Detecting Episodic Evolution through Bayesian Inference of Molecular Clock Models.

Molecular evolutionary rate variation is a key aspect of the evolution of many organisms that can be modeled using molecular clock models. For example, fixed local clocks revealed the role of episodic evolution in the emergence of SARS-CoV-2 variants of concern. Like all statistical models, however, the reliability of such inferences is contingent on an assessment of statistical evidence. We present a novel Bayesian phylogenetic approach for detecting episodic evolution. It consists of computing Bayes factors, as the ratio of posterior and prior odds of evolutionary rate increases, effectively quantifying support for the effect size. We conducted an extensive simulation study to illustrate the power of this method and benchmarked it to formal model comparison of a range of molecular clock models using (log) marginal likelihood estimation, and to inference under a random local clock model. Quantifying support for the effect size has higher sensitivity than formal model testing and is straight-forward to compute, because it only needs samples from the posterior and prior distribution. However, formal model testing has the advantage of accommodating a wide range molecular clock models. We also assessed the ability of an automated approach, known as the random local clock, where branches under episodic evolution may be detected without their a priori definition. In an empirical analysis of a data set of SARS-CoV-2 genomes, we find "very strong" evidence for episodic evolution. Our results provide guidelines and practical methods for Bayesian detection of episodic evolution, as well as avenues for further research into this phenomenon.

Bayesian adaptive model selection design for optimal biological dose finding in phase I/II clinical trials.

Identification of the optimal dose presents a major challenge in drug development with molecularly targeted agents, immunotherapy, as well as chimeric antigen receptor T-cell treatments. By casting dose finding as a Bayesian model selection problem, we propose an adaptive design by simultaneously incorporating the toxicity and efficacy outcomes to select the optimal biological dose (OBD) in phase I/II clinical trials. Without imposing any parametric assumption or shape constraint on the underlying dose-response curves, we specify curve-free models for both the toxicity and efficacy endpoints to determine the OBD. By integrating the observed data across all dose levels, the proposed design is coherent in dose assignment and thus greatly enhances efficiency and accuracy in pinning down the right dose. Not only does our design possess a completely new yet flexible dose-finding framework, but it also has satisfactory and robust performance as demonstrated by extensive simulation studies. In addition, we show that our design enjoys desirable coherence properties, while most of existing phase I/II designs do not. We further extend the design to accommodate late-onset outcomes which are common in immunotherapy. The proposed design is exemplified with a phase I/II clinical trial in chronic lymphocytic leukemia.

Flexible cost-penalized Bayesian model selection: Developing inclusion paths with an application to diagnosis of heart disease.

We propose a Bayesian model selection approach that allows medical practitioners to select among predictor variables while taking their respective costs into account. Medical procedures almost always incur costs in time and/or money. These costs might exceed their usefulness for modeling the outcome of interest. We develop Bayesian model selection that uses flexible model priors to penalize costly predictors a priori and select a subset of predictors useful relative to their costs. Our approach (i) gives the practitioner control over the magnitude of cost penalization, (ii) enables the prior to scale well with sample size, and (iii) enables the creation of our proposed inclusion path visualization, which can be used to make decisions about individual candidate predictors using both probabilistic and visual tools. We demonstrate the effectiveness of our inclusion path approach and the importance of being able to adjust the magnitude of the prior's cost penalization through a dataset pertaining to heart disease diagnosis in patients at the Cleveland Clinic Foundation, where several candidate predictors with various costs were recorded for patients, and through simulated data.

Revisiting Fishery Sustainability Targets.

Density-dependent population dynamic models strongly influence many of the world's most important harvest policies. Nearly all classic models (e.g. Beverton-Holt and Ricker) recommend that managers maintain a population size of roughly 40-50 percent of carrying capacity to maximize sustainable harvest, no matter the species' population growth rate. Such insights are the foundational logic behind most sustainability targets and biomass reference points for fisheries. However, a simple, less-commonly used model, called the Hockey-Stick model, yields very different recommendations. We show that the optimal population size to maintain in this model, as a proportion of carrying capacity, is one over the population growth rate. This leads to more conservative optimal harvest policies for slow-growing species, compared to other models, if all models use the same growth rate and carrying capacity values. However, parameters typically are not fixed; they are estimated after model-fitting. If the Hockey-Stick model leads to lower estimates of carrying capacity than other models, then the Hockey-Stick policy could yield lower absolute population size targets in practice. Therefore, to better understand the population size targets that may be recommended across real fisheries, we fit the Hockey-Stick, Ricker and Beverton-Holt models to population time series data across 284 fished species from the RAM Stock Assessment database. We found that the Hockey-Stick model usually recommended fisheries maintain population sizes higher than all other models (in 69-81% of the data sets). Furthermore, in 77% of the datasets, the Hockey-Stick model recommended an optimal population target even higher than 60% of carrying capacity (a widely used target, thought to be conservative). However, there was considerable uncertainty in the model fitting. While Beverton-Holt fit several of the data sets best, Hockey-Stick also frequently fit similarly well. In general, the best-fitting model rarely had overwhelming support (a model probability of greater than 95% was achieved in less than five percent of the datasets). A computational experiment, where time series data were simulated from all three models, revealed that Beverton-Holt often fit best even when it was not the true model, suggesting that fisheries data are likely too small and too noisy to resolve uncertainties in the functional forms of density-dependent growth. Therefore, sustainability targets may warrant revisiting, especially for slow-growing species.

The Emergence of SARS-CoV-2 Variants of Concern Is Driven by Acceleration of the Substitution Rate.

The ongoing SARS-CoV-2 pandemic has seen an unprecedented amount of rapidly generated genome data. These data have revealed the emergence of lineages with mutations associated to transmissibility and antigenicity, known as variants of concern (VOCs). A striking aspect of VOCs is that many of them involve an unusually large number of defining mutations. Current phylogenetic estimates of the substitution rate of SARS-CoV-2 suggest that its genome accrues around two mutations per month. However, VOCs can have 15 or more defining mutations and it is hypothesized that they emerged over the course of a few months, implying that they must have evolved faster for a period of time. We analyzed genome sequence data from the GISAID database to assess whether the emergence of VOCs can be attributed to changes in the substitution rate of the virus and whether this pattern can be detected at a phylogenetic level using genome data. We fit a range of molecular clock models and assessed their statistical performance. Our analyses indicate that the emergence of VOCs is driven by an episodic increase in the substitution rate of around 4-fold the background phylogenetic rate estimate that may have lasted several weeks or months. These results underscore the importance of monitoring the molecular evolution of the virus as a means of understanding the circumstances under which VOCs may emerge.

Anxiety attenuates learning advantages conferred by statistical stability and induces loss of volatility-attuning in brain activity.

Anxiety can alter an individual's perception of their external sensory environment. Previous studies suggest that anxiety can increase the magnitude of neural responses to unexpected (or surprising) stimuli. Additionally, surprise responses are reported to be boosted during stable compared to volatile environments. Few studies, however, have examined how learning is impacted by both threat and volatility. To investigate these effects, we used threat-of-shock to transiently increase subjective anxiety in healthy adults while they performed an auditory oddball task under stable and volatile environments and while undergoing functional Magnetic Resonance Imaging (fMRI) scanning. We then used Bayesian Model Selection (BMS) mapping to identify the brain areas where different models of anxiety displayed the highest evidence. Behaviourally, we found that threat-of-shock eliminated the accuracy advantage conferred by environmental stability over volatility. Neurally, we found that threat-of-shock led to attenuation and loss of volatility-attuning of brain activity evoked by surprising sounds across most subcortical and limbic regions including the thalamus, basal ganglia, claustrum, insula, anterior cingulate, hippocampal gyrus and the superior temporal gyrus. Taken together, our findings suggest that threat eliminates learning advantages conferred by statistical stability compared to volatility. Thus, we propose that anxiety disrupts behavioural adaptation to environmental statistics, and that multiple subcortical and limbic regions are implicated in this process.

A Bayesian phase I-II clinical trial design to find the biological optimal dose on drug combination.

In recent years, combined therapy shows expected treatment effect as they increase dose intensity, work on multiple targets and benefit more patients for antitumor treatment. However, dose -finding designs for combined therapy face a number of challenges. Therefore, under the framework of phase I-II, we propose a two-stage dose -finding design to identify the biologically optimal dose combination (BODC), defined as the one with the maximum posterior mean utility under acceptable safety. We model the probabilities of toxicity and efficacy by using linear logistic regression models and conduct Bayesian model selection (BMS) procedure to define the most likely pattern of dose-response surface. The BMS can adaptively select the most suitable model during the trial, making the results robust. We investigated the operating characteristics of the proposed design through simulation studies under various practical scenarios and showed that the proposed design is robust and performed well.

Yeast ATM and ATR kinases use different mechanisms to spread histone H2A phosphorylation around a DNA double-strand break.

One of the hallmarks of DNA damage is the rapid spreading of phosphorylated histone H2A (γ-H2AX) around a DNA double-strand break (DSB). In the budding yeast Saccharomyces cerevisiae, nearly all H2A isoforms can be phosphorylated, either by Mec1ATR or Tel1ATM checkpoint kinases. We induced a site-specific DSB with HO endonuclease at the MAT locus on chromosome III and monitored the formation of γ-H2AX by chromatin immunoprecipitation (ChIP)-qPCR in order to uncover the mechanisms by which Mec1ATR and Tel1ATM propagate histone modifications across chromatin. With either kinase, γ-H2AX spreads as far as ∼50 kb on both sides of the lesion within 1 h; but the kinetics and distribution of modification around the DSB are significantly different. The total accumulation of phosphorylation is reduced by about half when either of the two H2A genes is mutated to the nonphosphorylatable S129A allele. Mec1 activity is limited by the abundance of its ATRIP partner, Ddc2. Moreover, Mec1 is more efficient than Tel1 at phosphorylating chromatin in trans-at distant undamaged sites that are brought into physical proximity to the DSB. We compared experimental data to mathematical models of spreading mechanisms to determine whether the kinases search for target nucleosomes by primarily moving in three dimensions through the nucleoplasm or in one dimension along the chromatin. Bayesian model selection indicates that Mec1 primarily uses a three-dimensional diffusive mechanism, whereas Tel1 undergoes directed motion along the chromatin.

Bayesian Noise Modelling for State Estimation of the Spread of COVID-19 in Saudi Arabia with Extended Kalman Filters.

The epistemic uncertainty in coronavirus disease (COVID-19) model-based predictions using complex noisy data greatly affects the accuracy of pandemic trend and state estimations. Quantifying the uncertainty of COVID-19 trends caused by different unobserved hidden variables is needed to evaluate the accuracy of the predictions for complex compartmental epidemiological models. A new approach for estimating the measurement noise covariance from real COVID-19 pandemic data has been presented based on the marginal likelihood (Bayesian evidence) for Bayesian model selection of the stochastic part of the Extended Kalman filter (EKF), with a sixth-order nonlinear epidemic model, known as the SEIQRD (Susceptible-Exposed-Infected-Quarantined-Recovered-Dead) compartmental model. This study presents a method for testing the noise covariance in cases of dependence or independence between the infected and death errors, to better understand their impact on the predictive accuracy and reliability of EKF statistical models. The proposed approach is able to reduce the error in the quantity of interest compared to the arbitrarily chosen values in the EKF estimation.

Dissociating Perceptual Awareness and Postperceptual Processing: The P300 Is Not a Reliable Marker of Somatosensory Target Detection.

A central challenge in the study of conscious perception lies in dissociating the neural correlates of perceptual awareness from those reflecting its precursors and consequences. No-report paradigms have been instrumental in this endeavor, demonstrating that the event-related potential P300, recorded from the human scalp, reflects reports rather than awareness. However, these paradigms cannot probe the degree to which stimuli are consciously processed from trial to trial and, thus, leave open the possibility that the P300 is a genuine correlate of conscious access enabling reports. Here, instead of removing report requirements, we took the opposite approach and equated postperceptual task demands across conscious and unconscious trials by orthogonalizing target detection and overt reports in a somatosensory detection task. We used Bayesian model selection to track the transformation from physical to perceptual processing stages in the EEG data of 24 male and female participants and show that the early P50 component scaled with physical stimulus intensity, whereas the N140 component was the first correlate of target detection. The late P300 component was elicited for both perceived and unperceived stimuli and was not substantially modulated by target detection. This was in stark contrast to a control experiment using a classical direct report task, which replicated the P50 and N140 effects but additionally showed a strong effect of target detection in the P300 time range. Our results demonstrate the task dependence of the P300 in the somatosensory modality and show that late cortical potentials dissociate from perceptual awareness even when stimuli are always reported.SIGNIFICANCE STATEMENT The time it takes for sensory information to enter our conscious experience can be an indicator of the neural processing stages that lead to perceptual awareness. However, because many cognitive processes routinely correlate with perception, isolating those signals that uniquely reflect perceptual awareness is not a trivial task. Here, we show that late electroencephalography signals cease to correlate with somatosensory awareness when common task confounds are controlled. Importantly, by balancing report requirements instead of abolishing them, we show that the lack of late effects cannot be explained by a lack of conscious access. Instead, we propose that conscious access occurs earlier, at ∼150 ms, supporting the view that early activity in sensory cortices is a neural correlate of conscious perception.

A Bayesian framework to integrate multi-level genome-scale data for Autism risk gene prioritization.

BACKGROUND: Autism spectrum disorder (ASD) is a group of complex neurodevelopment disorders with a strong genetic basis. Large scale sequencing studies have identified over one hundred ASD risk genes. Nevertheless, the vast majority of ASD risk genes remain to be discovered, as it is estimated that more than 1000 genes are likely to be involved in ASD risk. Prioritization of risk genes is an effective strategy to increase the power of identifying novel risk genes in genetics studies of ASD. As ASD risk genes are likely to exhibit distinct properties from multiple angles, we reason that integrating multiple levels of genomic data is a powerful approach to pinpoint genuine ASD risk genes. RESULTS: We present BNScore, a Bayesian model selection framework to probabilistically prioritize ASD risk genes through explicitly integrating evidence from sequencing-identified ASD genes, biological annotations, and gene functional network. We demonstrate the validity of our approach and its improved performance over existing methods by examining the resulting top candidate ASD risk genes against sets of high-confidence benchmark genes and large-scale ASD genome-wide association studies. We assess the tissue-, cell type- and development stage-specific expression properties of top prioritized genes, and find strong expression specificity in brain tissues, striatal medium spiny neurons, and fetal developmental stages. CONCLUSIONS: In summary, we show that by integrating sequencing findings, functional annotation profiles, and gene-gene functional network, our proposed BNScore provides competitive performance compared to current state-of-the-art methods in prioritizing ASD genes. Our method offers a general and flexible strategy to risk gene prioritization that can potentially be applied to other complex traits as well.

Bayesian analysis of one-inflated models for elusive population size estimation.

The identification and treatment of "one-inflation" in estimating the size of an elusive population has received increasing attention in capture-recapture literature in recent years. The phenomenon occurs when the number of units captured exactly once clearly exceeds the expectation under a baseline count distribution. Ignoring one-inflation has serious consequences for estimation of the population size, which can be drastically overestimated. In this paper we propose a Bayesian approach for Poisson, geometric, and negative binomial one-inflated count distributions. Posterior inference for population size will be obtained applying a Gibbs sampler approach. We also provide a Bayesian approach to model selection. We illustrate the proposed methodology with simulated and real data and propose a new application in official statistics to estimate the number of people implicated in the exploitation of prostitution in Italy.

Bayesian model selection favors parametric over categorical fMRI subsequent memory models in young and older adults.

Subsequent memory paradigms allow to identify neural correlates of successful encoding by separating brain responses as a function of memory performance during later retrieval. In functional magnetic resonance imaging (fMRI), the paradigm typically elicits activations of medial temporal lobe, prefrontal and parietal cortical structures in young, healthy participants. This categorical approach is, however, limited by insufficient memory performance in older and particularly memory-impaired individuals. A parametric modulation of encoding-related activations with memory confidence could overcome this limitation. Here, we applied cross-validated Bayesian model selection (cvBMS) for first-level fMRI models to a visual subsequent memory paradigm in young (18-35 years) and older (51-80 years) adults. Nested cvBMS revealed that parametric models, especially with non-linear transformations of memory confidence ratings, outperformed categorical models in explaining the fMRI signal variance during encoding. We thereby provide a framework for improving the modeling of encoding-related activations and for applying subsequent memory paradigms to memory-impaired individuals.

Adiabatic dynamic causal modelling.

This technical note introduces adiabatic dynamic causal modelling, a method for inferring slow changes in biophysical parameters that control fluctuations of fast neuronal states. The application domain we have in mind is inferring slow changes in variables (e.g., extracellular ion concentrations or synaptic efficacy) that underlie phase transitions in brain activity (e.g., paroxysmal seizure activity). The scheme is efficient and yet retains a biophysical interpretation, in virtue of being based on established neural mass models that are equipped with a slow dynamic on the parameters (such as synaptic rate constants or effective connectivity). In brief, we use an adiabatic approximation to summarise fast fluctuations in hidden neuronal states (and their expression in sensors) in terms of their second order statistics; namely, their complex cross spectra. This allows one to specify and compare models of slowly changing parameters (using Bayesian model reduction) that generate a sequence of empirical cross spectra of electrophysiological recordings. Crucially, we use the slow fluctuations in the spectral power of neuronal activity as empirical priors on changes in synaptic parameters. This introduces a circular causality, in which synaptic parameters underwrite fast neuronal activity that, in turn, induces activity-dependent plasticity in synaptic parameters. In this foundational paper, we describe the underlying model, establish its face validity using simulations and provide an illustrative application to a chemoconvulsant animal model of seizure activity.

Dynamic ordering design for dose finding in drug-combination trials.

Drug-combination studies have become increasingly popular in oncology. One of the critical concerns in phase I drug-combination trials is the uncertainty in toxicity evaluation. Most of the existing phase I designs aim to identify the maximum tolerated dose (MTD) by reducing the two-dimensional searching space to one dimension via a prespecified model or splitting the two-dimensional space into multiple one-dimensional subspaces based on the partially known toxicity order. Nevertheless, both strategies often lead to complicated trials which may either be sensitive to model assumptions or induce longer trial durations due to subtrial split. We develop two versions of dynamic ordering design (DOD) for dose finding in drug-combination trials, where the dose-finding problem is cast in the Bayesian model selection framework. The toxicity order of dose combinations is continuously updated via a two-dimensional pool-adjacent-violators algorithm, and then the dose assignment for each incoming cohort is selected based on the optimal model under the dynamic toxicity order. We conduct extensive simulation studies to evaluate the performance of DOD in comparison with four other commonly used designs under various scenarios. Simulation results show that the two versions of DOD possess competitive performances in terms of correct MTD selection as well as safety, and we apply both versions of DOD to two real oncology trials for illustration.

TopoFilter: a MATLAB package for mechanistic model identification in systems biology.

BACKGROUND: To develop mechanistic dynamic models in systems biology, one often needs to identify all (or minimal) representations of the biological processes that are consistent with experimental data, out of a potentially large set of hypothetical mechanisms. However, a simple enumeration of all alternatives becomes quickly intractable when the number of model parameters grows. Selecting appropriate dynamic models out of a large ensemble of models, taking the uncertainty in our biological knowledge and in the experimental data into account, is therefore a key current problem in systems biology. RESULTS: The TopoFilter package addresses this problem in a heuristic and automated fashion by implementing the previously described topological filtering method for Bayesian model selection. It includes a core heuristic for searching the space of submodels of a parametrized model, coupled with a sampling-based exploration of the parameter space. Recent developments of the method allow to balance exhaustiveness and speed of the model space search, to efficiently re-sample parameters, to parallelize the search, and to use custom scoring functions. We use a theoretical example to motivate these features and then demonstrate TopoFilter's applicability for a yeast signaling network with more than 250'000 possible model structures. CONCLUSIONS: TopoFilter is a flexible software framework that makes Bayesian model selection and reduction efficient and scalable to network models of a complexity that represents contemporary problems in, for example, cell signaling. TopoFilter is open-source, available under the GPL-3.0 license at https://gitlab.com/csb.ethz/TopoFilter. It includes installation instructions, a quickstart guide, a description of all package options, and multiple examples.

A Bayesian multi-risks survival (MRS) model in the presence of double censorings.

Semi-competing risks data include the time to a nonterminating event and the time to a terminating event, while competing risks data include the time to more than one terminating event. Our work is motivated by a prostate cancer study, which has one nonterminating event and two terminating events with both semi-competing risks and competing risks present as well as two censoring times. In this paper, we propose a new multi-risks survival (MRS) model for this type of data. In addition, the proposed MRS model can accommodate noninformative right-censoring times for nonterminating and terminating events. Properties of the proposed MRS model are examined in detail. Theoretical and empirical results show that the estimates of the cumulative incidence function for a nonterminating event may be biased if the information on a terminating event is ignored. A Markov chain Monte Carlo sampling algorithm is also developed. Our methodology is further assessed using simulations and also an analysis of the real data from a prostate cancer study. As a result, a prostate-specific antigen velocity greater than 2.0 ng/mL per year and higher biopsy Gleason scores are positively associated with a shorter time to death due to prostate cancer.

Bayesian model selection for the Drosophila gap gene network.

BACKGROUND: The gap gene system controls the early cascade of the segmentation pathway in Drosophila melanogaster as well as other insects. Owing to its tractability and key role in embryo patterning, this system has been the focus for both computational modelers and experimentalists. The gap gene expression dynamics can be considered strictly as a one-dimensional process and modeled as a system of reaction-diffusion equations. While substantial progress has been made in modeling this phenomenon, there still remains a deficit of approaches to evaluate competing hypotheses. Most of the model development has happened in isolation and there has been little attempt to compare candidate models. RESULTS: The Bayesian framework offers a means of doing formal model evaluation. Here, we demonstrate how this framework can be used to compare different models of gene expression. We focus on the Papatsenko-Levine formalism, which exploits a fractional occupancy based approach to incorporate activation of the gap genes by the maternal genes and cross-regulation by the gap genes themselves. The Bayesian approach provides insight about relationship between system parameters. In the regulatory pathway of segmentation, the parameters for number of binding sites and binding affinity have a negative correlation. The model selection analysis supports a stronger binding affinity for Bicoid compared to other regulatory edges, as shown by a larger posterior mean. The procedure doesn't show support for activation of Kruppel by Bicoid. CONCLUSIONS: We provide an efficient solver for the general representation of the Papatsenko-Levine model. We also demonstrate the utility of Bayes factor for evaluating candidate models for spatial pattering models. In addition, by using the parallel tempering sampler, the convergence of Markov chains can be remarkably improved and robust estimates of Bayes factors obtained.

BAMSE: Bayesian model selection for tumor phylogeny inference among multiple samples.

BACKGROUND: Intra-tumor heterogeneity is known to contribute to cancer complexity and drug resistance. Understanding the number of distinct subclones and the evolutionary relationships between them is scientifically and clinically very important and still a challenging problem. RESULTS: In this paper, we present BAMSE (BAyesian Model Selection for tumor Evolution), a new probabilistic method for inferring subclonal history and lineage tree reconstruction of heterogeneous tumor samples. BAMSE uses somatic mutation read counts as input and can leverage multiple tumor samples accurately and efficiently. In the first step, possible clusterings of mutations into subclones are scored and a user defined number are selected for further analysis. In the next step, for each of these candidates, a list of trees describing the evolutionary relationships between the subclones is generated. These trees are sorted by their posterior probability. The posterior probability is calculated using a Bayesian model that integrates prior belief about the number of subclones, the composition of the tumor and the process of subclonal evolution. BAMSE also takes the sequencing error into account. We benchmarked BAMSE against state of the art software using simulated datasets. CONCLUSIONS: In this work we developed a flexible and fast software to reconstruct the history of a tumor's subclonal evolution using somatic mutation read counts across multiple samples. BAMSE software is implemented in Python and is available open source under GNU GLPv3 at https://github.com/HoseinT/BAMSE .

Ventromedial prefrontal cortex contributes to performance success by controlling reward-driven arousal representation in amygdala.

When preparing for a challenging task, potential rewards can cause physiological arousal that may impair performance. In this case, it is important to control reward-driven arousal while preparing for task execution. We recently examined neural representations of physiological arousal and potential reward magnitude during preparation, and found that performance failure was explained by relatively increased reward representation in the left caudate nucleus and arousal representation in the right amygdala (Watanabe, et al., 2019). Here we examine how prefrontal cortex influences the amygdala and caudate to control reward-driven arousal. Ventromedial prefrontal cortex (VMPFC) exhibited activity that was negatively correlated with trial-wise physiological arousal change, which identified this region as a potential modulator of amygdala and caudate. Next we tested the VMPFC - amygdala - caudate effective network using dynamic causal modeling (Friston et al., 2003). Post-hoc Bayesian model selection (Friston and Penny, 2011) identified a model that best fit data, in which amygdala activation was suppressively controlled by the VMPFC only in success trials. Furthermore, fixed connectivity strength from VMPFC to amygdala explained individual task performance. These findings highlight the role of effective connectivity from VMPFC to amygdala in order to control arousal during preparation for successful performance.