Comparison of Langevin and Markov channel noise models for neuronal signal generation

The stochastic opening and closing of voltage-gated ion channels produces noise in neurons. The effect of this noise on the neuronal performance has been modelled using either approximate or Langevin model, based on stochastic differential equations or an exact model, based on a Markov process model of channel gating. Yet whether the Langevin model accurately reproduces the channel noise produced by the Markov model remains unclear. Here we present a comparison between Langevin and Markov models of channel noise in neurons using single compartment Hodgkin-Huxley models containing either $Na^{+}$ and $K^{+}$, or only $K^{+}$ voltage-gated ion channels. The performance of the Langevin and Markov models was quantified over a range of stimulus statistics, membrane areas and channel numbers. We find that in comparison to the Markov model, the Langevin model underestimates the noise contributed by voltage-gated ion channels, overestimating information rates for both spiking and non-spiking membranes. Even with increasing numbers of channels the difference between the two models persists. This suggests that the Langevin model may not be suitable for accurately simulating channel noise in neurons, even in simulations with large numbers of ion channels

Improved Detection of Common Variants Associated with Schizophrenia and Bipolar Disorder Using Pleiotropy-Informed Conditional False Discovery Rate

Several lines of evidence suggest that genome-wide association studies (GWAS) have the potential to explain more of the “missing heritability” of common complex phenotypes. However, reliable methods to identify a larger proportion of single nucleotide polymorphisms (SNPs) that impact disease risk are currently lacking. Here, we use a genetic pleiotropy-informed conditional false discovery rate (FDR) method on GWAS summary statistics data to identify new loci associated with schizophrenia (SCZ) and bipolar disorders (BD), two highly heritable disorders with significant missing heritability. Epidemiological and clinical evidence suggest similar disease characteristics and overlapping genes between SCZ and BD. Here, we computed conditional Q–Q curves of data from the Psychiatric Genome Consortium (SCZ; n = 9,379 cases and n = 7,736 controls; BD: n = 6,990 cases and n = 4,820 controls) to show enrichment of SNPs associated with SCZ as a function of association with BD and vice versawith a corresponding reduction in FDR. Applying the conditional FDR method, we identified 58 loci associated with SCZ and 35 loci associated with BD below the conditional FDR level of 0.05. Of these, 14 loci were associated with both SCZ and BD (conjunction FDR). Together, these findings show the feasibility of genetic pleiotropy-informed methods to improve gene discovery in SCZ and BD and indicate overlapping genetic mechanisms between these two disorders

All SNPs Are Not Created Equal: Genome-Wide Association Studies Reveal a Consistent Pattern of Enrichment among Functionally Annotated SNPs

Recent results indicate that genome-wide association studies (GWAS) have the potential to explain much of the heritability of common complex phenotypes, but methods are lacking to reliably identify the remaining associated single nucleotide polymorphisms (SNPs). We applied stratified False Discovery Rate (sFDR) methods to leverage genic enrichment in GWAS summary statistics data to uncover new loci likely to replicate in independent samples. Specifically, we use linkage disequilibrium-weighted annotations for each SNP in combination with nominal p-values to estimate the True Discovery Rate (TDR = 1−FDR) for strata determined by different genic categories. We show a consistent pattern of enrichment of polygenic effects in specific annotation categories across diverse phenotypes, with the greatest enrichment for SNPs tagging regulatory and coding genic elements, little enrichment in introns, and negative enrichment for intergenic SNPs. Stratified enrichment directly leads to increased TDR for a given p-value, mirrored by increased replication rates in independent samples. We show this in independent Crohn's disease GWAS, where we find a hundredfold variation in replication rate across genic categories. Applying a well-established sFDR methodology we demonstrate the utility of stratification for improving power of GWAS in complex phenotypes, with increased rejection rates from 20% in height to 300% in schizophrenia with traditional FDR and sFDR both fixed at 0.05. Our analyses demonstrate an inherent stratification among GWAS SNPs with important conceptual implications that can be leveraged by statistical methods to improve the discovery of loci

Quantitative Characterization of the Filiform Mechanosensory Hair Array on the Cricket Cercus

Crickets and other orthopteran insects sense air currents with a pair of abdominal appendages resembling antennae, called cerci. Each cercus in the common house cricket Acheta domesticus is approximately 1 cm long, and is covered with 500 to 750 filiform mechanosensory hairs. The distribution of the hairs on the cerci, as well as the global patterns of their movement vectors, have been characterized semi-quantitatively in studies over the last 40 years, and have been shown to be very stereotypical across different animals in this species. Although the cercal sensory system has been the focus of many studies in the areas of neuroethology, development, biomechanics, sensory function and neural coding, there has not yet been a quantitative study of the functional morphology of the receptor array of this important model system.We present a quantitative characterization of the structural characteristics and functional morphology of the cercal filiform hair array. We demonstrate that the excitatory direction along each hair's movement plane can be identified by features of its socket that are visible at the light-microscopic level, and that the length of the hair associated with each socket can also be estimated accurately from a structural parameter of the socket. We characterize the length and directionality of all hairs on the basal half of a sample of three cerci, and present statistical analyses of the distributions.The inter-animal variation of several global organizational features is low, consistent with constraints imposed by functional effectiveness and/or developmental processes. Contrary to previous reports, however, we show that the filiform hairs are not re-identifiable in the strict sense

The Shoulder Pain and Disability Index demonstrates factor, construct and longitudinal validity

BACKGROUND: The Shoulder Pain and Disability Index (SPADI) is a self-report measure developed to evaluate patients with shoulder pathology. While some validation has been conducted, broader analyses are indicated. This study determined aspects of cross-sectional and longitudinal validity of the SPADI. METHODS: Community volunteers (n = 129) who self-identified as having shoulder pain were enrolled. Patients were examined by a physical therapist using a standardized assessment process to insure that their pain was musculoskeletal in nature. This included examination of pain reported during active and passive shoulder motion as reported on a visual analogue pain scale. Patients completed the SPADI, the Coping Strategies Questionnaire (CSQ) and the Sickness Impact Profile (SIP) at a baseline assessment and again 3 and 6 months later. Factor analysis with varimax rotation was used to assess subscale structure. Expectations regarding convergent and divergent subscales of CSQ and SIP were determined a priori and analysed using Pearson correlations. Constructed hypotheses that patients with a specific diagnosis or on pain medication would demonstrate higher SPADI scores were tested. Correlations between the observed changes recorded across different instruments were used to assess longitudinal validity. RESULTS: The internal consistencies of the SPADI subscales were high (α > 0.92). Factor analysis with varimax rotation indicated that the majority of items fell into 2 factors that represent pain and disability. Two difficult functional items tended to align with pain items. Higher pain and disability was correlated to passive or negative coping strategies, i.e., praying/hoping, catastrophizing on the CSQ. The correlations between subscales of the SPADI and SIP were low with divergent subscales and low to moderate with convergent subscales. Correlations, r > 0.60, were observed between the SPADI and pain reported on a VAS pain scale during active and passive movement. The two constructed validity hypotheses (on diagnosis and use of pain medications) were both supported (p < 0.01). The SPADI demonstrated significant changes over time, but these were poorly correlated to the SIP or CSQ suggesting that these scales measure different parameters. CONCLUSION: The SPADI is a valid measure to assess pain and disability in community-based patients reporting shoulder pain due to musculoskeletal pathology

Information Transmission in Cercal Giant Interneurons Is Unaffected by Axonal Conduction Noise

What are the fundamental constraints on the precision and accuracy with which nervous systems can process information? One constraint must reflect the intrinsic “noisiness” of the mechanisms that transmit information between nerve cells. Most neurons transmit information through the probabilistic generation and propagation of spikes along axons, and recent modeling studies suggest that noise from spike propagation might pose a significant constraint on the rate at which information could be transmitted between neurons. However, the magnitude and functional significance of this noise source in actual cells remains poorly understood. We measured variability in conduction time along the axons of identified neurons in the cercal sensory system of the cricket Acheta domesticus, and used information theory to calculate the effects of this variability on sensory coding. We found that the variability in spike propagation speed is not large enough to constrain the accuracy of neural encoding in this system

All-arthroscopic versus mini-open repair of small or moderate-sized rotator cuff tears: A protocol for a randomized trial [NCT00128076]

BACKGROUND: Rotator cuff tears are the most common source of shoulder pain and disability. Only poor quality studies have compared mini-open to arthroscopic repair, leaving surgeons with inadequate evidence to support optimal, minimally-invasive repair. METHODS/DESIGN: This randomized, multi-centre, national trial will determine whether an arthroscopic or mini-open repair provides better quality of life for patients with small or moderate-sized rotator cuff tears. A national consensus meeting of investigators in the Joint Orthopaedic Initiative for National Trials of the Shoulder (JOINTS Canada) identified this question as the top priority for shoulder surgeons across Canada. The primary outcome measure is a valid quality-of-life scale (Western Ontario Rotator Cuff (WORC)) that addresses 5 domains of health affected by rotator cuff disease. Secondary outcomes will assess rotator cuff functionality (ROM, strength, Constant score), secondary dimensions of health (general health status (SF-12) and work limitations), and repair integrity (MRI). Outcomes are measured at baseline, at 6 weeks, 3, 6, 12, and 24 months post-operatively by blinded research assistants and musculoskeletal radiologists. Patients (n = 250) with small or medium-sized cuff tears identified by clinical examination and MRI who meet eligibility criteria will be recruited. This sample size will provide 80% power to statistically detect a clinically important difference of 20% in WORC scores between procedures after controlling for baseline WORC score (α = 0.05). A central methods centre will manage randomization, data management, and monitoring under supervision of experienced epidemiologists. Surgeons will participate in either conventional or expertise-based designs according to defined criteria to avoid biases from differential surgeon expertise. Mini-open or all-arthroscopic repair procedures will be performed according to a standardized protocol. Central Adjudication (of cases), Trial Oversight and Safety Committees will monitor trial conduct. We will use an analysis of covariance (ANCOVA), where the baseline WORC score is used as a covariate, to compare the quality of life (WORC score) at 2 years post-operatively. As a secondary analysis, we will conduct the same statistical test but will include age and tear size as covariates with the baseline score. Enrollment will require 2 years and follow-up an additional 2 years. The trial will commence when funding is in place. DISCUSSION: These results will have immediate impact on the practice behaviors of practicing surgeons and surgical trainees at JOINTS centres across Canada. JOINTS Canada is actively engaged in knowledge exchange and will publish and present findings internationally to facilitate wider application. This trial will establish definitive evidence on this question at an international level