Stimulus Devaluation Induced by Stopping Action

Impulsive behavior in humans partly relates to inappropriate overvaluation of reward-associated stimuli. Hence, it is desirable to develop methods of behavioral modification that can reduce stimulus value. Here, we tested whether one kind of behavioral modification—the rapid stopping of actions in the face of reward-associated stimuli—could lead to subsequent devaluation of those stimuli. We developed a novel paradigm with three consecutive phases: implicit reward learning, a stop-signal task, and an auction procedure. In the learning phase, we associated abstract shapes with different levels of reward. In the stop-signal phase, we paired half those shapes with occasional stop-signals, requiring the rapid stopping of an initiated motor response, while the other half of shapes was not paired with stop signals. In the auction phase, we assessed the subjective value of each shape via willingness-to-pay. In 2 experiments, we found that participants bid less for shapes that were paired with stop-signals compared to shapes that were not. This suggests that the requirement to try to rapidly stop a response decrements stimulus value. Two follow-on control experiments suggested that the result was specifically due to stopping action rather than aversiveness, effort, conflict, or salience associated with stop signals. This study makes a theoretical link between research on inhibitory control and value. It also provides a novel behavioral paradigm with carefully operationalized learning, treatment, and valuation phases. This framework lends itself to both behavioral modification procedures in clinical disorders and research on the neural underpinnings of stimulus devaluation

Civil RICO Reform: The Gatekeeper Concept

Since coming into vogue in the mid-1980s, civil RICO has often been criticized and targeted for reform. Critics claim that civil RICO is too broad because it potentially applies to all commercial transactions.More specifically, opponents claim that RICO\u27s inclusion of mail and wire fraud as predicate acts unjustly subjects all legitimate businesses to liability.For example, Representative Rick Boucher, sponsor of the 1989 RICO reform legislation, has stated: Fraud allegations are commonly made in contract situations, and all that is needed to convert a simple contract dispute into a civil RICO case is the allegation that there was a contract and the additional allegation that either the mails or the telephones were used more than once in either forming or breaching the contract. Such criticism has led to numerous attempts by courts and legislators to curtail civil RICO. For the most part, these efforts have sought to emasculate civil RICO rather than to rectify isolated problems of abuse or over breadth

NAS-X: Neural Adaptive Smoothing via Twisting

We present Neural Adaptive Smoothing via Twisting (NAS-X), a method for learning and inference in sequential latent variable models based on reweighted wake-sleep (RWS). NAS-X works with both discrete and continuous latent variables, and leverages smoothing SMC to fit a broader range of models than traditional RWS methods. We test NAS-X on discrete and continuous tasks and find that it substantially outperforms previous variational and RWS-based methods in inference and parameter recovery

Towards a theory of learning dynamics in deep state space models

State space models (SSMs) have shown remarkable empirical performance on many long sequence modeling tasks, but a theoretical understanding of these models is still lacking. In this work, we study the learning dynamics of linear SSMs to understand how covariance structure in data, latent state size, and initialization affect the evolution of parameters throughout learning with gradient descent. We show that focusing on the learning dynamics in the frequency domain affords analytical solutions under mild assumptions, and we establish a link between one-dimensional SSMs and the dynamics of deep linear feed-forward networks. Finally, we analyze how latent state over-parameterization affects convergence time and describe future work in extending our results to the study of deep SSMs with nonlinear connections. This work is a step toward a theory of learning dynamics in deep state space models

Time-Dependent Statistical and Correlation Properties of Neural Signals during Handwriting

To elucidate the cortical control of handwriting, we examined time-dependent statistical and correlational properties of simultaneously recorded 64-channel electroencephalograms (EEGs) and electromyograms (EMGs) of intrinsic hand muscles. We introduced a statistical method, which offered advantages compared to conventional coherence methods. In contrast to coherence methods, which operate in the frequency domain, our method enabled us to study the functional association between different neural regions in the time domain. In our experiments, subjects performed about 400 stereotypical trials during which they wrote a single character. These trials provided time-dependent EMG and EEG data capturing different handwriting epochs. The set of trials was treated as a statistical ensemble, and time-dependent correlation functions between neural signals were computed by averaging over that ensemble. We found that trial-to-trial variability of both the EMGs and EEGs was well described by a log-normal distribution with time-dependent parameters, which was clearly distinguished from the normal (Gaussian) distribution. We found strong and long-lasting EMG/EMG correlations, whereas EEG/EEG correlations, which were also quite strong, were short-lived with a characteristic correlation durations on the order of 100 ms or less. Our computations of correlation functions were restricted to the spectral range (13–30 Hz) of EEG signals where we found the strongest effects related to handwriting. Although, all subjects involved in our experiments were right-hand writers, we observed a clear symmetry between left and right motor areas: inter-channel correlations were strong if both channels were located over the left or right hemispheres, and 2–3 times weaker if the EEG channels were located over different hemispheres. Although we observed synchronized changes in the mean energies of EEG and EMG signals, we found that EEG/EMG correlations were much weaker than EEG/EEG and EMG/EMG correlations. The absence of strong correlations between EMG and EEG signals indicates that (i) a large fraction of the EEG signal includes electrical activity unrelated to low-level motor variability; (ii) neural processing of cortically-derived signals by spinal circuitry may reduce the correlation between EEG and EMG signals

A framework for multi-scale intervention modeling: virtual cohorts, virtual clinical trials, and model-to-model comparisons

Computational models of disease progression have been constructed for a myriad of pathologies. Typically, the conceptual implementation for pathology-related in silico intervention studies has been ad hoc and similar in design to experimental studies. We introduce a multi-scale interventional design (MID) framework toward two key goals: tracking of disease dynamics from within-body to patient to population scale; and tracking impact(s) of interventions across these same spatial scales. Our MID framework prioritizes investigation of impact on individual patients within virtual pre-clinical trials, instead of replicating the design of experimental studies. We apply a MID framework to develop, organize, and analyze a cohort of virtual patients for the study of tuberculosis (TB) as an example disease. For this study, we use HostSim: our next-generation whole patient-scale computational model of individuals infected with Mycobacterium tuberculosis. HostSim captures infection within lungs by tracking multiple granulomas, together with dynamics occurring with blood and lymph node compartments, the compartments involved during pulmonary TB. We extend HostSim to include a simple drug intervention as an example of our approach and use our MID framework to quantify the impact of treatment at cellular and tissue (granuloma), patient (lungs, lymph nodes and blood), and population scales. Sensitivity analyses allow us to determine which features of virtual patients are the strongest predictors of intervention efficacy across scales. These insights allow us to identify patient-heterogeneous mechanisms that drive outcomes across scales

Integrated genome-wide association, coexpression network, and expression single nucleotide polymorphism analysis identifies novel pathway in allergic rhinitis

Background: Allergic rhinitis is a common disease whose genetic basis is incompletely explained. We report an integrated genomic analysis of allergic rhinitis. Methods: We performed genome wide association studies (GWAS) of allergic rhinitis in 5633 ethnically diverse North American subjects. Next, we profiled gene expression in disease-relevant tissue (peripheral blood CD4+ lymphocytes) collected from subjects who had been genotyped. We then integrated the GWAS and gene expression data using expression single nucleotide (eSNP), coexpression network, and pathway approaches to identify the biologic relevance of our GWAS. Results: GWAS revealed ethnicity-specific findings, with 4 genome-wide significant loci among Latinos and 1 genome-wide significant locus in the GWAS meta-analysis across ethnic groups. To identify biologic context for these results, we constructed a coexpression network to define modules of genes with similar patterns of CD4+ gene expression (coexpression modules) that could serve as constructs of broader gene expression. 6 of the 22 GWAS loci with P-value ≤ 1x10−6 tagged one particular coexpression module (4.0-fold enrichment, P-value 0.0029), and this module also had the greatest enrichment (3.4-fold enrichment, P-value 2.6 × 10−24) for allergic rhinitis-associated eSNPs (genetic variants associated with both gene expression and allergic rhinitis). The integrated GWAS, coexpression network, and eSNP results therefore supported this coexpression module as an allergic rhinitis module. Pathway analysis revealed that the module was enriched for mitochondrial pathways (8.6-fold enrichment, P-value 4.5 × 10−72). Conclusions: Our results highlight mitochondrial pathways as a target for further investigation of allergic rhinitis mechanism and treatment. Our integrated approach can be applied to provide biologic context for GWAS of other diseases

Neuronal Variability during Handwriting: Lognormal Distribution

We examined time-dependent statistical properties of electromyographic (EMG) signals recorded from intrinsic hand muscles during handwriting. Our analysis showed that trial-to-trial neuronal variability of EMG signals is well described by the lognormal distribution clearly distinguished from the Gaussian (normal) distribution. This finding indicates that EMG formation cannot be described by a conventional model where the signal is normally distributed because it is composed by summation of many random sources. We found that the variability of temporal parameters of handwriting - handwriting duration and response time - is also well described by a lognormal distribution. Although, the exact mechanism of lognormal statistics remains an open question, the results obtained should significantly impact experimental research, theoretical modeling and bioengineering applications of motor networks. In particular, our results suggest that accounting for lognormal distribution of EMGs can improve biomimetic systems that strive to reproduce EMG signals in artificial actuators