IL-6 Plasma Levels Correlate With Cerebral Perfusion Deficits and Infarct Sizes in Stroke Patients Without Associated Infections

Introduction: We aimed to investigate several blood-based biomarkers related to inflammation, immunity, and stress response in a cohort of patients without stroke-associated infections regarding their predictive abilities for functional outcome and explore whether they correlate with MRI markers, such as infarct size or location. Methods: We combined the clinical and radiological data of patients participating in two observational acute stroke cohorts: the PREDICT and 1000Plus studies. The following blood-based biomarkers were measured in these patients: monocytic HLA-DR, IL-6, IL-8, IL-10, LBP, MRproANP, MRproADM, CTproET, Copeptin, and PCT. Multiparametric stroke MRI was performed including T2*, DWI, FLAIR, TOF-MRA, and perfusion imaging. Standard descriptive sum statistics were used to describe the sample. Associations were analyzed using Fischer's exact test, independent samples t-test and Spearmans correlation, where appropriate. Results: Demographics and stroke characteristics were as follows: 94 patients without infections, mean age 68 years (SD 10.5), 32.2% of subjects were female, median NIHSS score at admission 3 (IQR 2-5), median mRS 3 months after stroke 1 (IQR 0-2), mean volume of DWI lesion at admission 5.7 ml (SD 12.8), mean FLAIR final infarct volume 10 ml (SD 14.9), cortical affection in 61% of infarctions. Acute DWI lesion volume on admission MRI was moderately correlated to admission/maximum IL-6 as well as maximum LBP. Extent of perfusion deficit and mismatch were moderately correlated to admission/maximum IL-6 levels. Final lesion volume on FLAIR was moderately correlated to admission IL-6 levels. Conclusion: We found IL-6 to be associated with several parameters from acute stroke MRI (acute DWI lesion, perfusion deficit, final infarct size, and affection of cortex) in a cohort of patients not influenced by infections

Electrical Brain Stimulation Improves Cognitive Performance by Modulating Functional Connectivity and Task-Specific Activation

Excitatory anodal transcranial direct current stimulation (atDCS) can improve human cognitive functions, but neural underpinnings of its mode of action remain elusive. In a cross-over placebo ("sham") controlled study we used functional magnetic resonance imaging (fMRI) to investigate neurofunctional correlates of improved language functions induced by atDCS over a core language area, the left inferior frontal gyrus (IFG). Intrascanner transcranial direct current stimulation-induced changes in overt semantic word generation assessed behavioral modulation; task-related and task-independent (resting-state) fMRI characterized language network changes. Improved word-retrieval during atDCS was paralleled by selectively reduced task-related activation in the left ventral IFG, an area specifically implicated in semantic retrieval processes. Under atDCS, resting-state fMRI revealed increased connectivity of the left IFG and additional major hubs overlapping with the language network. In conclusion, atDCS modulates endogenous low-frequency oscillations in a distributed set of functionally connected brain areas, possibly inducing more efficient processing in critical task-relevant areas and improved behavioral performance

Procalcitonin-Guided Antibiotic Therapy after Stroke

Background: Pneumonia is among the most common acute complications after stroke and is associated with poor long-term outcome. Biomarkers may help identifying stroke patients at high risk for developing stroke-associated pneumonia (SAP) and to guide early treatment. Aims: This trial investigated whether procalcitonin (PCT) ultrasensitive (PCTus)-guided antibiotic treatment of SAP can improve functional outcome after stroke. Methods: In this international, multicenter, randomized, controlled clinical trial with blinded assessment of outcomes, patients with severe ischemic stroke in the middle cerebral artery territory were randomly assigned within 40 h after symptom onset to PCTus-based antibiotic therapy guidance in addition to stroke unit care or standard stroke unit care alone. The primary endpoint was functional outcome at 3 months, defined according to the modified Rankin Scale (mRS) and dichotomized as acceptable (≤4) or unacceptable (≥5). Secondary endpoints included usage of antibiotics, infection rates, days of fever, and mortality. The trial was registered with http://ClinicalTrials.gov (Identifier NCT01264549). Results: In the intention-to-treat-analysis based on 227 patients (112 in PCT and 115 in control group), 197 patients completed the 3-month follow-up. Adherence to PCT guidance was 65%. PCT-guided therapy did not improve functional outcome as measured by mRS (odds ratio 0.79; 95% confidence interval 0.45–1.35, p = 0.47). Pneumonia rate and mortality were similar in both groups. Days with fever tended to be lower (p = 0.055), whereas total number of days treated with antibiotics were higher (p = 0.004) in PCT compared to control group. A post hoc analysis including all PCT values in the intention-to-treat population demonstrated a significant increase on the first day of infection in patients with pneumonia and sepsis compared to patients with urinary tract infections or without infections (p < 0.0001). Conclusion: PCTus-guided antibiotic therapy did not improve functional outcome at 3 months after severe ischemic stroke. PCT is a promising biomarker for early detection of pneumonia and sepsis in acute stroke patients

Selection bias in clinical stroke trials depending on ability to consent

BACKGROUND Clinical trials are the hallmark of evidence-based medicine, but recruitment is often challenging, especially in stroke trials investigating patients not being able to give informed consent. In some nations, ethics committees will not approve of inclusion in a clinical study via consent of a legal representative. The ethical dilemma of including or excluding those patients has not been properly addressed, as there is little data on the effect of stroke characteristics on the ability to give informed consent. METHODS To examine differences between patients able and unable to consent at inclusion to an acute stroke trial, we conducted a post-hoc analysis of monitoring records from a multicentric interventional trial. These records listed patients who gave informed consent by themselves and those who needed a legal representative to do so. This exemplary STRAWINSKI trial aimed at improving stroke outcome by biomarker-guided antibiotic treatment of stroke associated pneumonia and included patients within 40 h after stroke onset, suffering from MCA infarctions with an NIHSS score > 9 at admission. Standard descriptive and associative statistics were calculated to compare baseline characteristics and outcome measures between patients who were able to consent and those who were not. RESULTS We identified the person giving consent in 228 out of 229 subjects. Patients with inability to consent were older (p < 0.01), suffered from more left-hemispheric (p < 0.01) and more severe strokes (NIHSS, p < 0.01), were more likely to die during hospitalisation (p < 0.01) or have unfavourable outcome at discharge (mRS, p < 0.01), to develop fever (p < 0.01) and tended to be more susceptible to infections (p = 0.06) during the acute course of the disorder. CONCLUSIONS Demographics, stroke characteristics and outcomes significantly affect stroke patients in their ability to consent. Where selection criteria and primary outcome measures of a trial are significantly affected by ability to consent, excluding patients unable to consent might be unethical. TRIAL REGISTRATION URL http://www.clinicaltrials.gov . Unique identifier: NCT01264549

IL-6 Plasma Levels Correlate With Cerebral Perfusion Deficits and Infarct Sizes in Stroke Patients Without Associated Infections

Introduction: We aimed to investigate several blood-based biomarkers related to inflammation, immunity, and stress response in a cohort of patients without stroke-associated infections regarding their predictive abilities for functional outcome and explore whether they correlate with MRI markers, such as infarct size or location.Methods: We combined the clinical and radiological data of patients participating in two observational acute stroke cohorts: the PREDICT and 1000Plus studies. The following blood-based biomarkers were measured in these patients: monocytic HLA-DR, IL-6, IL-8, IL-10, LBP, MRproANP, MRproADM, CTproET, Copeptin, and PCT. Multiparametric stroke MRI was performed including T2*, DWI, FLAIR, TOF-MRA, and perfusion imaging. Standard descriptive sum statistics were used to describe the sample. Associations were analyzed using Fischer's exact test, independent samples t-test and Spearmans correlation, where appropriate.Results: Demographics and stroke characteristics were as follows: 94 patients without infections, mean age 68 years (SD 10.5), 32.2% of subjects were female, median NIHSS score at admission 3 (IQR 2–5), median mRS 3 months after stroke 1 (IQR 0–2), mean volume of DWI lesion at admission 5.7 ml (SD 12.8), mean FLAIR final infarct volume 10 ml (SD 14.9), cortical affection in 61% of infarctions. Acute DWI lesion volume on admission MRI was moderately correlated to admission/maximum IL-6 as well as maximum LBP. Extent of perfusion deficit and mismatch were moderately correlated to admission/maximum IL-6 levels. Final lesion volume on FLAIR was moderately correlated to admission IL-6 levels.Conclusion: We found IL-6 to be associated with several parameters from acute stroke MRI (acute DWI lesion, perfusion deficit, final infarct size, and affection of cortex) in a cohort of patients not influenced by infections.Clinical Trial Registration:www.ClinicalTrials.gov, identifiers NCT01079728 and NCT0071553

The Role of Connexin Expression, Regulation and Function

Die Ausbildung eines hierarchischen Gefäßnetzwerks ist Folge eines komplexen Wechselspiels zwischen genetischen Faktoren und epigenetischen Faktoren wie Oxygenierung und Hämodynamik. Die Differenzierung von Gefäßen in Arterien und Venen wurde anfänglich ausschließlich für ein Resultat hämodynamischer Kräfte gehalten. Diese Theorie wurde in Frage gestellt, da endotheliale Vorläuferzellen schon vor ihrer Zusammenlagerung zu primären Gefäßnetzwerken und dem Beginn der Blutströmung arteriell und venös spezifische Gene exprimieren. Die Identifikation dieser Gene und die Aufklärung ihrer gefäßspezifischen Funktion sind für ein tieferes Verständnis der Gefäßentwicklung von essentieller Bedeutung. Die vorliegende Arbeit untersuchte die Fragen, ob 1) das Expressionsmuster der vaskulär exprimierten Connexine 37, 40 und 43 in der Embryonalentwicklung spezifisch für Gefäße des arteriellen oder venösen Gefäßbaums ist, 2) die Expression von Cx40 durch epigenetische Faktoren (Sauerstoff, Blutströmung) reguliert wird, 3) hämodynamische Parameter existieren, die für embryonale Arterien und Venen in vivo charakteristisch sind und so zu einer selektiven Expression von Genen führen könnten und 4) Connexine in embryonalen Gefäßnetzwerken eine spezifische Funktion ausüben. Fazit: Cx40 ist ein guter Marker für Arterien. Es ist anzunehmen, dass die Expression von Cx40 in Blutgefäßen nicht durch Sauerstoff, wohl aber durch hämodynamische Parameter reguliert wird. Die charakteristischen Unterschiede zwischen Arterien und Venen der Dottersackzirkulation sind 1) die Pulsatilität der Blutströmung (ausgedrückt durch relative Amplitude und relative Maximalbeschleunigung) und 2) die Geschwindigkeit (und die daraus resultierende Scherrate). Die höchste Trennschärfe dieser Parameter hat die relative Maximalbeschleunigung. Kombination der relativen Maximalbeschleunigung und der mittleren Pseudo- Scherrate in Form eines Quotienten, des Pulse Slope Index (PSI), optimiert die Separation von arteriellen und venösen hämodynamischen Eigenschaften. Die beobachteten Unterschiede könnten der arteriell-spezifischen Expression von Cx40 zugrunde liegen. Da Effekte einer Connexin-Hemmung zuerst in Arterien stattfinden, scheinen Connexine eine spezifische Rolle in diesen Gefäßen auszuüben. Auch eine gestörte retinale Gefäßnetzwerkstruktur Cx40-defizienter Mäuse weist auf eine zentrale Bedeutung von Cx40 für die Entwicklung von Gefäßnetzwerken hin.The formation of hierarchical vascular networks results from the complex interplay between genetic factors and epigenetic factors such as oxygen and hemodynamics. The differentiation of blood vessels into arteries and veins was initially thought to be exclusively mediated by hemodynamic forces. This theory has been questioned, because endothelial progenitor cells express arterial and venous specific (marker-) genes even before their assembly in primary networks and the start of blood flow. The identification of marker- genes and the evaluation of their specific function in the vasculature are of essential importance for a deeper understanding of vascular development. The present study examined whether 1) the expression-patterns of the connexins known to be expressed in the vasculature: Cx37, Cx40 and Cx43 are specific for arteries or veins during embryonic development, 2) the expression of Cx40 is regulated by epigenetic factors such as oxygen and blood flow, 3) hemodynamic parameters that are characteristic for embryonic arteries and veins exist in vivo 4) the function of connexins is essential for the embryonic vasculature. Conclusions: Cx40 is a good marker for developing arteries and its expression is likely not to be regulated by oxygen, but by hemodynamics. Characteristic differences of blood flow in developing arteries and veins of the yolk sac are 1) the pulsatility (determined by relative amplitude and relative maximum acceleration) and 2) the velocity (accompanied by the resulting shear rate). The relative maximum acceleration is the most selective of these parameters. Combination of the maximum acceleration and the mean relative pseudo-shear rate in the form of a quotient, the Pulse Slope Index (PSI), optimizes the separation of arterial and venous hemodynamic properties. The observed differences may explain the artery-specific expression pattern of Cx40. Since the effects of inhibiting connexins were first observed in arteries, connexins appear to exert an essential role specifically in these vessels. Moreover, the aberrance of the retinal vasculature in postnatal Cx40-deficient mice indicates a key role of Cx40 in the development of vascular networks

Neural mechanisms underlying perilesional transcranial direct current stimulation in aphasia: a feasibility study

Little is known about the neural mechanisms by which transcranial direct current stimulation (tDCS) impacts on language processing in post-stroke aphasia. This was addressed in a proof-of-principle study that explored the effects of tDCS application in aphasia during simultaneous functional magnetic resonance imaging (fMRI). We employed a single subject, cross-over, sham-tDCS controlled design, and the stimulation was administered to an individualized perilesional stimulation site that was identified by a baseline fMRI scan and a picture naming task. Peak activity during the baseline scan was located in the spared left inferior frontal gyrus and this area was stimulated during a subsequent cross-over phase. tDCS was successfully administered to the target region and anodal- vs. sham-tDCS resulted in selectively increased activity at the stimulation site. Our results thus demonstrate that it is feasible to precisely target an individualized stimulation site in aphasia patients during simultaneous fMRI, which allows assessing the neural mechanisms underlying tDCS application. The functional imaging results of this case report highlight one possible mechanism that may have contributed to beneficial behavioral stimulation effects in previous clinical tDCS trials in aphasia. In the future, this approach will allow identifying distinct patterns of stimulation effects on neural processing in larger cohorts of patients. This may ultimately yield information about the variability of tDCS effects on brain functions in aphasia

A new era of systems neuroscience in aphasia?

Background: Systems neuroscience acknowledges that human brain function relies on complex interactions between specialised brain regions that are organised in widely distributed functional brain networks. This approach provides a powerful framework to investigate how local structural damage such as a stroke impacts language network reorganisation in aphasia patients and its relation to recovery. Aims: In this paper we aim to familiarise the readers with the concept of systems neuroscience and its application in aphasia imaging. Main Contribution: We briefly describe common analytic methods used in systems neuroscience with a focus on magnetic resonance imaging (MRI) based connectivity analyses. We describe task-based and resting-state functional MRI and diffusion weighted imaging based approaches that allow assessing functional and structural network characteristics in the human brain. Subsequently, we discuss recent studies that have used different network-level approaches to investigate recovery and treatment-induced neural reorganisation in aphasia. Conclusions: This illustrative review highlights the potential of the novel systems neuroscience approach to improve our understanding of the neural mechanisms underlying recovery and treatment response in aphasia. We also discuss a number of key issues that need to be addressed in this emerging field before it can effectively contribute to clinical decision-making

Changes in chronotype after stroke: a pilot study

This study aimed to elucidate associations between stroke onset and severity as well as chronotype (phase of entrainment) and internal time of stroke. Fifty-six first-ever ischemic stroke patients participated in a cross-sectional study assessing chronotype (mid-sleep on work-free days corrected for sleep deficit on workdays; MSFsc) by applying the Munich ChronoType Questionnaire (MCTQ). The MCTQ was completed twice, on average 68 24 (SD) days post stroke and retrospectively for the time before stroke. To assess the impact of stroke in relation to internal time, InTstroke was calculated as MSFsc minus local time of stroke. Stroke severity was assessed via the standard clinical National Institute Health Stroke Scale (NIHSS) and modified Ranking Scale (mRS), both at hospital admission and discharge. Overall, most strokes occurred between noon and midnight. There was no significant association between MSFsc and stroke onset. MSFsc changed significantly after stroke, especially in patients with more severe strokes. Changes in MSFsc varied with InTstroke - the earlier the internal time of a stroke relative to MSFsc-before-stroke, the more MSFsc advanced after stroke. In addition, we provide first evidence that MSFsc changes varied between stroke locations. Larger trials are needed to confirm these findings

Histomorphometric analysis of the palatal soft tissue as donor region for retrieval of connective tissue grafts

Objectives The soft tissue of the palate is the most frequently used donor side for connective tissue grafts. Various techniques have been described to harvest the connective tissue in anterior and posterior regions of the palate (Hürzeler 1999, Jung 2008, Zucchelli 2010). The present study assessed the histological composition of the soft tissue of the palate in the premolar and tuberosity region and compared the histological composition of connective tissue grafts harvested by two different techniques. Methods Tissue samples of the palatal soft tissue of 10 fresh human dentate cadaver heads were harvested in the premolar and tuberosity region. After histological processing, a histomorphometric analysis on the ratio between epithelium, connective tissue, fatty/glandular tissue, and vascular tissue was performed. Height and composition of the total palatal tissue and of digitally marked grafts (two different harvesting techniques: split-flap- and de-epithelialization-technique) were assessed in both regions (premolar and tuberosity) in an area close and more distant from the teeth (Figure 1). Results The height measurements of the palatal soft tissue ranged from 2.4 to 6.9mm. The main parameters (ratio of connective tissue and fatty/glandular tissue) presented no significant difference between the various regions (close and distant areas in the premolar and tuberosity region; p>0.145; Table 1). But significant differences were detected for the histological compositions of the connective tissue grafts (Table 2); the tissue gained by de-epithelialization in the tuberosity region contained a significantly higher amount of connective tissue, than the tissue gained by split-flap-technique in the premolar region (73.3 vs. 56.5%; p=0.041; Figure 2). Altogether, both, height measurements and composition of the palatal tissue, presented a high inter-individual variability (e.g., percentage of fatty/glandular tissue ranged from 0.04 to 73.8%; Figure 3). Comparison between genders revealed significantly higher values of connective tissue in the premolar region of males (p=0.045); all other parameters presented no relevant gender differences (p>0.077). Conclusions Thus far, the connective tissue harvested in the tuberosity region, which is most often done by de-epithelialization to prevent injury to the greater palatine artery (Figure 1), was clinically described to be denser and more firm compared to the tissue gained in the premolar region (most often by split-flap-technique) (Zuhr 2014). The present study is, to the best of our knowledge, the first to prove this clinical assumption with a histomorphometric analysis. Topic of future clinical trials will be to assess, whether the outcome of root coverage procedures is influenced by the histological composition of the graft (more or less fatty)