Investigating neuromagnetic brain responses against chromatic flickering stimuli by wavelet entropies

BACKGROUND: Photosensitive epilepsy is a type of reflexive epilepsy triggered by various visual stimuli including colourful ones. Despite the ubiquitous presence of colorful displays, brain responses against different colour combinations are not properly studied. METHODOLOGY/PRINCIPAL FINDINGS: Here, we studied the photosensitivity of the human brain against three types of chromatic flickering stimuli by recording neuromagnetic brain responses (magnetoencephalogram, MEG) from nine adult controls, an unmedicated patient, a medicated patient, and two controls age-matched with patients. Dynamical complexities of MEG signals were investigated by a family of wavelet entropies. Wavelet entropy is a newly proposed measure to characterize large scale brain responses, which quantifies the degree of order/disorder associated with a multi-frequency signal response. In particular, we found that as compared to the unmedicated patient, controls showed significantly larger wavelet entropy values. We also found that Renyi entropy is the most powerful feature for the participant classification. Finally, we also demonstrated the effect of combinational chromatic sensitivity on the underlying order/disorder in MEG signals. CONCLUSIONS/SIGNIFICANCE: Our results suggest that when perturbed by potentially epileptic-triggering stimulus, healthy human brain manages to maintain a non-deterministic, possibly nonlinear state, with high degree of disorder, but an epileptic brain represents a highly ordered state which making it prone to hyper-excitation. Further, certain colour combination was found to be more threatening than other combinations

CHD2 variants are a risk factor for photosensitivity in epilepsy

Photosensitivity is a heritable abnormal cortical response to flickering light, manifesting as particular electroencephalographic changes, with or without seizures. Photosensitivity is prominent in a very rare epileptic encephalopathy due to de novo CHD2 mutations, but is also seen in epileptic encephalopathies due to other gene mutations. We determined whether CHD2 variation underlies photosensitivity in common epilepsies, specific photosensitive epilepsies and individuals with photosensitivity without seizures. We studied 580 individuals with epilepsy and either photosensitive seizures or abnormal photoparoxysmal response on electroencephalography, or both, and 55 individuals with photoparoxysmal response but no seizures. We compared CHD2 sequence data to publicly available data from 34 427 individuals, not enriched for epilepsy. We investigated the role of unique variants seen only once in the entire data set. We sought CHD2 variants in 238 exomes from familial genetic generalized epilepsies, and in other public exome data sets. We identified 11 unique variants in the 580 individuals with photosensitive epilepsies and 128 unique variants in the 34 427 controls: unique CHD2 variation is over-represented in cases overall (P = 2·17 × 10−5). Among epilepsy syndromes, there was over-representation of unique CHD2 variants (3/36 cases) in the archetypal photosensitive epilepsy syndrome, eyelid myoclonia with absences (P = 3·50 × 10−4). CHD2 variation was not over-represented in photoparoxysmal response without seizures. Zebrafish larvae with chd2 knockdown were tested for photosensitivity. Chd2 knockdown markedly enhanced mild innate zebrafish larval photosensitivity. CHD2 mutation is the first identified cause of the archetypal generalized photosensitive epilepsy syndrome, eyelid myoclonia with absences. Unique CHD2 variants are also associated with photosensitivity in common epilepsies. CHD2 does not encode an ion channel, opening new avenues for research into human cortical excitability

Epilepsy Caused by an Abnormal Alternative Splicing with Dosage Effect of the SV2A Gene in a Chicken Model

Photosensitive reflex epilepsy is caused by the combination of an individual's enhanced sensitivity with relevant light stimuli, such as stroboscopic lights or video games. This is the most common reflex epilepsy in humans; it is characterized by the photoparoxysmal response, which is an abnormal electroencephalographic reaction, and seizures triggered by intermittent light stimulation. Here, by using genetic mapping, sequencing and functional analyses, we report that a mutation in the acceptor site of the second intron of SV2A (the gene encoding synaptic vesicle glycoprotein 2A) is causing photosensitive reflex epilepsy in a unique vertebrate model, the Fepi chicken strain, a spontaneous model where the neurological disorder is inherited as an autosomal recessive mutation. This mutation causes an aberrant splicing event and significantly reduces the level of SV2A mRNA in homozygous carriers. Levetiracetam, a second generation antiepileptic drug, is known to bind SV2A, and SV2A knock-out mice develop seizures soon after birth and usually die within three weeks. The Fepi chicken survives to adulthood and responds to levetiracetam, suggesting that the low-level expression of SV2A in these animals is sufficient to allow survival, but does not protect against seizures. Thus, the Fepi chicken model shows that the role of the SV2A pathway in the brain is conserved between birds and mammals, in spite of a large phylogenetic distance. The Fepi model appears particularly useful for further studies of physiopathology of reflex epilepsy, in comparison with induced models of epilepsy in rodents. Consequently, SV2A is a very attractive candidate gene for analysis in the context of both mono- and polygenic generalized epilepsies in humans

Revisiting the Twentieth Century Through the Lens of Generation X and Digital Games: A Scoping Review

Video games have been around since the 1960s and have impacted upon society in a myriad of different ways. The purpose of this scoping review is to identify existing literature within the domain of video games which recruited participants from the Generation X (1965–1980) cohort. Six databases were searched (ACM, CINHAL Google Scholar, PubMed, Scopus, and Web of Science) focusing on published journal papers between 1970 and 2000. Search results identified 3186 articles guided by the PRISMA Extension for Scoping Reviews (PRISMA-ScR); 4 papers were irretrievable, 138 duplicated papers were removed, leaving 3048 were assessed for eligibility and 3026 were excluded. Articles (n = 22) were included into this review, with four papers primarily published in 1997 and in 1999. Thematic analysis identified five primary themes: purpose and objectives, respective authors’ reporting, technology, ethics and environment) and seven secondary themes: populations, type of participants (e.g. children, students), ethical approval, study design, reimbursement, language, type of assessments. This scoping review is distinctive because it primarily focuses on Generation X, who have experienced and grown-up with videogames, and contributes to several disciplines including: game studies, gerontology and health, and has wider implications from a societal, design and development perspective of video games

Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies

The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology

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

Migraine in the borderland of epilepsy. ‘‘Migralepsy’’ an overlapping syndrome of children and adults?

Gowers gave migraine a place in the borderland of epilepsy, justified by many relations and the fact that distinction of these two diseases is difficult. Gowers based his ideas on clinical histories from his patients, and he concluded that in extremely rare instances one may develop while the other goes on. In modern times, patient testimonies of the problem of differentiating migraine from epilepsy are given in health-chat Websites. It shows clearly that distinction between the two conditions is still problematic and that migralepsy is either nonexisting or extremely rare as Gowers noticed

Photic stimulations in rats and what does it tell us about absence epilepsy

Albino rats have a higher amplitude of the late complex of the flash-induced visual evoked potential (VEPs) and afterdischarges (AD), the latter in particular during low states of arousal and vigilance than hooded and pigmented rats. These ADs are generated in cortico-geniculate-cortical pathways and have been used as a model for the evaluation of putative anti-absence drugs, while properties of flash-evoked VEPs were also used to predict toxic effects of new compounds, including putative anticonvulsant drugs. Flash VEPs made during spike-wave discharges (SWDs) in the genetic animal absence models have revealed that their sensory system is largely intact; interestingly the state of the brain during SWDs mimics that of slow-wave sleep. Photic stimulation in the genetic epileptic models does not provoke a photoparoxysmal response, as has been found in some absence epilepsy patients. However, trains of intense photic stimulation was efficacious in inducing neuroplastic changes leading to photoparoxysmal activity in normal young adult Sprague-Dawley rats. SWDs originating from the somatosensory cortex in the genetic rat models were reduced during photic stimulation due to enhanced arousal. Moreover, outcomes from fMRI studies in absence patients showed that the pathways and the brain regions involved in the occurrence of spontaneous occurring SWDs differ from those involved in the SWDs elicited by photic stimulation. Although both SWDs and flash-evoked AD are cortico-thalamo-cortical oscillations, it seems that there are important differences between the rodent absence models, regarding the brain networks and mechanisms and humans with absence seizures between physiological elicited photically induced ADs and the spontaneous occurring pathological SWDs