Investigating the neural mechanisms of transcranial direct current stimulation effects on human cognition: current issues and potential solutions.

Transcranial direct current stimulation (tDCS) has been studied extensively for its potential to enhance human cognitive functions in healthy individuals and to treat cognitive impairment in various clinical populations. However, little is known about how tDCS modulates the neural networks supporting cognition and the complex interplay with mediating factors that may explain the frequently observed variability of stimulation effects within and between studies. Moreover, research in this field has been characterized by substantial methodological variability, frequent lack of rigorous experimental control and small sample sizes, thereby limiting the generalizability of findings and translational potential of tDCS. The present manuscript aims to delineate how these important issues can be addressed within a neuroimaging context, to reveal the neural underpinnings, predictors and mediators of tDCS-induced behavioral modulation. We will focus on functional magnetic resonance imaging (fMRI), because it allows the investigation of tDCS effects with excellent spatial precision and sufficient temporal resolution across the entire brain. Moreover, high resolution structural imaging data can be acquired for precise localization of stimulation effects, verification of electrode positions on the scalp and realistic current modeling based on individual head and brain anatomy. However, the general principles outlined in this review will also be applicable to other imaging modalities. Following an introduction to the overall state-of-the-art in this field, we will discuss in more detail the underlying causes of variability in previous tDCS studies. Moreover, we will elaborate on design considerations for tDCS-fMRI studies, optimization of tDCS and imaging protocols and how to assure high-level experimental control. Two additional sections address the pressing need for more systematic investigation of tDCS effects across the healthy human lifespan and implications for tDCS studies in age-associated disease, and potential benefits of establishing large-scale, multidisciplinary consortia for more coordinated tDCS research in the future. We hope that this review will contribute to more coordinated, methodologically sound, transparent and reproducible research in this field. Ultimately, our aim is to facilitate a better understanding of the underlying mechanisms by which tDCS modulates human cognitive functions and more effective and individually tailored translational and clinical applications of this technique in the future.

Model-Based Approaches to Investigating Mismatch Responses in Schizophrenia.

Alterations of mismatch responses (ie, neural activity evoked by unexpected stimuli) are often considered a potential biomarker of schizophrenia. Going beyond establishing the type of observed alterations found in diagnosed patients and related cohorts, computational methods can yield valuable insights into the underlying disruptions of neural mechanisms and cognitive function. Here, we adopt a typology of model-based approaches from computational cognitive neuroscience, providing an overview of the study of mismatch responses and their alterations in schizophrenia from four complementary perspectives: (a) connectivity models, (b) decoding models, (c) neural network models, and (d) cognitive models. Connectivity models aim at inferring the effective connectivity patterns between brain regions that may underlie mismatch responses measured at the sensor level. Decoding models use multivariate spatiotemporal mismatch response patterns to infer the type of sensory violations or to classify participants based on their diagnosis. Neural network models such as deep convolutional neural networks can be used for improved classification performance as well as for a systematic study of various aspects of empirical data. Finally, cognitive models quantify mismatch responses in terms of signaling and updating perceptual predictions over time. In addition to describing the available methodology and reviewing the results of recent computational psychiatry studies, we offer suggestions for future work applying model-based techniques to advance the study of mismatch responses in schizophrenia.

A multimodal cortical network of sensory expectation violation revealed by fMRI.

The brain is subjected to multi-modal sensory information in an environment governed by statistical dependencies. Mismatch responses (MMRs), classically recorded with EEG, have provided valuable insights into the brain's processing of regularities and the generation of corresponding sensory predictions. Only few studies allow for comparisons of MMRs across multiple modalities in a simultaneous sensory stream and their corresponding cross-modal context sensitivity remains unknown. Here, we used a tri-modal version of the roving stimulus paradigm in fMRI to elicit MMRs in the auditory, somatosensory and visual modality. Participants (N = 29) were simultaneously presented with sequences of low and high intensity stimuli in each of the three senses while actively observing the tri-modal input stream and occasionally reporting the intensity of the previous stimulus in a prompted modality. The sequences were based on a probabilistic model, defining transition probabilities such that, for each modality, stimuli were more likely to repeat (p = .825) than change (p = .175) and stimulus intensities were equiprobable (p = .5). Moreover, each transition was conditional on the configuration of the other two modalities comprising global (cross-modal) predictive properties of the sequences. We identified a shared mismatch network of modality general inferior frontal and temporo-parietal areas as well as sensory areas, where the connectivity (psychophysiological interaction) between these regions was modulated during mismatch processing. Further, we found deviant responses within the network to be modulated by local stimulus repetition, which suggests highly comparable processing of expectation violation across modalities. Moreover, hierarchically higher regions of the mismatch network in the temporo-parietal area around the intraparietal sulcus were identified to signal cross-modal expectation violation. With the consistency of MMRs across audition, somatosensation and vision, our study provides insights into a shared cortical network of uni- and multi-modal expectation violation in response to sequence regularities.

EEG mismatch responses in a multimodal roving stimulus paradigm provide evidence for probabilistic inference across audition, somatosensation, and vision.

The human brain is constantly subjected to a multimodal stream of probabilistic sensory inputs. Electroencephalography (EEG) signatures, such as the mismatch negativity (MMN) and the P3, can give valuable insight into neuronal probabilistic inference. Although reported for different modalities, mismatch responses have largely been studied in isolation, with a strong focus on the auditory MMN. To investigate the extent to which early and late mismatch responses across modalities represent comparable signatures of uni- and cross-modal probabilistic inference in the hierarchically structured cortex, we recorded EEG from 32 participants undergoing a novel tri-modal roving stimulus paradigm. The employed sequences consisted of high and low intensity stimuli in the auditory, somatosensory and visual modalities and were governed by unimodal transition probabilities and cross-modal conditional dependencies. We found modality specific signatures of MMN (~100-200 ms) in all three modalities, which were source localized to the respective sensory cortices and shared right lateralized prefrontal sources. Additionally, we identified a cross-modal signature of mismatch processing in the P3a time range (~300-350 ms), for which a common network with frontal dominance was found. Across modalities, the mismatch responses showed highly comparable parametric effects of stimulus train length, which were driven by standard and deviant response modulations in opposite directions. Strikingly, P3a responses across modalities were increased for mispredicted stimuli with low cross-modal conditional probability, suggesting sensitivity to multimodal (global) predictive sequence properties. Finally, model comparisons indicated that the observed single trial dynamics were best captured by Bayesian learning models tracking unimodal stimulus transitions as well as cross-modal conditional dependencies.

Active inference and the two-step task.

Sequential decision problems distill important challenges frequently faced by humans. Through repeated interactions with an uncertain world, unknown statistics need to be learned while balancing exploration and exploitation. Reinforcement learning is a prominent method for modeling such behaviour, with a prevalent application being the two-step task. However, recent studies indicate that the standard reinforcement learning model sometimes describes features of human task behaviour inaccurately and incompletely. We investigated whether active inference, a framework proposing a trade-off to the exploration-exploitation dilemma, could better describe human behaviour. Therefore, we re-analysed four publicly available datasets of the two-step task, performed Bayesian model selection, and compared behavioural model predictions. Two datasets, which revealed more model-based inference and behaviour indicative of directed exploration, were better described by active inference, while the models scored similarly for the remaining datasets. Learning using probability distributions appears to contribute to the improved model fits. Further, approximately half of all participants showed sensitivity to information gain as formulated under active inference, although behavioural exploration effects were not fully captured. These results contribute to the empirical validation of active inference as a model of human behaviour and the study of alternative models for the influential two-step task.

Neural surprise in somatosensory Bayesian learning.

Tracking statistical regularities of the environment is important for shaping human behavior and perception. Evidence suggests that the brain learns environmental dependencies using Bayesian principles. However, much remains unknown about the employed algorithms, for somesthesis in particular. Here, we describe the cortical dynamics of the somatosensory learning system to investigate both the form of the generative model as well as its neural surprise signatures. Specifically, we recorded EEG data from 40 participants subjected to a somatosensory roving-stimulus paradigm and performed single-trial modeling across peri-stimulus time in both sensor and source space. Our Bayesian model selection procedure indicates that evoked potentials are best described by a non-hierarchical learning model that tracks transitions between observations using leaky integration. From around 70ms post-stimulus onset, secondary somatosensory cortices are found to represent confidence-corrected surprise as a measure of model inadequacy. Indications of Bayesian surprise encoding, reflecting model updating, are found in primary somatosensory cortex from around 140ms. This dissociation is compatible with the idea that early surprise signals may control subsequent model update rates. In sum, our findings support the hypothesis that early somatosensory processing reflects Bayesian perceptual learning and contribute to an understanding of its underlying mechanisms.