Ipsilateral hand impairment predicts long-term outcome in patients with subacute stroke.

BACKGROUND: Ipsilateral hand (ILH) impairment is documented following motor stroke, but its impact on long-term outcome remains unknown. We assessed ILH impairment in subacute stroke and tested whether ILH impairment predicted long-term outcome. METHODS: We performed a longitudinal study in 209 consecutive patients with unilateral stroke and sensorimotor deficit at admission. ILH impairment was evaluated using the Purdue Pegboard Test (PPT) and handgrip strength and defined as mild (z-score < -1) or moderate (z-score < -1.65). We used logistic regression (LR) to predict outcome assessed 9 (range, 7-12) months post-stroke with the modified Rankin scale (mRS) categorized into good (mRS ≤ 1) and poor outcome (mRS ≥ 2). For internal validation, LR-bootstrapping and cross-validation with LASSO and Random Forest were performed. RESULTS: ILH impairment assessed at 89.04 ± 45.82 days post-stroke was moderate in 10.53% (95% CI 6.7, 14.83) for PPT and 17.22% (95% CI 11.96, 22.49) for grip, and mild in 21.05% (95% CI 15.78, 26.79) for PPT and 35.89 (95% CI 29.67, 42.58) for grip. Good outcome was predicted by ILH-PPT (B = 1.03 [95% CI 0.39, 3.31]), ILH-grip (B = 1.16 [95% CI 0.54, 3.53]), low NIHSS-discharge (B = -1.57 [95% CI -4.0, -1.19]), and no depression (B = -0.62 [95% CI -1.63, -0.43]), accounting for stroke delay (B = -0.011 [95% CI -0.06, 0.01]). Model efficiency was 91.6% (AUC = 0.977; 95% CI 0.959, 0.996). LASSO and Random Forest methods provided similar results, confirming the LR model robustness. CONCLUSIONS: ILH impairment is frequent after motor stroke and predicts long-term outcome. We propose to integrate ILH impairment into rehabilitation programs to improve recovery and serve research interventions such as neuromodulation.

White matter tract disruption is associated with ipsilateral hand impairment in subacute stroke: a diffusion MRI study.

PURPOSE: The ipsilateral hand (ILH) is impaired after unilateral stroke, but the underlying mechanisms remain unresolved. Based on the degeneracy theory of network connectivity that many connectivity patterns are functionally equivalent, we hypothesized that ILH impairment would result from the summation of microstructural white matter (WM) disruption in the motor network, with a task-related profile. We aimed to determine the WM disruption patterns associated with ILH impairment. METHODS: This was a cross-sectional analysis of patients in the ISIS-HERMES Study with ILH and diffusion-MRI data collected 1 month post-stroke. Patients performed three tasks, the Purdue Pegboard Test (PPT), handgrip strength, and movement time. Fractional anisotropy (FA) derived from diffusion MRI was measured in 33 WM regions. We used linear regression models controlling for age, sex, and education to determine WM regions associated with ILH impairment. RESULTS: PPT was impaired in 42%, grip in 59%, and movement time in 24% of 29 included patients (mean age, 51.9 ± 10.5 years; 21 men). PPT was predicted by ipsilesional corticospinal tract (i-CST) (B = 17.95; p = 0.002) and superior longitudinal Fasciculus (i-SLF) (B = 20.52; p = 0.008); handgrip by i-CST (B = 109.58; p = 0.016) and contralesional anterior corona radiata (B = 42.69; p = 0.039); and movement time by the corpus callosum (B = - 1810.03; p = 0.003) i-SLF (B = - 917.45; p = 0.015), contralesional pons-CST (B = 1744.31; p = 0.016), and i-corticoreticulospinal pathway (B = - 380.54; p = 0.037). CONCLUSION: ILH impairment was associated with WM disruption to a combination of ipsilateral and contralesional tracts with a pattern influenced by task-related processes, supporting the degeneracy theory. We propose to integrate ILH assessment in rehabilitation programs and treatment interventions such as neuromodulation.

Blood-based biomarkers and stem cell therapy in human stroke: a systematic review.

Stroke is one of the main causes of death and disability worldwide. Cell therapy represents a promising therapeutic approach to improve stroke outcome. Measurement of blood-based biomarkers might serve as a proof-of-concept to monitor the mechanisms undergirding these treatments, and such compounds could be used as surrogate biomarkers to monitor the safety and efficacy of cell therapies in the future. Additionally, the measurement of biomarkers that correlate with circulating stem cells in observational studies might be of interest to improve the understanding of how these cells are spontaneously mobilized and carry out their action after stroke. Thus, a systematic review has been herein performed on blood-based biomarkers assessed in stroke patients treated with cell therapy or in observational studies in which circulating stem cells have been measured after stroke.

Positive Predictive Value of French Hospitalization Discharge Codes for Stroke and Transient Ischemic Attack.

BACKGROUND: We aimed at measuring the positive predictive value (PPV) of data in the French Hospital Medical Information Database (FHD). SUMMARY: This retrospective multicenter study included 31 hospitals from where 56 hospital stays were randomly selected among all hospitalizations for the years 2009 and 2010 with at least 1 principal diagnosis of stroke or transient ischemic attack (TIA). Three algorithms were evaluated. Algorithm 1 selected discharge abstracts with at least 1 principal diagnosis identified by one of the relevant International Classification of Diseases, 10th revision codes. Algorithm 2 selected stays with 1 principal diagnosis of the whole stay, but without the dates of the stay. Algorithm 3 took into account the kind of medical wards. The PPV of each algorithm was calculated using medical records as the reference. We found 1,669 discharge abstracts with a diagnosis of stroke among the 1,680 that were randomly selected. The neurologist's review revealed 196 false-positive cases providing a global PPV of 88.26% for algorithm 1, 89.96% for algorithm 2 and 92.74% for algorithm 3. KEY MESSAGES: It was possible to build an algorithm to optimize the FHD for stroke and TIA reporting, with a PPV at 90%. The FHD could be a good tool to measure the burden of stroke in France.

Upper limb recovery after stroke is associated with ipsilesional primary motor cortical activity: a meta-analysis.

BACKGROUND AND PURPOSE: Although neuroimaging studies have revealed specific patterns of reorganization in the sensorimotor control network after stroke, their role in recovery remains unsettled. To review the existing evidence systematically, we performed activation likelihood estimation meta-analysis of functional neuroimaging studies investigating upper limb movement-related brain activity after stroke. METHODS: Twenty-four studies using sensorimotor tasks in standardized coordinates were included, totaling 255 patients and 145 healthy controls. Across the entire brain, we compared task-related activity patterns in good and poor recovery and assessed the magnitude of spatial shifts in sensorimotor activity in cortical motor areas after stroke. RESULTS: When compared with healthy controls, patients showed higher activation likelihood estimation values in contralesional primary motor soon after stroke that abated with time, but were not related to motor outcome. The observed activity changes were consistent with restoration of typical interhemispheric balance. In contrast, activation likelihood estimation values in ipsilesional medial-premotor and primary motor cortex were associated with good outcome, reorganization that may reflect vicarious processes associated with ventral activity shifts from BA4a to 4p. In the anterior cerebellum, a novel finding was the association of poor recovery with increased vermal activity, possibly reflecting behaviorally inadequate compensatory strategies engaging the fastigio-thalamo-cortical and corticoreticulospinal systems. CONCLUSIONS: Activity in ipsilesional primary motor and medial-premotor cortices in chronic stroke signals good motor recovery, whereas cerebellar vermis activity signals poor recovery. Functional MRI may be useful in identifying recovery biomarkers.

Recovery of balance and gait after stroke is deteriorated by confluent white matter hyperintensities: Cohort study.

BACKGROUND: White matter hyperintensities (WMHs) are well known to affect post-stroke disability, mainly by cognitive impairment. Their impact on post-stroke balance and gait disorders is unclear. OBJECTIVES: We aimed to test the hypothesis that WMHs would independently deteriorate post-stroke balance and gait recovery. METHODS: This study was performed in 210 individuals of the cohort Determinants of Balance Recovery After Stroke (DOBRAS), consecutively enrolled after a first-ever hemisphere stroke. Clinical data were systematically collected on day 30±3 (D30) post-stroke and at discharge from the rehabilitation ward. WMHs were searched on MRI, graded with the Fazekas scale, and dichotomized as no/mild (absence/sparse) or moderate/severe (confluent). The primary endpoint was the recovery of the single limb stance, assessed with the Postural Assessment Scale for Stroke (PASS). The secondary endpoint was the recovery of independent gait, assessed with the modified Fugl-Meyer Gait Assessment (mFMA). The adjusted hazard ratios (aHRs) of achievements of these endpoints by level of WMHs were estimated by using Cox models, accounting for other relevant clinical and imaging factors. RESULTS: Individuals with moderate/severe WMHs (n=86, 41%) had greater balance and gait disorders and were more often fallers than others (n=124, 59%). Overall, they had worse and slower recovery of single limb stance and independent gait (P<0.001). Moderate/severe WMHs was the most detrimental factor for recovery of balance (aHR 0.46, 95% confidence interval [CI] 0.32-0.68, P<0.001) and gait (0.51, 0.35-0.74, P<0.001), along with age, stroke severity, lesion volume and disrupted corticospinal tract. With cerebral infarct, endovascular treatments had an independent positive effect, both on the recovery of balance (aHR 1.65, 95% CI 1.13-2.4, P=0.009) and gait (1.78, 1.24-2.55, P=0.002). CONCLUSIONS: WMHs magnify balance and gait disorders after stroke and worsen their recovery. They should be better accounted for in post-stroke rehabilitation, especially to help establish a prognosis of mobility. CLINICALTRIALS. GOV REGISTRATION: NCT03203109.

Solving the Evidence Interpretability Crisis in Health Technology Assessment: A Role for Mechanistic Models?

Health technology assessment (HTA) aims to be a systematic, transparent, unbiased synthesis of clinical efficacy, safety, and value of medical products (MPs) to help policymakers, payers, clinicians, and industry to make informed decisions. The evidence available for HTA has gaps-impeding timely prediction of the individual long-term effect in real clinical practice. Also, appraisal of an MP needs cross-stakeholder communication and engagement. Both aspects may benefit from extended use of modeling and simulation. Modeling is used in HTA for data-synthesis and health-economic projections. In parallel, regulatory consideration of model informed drug development (MIDD) has brought attention to mechanistic modeling techniques that could in fact be relevant for HTA. The ability to extrapolate and generate personalized predictions renders the mechanistic MIDD approaches suitable to support translation between clinical trial data into real-world evidence. In this perspective, we therefore discuss concrete examples of how mechanistic models could address HTA-related questions. We shed light on different stakeholder's contributions and needs in the appraisal phase and suggest how mechanistic modeling strategies and reporting can contribute to this effort. There are still barriers dissecting the HTA space and the clinical development space with regard to modeling: lack of an adapted model validation framework for decision-making process, inconsistent and unclear support by stakeholders, limited generalizable use cases, and absence of appropriate incentives. To address this challenge, we suggest to intensify the collaboration between competent authorities, drug developers and modelers with the aim to implement mechanistic models central in the evidence generation, synthesis, and appraisal of HTA so that the totality of mechanistic and clinical evidence can be leveraged by all relevant stakeholders.

Using numerical modeling and simulation to assess the ethical burden in clinical trials and how it relates to the proportion of responders in a trial sample.

In order to propose a more precise definition and explore how to reduce ethical losses in randomized controlled clinical trials (RCTs), we set out to identify trial participants who do not contribute to demonstrating that the treatment in the experimental arm is superior to that in the control arm. RCTs emerged mid-last century as the gold standard for assessing efficacy, becoming the cornerstone of the value of new therapies, yet their ethical grounds are a matter of debate. We introduce the concept of unnecessary participants in RCTs, the sum of non-informative participants and non-responders. The non-informative participants are considered not informative with respect to the efficacy measured in the trial in contrast to responders who carry all the information required to conclude on the treatment's efficacy. The non-responders present the event whether or not they are treated with the experimental treatment. The unnecessary participants carry the burden of having to participate in a clinical trial without benefiting from it, which might include experiencing side effects. Thus, these unnecessary participants carry the ethical loss that is inherent to the RCT methodology. On the contrary, responders to the experimental treatment bear its entire efficacy in the RCT. Starting from the proportions observed in a real placebo-controlled trial from the literature, we carried out simulations of RCTs progressively increasing the proportion of responders up to 100%. We show that the number of unnecessary participants decreases steadily until the RCT's ethical loss reaches a minimum. In parallel, the trial sample size decreases (presumably its cost as well), although the trial's statistical power increases as shown by the increase of the chi-square comparing the event rates between the two arms. Thus, we expect that increasing the proportion of responders in RCTs would contribute to making them more ethically acceptable, with less false negative outcomes.

Lateropulsion After Hemispheric Stroke: A Form of Spatial Neglect Involving Graviception.

OBJECTIVE: To test the hypothesis that lateropulsion is an entity expressing an impaired body orientation with respect to gravity in relation to a biased graviception and spatial neglect. METHODS: Data from the DOBRAS cohort (ClinicalTrials.gov: NCT03203109) were collected 30 days after a first hemisphere stroke. Lateral body tilt, pushing, and resistance were assessed with the Scale for Contraversive Pushing. RESULTS: Among 220 individuals, 72% were upright and 28% showed lateropulsion (tilters [14%] less severe than pushers [14%]). The 3 signs had very high factor loadings (>0.90) on a same dimension, demonstrating that lateropulsion was effectively an entity comprising body tilt (cardinal sign), pushing, and resistance. The factorial analyses also showed that lateropulsion was inseparable from the visual vertical (VV), a criterion referring to vertical orientation (graviception). Contralesional VV biases were frequent (44%), with a magnitude related to lateropulsion severity: upright -0.6° (-2.9; 2.4), tilters -2.9° (-7; 0.8), and pushers -12.3° (-15.4; -8.5). Ipsilesional VV biases were less frequent and milder (p < 0.001). They did not deal with graviception, 84% being found in upright individuals. Multivariate, factorial, contingency, and prediction analyses congruently showed strong similarities between lateropulsion and spatial neglect, the latter encompassing the former. CONCLUSIONS: Lateropulsion (pusher syndrome) is a trinity constituted by body tilt, pushing, and resistance. It is a way to adjust the body orientation in the roll plane to a wrong reference of verticality. Referring to straight above, lateropulsion might correspond to a form of spatial neglect (referring to straight ahead), which would advocate for 3D maps in the human brain involving the internal model of verticality.

Balance, Lateropulsion, and Gait Disorders in Subacute Stroke.

OBJECTIVE: To test the hypothesis that impaired body orientation with respect to gravity (lateropulsion) would play a key role in poststroke balance and gait disorders. METHODS: Cohort study of 220 individuals consecutively admitted to a neurorehabilitation ward after a first hemisphere stroke (DOBRAS cohort [Determinants of Balance Recovery After Stroke] 2012-2018, ClinicalTrials.gov: NCT03203109), with clinical data systematically collected at 1 month, then at discharge. Primary outcomes were balance and gait disorders, quantified by the Postural Assessment Scale for Stroke and the modified Fugl-Meyer Gait Assessment, to be explained by all deficits on day 30, including lateropulsion assessed with the Scale for Contraversive Pushing. Statistics comprised linear regression analysis, univariate and multivariate analyses, and receiver operating characteristic curves. RESULTS: Lateropulsion was frequent, especially after right hemisphere stroke (RHS, D30, 48%; discharge 24%), almost always in right-handers. Among all deficits, impaired body orientation (lateropulsion) had the most detrimental effect on balance and gait. After RHS, balance disorders were proportional to lateropulsion severity, which alone explained almost all balance disorders at initial assessment (90%; 95% confidence interval [CI] [86-94], p < 0.001) and at discharge (92%; 95% CI 89-95, p < 0.001) and also the greatest part of gait disorders at initial assessment (66%; 95% CI 56-77, p < 0.001) and at discharge (68%; 95% CI 57-78, p < 0.001). CONCLUSION: Lateropulsion is the primary factor altering poststroke balance and gait at the subacute stage and therefore should be systematically assessed. Poststroke balance and gait rehabilitation should incorporate techniques devoted to misorientation with respect to gravity.

Predicting cognitive dysfunctioning in nondemented patients early after stroke.

BACKGROUND: Cognitive dysfunctioning (CDF) is an important issue in stroke, interfering with recovery and social dysfunctioning. We aimed to investigate the clinical and imaging correlates of CDF in patients with a first-ever subacute ischemic stroke and no dementia. METHODS: We evaluated CDF 15 days after stroke in a prospective cohort of consecutive patients with a Mini Mental State Examination score > or =23 using a comprehensive neuropsychological battery. CDF was ranked into 3 categories according to Z scores calculated for each test and adjusted for age and education. CDF was analyzed in relation to stroke features. Imaging was assessed using MRI. An ordinal regression procedure was used to determine the clinical correlates of CDF and to compute probabilities. RESULTS: Cognitive evaluation was achieved in 177 consecutive patients (age 50.0 +/- 16.0 years). In bivariate analysis, CDF was associated with age, low level of education, depression, neurological deficit at day 15, stroke subtype, arterial territory and leukoaraiosis but not with stroke volume or location. The predictors of CDF were NIHSS score at day 15 (OR = 1.35; 95% CI = 1.05-1.73), middle cerebral artery infarct (OR = 2.96; 95% CI = 1.30-6.73), depression interacting with left stroke side (OR = 1.09; 95% CI = 1.03-1.15), and female gender interacting with high level of education (OR = 0.209; 95% CI = 0.085-0.514). CONCLUSIONS: Stroke features correlate with CDF in nondemented patients. These simple criteria may help to predict CDF at bedside in the subacute phase after stroke and to recommend a neuropsychological evaluation for patients' management. Modeling CDF soon after stroke using simple neurological criteria may be a useful tool for designing clinical trials.

In silico study of the influence of intensity and duration of blood flow reduction on cell death through necrosis or apoptosis during acute ischemic stroke.

Ischemic stroke involves numerous and complex pathophysiological mechanisms including blood flow reduction, ionic exchanges, spreading depressions and cell death through necrosis or apoptosis. We used a mathematical model based on these phenomena to study the influences of intensity and duration of ischemia on the final size of the infarcted area. This model relies on a set of ordinary and partial differential equations. After a sensibility study, the model was used to carry out in silico experiments in various ischemic conditions. The simulation results show that the proportion of apoptotic cells increases when the intensity of ischemia decreases, which contributes to the model validation. The simulation results also show that the influence of ischemia duration on the infarct size is more complicated. They suggest that reperfusion is beneficial when performed in the early stroke but may be either inefficacious or even deleterious when performed later after the stroke onset. This aggravation could be explained by the depolarisation waves which might continue to spread ischemic damage and by the speeding up of the apoptotic process leading to cell death. The effect of reperfusion on cell death through these two phenomena needs to be further studied in order to develop new therapeutic strategies for stroke patients.

Autologous Mesenchymal Stem Cells Improve Motor Recovery in Subacute Ischemic Stroke: a Randomized Clinical Trial.

While preclinical stroke studies have shown that mesenchymal stem cells (MSCs) promote recovery, few randomized controlled trials (RCT) have assessed cell therapy in humans. In this RCT, we assessed the safety, feasibility, and efficacy of intravenous autologous bone marrow-derived MSCs in subacute stroke. ISIS-HERMES was a single-center, open-label RCT, with a 2-year follow-up. We enrolled patients aged 18-70 years less than 2 weeks following moderate-severe ischemic carotid stroke. Patients were randomized 2:1 to receive intravenous MSCs or not. Primary outcomes assessed feasibility and safety. Secondary outcomes assessed global and motor recovery. Passive wrist movement functional MRI (fMRI) activity in primary motor cortex (MI) was employed as a motor recovery biomarker. We compared "treated" and "control" groups using as-treated analyses. Of 31 enrolled patients, 16 patients received MSCs. Treatment feasibility was 80%, and there were 10 and 16 adverse events in treated patients, and 12 and 24 in controls at 6-month and 2-year follow-up, respectively. Using mixed modeling analyses, we observed no treatment effects on the Barthel Index, NIHSS, and modified-Rankin scores, but significant improvements in motor-NIHSS (p = 0.004), motor-Fugl-Meyer scores (p = 0.028), and task-related fMRI activity in MI-4a (p = 0.031) and MI-4p (p = 0.002). Intravenous autologous MSC treatment following stroke was safe and feasible. Motor performance and task-related MI activity results suggest that MSCs improve motor recovery through sensorimotor neuroplasticity. ClinicalTrials.gov Identifier NCT00875654.

Hidden dysfunctioning in subacute stroke.

BACKGROUND AND PURPOSE: Determining cognitive dysfunctioning (CDF) after stroke is an important issue because it influences choices for management in terms of return to previous activities. Because previous research in subacute stroke has shown important variations in CDF rates, we aimed to describe the frequency and neuropsychological profile of CDF in subacute stroke outside dementia. We used a large battery of tests to screen any potentially hidden CDF. METHODS: Patients with Mini-Mental State Examination scores >or=23 were prospectively and consecutively included 2 weeks after a first-ever ischemic brain infarct. Stroke features were based on MRI. Four domains were evaluated: instrumental and executive functions, episodic memory, and working memory (WM). Patients were scored using means and compared with education- and age-matched control subjects. Then we attributed Z-scores for each test and each domain. The most relevant cognitive tests characterizing CDF were determined using logistic regression. RESULTS: Among 177 patients (mean age, 50.6 years), 91.5% failed in at least one cognitive domain. WM was the most impaired domain (87.6%) with executive functions (64.4%), episodic memory (64.4%), and instrumental functions (24.9%) being relatively preserved. CDF was associated with age, education, depression, neurological deficit, and leukoaraiosis in bivariate analysis. Using logistic regression, WM tests and age predicted CDF (Modified Paced Auditorial Serial Addition Test: OR=0.96 CI=0.93 to 0.98; Owen-spatial-WM: OR=1.07 CI=1.02 to 1.12; age: OR=0.96 CI=0.93 to 0.98). CONCLUSIONS: CDF appears to be almost constant, although underestimated, in subacute stroke. WM could reflect some hidden dysfunctioning, which may interfere with rehabilitation and return to work. Clinical routine may include WM tests in young patients with mild stroke.

A modelling approach to explore some hypotheses of the failure of neuroprotective trials in ischemic stroke patients.

Ischemic stroke is the third cause of death in industrialised countries, but no satisfactory treatment is currently available. The hundreds of neuroprotective drugs developed to block the ischemic cascade gave very promising results in animal models but the clinical trials performed with these drugs showed no beneficial effects in stroke patients. Many hypotheses were advanced to explain this discrepancy, among which the morphological and functional differences between human and rodent brains. This discrepancy could be partly due to the differences in white matter and glial cell proportions between human and rodent brains. In order to test this hypothesis, we built a mathematical model of the main early pathophysiological mechanisms of stroke in rodent and in human brains. This model is a two-scale model and relies on a set of ordinary differential equations. We built two versions of this model (for human and rodent brains) differing in their white matter and glial cell proportions. Then, we carried out in silico experiments with various neuroprotective drugs. The simulation results obtained with a sodium channel blocker show that the proportion of penumbra recovery is much higher in rodent than in human brain and the results are similar with some other neuroprotective drugs tested during phase III trials. This in silico investigation suggests that the proportions of glial cells and white matter have an influence on neuroprotective drug efficacy. It reinforces the hypothesis that histological and morphological differences between rodent and human brains can partly explain the failure of these agents in clinical trials.

The Virtual International Stroke Trials Archive.

BACKGROUND AND PURPOSE: Stroke has global importance and it causes an increasing amount of human suffering and economic burden, but its management is far from optimal. The unsuccessful outcome of several research programs highlights the need for reliable data on which to plan future clinical trials. The Virtual International Stroke Trials Archive aims to aid the planning of clinical trials by collating and providing access to a rich resource of patient data to perform exploratory analyses. METHODS: Data were contributed by the principal investigators of numerous trials from the past 16 years. These data have been centrally collated and are available for anonymized analysis and hypothesis testing. RESULTS: Currently, the Virtual International Stroke Trials Archive contains 21 trials. There are data on >15,000 patients with both ischemic and hemorrhagic stroke. Ages range between 18 and 103 years, with a mean age of 69+/-12 years. Outcome measures include the Barthel Index, Scandinavian Stroke Scale, National Institutes of Health Stroke Scale, Orgogozo Scale, and modified Rankin Scale. Medical history and onset-to-treatment time are readily available, and computed tomography lesion data are available for selected trials. CONCLUSIONS: This resource has the potential to influence clinical trial design and implementation through data analyses that inform planning.

Role of astrocytes in grey matter during stroke: a modelling approach.

The astrocytic response to stroke is extremely complex and incompletely understood. On the one hand, astrocytes are known to be neuroprotective when extracellular glutamate or potassium is slightly increased. But, on the other hand, they are considered to contribute to the extracellular glutamate increase during severe ischaemia. A mathematical model is used to reproduce the dynamics of the membrane potentials, intracellular and extracellular concentrations and volumes of neurons and astrocytes during ischaemia in order to study the role of astrocytes in grey matter during the first hour of a stroke. Under conditions of mild ischaemia, astrocytes are observed to take up glutamate via the glutamate transporter, and potassium via the Na/K/Cl cotransporter, which limits glutamate and potassium increase in the extracellular space. On the contrary, under conditions of severe ischaemia, astrocytes appear to be unable to maintain potassium homeostasis. Moreover, they are shown to contribute to the excitotoxicity process by expelling glutamate out of the cells via the reversed glutamate transporter. A detailed understanding of astrocytic function and influence on neuron survival during stroke is necessary to improve the neuroprotective strategies for stroke patients.

Improvement of the comprehension of written information given to healthy volunteers in biomedical research: a single-blind randomized controlled study.

Writing an informed consent form (ICF) for biomedical research is a difficult task. We conducted a multicenter single-blind randomized controlled trial to identify whether a working group or the systematic improvement in lexico-syntactic readability or an association of the two could increase the comprehension of the written information given to healthy volunteers enrolled in biomedical research. Participants were randomized to read one of four versions of the ICF: unchanged ICF (A), ICF with systematic lexico-syntactic readability improvement (B), ICF modified by a working group (C), and ICF modified by the working group followed by systematic lexico-syntactic improvement (D). The primary end-point was the objective comprehension score at day 0 for each study group. The scores of objective comprehension at day 0 were statistically different between the four study groups (anovaP = 0.020). The pairwise analysis showed an improvement in the working group vs. the unchanged group (P = 0.003), and a tendency to improvement in the group who read the ICF modified using lexico-syntactic readability and in the group who read the ICF modified using the two methods (P = 0.020 and 0.027 respectively). We conducted a two-way anova to identify some characteristics of the population which could explain this score. There was a significant interaction between the type of informed consent document (ICD) and the gender. Improving the ICD in phase I biomedical research leads to better comprehension, whether the method used is systematic lexico-syntactic improvement or a review by a working group. The improvement is specifically observed in men compared with women. Conversely, while both methods diverge in their effect on lexico-syntactic readability, their association is not mandatory. We suggest that in all phase I clinical trials, the ICF be improved by either method.

Controlled clinical trials of cell therapy in stroke: Meta-analysis at six months after treatment.

Background Cell therapy is promising in experimental studies and has been assessed only in a few studies on humans. Aims To evaluate the effect of cell therapy in humans. Methods We included clinical trials with a control group that reported safety and efficacy six months following treatment. Quality was evaluated and clinical scales data were extracted. Quantitative analysis was based on the standardized means difference (SMD). Among 28 trials published from 1995 to 2016, nine studies (194 patients; 191 controls) were eligible. Publication biases were assessed with the funnel plot and pre-specified explanatory variables were tested with a group analysis and a meta-regression. Results The overall quality was moderate. Cell therapy had a positive effect on the outcome (SMD: 0.57, 95% CI: 0.22-0.92; p = 0.002). The sensitivity analysis showed an upper level of effect size of 0.81 (95% CI: 0.34-1.27; p = 0.001) and a lower level of 0.455 (95% CI: 0.04-0.87; p = 0.03). None of the pre-specified explanatory variable was significantly correlated to outcome: age, ratio infarction/hemorrhage, delay from stroke to treatment, route of administration, cell type, randomization, and blinded outcome assessment. The significant heterogeneity (p = 0.03) was not explained by publication biases (p = 0.09) and was more likely due to methodological and quality differences between the trials. Conclusions This result suggests that cell therapy is beneficial in stroke and is expected to help in the designing of stem cells controlled clinical trials (CCT) in large populations.

Parietal operculum and motor cortex activities predict motor recovery in moderate to severe stroke.

While motor recovery following mild stroke has been extensively studied with neuroimaging, mechanisms of recovery after moderate to severe strokes of the types that are often the focus for novel restorative therapies remain obscure. We used fMRI to: 1) characterize reorganization occurring after moderate to severe subacute stroke, 2) identify brain regions associated with motor recovery and 3) to test whether brain activity associated with passive movement measured in the subacute period could predict motor outcome six months later. Because many patients with large strokes involving sensorimotor regions cannot engage in voluntary movement, we used passive flexion-extension of the paretic wrist to compare 21 patients with subacute ischemic stroke to 24 healthy controls one month after stroke. Clinical motor outcome was assessed with Fugl-Meyer motor scores (motor-FMS) six months later. Multiple regression, with predictors including baseline (one-month) motor-FMS and sensorimotor network regional activity (ROI) measures, was used to determine optimal variable selection for motor outcome prediction. Sensorimotor network ROIs were derived from a meta-analysis of arm voluntary movement tasks. Bootstrapping with 1000 replications was used for internal model validation. During passive movement, both control and patient groups exhibited activity increases in multiple bilateral sensorimotor network regions, including the primary motor (MI), premotor and supplementary motor areas (SMA), cerebellar cortex, putamen, thalamus, insula, Brodmann area (BA) 44 and parietal operculum (OP1-OP4). Compared to controls, patients showed: 1) lower task-related activity in ipsilesional MI, SMA and contralesional cerebellum (lobules V-VI) and 2) higher activity in contralesional MI, superior temporal gyrus and OP1-OP4. Using multiple regression, we found that the combination of baseline motor-FMS, activity in ipsilesional MI (BA4a), putamen and ipsilesional OP1 predicted motor outcome measured 6 months later (adjusted-R2 = 0.85; bootstrap p < 0.001). Baseline motor-FMS alone predicted only 54% of the variance. When baseline motor-FMS was removed, the combination of increased activity in ipsilesional MI-BA4a, ipsilesional thalamus, contralesional mid-cingulum, contralesional OP4 and decreased activity in ipsilesional OP1, predicted better motor outcome (djusted-R2 = 0.96; bootstrap p < 0.001). In subacute stroke, fMRI brain activity related to passive movement measured in a sensorimotor network defined by activity during voluntary movement predicted motor recovery better than baseline motor-FMS alone. Furthermore, fMRI sensorimotor network activity measures considered alone allowed excellent clinical recovery prediction and may provide reliable biomarkers for assessing new therapies in clinical trial contexts. Our findings suggest that neural reorganization related to motor recovery from moderate to severe stroke results from balanced changes in ipsilesional MI (BA4a) and a set of phylogenetically more archaic sensorimotor regions in the ventral sensorimotor trend, in which OP1 and OP4 processes may complement the ipsilesional dorsal motor cortex in achieving compensatory sensorimotor recovery.