Evidence for an optimal algorithm underlying signal combination in human visual cortex

How does the cortex combine information from multiple sources? We tested several computational models against data from steady-state EEG experiments in humans, using periodic visual stimuli combined across either retinal location or eye-of-presentation. A model in which signals are raised to an exponent before being summed in both the numerator and the denominator of a gain control nonlinearity gave the best account of the data. This model also predicted the pattern of responses in a range of additional conditions accurately and with no free parameters, as well as predicting responses at harmonic and intermodulation frequencies between 1 and 30Hz. We speculate that this model implements the optimal algorithm for combining multiple noisy inputs, in which responses are proportional to the weighted sum of both inputs. This suggests a novel purpose for cortical gain control: implementing optimal signal combination via mutual inhibition, perhaps explaining its ubiquity as a neural computation

Circadian rhythms in visual responsiveness in the behaviourally arrhythmic Drosophila clock mutant ClkJrk

An organism’s biological day is characterised by a pattern of anticipatory physiological and behavioural changes that are governed by circadian clocks to align with the 24-hour cycling environment. Here, we used flash electroretinograms (ERGs) and Steady State Visually Evoked Potentials (SSVEPs) to examine how visual responsiveness in wild-type Drosophila melanogaster and the circadian clock mutant ClkJrk varies over circadian time. We show that the ERG parameters of wild-type flies vary over the circadian day with a higher luminance response during the subjective night. The SSVEP response that assesses contrast sensitivity also showed a time of day dependence including two prominent peaks within a 24-hour period and a maximal response at the end of the subjective day, indicating a trade-off between luminance and contrast sensitivity. Moreover, the behaviourally arrhythmic ClkJrk mutants maintained a circadian profile in both luminance and contrast sensitivity but unlike the wild-types, which show bimodal profiles in their visual response, ClkJrk flies show a weakening of the bimodal character with visual responsiveness tending to peak once a day. We conclude that the ClkJrk mutation mainly affects one of two functionally coupled oscillators, and that the visual system is partially separated from the locomotor circadian circuits that drive bouts of morning and evening activity. As light exposure is a major mechanism for entrainment, our work suggests that a detailed temporal analysis of electrophysiological responses is warranted to better identify the time window at which circadian rhythms are most receptive to light-induced phase shifting

The effect of locomotion on early visual contrast processing in humans

Most of our knowledge about vision comes from experiments in which stimuli are presented to immobile human subjects or animals. In the case of human subjects, movement during psychophysical, electrophysiological or neuroimaging experiments is considered to be a source of noise to be eliminated. Animals used in visual neuroscience experiments are typically restrained and, in many cases, anaesthetized. In reality however, vision is often used to guide the motion of awake, ambulating organisms. Recent work in mice has shown that locomotion elevates visual neuronal response amplitudes (Erisken et al., 2014; Fu et al., 2014; Lee et al., 2014; Mineault et al., 2016; Niell and Stryker, 2010) and reduces long-range gain control (Ayaz et al., 2013). Here we use both psychophysics and steady-state electrophysiology to ask whether similar effects of locomotion on early visual processing can be measured in humans. Our psychophysical results show that brisk walking has little effect on subjects’ ability to detect briefly-presented contrast changes and that co-oriented flankers are, if anything, more effective masks when subjects are walking. Our electrophysiological data were consistent with the psychophysics, indicating no increase in stimulus-driven neuronal responses whilst walking and no reduction in surround suppression. In summary we find evidence that early contrast processing is altered by locomotion in humans but in a manner that differs from that reported in mice. The effects of locomotion on very low-level visual processing may differ on a species-by-species basis and may reflect important differences in the levels of arousal associated with locomotion

Autism sensory dysfunction in an evolutionarily conserved system

There is increasing evidence for a strong genetic basis for autism, with many genetic models being developed in an attempt to replicate autistic symptoms in animals. However, current animal behaviour paradigms rarely match the social and cognitive behaviours exhibited by autistic individuals. Here we instead assay another functional domain – sensory processing – known to be affected in autism to test a novel genetic autism model in Drosophila melanogaster. We show similar visual response alterations and a similar development trajectory in Nhe3 mutant flies (total N=72) and in autistic human participants (total N=154). We report a dissociation between first- and second-order electrophysiological visual responses to steady-state stimulation in adult mutant fruit flies that is strikingly similar to the response pattern in human adults with ASD as well as that of a large sample of neurotypical individuals with high numbers of autistic traits. We explain this as a genetically driven, selective signalling alteration in transient visual dynamics. In contrast to adults, autistic children show a decrease in the first-order response that is matched by the fruit fly model, suggesting that a compensatory change in processing occurs during development. Our results provide the first animal model of autism comprising a differential developmental phenotype in visual processing

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe