Effect of high-definition transcranial direct current stimulation among late-subacute and chronic stroke survivors with fatigue: A randomized-controlled crossover trial protocol.

Post-stroke fatigue (PSF) is a commonly overlooked symptom that impacts daily functioning and quality of life. It is caused by altered functional connectivity within the brain networks, which can potentially be influenced by neuromodulation. Multiple cortical regions have been targeted to reduce PSF, but the most efficient ones remain uncertain. Therefore, we aim to identify the most appropriate cortical stimulation site to reduce PSF. Twenty participants with PSF will be included in this cross-over trial. Each participant will receive one session of active anodal high definition- transcranial direct current stimulation (HD-tDCS) over three different cortical areas and one session of sham tDCS in a cross-over manner, with a two-week of washout period in between. Pre- and post- fatigue will be assessed using Fatigue Severity Scale and fatigability using electromyography by determining the time to task failure. Resting-state electroencephalography will be performed before and after each stimulation session to determine the functional connectivity of the cortical areas stimulated.

Influence of Perceptual Load on Attentional Orienting in Post-Stroke Fatigue: A Study of Auditory Evoked Potentials.

OBJECTIVE: Increasing perceptual load alters behavioral outcomes in post-stroke fatigue (PSF). While the effect of perceptual load on top-down attentional processing is known, here we investigate if increasing perceptual load modulates bottom-up attentional processing in a fatigue dependent manner. METHODS: In this cross-sectional observational study, in 29 first-time stroke survivors with no clinical depression, an auditory oddball task consisting of target, standard, and novel tones was performed in conditions of low and high perceptual load. Electroencephalography was used to measure auditory evoked potentials. Perceived effort was rated using the visual analog scale at regular intervals during the experiment. Fatigue was measured using the fatigue severity scale. The effect of fatigue and perceptual load on behavior (response time, accuracy, and effort rating) and auditory evoked potentials (amplitude and latency) was examined using mixed model ananlysis of variances (ANOVA). RESULTS: Response time was prolonged with greater perceptual load and fatigue. There was no effect of load or fatigue on accuracy. Greater effort was reported with higher perceptual load both in high and low fatigue. p300a amplitude of auditory evoked potentials (AEP) for novel stimuli was attenuated in high fatigue with increasing load when compared to low fatigue. Latency of p300a was longer in low fatigue with increasing load when compared to high fatigue. There were no effects on p300b components, with smaller N100 in high load conditions. INTERPRETATION: High fatigue specific modulation of p300a component of AEP with increasing load is indicative of distractor driven alteration in orienting response, suggestive of compromise in bottom-up selective attention in PSF.

The role of clinical neurophysiology in the definition and assessment of fatigue and fatigability.

Though a common symptom, fatigue is difficult to define and investigate, occurs in a wide variety of neurological and systemic disorders, with differing pathological causes. It is also often accompanied by a psychological component. As a symptom of long-term COVID-19 it has gained more attention. In this review, we begin by differentiating fatigue, a perception, from fatigability, quantifiable through biomarkers. Central and peripheral nervous system and muscle disorders associated with these are summarised. We provide a comprehensive and objective framework to help identify potential causes of fatigue and fatigability in a given disease condition. It also considers the effectiveness of neurophysiological tests as objective biomarkers for its assessment. Among these, twitch interpolation, motor cortex stimulation, electroencephalography and magnetencephalography, and readiness potentials will be described for the assessment of central fatigability, and surface and needle electromyography (EMG), single fibre EMG and nerve conduction studies for the assessment of peripheral fatigability. The purpose of this review is to guide clinicians in how to approach fatigue, and fatigability, and to suggest that neurophysiological tests may allow an understanding of their origin and interactions. In this way, their differing types and origins, and hence their possible differing treatments, may also be defined more clearly.

A roadmap for research in post-stroke fatigue: Consensus-based core recommendations from the third Stroke Recovery and Rehabilitation Roundtable.

RATIONALE: Fatigue affects almost half of all people living with stroke. Stroke survivors rank understanding fatigue and how to reduce it as one of the highest research priorities. METHODS: We convened an interdisciplinary, international group of clinical and pre-clinical researchers and lived experience experts. We identified four priority areas: (1) best measurement tools for research, (2) clinical identification of fatigue and potentially modifiable causes, (3) promising interventions and recommendations for future trials, and (4) possible biological mechanisms of fatigue. Cross-cutting themes were aphasia and the voice of people with lived experience. Working parties were formed and structured consensus building processes were followed. RESULTS: We present 20 recommendations covering outcome measures for research, development, and testing of new interventions and priority areas for future research on the biology of post-stroke fatigue. We developed and recommend the use of the Stroke Fatigue Clinical Assessment Tool. CONCLUSIONS: By synthesizing current knowledge in post-stroke fatigue across clinical and pre-clinical fields, our work provides a roadmap for future research into post-stroke fatigue.

A roadmap for research in post-stroke fatigue: Consensus-based core recommendations from the third Stroke Recovery and Rehabilitation Roundtable.

RATIONALE: Fatigue affects almost half of all people living with stroke. Stroke survivors rank understanding fatigue and how to reduce it as one of the highest research priorities. METHODS: We convened an interdisciplinary, international group of clinical and pre-clinical researchers and lived experience experts. We identified four priority areas: (1) best measurement tools for research, (2) clinical identification of fatigue and potentially modifiable causes, (3) promising interventions and recommendations for future trials, and (4) possible biological mechanisms of fatigue. Cross-cutting themes were aphasia and the voice of people with lived experience. Working parties were formed and structured consensus building processes were followed. RESULTS: We present 20 recommendations covering outcome measures for research, development, and testing of new interventions and priority areas for future research on the biology of post-stroke fatigue. We developed and recommend the use of the Stroke Fatigue Clinical Assessment Tool. CONCLUSIONS: By synthesizing current knowledge in post-stroke fatigue across clinical and pre-clinical fields, our work provides a roadmap for future research into post-stroke fatigue.

Lesioned hemisphere-specific phenotypes of post-stroke fatigue emerge from motor and mood characteristics in chronic stroke.

BACKGROUND AND PURPOSE: Post-stroke fatigue commonly presents alongside several comorbidities. The interaction between comorbidities and their relationship to fatigue is not known. In this study, we focus on physical and mood comorbidities, alongside lesion characteristics. We predict the emergence of distinct fatigue phenotypes with distinguishable physical and mood characteristics. METHODS: In this cross-sectional observational study, in 94 first time, non-depressed, moderate to minimally impaired chronic stroke survivors, the relationship between measures of motor function (grip strength, nine-hole peg test time), motor cortical excitability (resting motor threshold), Hospital Anxiety and Depression Scale and Fatigue Severity Scale-7 (FSS-7) scores, age, gender and side of stroke was established using Spearman's rank correlation. Mood and motor variables were then entered into a k-means clustering algorithm to identify the number of unique clusters, if any. Post hoc pairwise comparisons followed by corrections for multiple comparisons were performed to characterize differences among clusters in the variables included in k-means clustering. RESULTS: Clustering analysis revealed a four-cluster model to be the best model (average silhouette score of 0.311). There was no significant difference in FSS-7 scores among the four high-fatigue clusters. Two clusters consisted of only left-hemisphere strokes, and the remaining two were exclusively right-hemisphere strokes. Factors that differentiated hemisphere-specific clusters were the level of depressive symptoms and anxiety. Motor characteristics distinguished the low-depressive left-hemisphere from the right-hemisphere clusters. CONCLUSION: The significant differences in side of stroke and the differential relationship between mood and motor function in the four clusters reveal the heterogenous nature of post-stroke fatigue, which is amenable to categorization. Such categorization is critical to an understanding of the interactions between post-stroke fatigue and its presenting comorbid deficits, with significant implications for the development of context-/category-specific interventions.

Mechanisms of Post-Stroke Fatigue: A Follow-Up From the Third Stroke Recovery and Rehabilitation Roundtable.

BACKGROUND: Post-stroke fatigue (PSF) is a significant and highly prevalent symptom, whose mechanisms are poorly understood. The third Stroke Recovery and Rehabilitation Roundtable paper on PSF focussed primarily on defining and measuring PSF while mechanisms were briefly discussed. This companion paper to the main paper is aimed at elaborating possible mechanisms of PSF. METHODS: This paper reviews the available evidence that potentially explains the pathophysiology of PSF and draws parallels from fatigue literature in other conditions. We start by proposing a case for phenotyping PSF based on structural, functional, and behavioral characteristics of PSF. This is followed by discussion of a potentially significant role of early inflammation in the development of fatigue, specifically the impact of low-grade inflammation and its long-term systemic effects resulting in PSF. Of the many neurotransmitter systems in the brain, the dopaminergic systems have the most evidence for a role in PSF, along with a role in sensorimotor processing. Sensorimotor neural network dynamics are compromised as highlighted by evidence from both neurostimulation and neuromodulation studies. The double-edged sword effect of exercise on PSF provides further insight into how PSF might emerge and the importance of carefully titrating interventional paradigms. CONCLUSION: The paper concludes by synthesizing the presented evidence into a unifying model of fatigue which distinguishes between factors that pre-dispose, precipitate, and perpetuate PSF. This framework will help guide new research into the biological mechanisms of PSF which is a necessary prerequisite for developing treatments to mitigate the debilitating effects of post-stroke fatigue.

Long-term psychological outcomes following stroke: the OX-CHRONIC study.

BACKGROUND: Stroke survivors rate longer-term (> 2 years) psychological recovery as their top priority, but data on how frequently psychological consequences occur is lacking. Prevalence of cognitive impairment, depression/anxiety, fatigue, apathy and related psychological outcomes, and whether rates are stable in long-term stroke, is unknown. METHODS: N = 105 long-term stroke survivors (M [SD] age = 72.92 [13.01]; M [SD] acute NIH Stroke Severity Score = 7.39 [6.25]; 59.0% Male; M [SD] years post-stroke = 4.57 [2.12]) were recruited (potential N = 208). Participants completed 3 remote assessments, including a comprehensive set of standardized cognitive neuropsychological tests comprising domains of memory, attention, language, and executive function, and questionnaires on emotional distress, fatigue, apathy and other psychological outcomes. Ninety participants were re-assessed one year later. Stability of outcomes was assessed by Cohen's d effect size estimates and percent Minimal Clinically Important Difference changes between time points. RESULTS: On the Montreal Cognitive Assessment 65.3% scored < 26. On the Oxford Cognitive Screen 45.9% had at least one cognitive impairment. Attention (27.1%) and executive function (40%) were most frequently impaired. 23.5% and 22.5% had elevated depression/anxiety respectively. Fatigue (51.4%) and apathy (40.5%) rates remained high, comparable to estimates in the first-year post-stroke. Attention (d = -0.12; 85.8% stable) and depression (d = 0.09, 77.1% stable) were the most stable outcomes. Following alpha-adjustments, only perceptuomotor abilities (d = 0.69; 40.4% decline) and fatigue (d = -0.33; 45.3% decline) worsened over one year. Cognitive impairment, depression/anxiety, fatigue and apathy all correlated with worse quality of life. CONCLUSION: Nearly half of participants > 2 years post-event exhibited psychological difficulties including domains of cognition, mood, and fatigue, which impact long-term quality of life. Stroke is a chronic condition with highly prevalent psychological needs, which require monitoring and intervention development.

Electroencephalography-Derived Functional Connectivity in Sensorimotor Networks in Post Stroke Fatigue.

BACKGROUND: Poor suppression of anticipated sensory information from muscle contractions is thought to underlie high fatigue. Such diminished task-related sensory attenuation is reflected in resting state connectivity. Here we test the hypothesis 'altered electroencephalography (EEG)-derived functional connectivity in somatosensory network in the beta band, is a signature of fatigue in post-stroke fatigue'. METHODS: In non-depressed, minimally impaired stroke survivors (n = 29), with median disease duration of 5 years, resting state neuronal activity was measured using 64-channel EEG. Graph theory-based network analysis measure of functional connectivity via small-world index (SW) was calculated focusing on right and left motor (Brodmann areas 4, 6, 8, 9, 24 and 32) and sensory (Brodmann areas 1, 2, 3, 5, 7, 40 and 43) networks, in the beta (13-30 Hz) frequency range. Fatigue was measured using Fatigue Severity Scale - FSS (Stroke), with scores of > 4, defined as high fatigue. RESULTS: Results confirmed the working hypothesis, with high fatigue stroke survivors showing higher small-worldness in the somatosensory networks when compared to low fatigue. CONCLUSION: High levels of small-worldness in somatosensory networks indicates altered processing of somesthetic input. Such altered processing would explain high effort perception within the sensory attenuation model of fatigue.

Role of selective attention in fatigue in neurological disorders.

BACKGROUND: Chronic fatigue is a significant symptom in several diseases including traumatic and degenerative neurological disorders. While several studies have investigated the correlates of chronic fatigue, there is as yet no unifying framework to explain chronic fatigue. METHODS: In this narrative review, I investigate the role of selective attention in the development of chronic fatigue and discuss results within the framework of the sensory attenuation model of fatigue, which posits that fatigue is the phenomenological output of altered attention to sensory input. Following a short introduction of this framework, I present results from investigations that address attentional mechanisms in fatigue in multiple sclerosis, stroke, traumatic brain injury and Parkinson's disease. RESULTS: Attention was quantified in all four disease models using a variety of outcome measures, including behavioural, neurophysiological, structural and functional brain connectivity. The range of measures precluded direct comparison of results across disease conditions; however, in all four disease models there was evidence of poor selective attention that explained levels of chronic fatigue, supporting the sensory attenuation model of fatigue as a disease-independent mechanism of fatigue. Evidence was lacking to draw any conclusions about the direction of causality. CONCLUSION: The role of selective attention in development of fatigue is indicated. Future studies must focus on establishing causality and exploring attentional circuitry as a potential therapeutic target.

The Neurobiology of Pathological Fatigue: New Models, New Questions.

The last decade has seen the emergence of new theoretical frameworks to explain pathological fatigue, a much neglected, yet highly significant symptom across a wide range of diseases. While the new models of fatigue provide new hypotheses to test, they also raise a number of questions. The primary purpose of this essay is to examine the predictions of three recently proposed models of fatigue, the overlap and differences between them, and the evidence from diseases that may lend support to the models of fatigue. I also present expansions for the sensory attenuation model of fatigue. Further questions examined here are the following: What are the neural substrates of fatigue? How can sensory attenuation, which underpins agency also explain fatigue? Are fatigue and agency related?

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.

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".

Long-term psychological consequences of stroke (OX-CHRONIC): A longitudinal study of cognition in relation to mood and fatigue after stroke: Protocol.

Background: The long-term psychological consequences of stroke and how cognitive problems change over time after the first-year following stroke remain unclear. Particularly, trajectories of domain-specific and domain-general cognitive functions and how cognition interacts with mood, fatigue and quality of life are not well described. Aims: To determine the prevalence, trajectories and wider impact of domain-specific cognitive impairment in long-term stroke survivors, in relation to mood, fatigue and quality of life. Methods: Participants who previously took part in the Oxford Cognitive Screening study, completed the 6-month follow-up with cognitive, mood, fatigue and quality of life assessments and agreed to be contacted for future research will be recruited into OX-CHRONIC. The eligible cohort is between 2- and 9-years post-stroke. Cognition will be assessed with a detailed neuropsychological battery, alongside questionnaire measures of mood, fatigue, activities of daily life and quality of life measures at two timepoints, 1 year apart. Additionally, medical records will be accessed to extract further clinical information about the stroke and patients may opt-in to wear an activity monitor for 1 week to provide fine-grained measures of sleep and activity. The study protocol and study materials were approved by the national ethics committee (REC Ref: 19/SC/0520). Planned outputs: OX-CHRONIC will provide detailed data on the evolving cognitive profiles of stroke survivors over several years post-stroke. Estimates of long-term prevalence as well as the effect of changes in cognitive profiles on mood, fatigue and quality of life will be examined. This study is funded by a Priority Programme Grant from the Stroke Association (SA PPA 18/100032).

Influence of post-stroke fatigue on reaction times and corticospinal excitability during movement preparation.

OBJECTIVES: Reduced corticospinal excitability at rest is associated with post-stroke fatigue (PSF). However, it is not known if corticospinal excitability prior to a movement is also altered in fatigue which may then influence subsequent behaviour. We hypothesized that the levels of PSF can be explained by differences in modulation of corticospinal excitability during movement preparation. METHODS: 73 stroke survivors performed an auditory reaction time task. Corticospinal excitability was measured using transcranial magnetic stimulation. Fatigue was quantified using the fatigue severity scale. The effect of time and fatigue on corticospinal excitability and reaction time was analysed using a mixed effects model. RESULTS: Those with greater levels of PSF showed reduced suppression of corticospinal excitability during movement preparation and increased facilitation immediately prior to movement onset (ß = -0.0066, t = -2.22, p = 0.0263). Greater the fatigue, slower the reaction times the closer the stimulation time to movement onset (ß = 0.0024, t = 2.47, p = 0.0159). CONCLUSIONS: Lack of pre-movement modulation of corticospinal excitability in high fatigue may indicate poor sensory processing supporting the sensory attenuation model of fatigue. SIGNIFICANCE: We take a systems-based approach and investigate the motor system and its role in pathological fatigue allowing us to move towards gaining a mechanistic understanding of chronic pathological fatigue.

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.

Mechanisms of poststroke fatigue.

Poststroke fatigue is a debilitating symptom and is poorly understood. Here we summarise molecular, behavioural and neurophysiological changes related to poststroke fatigue and put forward potential theories for mechanistic understanding of poststroke fatigue.

Prior physical exertion modulates allocentric distance perception: a demonstration of task-irrelevant cross-modal transfer.

Physical exertion has been previously shown to influence distance perception in the egocentric framework. In this study, we show that physical exertion influences allocentric distance perception. Twenty healthy volunteers made allocentric line length estimates following varying levels of physical exertion. Each participant was presented with 30 different line lengths ranging from 1 to 12 cm, and each length was presented three times. Each line presentation was preceded by the participant exerting one of the following three levels of their maximal voluntary force (MVF): 20, 50, or 80 % MVF using their hand in the pinch force task. Psychometric curves were obtained for the lines perceived as 'long' following each of the three force levels. Lines that were perceived as 'short' following 20 and 50 % MVF were perceived as 'long' following 80 % MVF; that is, there was a significant leftward shift in the psychometric curve following 80 % MVF when compared to 20 and 50 % MVF. Here, we demonstrate that physical exertion influences perception of distances in the allocentric framework. We discuss our findings with respect to cross-modal interactions, fatigue physiology, peri- and extra-personal space interactions.