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, specifcally of the afected 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 efort were also assessed pre, immediately post, a week and 5 weeks post stimulation. Results: Anodal tDCS signifcantly improved fatigue symptoms a week after real stimulation when compared to sham stimulation. There was also a signifcant change in motor cortex neurophysiology of the afected hemisphere and perceived efort, 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 efect 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

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

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 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' magnetic resonance imaging (rs-fMRI), single-pulse and paired-pulse transcranial magnetic stimulation (pp-TMS). In the first session of Experiment 1, we assessed resting motor thresholds (RMTs) - a typical measure of cortical excitability-by applying TMS to the primary motor cortex (M1) and measuring motor-evoked potential in the hand affected by stroke. In the second session, we measured their brain activity with rs-fMRI to assess effective connectivity interactions at rest. In Experiment 2 we examined effective inter-hemispheric connectivity in an independent sample of patients using pp-TMS. We also assessed the levels of non-exercise induced, persistent fatigue using Fatigue Severity Scale (FSS-7), a self-report questionnaire which has been widely applied and validated across different conditions. We employed spectral dynamic causal modelling (sp-DCM) in Experiment 1 and pp-TMS in Experiment 2 to characterise how neuronal effective connectivity relates to self-reported post-stroke fatigue. In a multiple regression we used the balance in inhibitory connectivity between homologue regions in M1 as the main predictor, and have included lesioned hemisphere, RMT 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 (β  =  1.524, p = 7.56e-05, CI[0.921, 2.127]) and in Experiment 2 (β  =  0.541, p = 0.049, CI[0.002, 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

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

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

The multiform motor cortical output: kinematic, predictive and response coding

Observing actions performed by others entails a subliminal activation of primary motor cortex reflecting the components encoded in the observed action. One of the most debated issues concerns the role of this output: Is it a mere replica of the incoming flow of information (kinematic coding), is it oriented to anticipate the forthcoming events (predictive coding) or is it aimed at responding in a suitable fashion to the actions of others (response coding)? The aim of the present study was to disentangle the relative contribution of these three levels and unify them into an integrated view of cortical motor coding. We combined transcranial magnetic stimulation (TMS) and electromyography recordings at different timings to probe the excitability of corticospinal projections to upper and lower limb muscles of participants observing a soccer player performing: (i) a penalty kick straight in their direction and then coming to a full stop, (ii) a penalty kick straight in their direction and then continuing to run, (iii) a penalty kick to the side and then continuing to run. The results show a modulation of the observer's corticospinal excitability in different effectors at different times reflecting a multiplicity of motor coding. The internal replica of the observed action, the predictive activation, and the adaptive integration of congruent and non-congruent responses to the actions of others can coexist in a not mutually exclusive way. Such a view offers reconciliation among different (and apparently divergent) frameworks in action observation literature, and will promote a more complete and integrated understanding of recent findings on motor simulation, motor resonance and automatic imitation

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

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

From heart to mind: Linking interoception, emotion, and theory of mind

Theory of Mind (ToM) is traditionally characterized as the ability to represent mental states. Such a characterization leaves little room for studying individual differences in ToM – individuals either can, or cannot, represent mental states – and this binary classification cannot quantify the subtle individual differences observed in typical and atypical populations. In recognition of this problem, attempts have been made to provide a more detailed characterization of the constituent psychological processes which support the representation of mental states, and the neurocomputational principles underpinning ToM, in order to identify the source of individual differences. A recent model is of interest as it forwards the novel argument that interoception, perception of the internal state of the body, is a fundamental component of ToM. Here we report the first test of the link between interoception and ToM