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Christoph Mathys

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YNIMG Journal 2021 Journal Article

Cholinergic and dopaminergic effects on prediction error and uncertainty responses during sensory associative learning

Sandra Iglesias
Lars Kasper
Samuel J. Harrison
Robert Manka
Christoph Mathys
Klaas E. Stephan

Navigating the physical world requires learning probabilistic associations between sensory events and their change in time (volatility). Bayesian accounts of this learning process rest on hierarchical prediction errors (PEs) that are weighted by estimates of uncertainty (or its inverse, precision). In a previous fMRI study we found that low-level precision-weighted PEs about visual outcomes (that update beliefs about associations) activated the putative dopaminergic midbrain; by contrast, precision-weighted PEs about cue-outcome associations (that update beliefs about volatility) activated the cholinergic basal forebrain. These findings suggested selective dopaminergic and cholinergic influences on precision-weighted PEs at different hierarchical levels. Here, we tested this hypothesis, repeating our fMRI study under pharmacological manipulations in healthy participants. Specifically, we performed two pharmacological fMRI studies with a between-subject double-blind placebo-controlled design: study 1 used antagonists of dopaminergic (amisulpride) and muscarinic (biperiden) receptors, study 2 used enhancing drugs of dopaminergic (levodopa) and cholinergic (galantamine) modulation. Pooled across all pharmacological conditions of study 1 and study 2, respectively, we found that low-level precision-weighted PEs activated the midbrain and high-level precision-weighted PEs the basal forebrain as in our previous study. However, we found pharmacological effects on brain activity associated with these computational quantities only when splitting the precision-weighted PEs into their PE and precision components: in a brainstem region putatively containing cholinergic (pedunculopontine and laterodorsal tegmental) nuclei, biperiden (compared to placebo) enhanced low-level PE responses and attenuated high-level PE activity, while amisulpride reduced high-level PE responses. Additionally, in the putative dopaminergic midbrain, galantamine compared to placebo enhanced low-level PE responses (in a body-weight dependent manner) and amisulpride enhanced high-level precision activity. Task behaviour was not affected by any of the drugs. These results do not support our hypothesis of a clear-cut dichotomy between different hierarchical inference levels and neurotransmitter systems, but suggest a more complex interaction between these neuromodulatory systems and hierarchical Bayesian quantities. However, our present results may have been affected by confounds inherent to pharmacological fMRI. We discuss these confounds and outline improved experimental tests for the future.

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YNIMG Journal 2013 Journal Article

Variational Bayesian mixed-effects inference for classification studies

Kay H. Brodersen
Jean Daunizeau
Christoph Mathys
Justin R. Chumbley
Joachim M. Buhmann
Klaas E. Stephan

Multivariate classification algorithms are powerful tools for predicting cognitive or pathophysiological states from neuroimaging data. Assessing the utility of a classifier in application domains such as cognitive neuroscience, brain–computer interfaces, or clinical diagnostics necessitates inference on classification performance at more than one level, i. e. , both in individual subjects and in the population from which these subjects were sampled. Such inference requires models that explicitly account for both fixed-effects (within-subjects) and random-effects (between-subjects) variance components. While models of this sort are standard in mass-univariate analyses of fMRI data, they have not yet received much attention in multivariate classification studies of neuroimaging data, presumably because of the high computational costs they entail. This paper extends a recently developed hierarchical model for mixed-effects inference in multivariate classification studies and introduces an efficient variational Bayes approach to inference. Using both synthetic and empirical fMRI data, we show that this approach is equally simple to use as, yet more powerful than, a conventional t-test on subject-specific sample accuracies, and computationally much more efficient than previous sampling algorithms and permutation tests. Our approach is independent of the type of underlying classifier and thus widely applicable. The present framework may help establish mixed-effects inference as a future standard for classification group analyses.

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JMLR Journal 2012 Journal Article

Bayesian Mixed-Effects Inference on Classification Performance in Hierarchical Data Sets

Kay H. Brodersen
Christoph Mathys
Justin R. Chumbley
Jean Daunizeau
Cheng Soon Ong
Joachim M. Buhmann
Klaas E. Stephan

Classification algorithms are frequently used on data with a natural hierarchical structure. For instance, classifiers are often trained and tested on trial-wise measurements, separately for each subject within a group. One important question is how classification outcomes observed in individual subjects can be generalized to the population from which the group was sampled. To address this question, this paper introduces novel statistical models that are guided by three desiderata. First, all models explicitly respect the hierarchical nature of the data, that is, they are mixed-effects models that simultaneously account for within-subjects (fixed-effects) and across-subjects (random-effects) variance components. Second, maximum-likelihood estimation is replaced by full Bayesian inference in order to enable natural regularization of the estimation problem and to afford conclusions in terms of posterior probability statements. Third, inference on classification accuracy is complemented by inference on the balanced accuracy, which avoids inflated accuracy estimates for imbalanced data sets. We introduce hierarchical models that satisfy these criteria and demonstrate their advantages over conventional methods using MCMC implementations for model inversion and model selection on both synthetic and empirical data. We envisage that our approach will improve the sensitivity and validity of statistical inference in future hierarchical classification studies. [abs] [ pdf ][ bib ] &copy JMLR 2012. ( edit, beta )

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