at follow-up exhibited increased ALFF values in the left medial frontal gyrus, as well as reduced FC values in the left inferior parietal gyrus (IPG) within the DMN. Patients with TLE revealed executive dysfunction, but no progressive deterioration was observed during follow-up. This study revealed the abnormal distribution of ALFF values and Rs-FC changes over a two-year follow-up period in TLE, both of which demonstrated different reorganization trajectories and loss of efficiency.

Voxel-based analysis and multivariate pattern analysis of diffusion tensor imaging study in anti-NMDA receptor encephalitis.

PURPOSE: This study aimed to investigate brain white matter (WM) changes and their relationship to cognition in patients with anti-N-methyl-D-aspartate (anti-NMDA) receptor encephalitis. Multivariate pattern analysis (MVPA) was used to explore brain regions that play an important role in classification. METHODS: Fifteen patients and fifteen controls underwent Montreal Cognitive Assessment (MoCA) and diffusion tensor imaging. Based on fractional anisotropy (FA) and mean diffusivity (MD) for MVPA classification, the weights of each brain region were calculated. RESULTS: Compared with the controls, the patients showed an FA reduction in right middle temporal gyrus, left middle cerebellar peduncle, right praecuneus, and an MD increase in left medial temporal gyrus and left frontal lobe. The MoCA score for patients was lower than controls, especially in executive function, fluency, delayed recall and visual perception items. The FA value of right praecuneus was positively correlated with total MoCA score and fluency score. The MD of left frontal lobe was negatively correlated with total MoCA score, and MD of the left medial temporal gyrus was positively correlated with delayed recall. The accuracy, sensitivity and specificity of classification based on FA were 70%, 60% and 80%, respectively. Based on MD, they were each 80%. The brain regions with large weights from FA and MD overlap in temporal lobe, cerebellum and hippocampus. CONCLUSIONS: These results suggest that WM changes are associated with cognitive deficits. MVPA based on FA and MD has good classification ability. Our study may provide new insights into the pathophysiological mechanisms of residual cognitive deficits.