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.

Inter-individual variability in current direction for common tDCS montages.

The direction of applied electric current relative to the cortical surface is a key determinant of transcranial direct current stimulation (tDCS) effects. Inter-individual differences in anatomy affect the consistency of current direction at a cortical target. However, the degree of this variability remains undetermined. Using current flow modelling (CFM), we quantified the inter-individual variability in tDCS current direction at a cortical target (left primary motor cortex, M1). Three montages targeting M1 using circular electrodes were compared: PA-tDCS directed current perpendicular to the central sulcus in a posterior-anterior direction relative to M1, ML-tDCS directed current parallel to the central sulcus in a medio-lateral direction, and conventional-tDCS applied electrodes over M1 and the contralateral forehead. In 50 healthy brain scans from the Human Connectome Project, we extracted current direction and intensity from the grey matter surface in the sulcal bank (M1BANK) and gyral crown (M1CROWN), and neighbouring primary somatosensory cortex (S1BANK and S1CROWN). Results confirmed substantial inter-individual variability in current direction (50%-150%) across all montages. Radial inward current produced by PA-tDCS was predominantly located in M1BANK, whereas for conventional-tDCS it was clustered in M1CROWN. The difference in radial inward current in functionally distinct subregions of M1 raises the testable hypothesis that PA-tDCS and conventional-tDCS modulate cortical excitability through different mechanisms. We show that electrode locations can be used to closely approximate current direction in M1 and precentral gyrus, providing a landmark-based method for tDCS application to address the hypothesis without the need for MRI. By contrast, ML-tDCS current was more tangentially orientated, which is associated with weaker somatic polarisation. Substantial inter-individual variability in current direction likely contributes to variable neuromodulation effects reported for these protocols, emphasising the need for individualised electrode montages, including the control of current direction.

Optimising rehabilitation and recovery after a stroke.

Stroke can cause significant disability and impact quality of life. Multidisciplinary neurorehabilitation that meets individual needs can help to optimise recovery. Rehabilitation is essential for best quality care but should start early, be ongoing and involve effective teamwork. We describe current stroke rehabilitation processes, from the hyperacute setting through to inpatient and community rehabilitation, to long-term care and report on which UK quality care standards are (or are not) being met. We also examine the gap between what stroke rehabilitation is recommended and what is being delivered, and suggest areas for further improvement.

Timing and Dose of Upper Limb Motor Intervention After Stroke: A Systematic Review.

This systematic review aimed to investigate timing, dose, and efficacy of upper limb intervention during the first 6 months poststroke. Three online databases were searched up to July 2020. Titles/abstracts/full-text were reviewed independently by 2 authors. Randomized and nonrandomized studies that enrolled people within the first 6 months poststroke, aimed to improve upper limb recovery, and completed preintervention and postintervention assessments were included. Risk of bias was assessed using Cochrane reporting tools. Studies were examined by timing (recovery epoch), dose, and intervention type. Two hundred and sixty-one studies were included, representing 228 (n=9704 participants) unique data sets. The number of studies completed increased from one (n=37 participants) between 1980 and 1984 to 91 (n=4417 participants) between 2015 and 2019. Timing of intervention start has not changed (median 38 days, interquartile range [IQR], 22-66) and study sample size remains small (median n=30, IQR 20-48). Most studies were rated high risk of bias (62%). Study participants were enrolled at different recovery epochs: 1 hyperacute (<24 hours), 13 acute (1-7 days), 176 early subacute (8-90 days), 34 late subacute (91-180 days), and 4 were unable to be classified to an epoch. For both the intervention and control groups, the median dose was 45 (IQR, 600-1430) min/session, 1 (IQR, 1-1) session/d, 5 (IQR, 5-5) d/wk for 4 (IQR, 3-5) weeks. The most common interventions tested were electromechanical (n=55 studies), electrical stimulation (n=38 studies), and constraint-induced movement (n=28 studies) therapies. Despite a large and growing body of research, intervention dose and sample size of included studies were often too small to detect clinically important effects. Furthermore, interventions remain focused on subacute stroke recovery with little change in recent decades. A united research agenda that establishes a clear biological understanding of timing, dose, and intervention type is needed to progress stroke recovery research. Prospective Register of Systematic Reviews ID: CRD42018019367/CRD42018111629.

EEG Fractal Analysis Reflects Brain Impairment after Stroke.

Stroke is the commonest cause of disability. Novel treatments require an improved understanding of the underlying mechanisms of recovery. Fractal approaches have demonstrated that a single metric can describe the complexity of seemingly random fluctuations of physiological signals. We hypothesize that fractal algorithms applied to electroencephalographic (EEG) signals may track brain impairment after stroke. Sixteen stroke survivors were studied in the hyperacute (<48 h) and in the acute phase (∼1 week after stroke), and 35 stroke survivors during the early subacute phase (from 8 days to 32 days and after ∼2 months after stroke): We compared resting-state EEG fractal changes using fractal measures (i.e., Higuchi Index, Tortuosity) with 11 healthy controls. Both Higuchi index and Tortuosity values were significantly lower after a stroke throughout the acute and early subacute stage compared to healthy subjects, reflecting a brain activity which is significantly less complex. These indices may be promising metrics to track behavioral changes in the very early stage after stroke. Our findings might contribute to the neurorehabilitation quest in identifying reliable biomarkers for a better tailoring of rehabilitation pathways.

Blowing up Neural Repair for Stroke Recovery: Preclinical and Clinical Trial Considerations.

The repair and recovery of the brain after stroke is a field that is emerging in its preclinical science and clinical trials. However, recent large, multicenter clinical trials have been negative, and conflicting results emerge on biological targets in preclinical studies. The coalescence of negative clinical translation and confusion in preclinical studies raises the suggestion that perhaps the field of stroke recovery faces a fate similar to stroke neuroprotection, with interesting science ultimately proving difficult to translate to the clinic. This review highlights improvements in 4 areas of the stroke neural repair field that should reorient the field toward successful clinical translation: improvements in rodent genetic models of stroke recovery, consideration of the biological target in stroke recovery, stratification in clinical trials, and the use of appropriate clinical trial end points.

Intracerebral implantation of human neural stem cells and motor recovery after stroke: multicentre prospective single-arm study (PISCES-2).

BACKGROUND: Human neural stem cell implantation may offer improved recovery from stroke. We investigated the feasibility of intracerebral implantation of the allogeneic human neural stem cell line CTX0E03 in the subacute-chronic recovery phase of stroke and potential measures of therapeutic response in a multicentre study. METHODS: We undertook a prospective, multicentre, single-arm, open-label study in adults aged >40 years with significant upper limb motor deficits 2-13 months after ischaemic stroke. 20 million cells were implanted by stereotaxic injection to the putamen ipsilateral to the cerebral infarct. The primary outcome was improvement by 2 or more points on the Action Research Arm Test (ARAT) subtest 2 at 3 months after implantation. FINDINGS: Twenty-three patients underwent cell implantation at eight UK hospitals a median of 7 months after stroke. One of 23 participants improved by the prespecified ARAT subtest level at 3 months, and three participants at 6 and 12 months. Improvement in ARAT was seen only in those with residual upper limb movement at baseline. Transient procedural adverse effects were seen, but no cell-related adverse events occurred up to 12 months of follow-up. Two deaths were unrelated to trial procedures. INTERPRETATION: Administration of human neural stem cells by intracerebral implantation is feasible in a multicentre study. Improvements in upper limb function occurred at 3, 6 and 12 months, but not in those with absent upper limb movement at baseline, suggesting a possible target population for future controlled trials. FUNDING: ReNeuron, Innovate UK (application no 32074-222145). TRIAL REGISTRATION NUMBER: EudraCT Number: 2012-003482-18.

Cortical beta oscillations are associated with motor performance following visuomotor learning.

People vary in their capacity to learn and retain new motor skills. Although the relationship between neuronal oscillations in the beta frequency range (15-30 Hz) and motor behaviour is well established, the electrophysiological mechanisms underlying individual differences in motor learning are incompletely understood. Here, we investigated the degree to which measures of resting and movement-related beta power from sensorimotor cortex account for inter-individual differences in motor learning behaviour in the young and elderly. Twenty young (18-30 years) and twenty elderly (62-77 years) healthy adults were trained on a novel wrist flexion/extension tracking task and subsequently retested at two different time points (45-60 min and 24 h after initial training). Scalp EEG was recorded during a separate simple motor task before each training and retest session. Although short-term motor learning was comparable between young and elderly individuals, there was considerable variability within groups with subsequent analysis aiming to find the predictors of this variability. As expected, performance during the training phase was the best predictor of performance at later time points. However, regression analysis revealed that movement-related beta activity significantly explained additional variance in individual performance levels 45-60 min, but not 24 h after initial training. In the context of disease, these findings suggest that measurements of beta-band activity may offer novel targets for therapeutic interventions designed to promote rehabilitative outcomes.

Intensive upper limb neurorehabilitation in chronic stroke: outcomes from the Queen Square programme.

OBJECTIVE: Persistent difficulty in using the upper limb remains a major contributor to physical disability post-stroke. There is a nihilistic view about what clinically relevant changes are possible after the early post-stroke phase. The Queen Square Upper Limb Neurorehabilitation programme delivers high-quality, high-dose, high-intensity upper limb neurorehabilitation during a 3-week (90 hours) programme. Here, we report clinical changes made by the chronic stroke patients treated on the programme, factors that might predict responsiveness to therapy and the relationship between changes in impairment and activity. METHODS: Upper limb impairment and activity were assessed on admission, discharge, 6 weeks and 6 months after treatment, with modified upper limb Fugl-Meyer (FM-UL, max-54), Action Research Arm Test (ARAT, max-57) and Chedoke Arm and Hand Activity Inventory (CAHAI, max-91). Patient-reported outcome measures were recorded with the Arm Activity Measure (ArmA) parts A (0-32) and B (0-52), where lower scores are better. RESULTS: 224 patients (median time post-stroke 18 months) completed the 6-month programme. Median scores on admission were as follows: FM-UL = 26 (IQR 16-37), ARAT=18 (IQR 7-33), CAHAI=40 (28-55), ArmA-A=8 (IQR 4.5-12) and ArmA-B=38 (IQR 24-46). The median scores 6 months after the programme were as follows: FM-UL=37 (IQR 24-48), ARAT=27 (IQR 12-45), CAHAI=52 (IQR 35-77), ArmA-A=3 (IQR 1-6.5) and ArmA-B=19 (IQR 8.5-32). We found no predictors of treatment response beyond admission scores. CONCLUSION: With intensive upper limb rehabilitation, chronic stroke patients can change by clinically important differences in measures of impairment and activity. Crucially, clinical gains continued during the 6-month follow-up period.

Interrogating cortical function with transcranial magnetic stimulation: insights from neurodegenerative disease and stroke.

Transcranial magnetic stimulation (TMS) is an accessible, non-invasive technique to study cortical function in vivo. TMS studies have provided important pathophysiological insights across a range of neurodegenerative disorders and enhanced our understanding of brain reorganisation after stroke. In neurodegenerative disease, TMS has provided novel insights into the function of cortical output cells and the related intracortical interneuronal networks. Characterisation of cortical hyperexcitability in amyotrophic lateral sclerosis and altered motor cortical function in frontotemporal dementia, demonstration of cholinergic deficits in Alzheimer's disease and Parkinson's disease are key examples where TMS has led to advances in understanding of disease pathophysiology and potential mechanisms of propagation, with the potential for diagnostic applications. In stroke, TMS methodology has facilitated the understanding of cortical reorganisation that underlie functional recovery. These insights are critical to the development of effective and targeted rehabilitation strategies in stroke. The present review will provide an overview of cortical function measures obtained using TMS and how such measures may provide insight into brain function. Through an improved understanding of cortical function across a range of neurodegenerative disorders, and identification of changes in neural structure and function associated with stroke that underlie clinical recovery, more targeted therapeutic approaches may now be developed in an evolving era of precision medicine.

Movement-related beta oscillations show high intra-individual reliability.

Oscillatory activity in the beta frequency range (15-30Hz) recorded from human sensorimotor cortex is of increasing interest as a putative biomarker of motor system function and dysfunction. Despite its increasing use in basic and clinical research, surprisingly little is known about the test-retest reliability of spectral power and peak frequency measures of beta oscillatory signals from sensorimotor cortex. Establishing that these beta measures are stable over time in healthy populations is a necessary precursor to their use in the clinic. Here, we used scalp electroencephalography (EEG) to evaluate intra-individual reliability of beta-band oscillations over six sessions, focusing on changes in beta activity during movement (Movement-Related Beta Desynchronization, MRBD) and after movement termination (Post-Movement Beta Rebound, PMBR). Subjects performed visually-cued unimanual wrist flexion and extension. We assessed Intraclass Correlation Coefficients (ICC) and between-session correlations for spectral power and peak frequency measures of movement-related and resting beta activity. Movement-related and resting beta power from both sensorimotor cortices was highly reliable across sessions. Resting beta power yielded highest reliability (average ICC=0.903), followed by MRBD (average ICC=0.886) and PMBR (average ICC=0.663). Notably, peak frequency measures yielded lower ICC values compared to the assessment of spectral power, particularly for movement-related beta activity (ICC=0.386-0.402). Our data highlight that power measures of movement-related beta oscillations are highly reliable, while corresponding peak frequency measures show greater intra-individual variability across sessions. Importantly, our finding that beta power estimates show high intra-individual reliability over time serves to validate the notion that these measures reflect meaningful individual differences that can be utilised in basic research and clinical studies.

Brain regions important for recovery after severe post-stroke upper limb paresis.

Background The ability to predict outcome after stroke is clinically important for planning treatment and for stratification in restorative clinical trials. In relation to the upper limbs, the main predictor of outcome is initial severity, with patients who present with mild to moderate impairment regaining about 70% of their initial impairment by 3 months post-stroke. However, in those with severe presentations, this proportional recovery applies in only about half, with the other half experiencing poor recovery. The reasons for this failure to recover are not established although the extent of corticospinal tract damage is suggested to be a contributory factor. In this study, we investigated 30 patients with chronic stroke who had presented with severe upper limb impairment and asked whether it was possible to differentiate those with a subsequent good or poor recovery of the upper limb based solely on a T1-weighted structural brain scan. Methods A support vector machine approach using voxel-wise lesion likelihood values was used to show that it was possible to classify patients as good or poor recoverers with variable accuracy depending on which brain regions were used to perform the classification. Results While considering damage within a corticospinal tract mask resulted in 73% classification accuracy, using other (non-corticospinal tract) motor areas provided 87% accuracy, and combining both resulted in 90% accuracy. Conclusion This proof of concept approach highlights the relative importance of different anatomical structures in supporting post-stroke upper limb motor recovery and points towards methodologies that might be used to stratify patients in future restorative clinical trials.

The Nottingham Fatigue after Stroke (NotFAST) study: factors associated with severity of fatigue in stroke patients without depression.

OBJECTIVE: To identify factors associated with post-stroke fatigue in a sample of stroke survivors without depression. DESIGN: Cross-sectional cohort study. SETTING: Recruitment was from four stroke units in the UK. SUBJECTS: Participants were assessed within four to six weeks of first stroke; those with high levels of depressive symptoms (score ⩾7 Brief Assessment Schedule Depression Cards) were excluded. MAIN MEASURES: Participants were assessed after stroke on the Fatigue Severity Scale of the Fatigue Assessment Inventory, the Rivermead Mobility Index, Nottingham Extended Activities of Daily Living scale, Beck Anxiety Index, Sleep Hygiene Index, 6m walk test, and measures of cognitive ability. RESULTS: Of the 371 participants recruited, 103 were excluded and 268 were assessed. Of the latter, the mean age was 67.7 years (SD 13.5) and 168 (63%) were men. The National Institutes of Health Stroke Scale mean score was 4.96 (SD 4.12). Post-stroke fatigue was reported by 115 (43%) of participants, with 71 (62%) reporting this to be a new symptom since their stroke. Multivariate analysis using the Fatigue Severity Scale as the outcome variable found pre-stroke fatigue, having a spouse/partner, lower Rivermead Mobility Index score, and higher scores on both the Brief Assessment Schedule Depression Cards and Beck Anxiety Index were independently associated with post-stroke fatigue, accounting for approximately 47% of the variance in Fatigue Severity Scale scores. CONCLUSIONS: Pre-stroke fatigue, lower mood, and poorer mobility were associated with post-stroke fatigue.

Concentrations of Campylobacter spp., Escherichia coli, Enterococci, and Yersinia spp. in the Feces of Farmed Red Deer in New Zealand.

Intensive deer farming can cause environmental issues, mainly by its impact on soils and water quality. In particular, there is a risk to the microbial quality of water, as high quantities of suspended sediment and fecal bacteria can enter into water systems. The feces of farmed red deer (, = 206) from Canterbury and Southland, New Zealand, were analyzed with regard to the presence of spp., , enterococci, and spp.. Enterococci and were isolated from all samples, with mean concentrations of 4.5 × 10 (95% CI 3.5 × 10, 5.6 10) and 1.3 × 10 (95% CI 1.1 × 10, 1.5 × 10) per gram of dry feces, respectively. spp. were isolated from 27 fecal samples, giving an overall prevalence of 13.1%. isolation rates were variable within and between regions (Canterbury 7.95% [95% CI 2-14%], Southland 16.95% [95% CI 10-24%]). Five out of 42 composite samples were positive for , and one sample for The overall prevalence ranges on a per-animal basis were therefore 2.43 to 11.17% and 0.49 to 2.91%, respectively. This study is the first to quantify the concentration of spp. present in healthy deer farmed in New Zealand. Deer feces are a potential source of human campylobacteriosis, with all genotypes isolated also previously observed among human cases. The fecal outputs from deer should be regarded as potentially pathogenic to humans and therefore be appropriately managed.

Computational modelling of movement-related beta-oscillatory dynamics in human motor cortex.

Oscillatory activity in the beta range, in human primary motor cortex (M1), shows interesting dynamics that are tied to behaviour and change systematically in disease. To investigate the pathophysiology underlying these changes, we must first understand how changes in beta activity are caused in healthy subjects. We therefore adapted a canonical (repeatable) microcircuit model used in dynamic causal modelling (DCM) previously used to model induced responses in visual cortex. We adapted this model to accommodate cytoarchitectural differences between visual and motor cortex. Using biologically plausible connections, we used Bayesian model selection to identify the best model of measured MEG data from 11 young healthy participants, performing a simple handgrip task. We found that the canonical M1 model had substantially more model evidence than the generic canonical microcircuit model when explaining measured MEG data. The canonical M1 model reproduced measured dynamics in humans at rest, in a manner consistent with equivalent studies performed in mice. Furthermore, the changes in excitability (self-inhibition) necessary to explain beta suppression during handgrip were consistent with the attenuation of sensory precision implied by predictive coding. These results establish the face validity of a model that can be used to explore the laminar interactions that underlie beta-oscillatory dynamics in humans in vivo. Our canonical M1 model may be useful for characterising the synaptic mechanisms that mediate pathophysiological beta dynamics associated with movement disorders, such as stroke or Parkinson's disease.

The contribution of lesion location to upper limb deficit after stroke.

BACKGROUND: Motor deficit after stroke is related to regional anatomical damage. OBJECTIVE: To examine the influence of lesion location on upper limb motor deficit in chronic patients with stroke. METHODS: Lesion likelihood maps were created from T1-weighted structural MRI in 33 chronic patients with stroke with either purely subcortical lesions (SC, n=19) or lesions extending to any of the cortical motor areas (CM, n=14). We estimated lesion likelihood maps over the whole brain and applied multivoxel pattern analysis to seek the contribution weight of lesion likelihood to upper limb motor deficit. Among 5 brain regions of interest, the brain region with the greatest contribution to motor deficit was determined for each subgroup. RESULTS: The corticospinal tract was most likely to be damaged in both subgroups. However, while damage in the corticospinal tract was the best indicator of motor deficit in the SC patients, motor deficit in the CM patients was best explained by damage in brain areas activated during handgrip. CONCLUSIONS: Quantification of structural damage can add to models explaining motor outcome after stroke, but assessment of corticospinal tract damage alone is unlikely to be sufficient when considering patients with stroke with a wide range of lesion topography.