The effect of computer-based cognitive flexibility training on recovery of executive function after stroke: rationale, design and methods of the TAPASS study

Background: Stroke survivors frequently suffer from executive impairments even in the chronic phase after stroke, and there is a need for improved rehabilitation of these functions. One way of improving current rehabilitation treatment may be by online cognitive training. Based on a review of the effectiveness of computer-based cognitive training in healthy elderly, we concluded that cognitive flexibility may be a key element for an effective training, which results in improvements not merely on trained tasks but also in untrained tasks (i.e., far transfer). The aim of the current study was to track the behavioral and neural effects of computer-based cognitive flexibility training after stroke. We expected that executive functioning would improve after the cognitive flexibility training, and that neural activity and connectivity would normalize towards what is seen in healthy elderly. Methods/design: The design was a multicenter, double blind, randomized controlled trial (RCT) with three groups: an experimental intervention group, an active control group who did a mock training, and a waiting list control group. Stroke patients (3 months to 5 years post-stroke) with cognitive complaints were included. Training consisted of 58 half-hour sessions spread over 12 weeks. The primary study outcome was objective executive function. Secondary measures were improvement on training tasks, cognitive flexibility, objective cognitive functioning in other domains than the executive domain, subjective cognitive and everyday life functioning, and neural correlates assessed by both structural and resting-state functional Magnetic Resonance Imaging. The three groups were compared at baseline, after six and twelve weeks of training, and four weeks after the end of the training. Furthermore, they were compared to healthy elderly who received the same training. Discussion: The cognitive flexibility training consisted of several factors deemed important for effects that go beyond improvement on merely the training task themselves. Due to the presence of two control groups, the effects of the training could be compared with spontaneous recovery and with the effects of a mock training. This study provides insight into the potential of online cognitive flexibility training after stroke. We also compared its results with the effectiveness of the same training in healthy elderly

Устройство советских мотоциклов

0|7|Введение [c. 7]0|11|Схема современного мотоцикла [c. 11]0|13|Принцип работы двигателя внутреннего сгорания [c. 13]0|28|Устройство деталей двигателей [c. 28]0|59|Охлаждение двигателя [c. 59]0|66|Смазка двигателя [c. 66]0|83|Карбюрация [c. 83]0|110|Электрооборудование мотоцикла [c. 110]0|150|Силовая передача [c. 150]0|172|Экипажная часть мотоцикла [c. 172]0|191|Органы управления мотоциклом [c. 191]0|198|Дополнительное оборудование мотоцикла [c. 198]0|199|Боковая прицепка [c. 199]0|202|Приспособления к мотоциклу для езды в условиях скользкого пути [c. 202]0|205|Управление мотоциклом [c. 205]0|212|Содержание [c. 212

Frequent cases of RAS-mutated Down syndrome acute lymphoblastic leukaemia lack JAK2 mutations

The final published article can be found here: http://dx.doi.org/10.1038/ncomms5654This work was supported by KKL632 grant from the Kay Kendall Leukaemia Fund, Jerome Lejeune Foundation project grant 2011B-960, the Wellcome Trust Strategic Award WT 098330/Z/12/Z (The LonDownS Consortium) and the Lee Kong Chian School of Medicine, Nanyang Technological University-Singapore start-up funding grant M4230024 to D.N.; Swiss Cancer League (LSCC 2939-02-2012) and Dinu Lipatti 2014 grants to S.I.N.; SNF 144082, ERC 249968 and Foundation ‘ChildCare’ grants to S.E.A.; and by Cariparo bando ricerca pediatrica and by European commission (FP7 ENCCA, 261474, Trancan PER-2011-2353841) to G.B

Trisomic dose of several chromosome 21 genes perturbs haematopoietic stem and progenitor cell differentiation in Down's syndrome

Children with Down's syndrome (DS) have 20–50-fold higher incidence of all leukaemias (lymphoid and myeloid), for reasons not understood. As incidence of many solid tumours is much lower in DS, we speculated that disturbed early haematopoietic differentiation could be the cause of increased leukaemia risk. If a common mechanism is behind the risk of both major leukaemia types, it would have to arise before the bifurcation to myeloid and lymphoid lineages. Using the transchromosomic system (mouse embryonic stem cells (ESCs)) bearing an extra human chromosome 21 (HSA21)) we analyzed the early stages of haematopoietic commitment (mesodermal colony formation) in vitro. We observed that trisomy 21 (T21) causes increased production of haemogenic endothelial cells, haematopoietic stem cell precursors and increased colony forming potential, with significantly increased immature progenitors. Transchromosomic colonies showed increased expression of Gata-2, c-Kit and Tie-2. A panel of partial T21 ESCs allowed us to assign these effects to HSA21 sub-regions, mapped by 3.5 kbp-resolution tiling arrays. The Gata-2 increase on one side, and c-Kit and Tie-2 increases on the other, could be attributed to two different, non-overlapping HSA21 regions. Using human-specific small interfering RNA silencing, we could demonstrate that an extra copy of RUNX1, but not ETS-2 or ERG, causes an increase in Tie-2/c-Kit levels. Finally, we detected significantly increased levels of RUNX1, C-KIT and PU.1 in human foetal livers with T21. We conclude that overdose of more than one HSA21 gene contributes to the disturbance of early haematopoiesis in DS, and that one of the contributors is RUNX1. As the observed T21-driven hyperproduction of multipotential immature precursors precedes the bifurcation to lymphoid and myeloid lineages, we speculate that this could create conditions of increased chance for acquisition of pre-leukaemogenic rearrangements/mutations in both lymphoid and myeloid lineages during foetal haematopoiesis, contributing to the increased risk of both leukaemia types in DS

The inclination for conscious motor control after stroke: Validating the Movement-Specific Reinvestment Scale for use in inpatient stroke patients

PURPOSE: Stroke survivors are inclined to consciously control their movements, a phenomenon termed "reinvestment". Preliminary evidence suggests reinvestment to impair patients' motor recovery. To investigate this hypothesis, an instrument is needed that can reliably assess reinvestment post-stroke. Therefore, this study aimed to validate the Movement-Specific Reinvestment Scale (MSRS) within inpatient stroke patients. METHOD: One-hundred inpatient stroke patients (<1 year post-stroke) and 100 healthy peers completed the MSRS, which was translated to Dutch for the study purpose. To assess structural validity, confirmatory factor analysis determined whether the scale measures two latent constructs, as previously reported in healthy adults. Construct validity was determined by testing whether patients had higher reinvestment than controls. Reliability analyses entailed assessment of retest reliability (ICC), internal consistency (Cronbach's alpha), and minimal detectable change. RESULTS: Both structural and construct validity of the MSRS were supported. Retest reliability and internal consistency indices were acceptable to good. The minimal detectable change was adequate on group level, but considerable on individual level. CONCLUSIONS: The MSRS is a valid and reliable tool and suitable to assess the relationship between reinvestment and motor recovery in the first months post-stroke. Eventually, this may help therapists to individualize motor learning interventions based on patients' reinvestment preferences. IMPLICATIONS FOR REHABILITATION: This study showed that the Movement-Specific Reinvestment Scale (MSRS) is a valid and reliable tool to objectify stroke patients' inclination for conscious motor control. The MSRS may be used to identify stroke patients who are strongly inclined to consciously control their movements, as this disposition may hinder their motor recovery. Eventually, the MSRS may enable clinicians to tailor motor learning interventions to stroke patients' motor control preferences

Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain

A population of >6 million people worldwide at high risk of Alzheimer’s disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of β-amyloid-(Aβ)-precursor-protein gene. We report AD-like pathology in cerebral organoids grown in vitro from non-invasively sampled strands of hair from 71% of DS donors. The pathology consisted of extracellular diffuse and fibrillar Aβ deposits, hyperphosphorylated/pathologically conformed Tau, and premature neuronal loss. Presence/absence of AD-like pathology was donor-specific (reproducible between individual organoids/iPSC lines/experiments). Pathology could be triggered in pathology-negative T21 organoids by CRISPR/Cas9-mediated elimination of the third copy of chromosome-21-gene BACE2, but prevented by combined chemical β and γ-secretase inhibition. We found that T21-organoids secrete increased proportions of Aβ-preventing (Aβ1-19) and Aβ-degradation products (Aβ1-20 and Aβ1-34). We show these profiles mirror in cerebrospinal fluid of people with DS. We demonstrate that this protective mechanism is mediated by BACE2-trisomy and cross-inhibited by clinically trialled BACE1-inhibitors. Combined, our data prove the physiological role of BACE2 as a dose-sensitive AD-suppressor gene, potentially explaining the dementia delay in ~30% of people with DS. We also show that DS cerebral organoids could be explored as pre-morbid AD-risk population detector and a system for hypothesis-free drug screens as well as identification of natural suppressor genes for neurodegenerative diseases

Stay focused! The effects of internal and external focus of attention on movement automaticity in patients with stroke

© 2015 Kal et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Dual-task performance is often impaired after stroke. This may be resolved by enhancing patients' automaticity of movement. This study sets out to test the constrained action hypothesis, which holds that automaticity of movement is enhanced by triggering an external focus (on movement effects), rather than an internal focus (on movement execution). Thirty-nine individuals with chronic, unilateral stroke performed a one-leg-stepping task with both legs in single- and dual-task conditions. Attentional focus was manipulated with instructions. Motor performance (movement speed), movement automaticity (fluency of movement), and dual-task performance (dual-task costs) were assessed. The effects of focus on movement speed, single- and dual-task movement fluency, and dual-task costs were analysed with generalized estimating equations. Results showed that, overall, singletask performance was unaffected by focus (p =.341). Regarding movement fluency, no main effects of focus were found in single- or dual-task conditions (p's ≥.13). However, focus by leg interactions suggested that an external focus reduced movement fluency of the paretic leg compared to an internal focus (single-task conditions: p =.068; dual-task conditions: p =.084). An external focus also tended to result in inferior dual-task performance (β = -2.38, p =.065). Finally, a near-significant interaction (β = 2.36, p =.055) suggested that dual-task performance was more constrained by patients' attentional capacity in external focus conditions. We conclude that, compared to an internal focus, an external focus did not result in more automated movements in chronic stroke patients. Contrary to expectations, trends were found for enhanced automaticity with an internal focus. These findings might be due to patients' strong preference to use an internal focus in daily life. Future work needs to establish the more permanent effects of learning with different attentional foci on re-automating motor control after stroke

Is implicit motor learning preserved after stroke? A systematic review with meta-analysis

© 2016 Kal et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Many stroke patients experience difficulty with performing dual-tasks. A promising intervention to target this issue is implicit motor learning, as it should enhance patients' automaticity of movement. Yet, although it is often thought that implicit motor learning is preserved poststroke, evidence for this claim has not been systematically analysed yet. Therefore, we systematically reviewed whether implicit motor learning is preserved post-stroke, and whether patients benefit more from implicit than from explicit motor learning. We comprehensively searched conventional (MEDLINE, Cochrane, Embase, PEDro, PsycINFO) and grey literature databases (BIOSIS, Web of Science, OpenGrey, British Library, trial registries) for relevant reports. Two independent reviewers screened reports, extracted data, and performed a risk of bias assessment. Overall, we included 20 out of the 2177 identified reports that allow for a succinct evaluation of implicit motor learning. Of these, only 1 study investigated learning on a relatively complex, whole-body (balance board) task. All 19 other studies concerned variants of the serial-reaction time paradigm, with most of these focusing on learning with the unaffected hand (N = 13) rather than the affected hand or both hands (both: N = 4). Four of the 20 studies compared explicit and implicit motor learning post-stroke. Meta-analyses suggest that patients with stroke can learn implicitly with their unaffected side (mean difference (MD) = 69 ms, 95% CI[45.1, 92.9], p < .00001), but not with their affected side (standardized MD = -.11, 95% CI[-.45, .25], p = .56). Finally, implicit motor learning seemed equally effective as explicit motor learning post-stroke (SMD = -.54, 95% CI[-1.37, .29], p = .20). However, overall, the high risk of bias, small samples, and limited clinical relevance of most studies make it impossible to draw reliable conclusions regarding the effect of implicit motor learning strategies post-stroke. High quality studies with larger samples are warranted to test implicit motor learning in clinically relevant contexts