Predicting Online Behavioural Responses to Transcranial Direct Current Stimulation in Stroke Patients with Anomia.

Anomia, or difficulty naming common objects, is the most common, acquired impairment of language. Effective therapeutic interventions for anomia typically involve massed practice at high doses. This requires significant investment from patients and therapists. Aphasia researchers have increasingly looked to neurostimulation to accelerate these treatment effects, but the evidence behind this intervention is sparse and inconsistent. Here, we hypothesised that group-level neurostimulation effects might belie a more systematic structure at the individual level. We sought to test the hypothesis by attempting to predict the immediate (online), individual-level behavioural effects of anodal and sham neurostimulation in 36 chronic patients with anomia, performing naming and size judgement tasks. Using clinical, (pre-stimulation) behavioural and MRI data, as well as Partial Least Squares regression, we attempted to predict neurostimulation effects on accuracies and reaction times of both tasks. Model performance was assessed via cross-validation. Predictive performances were compared to that of a null model, which predicted the mean neurostimulation effects for all patients. Models derived from pre-stimulation data consistently outperformed the null model when predicting neurostimulation effects on both tasks' performance. Notably, we could predict behavioural declines just as well as improvements. In conclusion, inter-patient variation in online responses to neurostimulation is, to some extent, systematic and predictable. Since declines in performance were just as predictable as improvements, the behavioural effects of neurostimulation in patients with anomia are unlikely to be driven by placebo effects. However, the online effect of the intervention appears to be as likely to interfere with task performance as to improve it.

Mapping spoken language and cognitive deficits in post-stroke aphasia.

Aphasia is an acquired disorder caused by damage, most commonly due to stroke, to brain regions involved in speech and language. While language impairment is the defining symptom of aphasia, the co-occurrence of non-language cognitive deficits and their importance in predicting rehabilitation and recovery outcomes is well documented. However, people with aphasia (PWA) are rarely tested on higher-order cognitive functions, making it difficult for studies to associate these functions with a consistent lesion correlate. Broca's area is a particular brain region of interest that has long been implicated in speech and language production. Contrary to classic models of speech and language, cumulative evidence shows that Broca's area and surrounding regions in the left inferior frontal cortex (LIFC) are involved in, but not specific to, speech production. In this study we aimed to explore the brain-behaviour relationships between tests of cognitive skill and language abilities in thirty-six adults with long-term speech production deficits caused by post-stroke aphasia. Our findings suggest that non-linguistic cognitive functions, namely executive functions and verbal working memory, explain more of the behavioural variance in PWA than classical language models imply. Additionally, lesions to the LIFC, including Broca's area, were associated with non-linguistic executive (dys)function, suggesting that lesions to this area are associated with non-language-specific higher-order cognitive deficits in aphasia. Whether executive (dys)function - and its neural correlate in Broca's area - contributes directly to PWA's language production deficits or simply co-occurs with it, adding to communication difficulties, remains unclear. These findings support contemporary models of speech production that place language processing within the context of domain-general perception, action and conceptual knowledge. An understanding of the covariance between language and non-language deficits and their underlying neural correlates will inform better targeted aphasia treatment and outcomes.

Neural effective connectivity explains subjective fatigue in stroke.

Persistent fatigue is a major debilitating symptom in many psychiatric and neurological conditions, including stroke. Post-stroke fatigue has been linked to low corticomotor excitability. Yet, it remains elusive as to what the neuronal mechanisms are that underlie motor cortex excitability and chronic persistence of fatigue. In this cross-sectional observational study, in two experiments we examined a total of 59 non-depressed stroke survivors with minimal motoric and cognitive impairments using 'resting-state' MRI and single- and paired-pulse transcranial magnetic stimulation. In the first session of Experiment 1, we assessed resting motor thresholds-a typical measure of cortical excitability-by applying transcranial magnetic stimulation to the primary motor cortex (M1) and measuring motor-evoked potentials in the hand affected by stroke. In the second session, we measured their brain activity with resting-state MRI to assess effective connectivity interactions at rest. In Experiment 2 we examined effective inter-hemispheric connectivity in an independent sample of patients using paired-pulse transcranial magnetic stimulation. We also assessed the levels of non-exercise induced, persistent fatigue using Fatigue Severity Scale (FSS-7), a self-report questionnaire that has been widely applied and validated across different conditions. We used spectral dynamic causal modelling in Experiment 1 and paired-pulse transcranial magnetic stimulation in Experiment 2 to characterize how neuronal effective connectivity relates to self-reported post-stroke fatigue. In a multiple regression analysis, we used the balance in inhibitory connectivity between homologue regions in M1 as the main predictor, and have included lesioned hemisphere, resting motor threshold and levels of depression as additional predictors. Our novel index of inter-hemispheric inhibition balance was a significant predictor of post-stroke fatigue in Experiment 1 (ß = 1.524, P = 7.56 × 10-5, confidence interval: 0.921 to 2.127) and in Experiment 2 (ß = 0.541, P = 0.049, confidence interval: 0.002 to 1.080). In Experiment 2, depression scores and corticospinal excitability, a measure associated with subjective fatigue, also significantly accounted for variability in fatigue. We suggest that the balance in inter-hemispheric inhibitory effects between primary motor regions can explain subjective post-stroke fatigue. Findings provide novel insights into neural mechanisms that underlie persistent fatigue.

Lesion site and therapy time predict responses to a therapy for anomia after stroke: a prognostic model development study.

Stroke is a leading cause of disability, and language impairments (aphasia) after stroke are both common and particularly feared. Most stroke survivors with aphasia exhibit anomia (difficulties with naming common objects), but while many therapeutic interventions for anomia have been proposed, treatment effects are typically much larger in some patients than others. Here, we asked whether that variation might be more systematic, and even predictable, than previously thought. 18 patients, each at least 6 months after left hemisphere stroke, engaged in a computerised treatment for their anomia over a 6-week period. Using only: (a) the patients' initial accuracy when naming (to-be) trained items; (b) the hours of therapy that they devoted to the therapy; and (c) whole-brain lesion location data, derived from structural MRI; we developed Partial Least Squares regression models to predict the patients' improvements on treated items, and tested them in cross-validation. Somewhat surprisingly, the best model included only lesion location data and the hours of therapy undertaken. In cross-validation, this model significantly out-performed the null model, in which the prediction for each patient was simply the mean treatment effect of the group. This model also made promisingly accurate predictions in absolute terms: the correlation between empirical and predicted treatment response was 0.62 (95% CI 0.27, 0.95). Our results indicate that individuals' variation in response to anomia treatment are, at least somewhat, systematic and predictable, from the interaction between where and how much lesion damage they have suffered, and the time they devoted to the therapy.

Effect of transcranial direct current stimulation on post-stroke fatigue.

BACKGROUND: Fatigue is one of the most commonly reported symptoms post-stroke, which has a severe impact on the quality of life. Post-stroke fatigue is associated with reduced motor cortical excitability, specifically of the affected hemisphere. OBJECTIVE: The aim of this exploratory study was to assess whether fatigue symptoms can be reduced by increasing cortical excitability using anodal transcranial direct current stimulation (tDCS). METHODS: In this sham-controlled, double-blind intervention study, tDCS was applied bilaterally over the primary motor cortex in a single session in thirty stroke survivors with high severity of fatigue. A questionnaire-based measure of trait fatigue (primary outcome) was obtained before, after a week and 5 weeks post stimulation. Secondary outcome measures of state fatigue, motor cortex neurophysiology and perceived effort were also assessed pre, immediately post, a week and 5 weeks post stimulation. RESULTS: Anodal tDCS significantly improved fatigue symptoms a week after real stimulation when compared to sham stimulation. There was also a significant change in motor cortex neurophysiology of the affected hemisphere and perceived effort, a week after stimulation. The degree of improvement in fatigue was associated with baseline anxiety levels. CONCLUSION: A single session of anodal tDCS improves fatigue symptoms with the effect lasting up to a week post stimulation. tDCS may therefore be a useful tool for managing fatigue symptoms post-stroke. TRIAL REGISTRATION: NCT04634864 DATE OF REGISTRATION: 17/11/2020-"retrospectively registered".

Exploring the relationship between effort perception and poststroke fatigue.

OBJECTIVE: To test the hypothesis that poststroke fatigue, a chronic, pathologic fatigue condition, is driven by altered effort perception. METHODS: Fifty-eight nondepressed, mildly impaired stroke survivors with varying severity of fatigue completed the study. Self-reported fatigue (trait and state), perceived effort (PE; explicit and implicit), and motor performance were measured in a handgrip task. Trait fatigue was measured with the Fatigue Severity Scale-7 and Neurologic Fatigue Index. State fatigue was measured with a visual analog scale (VAS). Length of hold at target force, overshoot above target force, and force variability in handgrip task were measures of motor performance. PE was measured with a VAS (explicit PE) and line length estimation, a novel implicit measure of PE. RESULTS: Regression analysis showed that 11.6% of variance in trait fatigue was explained by implicit PE (R = 0.34; p = 0.012). Greater fatigue was related to longer length of hold at target force (R = 0.421, p < 0.001). A backward regression showed that length of hold explained explicit PE in the 20% force condition (R = 0.306, p = 0.021) and length of hold and overshoot above target force explained explicit PE in the 40% (R = 0.399, p = 0.014 and 0.004) force condition. In the 60% force condition, greater explicit PE was explained by higher force variability (R = 0.315, p = 0.017). None of the correlations were significant for state fatigue. CONCLUSION: Trait fatigue, but not state fatigue, correlating with measures of PE and motor performance, may suggest that altered perception may lead to high fatigue mediated by changes in motor performance. This finding furthers our mechanistic understanding of poststroke fatigue.

Sensorimotor beta power reflects the precision-weighting afforded to sensory prediction errors.

It has been proposed that accurate motor control relies on Bayesian inference that integrates sensory input with prior contextual knowledge (Bays and Wolpert, 2007; Körding and Wolpert, 2004; Wolpert et al., 1995). Recent evidence has suggested that modulations in beta power (∼12-30 Hz) measured over sensorimotor cortices using electroencephalography (EEG) may represent parameters of Bayesian inference. While the well characterised post-movement beta synchronisation has been shown to correlate with prediction error (H. Tan, Jenkinson, & Brown, 2014; Huiling Tan, Wade, & Brown, 2016), recent evidence suggests that beta power may also represent uncertainty measures (Tan et al., 2016; Tzagarakis et al., 2015). The current study aimed to measure the neurophysiological correlates of uncertainty mediating Bayesian updating during a visuomotor adaptation paradigm in healthy human participants. In particular, sensory uncertainty was directly modulated to measure its effect on sensorimotor beta power. Participant's behaviour was modelled using the Hierarchical Gaussian Filter (HGF) in order to extract the latent variables involved in learning actions required by the task and correlate these with the measured EEG. We found that sensorimotor beta power correlated with inverse uncertainty afforded to sensory prediction errors both prior to and following a movement. This suggests that sensorimotor beta oscillations may more readily represent relative uncertainty within the sensorimotor system rather than error. Neurophysiological models describing the generation of beta oscillations offer a potential mechanism by which this neural signature may encode latent uncertainty parameters. This is essential for understanding how the brain controls behaviour.

Interoceptive inference: From computational neuroscience to clinic.

The central and autonomic nervous systems can be defined by their anatomical, functional and neurochemical characteristics, but neither functions in isolation. For example, fundamental components of autonomically mediated homeostatic processes are afferent interoceptive signals reporting the internal state of the body and efferent signals acting on interoceptive feedback assimilated by the brain. Recent predictive coding (interoceptive inference) models formulate interoception in terms of embodied predictive processes that support emotion and selfhood. We propose interoception may serve as a way to investigate holistic nervous system function and dysfunction in disorders of brain, body and behaviour. We appeal to predictive coding and (active) interoceptive inference, to describe the homeostatic functions of the central and autonomic nervous systems. We do so by (i) reviewing the active inference formulation of interoceptive and autonomic function, (ii) survey clinical applications of this formulation and (iii) describe how it offers an integrative approach to human physiology; particularly, interactions between the central and peripheral nervous systems in health and disease.

Active Inference, Curiosity and Insight.

This article offers a formal account of curiosity and insight in terms of active (Bayesian) inference. It deals with the dual problem of inferring states of the world and learning its statistical structure. In contrast to current trends in machine learning (e.g., deep learning), we focus on how people attain insight and understanding using just a handful of observations, which are solicited through curious behavior. We use simulations of abstract rule learning and approximate Bayesian inference to show that minimizing (expected) variational free energy leads to active sampling of novel contingencies. This epistemic behavior closes explanatory gaps in generative models of the world, thereby reducing uncertainty and satisfying curiosity. We then move from epistemic learning to model selection or structure learning to show how abductive processes emerge when agents test plausible hypotheses about symmetries (i.e., invariances or rules) in their generative models. The ensuing Bayesian model reduction evinces mechanisms associated with sleep and has all the hallmarks of "aha" moments. This formulation moves toward a computational account of consciousness in the pre-Cartesian sense of sharable knowledge (i.e., con: "together"; scire: "to know").

Functional neuroanatomy of speech signal decoding in primary progressive aphasias.

The pathophysiology of primary progressive aphasias remains poorly understood. Here, we addressed this issue using activation fMRI in a cohort of 27 patients with primary progressive aphasia (nonfluent, semantic, and logopenic variants) versus 15 healthy controls. Participants listened passively to sequences of spoken syllables in which we manipulated 3-key auditory speech signal characteristics: temporal regularity, phonemic spectral structure, and pitch sequence entropy. Relative to healthy controls, nonfluent variant patients showed reduced activation of medial Heschl's gyrus in response to any auditory stimulation and reduced activation of anterior cingulate to temporal irregularity. Semantic variant patients had relatively reduced activation of caudate and anterior cingulate in response to increased entropy. Logopenic variant patients showed reduced activation of posterior superior temporal cortex to phonemic spectral structure. Taken together, our findings suggest that impaired processing of core speech signal attributes may drive particular progressive aphasia syndromes and could index a generic physiological mechanism of reduced computational efficiency relevant to all these syndromes, with implications for development of new biomarkers and therapeutic interventions.

The role of interoceptive inference in theory of mind.

Inferring the intentions and beliefs of another is an ability that is fundamental for social and affiliative interactions. A substantial amount of empirical evidence suggests that making sense of another's intentional and belief states (i.e. theory of mind) relies on exteroceptive (e.g. visual and auditory) and proprioceptive (i.e. motor) signals. Yet, despite its pivotal role in the guidance of behaviour, the role of the observer's interoceptive (visceral) processing in understanding another's internal states remains unexplored. Predicting and keeping track of interoceptive bodily states - which inform intentions and beliefs that guide behaviour - is one of the fundamental purposes of the human brain. In this paper, we will focus on the role of interoceptive predictions, prescribed by the free energy principle, in making sense of internal states that cause another's behaviour. We will discuss how multimodal expectations induced at deep (high) hierarchical levels - that necessarily entail interoceptive predictions - contribute to inference about others that is at the heart of theory of mind.

Beta- and gamma-band activity reflect predictive coding in the processing of causal events.

In daily life, complex events are perceived in a causal manner, suggesting that the brain relies on predictive processes to model them. Within predictive coding theory, oscillatory beta-band activity has been linked to top-down predictive signals and gamma-band activity to bottom-up prediction errors. However, neurocognitive evidence for predictive coding outside lower-level sensory areas is scarce. We used magnetoencephalography to investigate neural activity during probability-dependent action perception in three areas pivotal for causal inference, superior temporal sulcus, temporoparietal junction and medial prefrontal cortex, using bowling action animations. Within this network, Granger-causal connectivity in the beta-band was found to be strongest for backward top-down connections and gamma for feed-forward bottom-up connections. Moreover, beta-band power in TPJ increased parametrically with the predictability of the action kinematics-outcome sequences. Conversely, gamma-band power in TPJ and MPFC increased with prediction error. These findings suggest that the brain utilizes predictive-coding-like computations for higher-order cognition such as perception of causal events.

Perception, as you make it.

The main question that Firestone & Scholl (F&S) pose is whether "what and how we see is functionally independent from what and how we think, know, desire, act, and so forth" (sect. 2, para. 1). We synthesize a collection of concerns from an interdisciplinary set of coauthors regarding F&S's assumptions and appeals to intuition, resulting in their treatment of visual perception as context-free.

Interplay Between Conceptual Expectations and Movement Predictions Underlies Action Understanding.

Recent accounts of understanding goal-directed action underline the importance of a hierarchical predictive architecture. However, the neural implementation of such an architecture remains elusive. In the present study, we used functional neuroimaging to quantify brain activity associated with predicting physical movements, as they were modulated by conceptual-expectations regarding the purpose of the object involved in the action. Participants observed object-related actions preceded by a cue that generated both conceptual goal expectations and movement goal predictions. In 2 tasks, observers judged whether conceptual or movement goals matched or mismatched the cue. At the conceptual level, expected goals specifically recruited the posterior cingulate cortex, irrespectively of the task and the perceived movement goal. At the movement level, neural activation of the parieto-frontal circuit, including inferior frontal gyrus and the inferior parietal lobe, reflected unpredicted movement goals. Crucially, this movement prediction error was only present when the purpose of the involved object was expected. These findings provide neural evidence that prior conceptual expectations influence processing of physical movement goals and thereby support the hierarchical predictive account of action processing.

Action recognition depends on observer's level of action control and social personality traits.

Humans recognize both the movement (physical) goals and action (conceptual) goals of individuals with whom they are interacting. Here, we assessed whether spontaneous recognition of others' goals depends on whether the observers control their own behavior at the movement or action level. We also examined the relationship between individual differences in empathy and ASD-like traits, and the processing of other individual's movement and action goals that are known to be encoded in the "mirroring" and "mentalizing" brain networks. In order to address these questions, we used a computer-based card paradigm that made it possible to independently manipulate movement and action congruency of observed and executed actions. In separate blocks, participants were instructed to select either the right or left card (movement-control condition) or the higher or lower card (action-control condition), while we manipulated action- and movement-congruency of both actors' goals. An action-congruency effect was present in all conditions and the size of this effect was significantly correlated with self-reported empathy and ASD-like traits. In contrast, movement-congruency effects were only present in the movement-control block and were strongly dependent on action-congruency. These results illustrate that spontaneous recognition of others' behavior depends on the control scheme that is currently adopted by the observer. The findings suggest that deficits in action recognition are related to abnormal synthesis of perceived movements and prior conceptual knowledge that are associated with activations in the "mirroring" and "mentalizing" cortical networks.

Hierarchy of idea-guided action and perception-guided movement.

The ideomotor theory of voluntary behavior assumes that the selection and control of a concrete goal-directed movement depends on imagining its direct perceptual consequences. However, this perception-guided assumption neglects the fact that behavioral control entails a hierarchical mechanism wherein conceptual expectations - action goals - can modulate lower level perceptuo-motor representations. In this paper, we focus on the hierarchical nature of voluntary behavior by distinguishing between perceptual representations of images that relate to attainment of concrete movement goals and conceptual representations of ideas that pertain to attainment of action goals. We review the dominant ideomotor principle of the direct perceptuo-motor relation and examine its limitation in the light of the proposed hierarchical view of voluntary behavior. Finally, we offer a revision of the ideomotor principle that allows extension of its explanatory domain from perception-guided movement to conceptual, idea-guided action.

Interplay between action and movement intentions during social interaction.

Observing the movements of another person influences the observer's intention to execute similar movements. However, little is known about how action intentions formed prior to movement planning influence this effect. In the experiment reported here, we manipulated the congruency of movement intentions and action intentions in a pair of jointly acting individuals (i.e., a participant paired with a confederate coactor) and investigated how congruency influenced performance. Overall, participants initiated actions faster when they had the same action intention as the coactor (i.e., when participants and the coactor were pursuing the same conceptual goal). Participants' responses were also faster when their and the coactor's movement intentions were directed to the same spatial location, but only when participants had the same action intention as the coactor. These findings suggest that observers use the same representation to implement their own action intentions that they use to infer other people's action intentions and also that a dynamic, multitiered intentional mechanism is involved in the processing of other people's actions.

Virtual Lesions of the IFG Abolish Response Facilitation for Biological and Non-Biological Cues.

Humans are faster to perform a given action following observation of that same action. Converging evidence suggests that the human mirror neuron system (MNS) plays an important role in this phenomenon. However, the specificity of the neural mechanisms governing this effect remain controversial. Specialist theories of imitation suggest that biological cues are maximally capable of eliciting imitative facilitation. Generalist models, on the other hand, posit a broader role for the MNS in linking visual stimuli with appropriate responses. In the present study, we investigated the validity of these two theoretical approaches by disrupting the left and right inferior frontal gyrus (IFG) during the preparation of congruent (imitative) and incongruent (complementary) actions cued by either biological (hand) or non-biological (static dot) stimuli. Delivery of TMS over IFG abolished imitative response facilitation. Critically, this effect was identical whether actions were cued by biological or non-biological stimuli. This finding argues against theories of imitation in which biological stimuli are treated preferentially and stresses the notion of the IFG as a vital center of general perception-action coupling in the human brain.