Simulated resections and RNS placement can optimize post-operative seizure outcomes when guided by fast ripple networks.

In medication-resistant epilepsy, the objective of epilepsy surgery is to render a patient seizure free with a resection/ablation that is as small as possible to minimize morbidity. The standard of care in planning the margins of epilepsy surgery involves electroclinical delineation of the seizure onset zone (SOZ) in the epilepsy monitoring unit (EMU) by an expert epileptologist, and incorporation of neuroimaging findings from MRI, PET, SPECT, and MEG modalities. Resecting cortical tissue generating high-frequency oscillations (HFOs) has been investigated as a more efficacious alternative to targeting the SOZ. In this study, we used support vector machines (SVMs) to compare the resection volumes of actual resections, defined using the clinical standard of care, with virtual resections of fast ripple (FR 350-600 Hz) networks. Cross-validation of the SVM that labeled patients as seizure free or not seizure free using FR metrics as factors demonstrated an accuracy of 0.78. In all the patients rendered seizure free after surgery, we found that the virtual resection, defined using FR generator sites with highest rate and greatest autonomy, was larger than the actual resection. In the patients who experienced seizures after the actual resection, a virtual resection that included the SOZ and other FR generating regions rendered half of these patients virtually seizure free. We also examined patients implanted with the responsive neurostimulator system (RNS) and virtually targeted the RNS stimulation contacts proximal to sites generating FR. We used the simulations to investigate if the likelihood of a RNS super response (>90% seizure reduction) would be increased.

Relationship between endoscopic gastroesophageal valve grading and mean nocturnal baseline impedance and postreflux swallow-induced peristaltic wave index in patients with gastroesophageal reflux disease.

This study aimed to investigate the relationship between endoscopic gastroesophageal valve grading and mean nocturnal baseline impedance (MNBI) and postreflux swallow-induced peristaltic wave index (PSPWI) in patients with gastroesophageal reflux disease (GERD). A total of 120 patients diagnosed with GERD disease were included in the study. According to the classification of endoscopic gastroesophageal valves, the patients were divided into 5 groups, group 1 as baseline group, and Group 2-4 as Hill grade I-IV. Basic information about the patients was collected, including age and gender. The mean nocturnal baseline impedance and creep wave index induced by swallowing after rumination were measured by high resolution creep measurement technique. Through statistical analysis, the relationship between valve classification and observation index was discussed. In terms of MNBI, impedance values gradually decreased with increasing valve classification. The average impedance of the Grade 1 group was 23.5 mm Hg/cm2, while the average impedance of the Grade 5 group was 15.2 mm Hg/cm2. This reduction showed a significant decreasing trend (P < .001). In addition, in terms of the peristaltic wave index caused by swallowing after regurgitation, the peristaltic wave index gradually increased with the increase of valve classification. The mean index in the Grade 1 group was 1.8 beats/min, while the mean index in the Grade 5 group was 3.6 beats/min. This increase showed a significant positive relationship (P < .001). Endoscopic gastroesophageal valve grading was significantly correlated with MNBI and PSPWI in patients with GERD. These observations can serve as useful tools for assessing the severity of GERD and monitoring disease progression.

Obesity is associated with poor outcomes of corticosteroid treatment in patients with primary immune thrombocytopenia.

Emerging evidence has demonstrated that obesity impacts multiple immune-related diseases. It remains unclear whether and how obesity alters treatment outcomes in patients with primary immune thrombocytopenia (ITP). Thus, we retrospectively investigated 214 treatment-naïve patients who received standard high-dose dexamethasone therapy in Qilu Hospital. Patients with obesity showed significantly lower overall initial response (underweight vs. normal vs. overweight vs. obese: 85.7% vs. 85.2% vs. 72.0% vs. 52.3%, p = 0.001) and initial complete response ([CR], 71.4% vs. 70.4% vs. 53.3% vs. 27.3%, p < 0.001) rates. The same trend was observed in the 6-month sustained response (63.6% vs. 52.3% vs. 35.6% vs. 22.7%, p = 0.03) and sustained CR (36.4% vs. 44.6% vs. 24.4% vs. 9.1%, p = 0.01). The Kaplan-Meier analysis revealed a shortened duration of remission in the obese group (median duration of remission, not reached vs. 16 months vs. 2 months vs. 1 month, p = 0.002). In multivariate regression analysis, obesity was independently associated with poor initial and sustained responses, and an increased risk for relapse. In conclusion, obesity is a negative predictor for outcomes of corticosteroid treatment. A stratified strategy according to body mass index status may facilitate the precision management of ITP.

Identification of novel NFKB1 and ICOS frameshift variants in patients with CVID.

Common variable immunodeficiency (CVID) is a 'late-onset' primary immunodeficiency characterized by variable manifestations and genetic heterogeneity. A monogenic cause of CVID has been reported in 10% of patients. In this study, we identified two novel pathogenic variants implicated in monogenic CVID by whole exome sequencing (WES) analysis: a heterozygous nuclear factor κB subunit 1 (NFKB1) p.G686fs mutation and a homozygous inducible T-cell co-stimulator (ICOS) p.L96Sfs mutation. The predicted crystal models indicated premature truncation of the two mutated proteins. Both variants were demonstrated as loss-of-function mutations and were associated with overlapped manifestations of respiratory fungal infection and splenomegaly. We further performed a detailed assessment of immunologic phenotypes and impaired lymphocyte functions in patients. Moreover, we discovered an association between monoclonal T-large granular lymphocyte proliferation and ICOS-deficient CVID for the first time. These observations lead to a new perspective on the underlying genetic heterogeneity of CVID.

Machine Learning to Classify Relative Seizure Frequency From Chronic Electrocorticography.

PURPOSE: Brain responsive neurostimulation (NeuroPace) treats patients with refractory focal epilepsy and provides chronic electrocorticography (ECoG). We explored how machine learning algorithms applied to interictal ECoG could assess clinical response to changes in neurostimulation parameters. METHODS: We identified five responsive neurostimulation patients each with ≥200 continuous days of stable medication and detection settings (median, 358 days per patient). For each patient, interictal ECoG segments for each month were labeled as "high" or "low" to represent relatively high or low long-episode (i.e., seizure) count compared with the median monthly long-episode count. Power from six conventional frequency bands from four responsive neurostimulation channels were extracted as features. For each patient, five machine learning algorithms were trained on 80% of ECoG, then tested on the remaining 20%. Classifiers were scored by the area-under-the-receiver-operating-characteristic curve. We explored how individual circadian cycles of seizure activity could inform classifier building. RESULTS: Support vector machine or gradient boosting models achieved the best performance, ranging from 0.705 (fair) to 0.892 (excellent) across patients. High gamma power was the most important feature, tending to decrease during low-seizure-frequency epochs. For two subjects, training on ECoG recorded during the circadian ictal peak resulted in comparable model performance, despite less data used. CONCLUSIONS: Machine learning analysis on retrospective background ECoG can classify relative seizure frequency for an individual patient. High gamma power was the most informative, whereas individual circadian patterns of seizure activity can guide model building. Machine learning classifiers built on interictal ECoG may guide stimulation programming.

Overlapping and distinct phenotypic profiles in Alzheimer's disease and late onset epilepsy: a biologically-based approach.

Due to shared hippocampal dysfunction, patients with Alzheimer's dementia and late-onset epilepsy (LOE) report memory decline. Multiple studies have described the epidemiological, pathological, neurophysiological, and behavioral overlap between Alzheimer's Disease and LOE, implying a bi-directional relationship. We describe the neurobiological decline occurring at different spatial in AD and LOE patients, which may explain why their phenotypes overlap and differ. We provide suggestions for clinical recognition of dual presentation and novel approaches for behavioral testing that reflect an "inside-out," or biologically-based approach to testing memory. New memory and language assessments could detect-and treat-memory impairment in AD and LOE at an earlier, actionable stage.

A consensus statement on detection of hippocampal sharp wave ripples and differentiation from other fast oscillations.

Decades of rodent research have established the role of hippocampal sharp wave ripples (SPW-Rs) in consolidating and guiding experience. More recently, intracranial recordings in humans have suggested their role in episodic and semantic memory. Yet, common standards for recording, detection, and reporting do not exist. Here, we outline the methodological challenges involved in detecting ripple events and offer practical recommendations to improve separation from other high-frequency oscillations. We argue that shared experimental, detection, and reporting standards will provide a solid foundation for future translational discovery.

Deciphering transcriptome alterations in bone marrow hematopoiesis at single-cell resolution in immune thrombocytopenia.

Immune thrombocytopenia (ITP) is an autoimmune disorder, in which megakaryocyte dysfunction caused by an autoimmune reaction can lead to thrombocytopenia, although the underlying mechanisms remain unclear. Here, we performed single-cell transcriptome profiling of bone marrow CD34+ hematopoietic stem and progenitor cells (HSPCs) to determine defects in megakaryopoiesis in ITP. Gene expression, cell-cell interactions, and transcriptional regulatory networks varied in HSPCs of ITP, particularly in immune cell progenitors. Differentially expressed gene (DEG) analysis indicated that there was an impaired megakaryopoiesis of ITP. Flow cytometry confirmed that the number of CD9+ and HES1+ cells from Lin-CD34+CD45RA- HSPCs decreased in ITP. Liquid culture assays demonstrated that CD9+Lin-CD34+CD45RA- HSPCs tended to differentiate into megakaryocytes; however, this tendency was not observed in ITP patients and more erythrocytes were produced. The percentage of megakaryocytes differentiated from CD9+Lin-CD34+CD45RA- HSPCs was 3-fold higher than that of the CD9- counterparts from healthy controls (HCs), whereas, in ITP patients, the percentage decreased to only 1/4th of that in the HCs and was comparable to that from the CD9- HSPCs. Additionally, when co-cultured with pre-B cells from ITP patients, the differentiation of CD9+Lin-CD34+CD45RA- HSPCs toward the megakaryopoietic lineage was impaired. Further analysis revealed that megakaryocytic progenitors (MkP) can be divided into seven subclusters with different gene expression patterns and functions. The ITP-associated DEGs were MkP subtype-specific, with most DEGs concentrated in the subcluster possessing dual functions of immunomodulation and platelet generation. This study comprehensively dissects defective hematopoiesis and provides novel insights regarding the pathogenesis of ITP.

Ion channel Piezo1 activation promotes aerobic glycolysis in macrophages.

Altered microenvironmental stiffness is a hallmark of inflammation. It is sensed by the mechanically activated cation channel Piezo1 in macrophages to induce subsequent immune responses. However, the mechanism by which the mechanosensitive signals shape the metabolic status of macrophages and tune immune responses remains unclear. We revealed that Piezo1-deficient macrophages exhibit reduced aerobic glycolysis in resting or liposaccharide (LPS)-stimulated macrophages with impaired LPS-induced secretion of inflammatory cytokines in vitro. Additionally, pretreatment with the Piezo1 agonist, Yoda1, or cyclical hydrostatic pressure (CHP) upregulated glycolytic activity and enhanced LPS-induced secretion of inflammatory cytokines. Piezo1-deficient mice were less susceptible to dextran sulfate sodium (DSS)-induced colitis, whereas Yoda1 treatment aggravated colitis. Mechanistically, we found that Piezo1 activation promotes aerobic glycolysis through the Ca2+-induced CaMKII-HIF1α axis. Therefore, our study revealed that Piezo1-mediated mechanosensitive signals Piezo1 can enhance aerobic glycolysis and promote the LPS-induced immune response in macrophages.

Empagliflozin modulates CD4+ T-cell differentiation via metabolic reprogramming in immune thrombocytopenia.

Immune thrombocytopenia (ITP) is an acquired autoimmune disease, in which the imbalance of CD4+ T cell subsets play a key role in the pathogenesis. Since T cells highly depend on metabolism for their function, we hypothesized that T cell dysfunction may be due to intracellular metabolic reprogramming. We found that in ITP, T cell metabolism shifts from oxidative phosphorylation to glycolysis. Empagliflozin, a sodium-glucose cotransporter 2 inhibitor, has shown regulatory metabolic effects on proximal tubular epithelial cells and cardiac cells beyond glucose lowering. However, the effects of empagliflozin on T cells remain unknown. To further investigate the metabolic dysfunction of CD4+ T cells in ITP, we explored the effect of empagliflozin on CD4+ T-cell differentiation in ITP. Our results are the first to show that increased glycolysis in CD4+ T cells resulted in an unbalanced CD4+ T-cell population. Furthermore, empagliflozin can affect the differentiation of CD4+ T-cell subsets by inhibiting Th1 and Th17 cell populations while increasing Tregs. Empagliflozin appears to regulate CD4+ T cells through inhibiting the mTOR signal pathway. Considering these results, we propose that empagliflozin could be used as a potential therapeutic option for ITP by modulating metabolic reprogramming in CD4+ T cells.

Religious conversion in an older male with longstanding epilepsy.

Religious experiences in epilepsy patients have provoked much interest with suggestions that hyperreligiosity is associated with temporal lobe seizures. Extreme varieties of religious behavior may be more frequent in epilepsy patients during ictal activity or during post-ictal psychotic episodes. We report a 75 year-old man with epilepsy who developed a progressive decline in cognition and behavior following a religious conversion 15 years earlier. He subsequently developed religious delusions of increasing severity and symptoms of Capgras syndrome. Brain imaging revealed bilateral posterior cortical atrophy, chronic right parieto-occipital encephalomalacia, and right mesial temporal sclerosis. Electroencephalograms and neuropsychological testing revealed initial right temporal lobe abnormalities followed by progressive frontal and bilateral dysfunction. The case highlights how a history of seizures, superimposed on sensory deprivation and a progressive impairment of right posterior and bilateral anterior brain function, may have contributed to religious conversion, which was followed by dementia and delusions involving religious content.

Is formal scoring better than just looking? A comparison of subjective and objective scoring methods of the Rey Complex Figure Test for lateralizing temporal lobe epilepsy.

ObjectiveNeuropsychologists labor over scoring the Rey Complex Figure Test (RCFT), a measure of visuospatial functioning and nonverbal memory. Compelling arguments suggest that pathognomonic signs of the RCFT are observable to the "naked eye." Standard scoring systems are insensitive to lateralizing temporal lobe epilepsy (TLE) and alternative "qualitative" scoring systems are ineffective and time-consuming. Method: We examined accuracy of TLE lateralization using subjective classifications and standard scoring. Participants were 84 TLE patients (53 female; mean age=36yrs) and 46 controls (27 female; mean age = 27.5). The former were classified as right (n = 41) or left (n = 43) TLE by neurologists using EEG and MRI studies. RCFT were scored using standard scoring with cut-offs of z ≤ -2 classified as impaired and were rated as "characteristic" of RTLE (Ugly) or LTLE (Not Ugly) performance by neuropsychologists. Accuracy of seizure lateralization for both methods was examined. Results: Neuropsychologists' ratings accuracy were at or below chance. Standard scoring criteria showed chance or slightly better lateralization prediction. Standard scoring predicted RTLE laterality more accurately than subjective ratings for copy trials; standard scoring was no better at lateralizing RTLE with delays. Subjective ratings were better at distinguishing TLE patients from controls. Conclusion: Findings highlight concerns regarding the usefulness of the RCFT in TLE lateralization, regardless of scoring approach.

Time-dependent transformations of memory representations differ along the long axis of the hippocampus.

Research has shown that sleep is beneficial for the long-term retention of memories. According to theories of memory consolidation, memories are gradually reorganized, becoming supported by widespread, distributed cortical networks, particularly during postencoding periods of sleep. However, the effects of sleep on the organization of memories in the hippocampus itself remains less clear. In a 3-d study, participants encoded separate lists of word-image pairs differing in their opportunity for sleep-dependent consolidation. Pairs were initially studied either before or after an overnight sleep period, and were then restudied in a functional magnetic resonance imaging (fMRI) scan session. We used multivariate pattern similarity analyses to examine fine-grained effects of consolidation on memory representations in the hippocampus. We provide evidence for a dissociation along the long axis of the hippocampus that emerges with consolidation, such that representational patterns for object-word memories initially formed prior to sleep become differentiated in anterior hippocampus and more similar, or overlapping, in posterior hippocampus. Differentiation in anterior hippocampal representations correlated with subsequent behavioral performance. Furthermore, representational overlap in posterior hippocampus correlated with the duration of intervening slow wave sleep. Together, these results demonstrate that sleep-dependent consolidation promotes the reorganization of memory traces along the long axis of the hippocampus.

Effects of hippocampal interictal discharge timing, duration, and spatial extent on list learning.

Interictal epileptiform discharges (IEDs) can impair memory. The properties of IEDs most detrimental to memory, however, are undefined. We studied the impact of temporal and spatial characteristics of IEDs on list learning. Subjects completed a memory task during intracranial EEG recordings including hippocampal depth and temporal neocortical subdural electrodes. Subjects viewed a series of objects, and after a distracting task, recalled the objects from the list. The impacts of IED presence, duration, and propagation to neocortex during encoding of individual stimuli were assessed. The effects of IED total number and duration during maintenance and recall periods on delayed recall performance were also determined. The influence of IEDs during recall was further investigated by comparing the likelihood of IEDs preceding correctly recalled items vs. periods of no verbal response. Across 6 subjects, we analyzed 28 hippocampal and 139 lateral temporal contacts. Recall performance was poor, with a median of 17.2% correct responses (range 10.4-21.9%). Interictal epileptiform discharges during encoding, maintenance, and recall did not significantly impact task performance, and there was no significant difference between the likelihood of IEDs during correct recall vs. periods of no response. No significant effects of discharge duration during encoding, maintenance, or recall were observed. Interictal epileptiform discharges with spread to lateral temporal cortex during encoding did not adversely impact recall. A post hoc analysis refining model assumptions indicated a negative impact of IED count during the maintenance period, but otherwise confirmed the above results. Our findings suggest no major effect of hippocampal IEDs on list learning, but study limitations, such as baseline hippocampal dysfunction, should be considered. The impact of IEDs during the maintenance period may be a focus of future research.

Spatiotemporal dynamics between interictal epileptiform discharges and ripples during associative memory processing.

We describe the spatiotemporal course of cortical high-gamma activity, hippocampal ripple activity and interictal epileptiform discharges during an associative memory task in 15 epilepsy patients undergoing invasive EEG. Successful encoding trials manifested significantly greater high-gamma activity in hippocampus and frontal regions. Successful cued recall trials manifested sustained high-gamma activity in hippocampus compared to failed responses. Hippocampal ripple rates were greater during successful encoding and retrieval trials. Interictal epileptiform discharges during encoding were associated with 15% decreased odds of remembering in hippocampus (95% confidence interval 6-23%). Hippocampal interictal epileptiform discharges during retrieval predicted 25% decreased odds of remembering (15-33%). Odds of remembering were reduced by 25-52% if interictal epileptiform discharges occurred during the 500-2000 ms window of encoding or by 41% during retrieval. During encoding and retrieval, hippocampal interictal epileptiform discharges were followed by a transient decrease in ripple rate. We hypothesize that interictal epileptiform discharges impair associative memory in a regionally and temporally specific manner by decreasing physiological hippocampal ripples necessary for effective encoding and recall. Because dynamic memory impairment arises from pathological interictal epileptiform discharge events competing with physiological ripples, interictal epileptiform discharges represent a promising therapeutic target for memory remediation in patients with epilepsy.

Learning hierarchical sequence representations across human cortex and hippocampus.

Sensory input arrives in continuous sequences that humans experience as segmented units, e.g., words and events. The brain's ability to discover regularities is called statistical learning. Structure can be represented at multiple levels, including transitional probabilities, ordinal position, and identity of units. To investigate sequence encoding in cortex and hippocampus, we recorded from intracranial electrodes in human subjects as they were exposed to auditory and visual sequences containing temporal regularities. We find neural tracking of regularities within minutes, with characteristic profiles across brain areas. Early processing tracked lower-level features (e.g., syllables) and learned units (e.g., words), while later processing tracked only learned units. Learning rapidly shaped neural representations, with a gradient of complexity from early brain areas encoding transitional probability, to associative regions and hippocampus encoding ordinal position and identity of units. These findings indicate the existence of multiple, parallel computational systems for sequence learning across hierarchically organized cortico-hippocampal circuits.

Eltrombopag inhibits Type I interferon-mediated antiviral signaling by decreasing cellular iron.

Thrombocytopenia is common among patients with viral hepatitis, limiting the use of antiviral therapy. Eltrombopag (EP) is a thrombopoietin receptor (TPO-R) agonist that has been approved for treatment of immune thrombocytopenia patients with hepatitis virus infection. Interferon-α (IFN-α) plays a crucial role in the antiviral response, and is recommended as the first-line agent for chronic hepatitis B patients. Here, we investigated whether EP inhibits the production of IFN-stimulated genes (ISGs) induced by IFN-α through the TPO-R-independent pathway by mediating reactive oxygen species production by iron chelation. Our results assessed the inhibitory effect of EP on IFN-α signaling, which contributes to the downregulation of ISGs produced by monocytes and sheds light on the underlying mechanisms using iron chelation to treat patients with hepatitis-related immunological thrombocytopenia.

Moderate exercise ameliorates osteoarthritis by reducing lipopolysaccharides from gut microbiota in mice.

Lipopolysaccharides (LPSs) released by gut microbiota are correlated with the pathophysiology of osteoarthritis (OA). Exercise remodels the composition of gut microbiota. The present study investigated the hypothesis that wheel-running exercise prevents knee OA induced by high-fat diet (HFD) via reducing LPS from intestinal microorganisms. Male C57BL/6 J mice were treated with sedentary or wheel-running exercise, standard diet (13.5% kcal) or HFD (60% kcal), berberine or not according to their grouping. Knee OA severity, blood and synovial fluid LPS, cecal microbiota, and TLR4 and MMP-13 expression levels were determined. Our findings reveal that HFD treatment decreased gut microbial diversity. Increase in endotoxin-producing bacteria, decrease in gut barrier-protecting bacteria, high LPS levels in the blood and synovial fluid, high TLR4 and MMP-13 expression levels, and severe cartilage degeneration were observed. By contrast, voluntary wheel running caused high gut microbial diversity. The gut microbiota were reshaped, LPS levels in the blood and synovial fluid and TLR4 and MMP-13 expression levels were low, and cartilage degeneration was ameliorated. Berberine treatment reduced LPS levels in the samples, but decreased the diversity of intestinal flora with similar changes to that caused by HFD. In conclusion, unlike taking drugs, exercising can remodel gut microbial ecosystems, reduce the circulating levels of LPS, and thereby contribute to the relief of chronic inflammation and OA. Our findings showed that moderate exercise is a potential therapeutic approach for preventing and treating obesity-related OA.

Concentration of fifteen elements in herbaceous stems of Ephedra intermedia and influence of its growing soil.

Mineral nutrients play important roles in the growth and metabolism of Ephedra intermedia, and are affected by soil factors. Fifteen elements were measured from wild E. intermedia as well as their growing soils using inductively coupled plasma mass spectroscopy to investigate the influences and characteristics of herb elements. The pH, cation exchange capacity, humus and soil mechanical composition were also determined in rhizosphere soils. Results showed that E. intermedia stems contained high N, low P concentrations in macronutrients and high Fe in micronutrients, and enriched N, S, Cl, P and Sr from soils. The 15 herb elements were affected by one or more soil factors, and K, P, Zn, Fe and Mn were important soil elements that influenced the mineral accumulation of E. intermedia. This study was useful for the artificial cultivation of wild E. intermedia.

Sounds of seizures.

PURPOSE: A phase I feasibility study to determine the accuracy of identifying seizures based on audio recordings. METHODS: We systematically generated 166 audio clips of 30 s duration from 83 patients admitted to an epilepsy monitoring unit between 1/2015 and 12/2016, with one clip during a seizure period and one clip during a non-seizure control period for each patient. Five epileptologists performed a blinded review of the audio clips and rated whether a seizure occurred or not, and indicated the confidence level (low or high) of their rating. The accuracy of individual and consensus ratings were calculated. RESULTS: The overall performance of the consensus rating between the five epileptologists showed a positive predictive value (PPV) of 0.91 and a negative predictive value (NPV) of 0.66. The performance improved when confidence was high (PPV of 0.96, NPV of 0.70). The agreement between the epileptologists was moderate with a kappa of 0.584. Hyperkinetic (PPV 0.92, NPV 0.86) and tonic-clonic (PPV and NPV 1.00) seizures were most accurately identified. Seizures with automatisms only and non-motor seizures could not be accurately identified. Specific seizure-related sounds associated with accurate identification included disordered breathing (PPV and NPV 1.00), rhythmic sounds (PPV 0.93, NPV 0.80), and ictal vocalizations (PPV 1.00, NPV 0.97). CONCLUSION: This phase I feasibility study shows that epileptologists are able to accurately identify certain seizure types from audio recordings when the seizures produce sounds. This provides guidance for the development of audio-based seizure detection devices and demonstrate which seizure types could potentially be detected.