Evaluation of Speech and Pause Alterations in Patients With Acute and Chronic Heart Failure.

Background Acute heart failure is the most frequent cause of unplanned hospital admission in elderly patients. Various biomarkers have been evaluated to better assess the status of these patients and prevent decompensation. Recently, voice has been suggested as a cost-effective and noninvasive way to monitor disease progression. This study evaluates speech and pause alterations in patients with acute decompensated and stable heart failure. Specifically, we aim to identify a vocal biomarker that could be used to monitor patients with heart failure and to prevent decompensation. Methods and Results Speech and pause patterns were evaluated in 68 patients with acute and 36 patients with stable heart failure. Voice recordings were performed using a web-browser based application that consisted of 5 tasks. Speech and pause patterns were automatically extracted and compared between acute and stable patients and with clinical markers. Compared with stable patients, pause ratio was up to 14.9% increased in patients with acute heart failure. This increase was largely independent of sex, age, and ejection fraction and persisted in patients with lower degrees of edema or dyspnea. Furthermore, pause ratio was positively correlated with NT-proBNP (N-terminal pro-B-type natriuretic peptide) after controlling for acute versus stable heart failure. Collectively, our findings indicate that the pause ratio could be useful in identifying acute heart failure, particularly in patients who do not display traditional indicators of decompensation. Conclusions Speech and pause patterns are altered in patients with acute heart failure. Particularly, we identified pause ratio as an easily interpretable vocal biomarker to support the monitoring of heart failure decompensation.

Auditory mismatch responses are differentially sensitive to changes in muscarinic acetylcholine versus dopamine receptor function.

The auditory mismatch negativity (MMN) has been proposed as a biomarker of NMDA receptor (NMDAR) dysfunction in schizophrenia. Such dysfunction may be caused by aberrant interactions of different neuromodulators with NMDARs, which could explain clinical heterogeneity among patients. In two studies (N = 81 each), we used a double-blind placebo-controlled between-subject design to systematically test whether auditory mismatch responses under varying levels of environmental stability are sensitive to diminishing and enhancing cholinergic vs. dopaminergic function. We found a significant drug × mismatch interaction: while the muscarinic acetylcholine receptor antagonist biperiden delayed and topographically shifted mismatch responses, particularly during high stability, this effect could not be detected for amisulpride, a dopamine D2/D3 receptor antagonist. Neither galantamine nor levodopa, which elevate acetylcholine and dopamine levels, respectively, exerted significant effects on MMN. This differential MMN sensitivity to muscarinic versus dopaminergic receptor function may prove useful for developing tests that predict individual treatment responses in schizophrenia.

Conductance-based dynamic causal modeling: A mathematical review of its application to cross-power spectral densities.

Dynamic Causal Modeling (DCM) is a Bayesian framework for inferring on hidden (latent) neuronal states, based on measurements of brain activity. Since its introduction in 2003 for functional magnetic resonance imaging data, DCM has been extended to electrophysiological data, and several variants have been developed. Their biophysically motivated formulations make these models promising candidates for providing a mechanistic understanding of human brain dynamics, both in health and disease. However, due to their complexity and reliance on concepts from several fields, fully understanding the mathematical and conceptual basis behind certain variants of DCM can be challenging. At the same time, a solid theoretical knowledge of the models is crucial to avoid pitfalls in the application of these models and interpretation of their results. In this paper, we focus on one of the most advanced formulations of DCM, i.e. conductance-based DCM for cross-spectral densities, whose components are described across multiple technical papers. The aim of the present article is to provide an accessible exposition of the mathematical background, together with an illustration of the model's behavior. To this end, we include step-by-step derivations of the model equations, point to important aspects in the software implementation of those models, and use simulations to provide an intuitive understanding of the type of responses that can be generated and the role that specific parameters play in the model. Furthermore, all code utilized for our simulations is made publicly available alongside the manuscript to allow readers an easy hands-on experience with conductance-based DCM.

Technical note: A fast and robust integrator of delay differential equations in DCM for electrophysiological data.

Dynamic causal models (DCMs) of electrophysiological data allow, in principle, for inference on hidden, bulk synaptic function in neural circuits. The directed influences between the neuronal elements of modeled circuits are subject to delays due to the finite transmission speed of axonal connections. Ordinary differential equations are therefore not adequate to capture the ensuing circuit dynamics, and delay differential equations (DDEs) are required instead. Previous work has illustrated that the integration of DDEs in DCMs benefits from sophisticated integration schemes in order to ensure rigorous parameter estimation and correct model identification. However, integration schemes that have been proposed for DCMs either emphasize speed (at the possible expense of accuracy) or robustness (but with computational costs that are problematic in practice). In this technical note, we propose an alternative integration scheme that overcomes these shortcomings and offers high computational efficiency while correctly preserving the nature of delayed effects. This integration scheme is available as open-source code in the Translational Algorithms for Psychiatry-Advancing Science (TAPAS) toolbox and can be easily integrated into existing software (SPM) for the analysis of DCMs for electrophysiological data. While this paper focuses on its application to the convolution-based formalism of DCMs, the new integration scheme can be equally applied to more advanced formulations of DCMs (e.g. conductance based models). Our method provides a new option for electrophysiological DCMs that offers the speed required for scientific projects, but also the accuracy required for rigorous translational applications, e.g. in computational psychiatry.

TAPAS: An Open-Source Software Package for Translational Neuromodeling and Computational Psychiatry.

Psychiatry faces fundamental challenges with regard to mechanistically guided differential diagnosis, as well as prediction of clinical trajectories and treatment response of individual patients. This has motivated the genesis of two closely intertwined fields: (i) Translational Neuromodeling (TN), which develops "computational assays" for inferring patient-specific disease processes from neuroimaging, electrophysiological, and behavioral data; and (ii) Computational Psychiatry (CP), with the goal of incorporating computational assays into clinical decision making in everyday practice. In order to serve as objective and reliable tools for clinical routine, computational assays require end-to-end pipelines from raw data (input) to clinically useful information (output). While these are yet to be established in clinical practice, individual components of this general end-to-end pipeline are being developed and made openly available for community use. In this paper, we present the Translational Algorithms for Psychiatry-Advancing Science (TAPAS) software package, an open-source collection of building blocks for computational assays in psychiatry. Collectively, the tools in TAPAS presently cover several important aspects of the desired end-to-end pipeline, including: (i) tailored experimental designs and optimization of measurement strategy prior to data acquisition, (ii) quality control during data acquisition, and (iii) artifact correction, statistical inference, and clinical application after data acquisition. Here, we review the different tools within TAPAS and illustrate how these may help provide a deeper understanding of neural and cognitive mechanisms of disease, with the ultimate goal of establishing automatized pipelines for predictions about individual patients. We hope that the openly available tools in TAPAS will contribute to the further development of TN/CP and facilitate the translation of advances in computational neuroscience into clinically relevant computational assays.

Model-based prediction of muscarinic receptor function from auditory mismatch negativity responses.

Drugs affecting neuromodulation, for example by dopamine or acetylcholine, take centre stage among therapeutic strategies in psychiatry. These neuromodulators can change both neuronal gain and synaptic plasticity and therefore affect electrophysiological measures. An important goal for clinical diagnostics is to exploit this effect in the reverse direction, i.e., to infer the status of specific neuromodulatory systems from electrophysiological measures. In this study, we provide proof-of-concept that the functional status of cholinergic (specifically muscarinic) receptors can be inferred from electrophysiological data using generative (dynamic causal) models. To this end, we used epidural EEG recordings over two auditory cortical regions during a mismatch negativity (MMN) paradigm in rats. All animals were treated, across sessions, with muscarinic receptor agonists and antagonists at different doses. Together with a placebo condition, this resulted in five levels of muscarinic receptor status. Using a dynamic causal model - embodying a small network of coupled cortical microcircuits - we estimated synaptic parameters and their change across pharmacological conditions. The ensuing parameter estimates associated with (the neuromodulation of) synaptic efficacy showed both graded muscarinic effects and predictive validity between agonistic and antagonistic pharmacological conditions. This finding illustrates the potential utility of generative models of electrophysiological data as computational assays of muscarinic function. In application to EEG data of patients from heterogeneous spectrum diseases, e.g. schizophrenia, such models might help identify subgroups of patients that respond differentially to cholinergic treatments. SIGNIFICANCE STATEMENT: In psychiatry, the vast majority of pharmacological treatments affect actions of neuromodulatory transmitters, e.g. dopamine or acetylcholine. As treatment is largely trial-and-error based, one of the goals for computational psychiatry is to construct mathematical models that can serve as "computational assays" and infer the status of specific neuromodulatory systems in individual patients. This translational neuromodeling strategy has great promise for electrophysiological data in particular but requires careful validation. The present study demonstrates that the functional status of cholinergic (muscarinic) receptors can be inferred from electrophysiological data using dynamic causal models of neural circuits. While accuracy needs to be enhanced and our results must be replicated in larger samples, our current results provide proof-of-concept for computational assays of muscarinic function using EEG.

Hemodynamic modeling of long-term aspirin effects on blood oxygenated level dependent responses at 7 Tesla in patients at cardiovascular risk.

Aspirin is considered a potential confound for functional magnetic resonance imaging (fMRI) studies. This is because aspirin affects the synthesis of prostaglandin, a vasoactive mediator centrally involved in neurovascular coupling, a process underlying blood oxygenated level dependent (BOLD) responses. Aspirin-induced changes in BOLD signal are a potential confound for fMRI studies of at-risk individuals or patients (e.g. with cardiovascular conditions or stroke) who receive low-dose aspirin prophylactically and are compared to healthy controls without aspirin. To examine the severity of this potential confound, we combined high field (7 Tesla) MRI during a simple hand movement task with a biophysically informed hemodynamic model. We compared elderly individuals receiving aspirin for primary or secondary prophylactic purposes versus age-matched volunteers without aspirin medication, testing for putative differences in BOLD responses. Specifically, we fitted hemodynamic models to BOLD responses from 14 regions activated by the task and examined whether model parameter estimates were significantly altered by aspirin. While our analyses indicate that hemodynamics differed across regions, consistent with the known regional variability of BOLD responses, we neither found a significant main effect of aspirin (i.e., an average effect across brain regions) nor an expected drug × region interaction. While our sample size is not sufficiently large to rule out small-to-medium global effects of aspirin, we had adequate statistical power for detecting the expected interaction. Altogether, our analysis suggests that patients with cardiovascular risk receiving low-dose aspirin for primary or secondary prophylactic purposes do not show strongly altered BOLD signals when compared to healthy controls without aspirin.

Predicting individual clinical trajectories of depression with generative embedding.

Patients with major depressive disorder (MDD) show heterogeneous treatment response and highly variable clinical trajectories: while some patients experience swift recovery, others show relapsing-remitting or chronic courses. Predicting individual clinical trajectories at an early stage is a key challenge for psychiatry and might facilitate individually tailored interventions. So far, however, reliable predictors at the single-patient level are absent. Here, we evaluated the utility of a machine learning strategy - generative embedding (GE) - which combines interpretable generative models with discriminative classifiers. Specifically, we used functional magnetic resonance imaging (fMRI) data of emotional face perception in 85 MDD patients from the NEtherlands Study of Depression and Anxiety (NESDA) who had been followed up over two years and classified into three subgroups with distinct clinical trajectories. Combining a generative model of effective (directed) connectivity with support vector machines (SVMs), we could predict whether a given patient would experience chronic depression vs. fast remission with a balanced accuracy of 79%. Gradual improvement vs. fast remission could still be predicted above-chance, but less convincingly, with a balanced accuracy of 61%. Generative embedding outperformed classification based on conventional (descriptive) features, such as functional connectivity or local activation estimates, which were obtained from the same data and did not allow for above-chance classification accuracy. Furthermore, predictive performance of GE could be assigned to a specific network property: the trial-by-trial modulation of connections by emotional content. Given the limited sample size of our study, the present results are preliminary but may serve as proof-of-concept, illustrating the potential of GE for obtaining clinical predictions that are interpretable in terms of network mechanisms. Our findings suggest that abnormal dynamic changes of connections involved in emotional face processing might be associated with higher risk of developing a less favorable clinical course.

Computational Dissociation of Dopaminergic and Cholinergic Effects on Action Selection and Inhibitory Control.

BACKGROUND: Patients with schizophrenia make more errors than healthy subjects in the antisaccade task. In this paradigm, participants are required to inhibit a reflexive saccade to a target and to select the correct action (a saccade in the opposite direction). While the precise origin of this deficit is not clear, it has been connected to aberrant dopaminergic and cholinergic neuromodulation. METHODS: To study the impact of dopamine and acetylcholine on inhibitory control and action selection, we administered two selective drugs (levodopa 200 mg/galantamine 8 mg) to healthy volunteers (N = 100) performing the antisaccade task. The computational model SERIA (stochastic early reaction, inhibition, and late action) was employed to separate the contribution of inhibitory control and action selection to empirical reaction times and error rates. RESULTS: Modeling suggested that levodopa improved action selection (at the cost of increased reaction times) but did not have a significant effect on inhibitory control. By contrast, according to our model, galantamine affected inhibitory control in a dose-dependent fashion, reducing inhibition failures at low doses and increasing them at higher levels. These effects were sufficiently specific that the computational analysis allowed for identifying the drug administered to an individual with 70% accuracy. CONCLUSIONS: Our results do not support the hypothesis that elevated tonic dopamine strongly impairs inhibitory control. Rather, levodopa improved the ability to select correct actions. However, inhibitory control was modulated by cholinergic drugs. This approach may provide a starting point for future computational assays that differentiate neuromodulatory abnormalities in heterogeneous diseases like schizophrenia.

Generative models for clinical applications in computational psychiatry.

Despite the success of modern neuroimaging techniques in furthering our understanding of cognitive and pathophysiological processes, translation of these advances into clinically relevant tools has been virtually absent until now. Neuromodeling represents a powerful framework for overcoming this translational deadlock, and the development of computational models to solve clinical problems has become a major scientific goal over the last decade, as reflected by the emergence of clinically oriented neuromodeling fields like Computational Psychiatry, Computational Neurology, and Computational Psychosomatics. Generative models of brain physiology and connectivity in the human brain play a key role in this endeavor, striving for computational assays that can be applied to neuroimaging data from individual patients for differential diagnosis and treatment prediction. In this review, we focus on dynamic causal modeling (DCM) and its use for Computational Psychiatry. DCM is a widely used generative modeling framework for functional magnetic resonance imaging (fMRI) and magneto-/electroencephalography (M/EEG) data. This article reviews the basic concepts of DCM, revisits examples where it has proven valuable for addressing clinically relevant questions, and critically discusses methodological challenges and recent methodological advances. We conclude this review with a more general discussion of the promises and pitfalls of generative models in Computational Psychiatry and highlight the path that lies ahead of us. This article is categorized under: Neuroscience > Computation Neuroscience > Clinical Neuroscience.

The Stochastic Early Reaction, Inhibition, and late Action (SERIA) model for antisaccades.

The antisaccade task is a classic paradigm used to study the voluntary control of eye movements. It requires participants to suppress a reactive eye movement to a visual target and to concurrently initiate a saccade in the opposite direction. Although several models have been proposed to explain error rates and reaction times in this task, no formal model comparison has yet been performed. Here, we describe a Bayesian modeling approach to the antisaccade task that allows us to formally compare different models on the basis of their evidence. First, we provide a formal likelihood function of actions (pro- and antisaccades) and reaction times based on previously published models. Second, we introduce the Stochastic Early Reaction, Inhibition, and late Action model (SERIA), a novel model postulating two different mechanisms that interact in the antisaccade task: an early GO/NO-GO race decision process and a late GO/GO decision process. Third, we apply these models to a data set from an experiment with three mixed blocks of pro- and antisaccade trials. Bayesian model comparison demonstrates that the SERIA model explains the data better than competing models that do not incorporate a late decision process. Moreover, we show that the early decision process postulated by the SERIA model is, to a large extent, insensitive to the cue presented in a single trial. Finally, we use parameter estimates to demonstrate that changes in reaction time and error rate due to the probability of a trial type (pro- or antisaccade) are best explained by faster or slower inhibition and the probability of generating late voluntary prosaccades.