•The A7 (‘algorithm #7’) detector uses 4 parameters to identify spindles that are visible in the original EEG.•A7 emulates human spindles scoring by maximizing performance against a human gold ...standard.•The ‘context classifier’ filters out spindles that are not in a typical NREM spectral context.•Identifying visible spindles may be useful because they have a high signal-to-noise ratio.
Sleep spindles are a marker of stage 2 NREM sleep that are linked to learning & memory and are altered by many neurological diseases. Although visual inspection of the EEG is considered the gold standard for spindle detection, it is time-consuming, costly and can introduce inter/ra-scorer bias.
Our goal was to develop a simple and efficient sleep-spindle detector (algorithm #7, or ‘A7’) that emulates human scoring. ‘A7’ runs on a single EEG channel and relies on four parameters: the absolute sigma power, relative sigma power, and correlation/covariance of the sigma band-passed signal to the original EEG signal. To test the performance of the detector, we compared it against a gold standard spindle dataset derived from the consensus of a group of human experts.
The by-event performance of the ‘A7’ spindle detector was 74% precision, 68% recall (sensitivity), and an F1-score of 0.70. This performance was equivalent to an individual human expert (average F1-score = 0.67).
The F1-score of ‘A7’ was 0.17 points higher than other spindle detectors tested. Existing detectors have a tendency to find large numbers of false positives compared to human scorers. On a by-subject basis, the spindle density estimates produced by A7 were well correlated with human experts (r2 = 0.82) compared to the existing detectors (average r2 = 0.27).
The ‘A7’ detector is a sensitive and precise tool designed to emulate human spindle scoring by minimizing the number of ‘hidden spindles’ detected. We provide an open-source implementation of this detector for further use and testing.
Sleep spindles are discrete, intermittent patterns of brain activity observed in human electroencephalographic data. Increasingly, these oscillations are of biological and clinical interest because ...of their role in development, learning and neurological disorders. We used an Internet interface to crowdsource spindle identification by human experts and non-experts, and we compared their performance with that of automated detection algorithms in data from middle- to older-aged subjects from the general population. We also refined methods for forming group consensus and evaluating the performance of event detectors in physiological data such as electroencephalographic recordings from polysomnography. Compared to the expert group consensus gold standard, the highest performance was by individual experts and the non-expert group consensus, followed by automated spindle detectors. This analysis showed that crowdsourcing the scoring of sleep data is an efficient method to collect large data sets, even for difficult tasks such as spindle identification. Further refinements to spindle detection algorithms are needed for middle- to older-aged subjects.
Objective:
Narcolepsy is caused by the loss of hypocretin/orexin neurons in the hypothalamus, which is likely the result of an autoimmune process. Recently, concern has been raised over reports of ...narcolepsy in northern Europe following H1N1 vaccination.
Methods:
The study is a retrospective analysis of narcolepsy onset in subjects diagnosed in Beijing, China (1998–2010). Self‐reported month and year of onset were collected from 629 patients (86% children). Graphical presentation, autocorrelations, chi‐square, and Fourier analysis were used to assess monthly variation in onset. Finally, 182 patients having developed narcolepsy after October 2009 were asked for vaccination history.
Results:
The occurrence of narcolepsy onset was seasonal, significantly influenced by month and calendar year. Onset was least frequent in November and most frequent in April, with a 6.7‐fold increase from trough to peak. Studying year‐to‐year variation, we found a 3‐fold increase in narcolepsy onset following the 2009 H1N1 winter influenza pandemic. The increase is unlikely to be explained by increased vaccination, as only 8 of 142 (5.6%) patients recalled receiving an H1N1 vaccination. Cross‐correlation indicated a significant 5‐ to 7‐month delay between the seasonal peak in influenza/cold or H1N1 infections and peak in narcolepsy onset occurrences.
Interpretation:
In China, narcolepsy onset is highly correlated with seasonal and annual patterns of upper airway infections, including H1N1 influenza. In 2010, the peak seasonal onset of narcolepsy was phase delayed by 6 months relative to winter H1N1 infections, and the correlation was independent of H1N1 vaccination in the majority of the sample. ANN NEUROL 2011;
Huntington disease (HD) is an inherited, fatal neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. The mutant protein causes neuronal dysfunction and degeneration ...resulting in motor dysfunction, cognitive decline, and psychiatric disturbances. Currently, there is no disease altering treatment, and symptomatic therapy has limited benefit. The pathogenesis of HD is complicated and multiple pathways are compromised. Addressing the problem at its genetic root by suppressing mutant huntingtin expression is a promising therapeutic strategy for HD. We have developed and evaluated antisense oligonucleotides (ASOs) targeting single nucleotide polymorphisms that are significantly enriched on HD alleles (HD-SNPs). We describe our structure-activity relationship studies for ASO design and find that adjusting the SNP position within the gap, chemical modifications of the wings, and shortening the unmodified gap are critical for potent, specific, and well tolerated silencing of mutant huntingtin. Finally, we show that using two distinct ASO drugs targeting the two allelic variants of an HD-SNP could provide a therapeutic option for all persons with HD; allele-specifically for roughly half, and non-specifically for the remainder.
Spindle event detection is a key component in analyzing human sleep. However, detection of these oscillatory patterns by experts is time consuming and costly. Automated detection algorithms are cost ...efficient and reproducible but require robust datasets to be trained and validated. Using the MODA (Massive Online Data Annotation) platform, we used crowdsourcing to produce a large open-source dataset of high quality, human-scored sleep spindles (5342 spindles, from 180 subjects). We evaluated the performance of three subtype scorers: "experts, researchers and non-experts", as well as 7 previously published spindle detection algorithms. Our findings show that only two algorithms had performance scores similar to human experts. Furthermore, the human scorers agreed on the average spindle characteristics (density, duration and amplitude), but there were significant age and sex differences (also observed in the set of detected spindles). This study demonstrates how the MODA platform can be used to generate a highly valid open source standardized dataset for researchers to train, validate and compare automated detectors of biological signals such as the EEG.
Sleep loss and structural plasticity Areal, Cassandra C; Warby, Simon C; Mongrain, Valérie
Current opinion in neurobiology,
06/2017, Letnik:
44
Journal Article
Recenzirano
Highlights • Acute sleep loss modifies synaptic structure in a region-dependent manner. • Sleep loss mostly reduces dendritic spine number in the mammalian brain. • Structural changes are ...mechanistically linked to sleep and learning/memory. • Diverse molecular mechanisms regulate sleep-dependent structural changes.
Cis-regulatory variants that alter gene expression can modify disease expressivity, but none have previously been identified in Huntington disease (HD). Here we provide in vivo evidence in HD ...patients that cis-regulatory variants in the HTT promoter are bidirectional modifiers of HD age of onset. HTT promoter analysis identified a NF-κB binding site that regulates HTT promoter transcriptional activity. A non-coding SNP, rs13102260:G > A, in this binding site impaired NF-κB binding and reduced HTT transcriptional activity and HTT protein expression. The presence of the rs13102260 minor (A) variant on the HD disease allele was associated with delayed age of onset in familial cases, whereas the presence of the rs13102260 (A) variant on the wild-type HTT allele was associated with earlier age of onset in HD patients in an extreme case-based cohort. Our findings suggest a previously unknown mechanism linking allele-specific effects of rs13102260 on HTT expression to HD age of onset and have implications for HTT silencing treatments that are currently in development.
Summary
Sleepwalking is a common non‐rapid eye movement (NREM) parasomnia and a significant cause of sleep‐related injuries. While evidence suggest that the occurrence of this condition is partly ...determined by genetic factors, its pattern of inheritance remains unclear, and few molecular studies have been conducted. One promising candidate is the adenosine deaminase (ADA) gene. Adenosine and the ADA enzyme play an important role in the homeostatic regulation of NREM sleep. In a single sleepwalking family, genome‐wide analysis identified a locus on chromosome 20, where ADA lies. In this study, we examined if variants in the ADA gene were associated with sleepwalking. In total, 251 sleepwalking patients were clinically assessed, and DNA samples were compared to those from 94 unaffected controls. Next‐generation sequencing of the whole ADA gene was performed. Bio‐informatic analysis enabled the identification of variants and assessed variants enrichment in our cohort compared to controls. We detected 25 different coding and non‐coding variants, of which 22 were found among sleepwalkers. None were enriched in the sleepwalking population. However, many missense variants were predicted as likely pathogenic by at least two in silico prediction algorithms. This study involves the largest sleepwalking cohort in which the role of a susceptibility gene was investigated. Our results did not reveal an association between ADA gene and sleepwalking, thus ruling out the possibility of ADA as a major genetic factor for this condition. Future work is needed to identify susceptibility genes.
Untreated obstructive sleep apnea (OSA) patients have an increased risk of cardiovascular disease (CVD). Adhesion molecules, including soluble E-selectin (sE-selectin), intercellular adhesion ...molecule-1 (ICAM-1), and vascular adhesion molecule-1 (VCAM-1), are associated with incident CVD. We hypothesized that specific genetic variants will be associated with plasma levels of adhesion molecules in suspected OSA patients. We also hypothesized that there may be an interaction between these variants and OSA.
We measured levels of sE-selectin, sICAM-1 and sVCAM-1 in 491 patients with suspected OSA and genotyped them for 20 polymorphisms.
The most significant association was between the ABO rs579459 polymorphism and sE-selectin levels (P = 7×10-21), with the major allele T associated with higher levels. The direction of effect and proportion of the variance in sE-selectin levels accounted for by rs579459 (16%) was consistent with estimates from non-OSA cohorts. In a multivariate regression analysis, addition of rs579459 improved the model performance in predicting sE-selectin levels. Three polymorphisms were nominally associated with sICAM-1 levels but none with sVCAM-1 levels. The combination of severe OSA and two rs579459 T alleles identified a group of patients with high sE-selectin levels; however, the increase in sE-selectin levels associated with severe OSA was greater in patients without two T alleles (P = 0.05 test for interaction).
These genetic polymorphisms may help to identify patients at greatest risk of incident CVD and may help in developing a more precision-based approach to OSA care.
Cleavage of huntingtin (htt) has been characterized in vitro, and accumulation of caspase cleavage fragments represents an early pathological change in brains of Huntington's disease (HD) patients. ...However, the relationship between htt proteolysis and the pathogenesis of HD is unknown. To determine whether caspase cleavage of htt is a key event in the neuronal dysfunction and selective neurodegeneration in HD, we generated YAC mice expressing caspase-3- and caspase-6-resistant mutant htt. Mice expressing mutant htt, resistant to cleavage by caspase-6 but not caspase-3, maintain normal neuronal function and do not develop striatal neurodegeneration. Furthermore, caspase-6-resistant mutant htt mice are protected against neurotoxicity induced by multiple stressors including NMDA, quinolinic acid (QA), and staurosporine. These results are consistent with proteolysis of htt at the caspase-6 cleavage site being an important event in mediating neuronal dysfunction and neurodegeneration and highlight the significant role of htt proteolysis and excitotoxicity in HD.
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