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”

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

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

Gene expression profiling of Leishmania (Leishmania) donovani: overcoming technical variation and exploiting biological variation

Gene expression profiling is increasingly used in the field of infectious diseases for characterization of host, pathogen and the nature of their interaction. The purpose of this study was to develop a robust, standardized method for comparative expression profiling and molecular characterization of Leishmania donovani clinical isolates. The limitations and possibilities associated with expression profiling in intracellular amastigotes and promastigotes were assessed through a series of comparative experiments in which technical and biological parameters were scrutinized. On a technical level, our results show that it is essential to use parasite harvesting procedures that involve minimal disturbance of the parasite's environment in order to ‘freeze' gene expression levels instantly; this is particularly a delicate task for intracellular amastigotes and for specific ‘sensory' genes. On the biological level, we demonstrate that gene expression levels fluctuate during in vitro development of both intracellular amastigotes and promastigotes. We chose to use expression-curves rather than single, specific, time-point measurements to capture this biological variation. Intracellular amastigote protocols need further refinement, but we describe a first generation tool for high-throughput comparative molecular characterization of patients' isolates, based on the changing expression profiles of promastigotes during in vitro differentiatio

Comparison of gene expression patterns among Leishmania braziliensis clinical isolates showing a different in vitro susceptibility to pentavalent antimony

Introduction. Evaluation of Leishmania drug susceptibility depends on in vitro SbV susceptibility assays, which are labour-intensive and may give a biased view of the true parasite resistance. Molecular markers are urgently needed to improve and simplify the monitoring of SbV-resistance. We analysed here the gene expression profile of 21 L. braziliensis clinical isolates in vitro defined as SbV-resistant and -sensitive, in order to identify potential resistance markers. Methods. The differential expression of 13 genes involved in SbV metabolism, oxidative stress or housekeeping functions was analysed during in vitro promastigote growth. Results. Expression profiles were up-regulated for 5 genes only, each time affecting a different set of isolates (mosaic picture of gene expression). Two genes, ODC (ornithine decarboxylase) and TRYR (trypanothione reductase), showed a significantly higher expression rate in the group of SbV-resistant compared to the group of SbV-sensitive parasites (P<0·01). However, analysis of individual isolates showed both markers to explain only partially the drug resistance. Discussion. Our results might be explained by (i) the occurrence of a pleiotropic molecular mechanism leading to the in vitro SbV resistance and/or (ii) the existence of different epi-phenotypes not revealed by the in vitro SbV susceptibility assays, but interfering with the gene expression pattern