42 research outputs found
Sleep deprivation and Modafinil affect cortical sources of resting state electroencephalographic rhythms in healthy young adults
Objective: It has been reported that sleep deprivation affects the neurophysiological mechanisms underpinning the vigilance. Here, we tested the following hypotheses in the PharmaCog project (www.pharmacog.org): (i) sleep deprivation may alter posterior cortical delta and alpha sources of resting state eyes-closed electroencephalographic (rsEEG) rhythms in healthy young adults; (ii) after the sleep deprivation, a vigilance enhancer may recover those rsEEG source markers. Methods: rsEEG data were recorded in 36 healthy young adults before (Pre-sleep deprivation) and after (Post-sleep deprivation) one night of sleep deprivation. In the Post-sleep deprivation, these data were collected after a single dose of PLACEBO or MODAFINIL. rsEEG cortical sources were estimated by eLORETA freeware. Results: In the PLACEBO condition, the sleep deprivation induced an increase and a decrease in posterior delta (2â4 Hz) and alpha (8â13 Hz) source activities, respectively. In the MODAFINIL condition, the vigilance enhancer partially recovered those source activities. Conclusions: The present results suggest that posterior delta and alpha source activities may be both related to the regulation of human brain arousal and vigilance in quiet wakefulness. Significance: Future research in healthy young adults may use this methodology to preselect new symptomatic drug candidates designed to normalize brain arousal and vigilance in seniors with dementia
GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture
Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment
Perceiving What Is Reachable Depends on Motor Representations: Evidence from a Transcranial Magnetic Stimulation Study
Background: Visually determining what is reachable in peripersonal space requires information about the egocentric location of objects but also information about the possibilities of action with the body, which are context dependent. The aim of the present study was to test the role of motor representations in the visual perception of peripersonal space. Methodology: Seven healthy participants underwent a TMS study while performing a right-left decision (control) task or perceptually judging whether a visual target was reachable or not with their right hand. An actual grasping movement task was also included. Single pulse TMS was delivered 80 % of the trials on the left motor and premotor cortex and on a control site (the temporo-occipital area), at 90 % of the resting motor threshold and at different SOA conditions (50ms, 100ms, 200ms or 300ms). Principal Findings: Results showed a facilitation effect of the TMS on reaction times in all tasks, whatever the site stimulated and until 200ms after stimulus presentation. However, the facilitation effect was on average 34ms lower when stimulating the motor cortex in the perceptual judgement task, especially for stimuli located at the boundary of peripersonal space. Conclusion: This study provides the first evidence that brain motor area participate in the visual determination of what is reachable. We discuss how motor representations may feed the perceptual system with information about possibl
Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals
Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy
Role of Basal Ganglia Circuits in Resisting Interference by Distracters: A swLORETA Study
BACKGROUND: The selection of task-relevant information requires both the focalization of attention on the task and resistance to interference from irrelevant stimuli. Both mechanisms rely on a dorsal frontoparietal network, while focalization additionally involves a ventral frontoparietal network. The role of subcortical structures in attention is less clear, despite the fact that the striatum interacts significantly with the frontal cortex via frontostriatal loops. One means of investigating the basal ganglia's contributions to attention is to examine the features of P300 components (i.e. amplitude, latency, and generators) in patients with basal ganglia damage (such as in Parkinson's disease (PD), in which attention is often impaired). Three-stimulus oddball paradigms can be used to study distracter-elicited and target-elicited P300 subcomponents. METHODOLOGY/PRINCIPAL FINDINGS: In order to compare distracter- and target-elicited P300 components, high-density (128-channel) electroencephalograms were recorded during a three-stimulus visual oddball paradigm in 15 patients with early PD and 15 matched healthy controls. For each subject, the P300 sources were localized using standardized weighted low-resolution electromagnetic tomography (swLORETA). Comparative analyses (one-sample and two-sample t-tests) were performed using SPM5Âź software. The swLORETA analyses showed that PD patients displayed fewer dorsolateral prefrontal (DLPF) distracter-P300 generators but no significant differences in target-elicited P300 sources; this suggests dysfunction of the DLPF cortex when the executive frontostriatal loop is disrupted by basal ganglia damage. CONCLUSIONS/SIGNIFICANCE: Our results suggest that the cortical attention frontoparietal networks (mainly the dorsal one) are modulated by the basal ganglia. Disruption of this network in PD impairs resistance to distracters, which results in attention disorders
Value of ultrasonography as a marker of early response to abatacept in patients with rheumatoid arthritis and an inadequate response to methotrexate: results from the APPRAISE study
Objectives: To study the responsiveness of a combined power Doppler and greyscale ultrasound (PDUS) score for assessing synovitis in biologic-naĂŻve patients with rheumatoid arthritis (RA) starting abatacept plus methotrexate (MTX). Methods: In this open-label, multicentre, single-arm study, patients with RA (MTX inadequate responders) received intravenous abatacept (âŒ10â
mg/kg) plus MTX for 24â
weeks. A composite PDUS synovitis score, developed by the Outcome Measures in RheumatologyâEuropean League Against Rheumatism (OMERACTâEULAR)-Ultrasound Task Force, was used to evaluate individual joints. The maximal score of each joint was added into a Global OMERACTâEULAR Synovitis Score (GLOESS) for bilateral metacarpophalangeal joints (MCPs) 2â5 (primary objective). The value of GLOESS containing other joint sets was explored, along with clinical efficacy. Results: Eighty-nine patients completed the 24-week treatment period. The earliest PDUS sign of improvement in synovitis was at week 1 (mean change in GLOESS (MCPs 2â5): â0.7 (95% CIs â1.2 to â0.1)), with continuous improvement to week 24. Early improvement was observed in the component scores (power Doppler signal at week 1, synovial hyperplasia at week 2, joint effusion at week 4). Comparable changes were observed for 22 paired joints and minimal joint subsets. Mean Disease Activity Score 28 (C reactive protein) was significantly reduced from weeks 1 to 24, reaching clinical meaningful improvement (change â„1.2) at week 8. Conclusions: In this first international prospective study, the composite PDUS score is responsive to abatacept. GLOESS demonstrated the rapid onset of action of abatacept, regardless of the number of joints examined. Ultrasound is an objective tool to monitor patients with RA under treatment. Trial registration number: NCT00767325
GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture
Epilepsy is a highly heritable disorder affecting over 50âmillion people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment
Influence of pre-existing dementia on the risk of post-stroke epileptic seizures
Background: Seizures occur in 10% of stroke patients, but their predictors have not been clearly identified. Pre-existing dementia is present in 12â16% of stroke patients and, at the community level, patients with dementia have increased risk of seizures. However, the question of whether pre-existing dementia is associated with a higher risk of seizures after stroke has never been studied. Aim: To evaluate whether pre-existing dementia is associated with an increased risk of seizures after stroke. Methods: The study was conducted on 202 consecutive stroke patients recruited to the Lille stroke/dementia study (97 men; median age, 75 years; range, 42â100). Pre-stroke cognitive functions were evaluated using the Informant Questionnaire on Cognitive Decline in the Elderly, with a cutoff value of 104 for the diagnosis of dementia. Seizures were defined as early seizures when occurring within seven days of stroke onset, and as late seizures when occurring more than seven days after stroke. Results: Of 202 patients, 33 (16.3%) met the criteria for pre-existing dementia, and 11 (5.4%) developed early seizures. During 289 person-years of follow up, 14 patients developed late seizures, resulting in an incidence rate of 4.8 new cases/100 person-years. Pre-existing dementia was not associated with the occurrence of early seizures, but was independently associated with the occurrence of late seizures (adjusted odds ratio, 4.66; 95% confidence interval, 1.34 to 16.21). Conclusion: Stroke patients with pre-existing dementia have an increased risk of late seizures. Any factor increasing the risk of seizures (drugs, metabolic changes) should be avoided in these patients
Early seizures in intracerebral hemorrhage: incidence, associated factors, and outcome
Objective: In patients with spontaneous intracerebral hemorrhage (ICH), the occurrence of early seizures (ES) may be a prognostic marker. Therefore, we aimed to identify incidence, associated factors, and influence on outcome of ES in patients with ICH.
Methods: Between November 2004 and March 2009, we prospectively recruited 562 consecutive adults with a spontaneous ICH (Prognosis of InTra-Cerebral Hemorrhage cohort). Patients with previous seizures (n = 40) were excluded. ES were defined as seizures occurring within 7 days of stroke onset, and their associated factors were identified with Cox regression. For a subgroup of onset seizures, we used logistic regression. Data influencing outcome (mortality at day 7 and month 6 and functional outcome at month 6) were studied using survival analyses.
Results: ES occurred in 71 (14%; 95% confidence interval [CI] 11-17) of 522 patients (274 male; median age 72 years, interquartile range 58-79 years). The only factor associated with ES was cortical involvement of ICH (odds ratio [OR] = 2.06; 95% CI 1.28-3.31). Regarding onset seizures (n = 38) (7%; 95% CI 5-10), associated factors were previous ICH (OR = 4.76; 95% CI 1.53-14.84), cortical involvement (OR = 2.21; 95% CI 1.11-4.43), younger age (OR = 0.97 per 1 year increase; 95% CI 0.95-0.99), and severity of the neurologic deficit at admission (OR = 1.03 per 1 point increase in the National Institutes of Health Stroke Scale score; 95% CI 1.01-1.06). ES did not influence vital or functional outcome.
Conclusions: ES are a frequent complication in patients with spontaneous ICH; however, their occurrence does not influence outcome at 6 months