Cross-Correlation of Motor Activity Signals from dc-Magnetoencephalography, Near-Infrared Spectroscopy, and Electromyography

Neuronal and vascular responses due to finger movements were synchronously measured using dc-magnetoencephalography (dcMEG) and time-resolved near-infrared spectroscopy (trNIRS). The finger movements were monitored with electromyography (EMG). Cortical responses related to the finger movement sequence were extracted by independent component analysis from both the dcMEG and the trNIRS data. The temporal relations between EMG rate, dcMEG, and trNIRS responses were assessed pairwise using the cross-correlation function (CCF), which does not require epoch averaging. A positive lag on a scale of seconds was found for the maximum of the CCF between dcMEG and trNIRS. A zero lag is observed for the CCF between dcMEG and EMG. Additionally this CCF exhibits oscillations at the frequency of individual finger movements. These findings show that the dcMEG with a bandwidth up to 8 Hz records both slow and faster neuronal responses, whereas the vascular response is confirmed to change on a scale of seconds

Red Blood Cell Contamination of the Final Cell Product Impairs the Efficacy of Autologous Bone Marrow Mononuclear Cell Therapy

ObjectivesThe aim of this study was to identify an association between the quality and functional activity of bone marrow-derived progenitor cells (BMCs) used for cardiovascular regenerative therapies and contractile recovery in patients with acute myocardial infarction included in the placebo-controlled REPAIR-AMI (Reinfusion of Enriched Progenitor cells And Infarct Remodeling in Acute Myocardial Infarction) trial.BackgroundIsolation procedures of autologous BMCs might affect cell functionality and therapeutic efficacy.MethodsQuality of cell isolation was assessed by measuring the total number of isolated BMCs, CD34+ and CD133+ cells, their colony-forming unit (CFU) and invasion capacity, cell viability, and contamination of the final BMC preparation with thrombocytes and red blood cells (RBCs).ResultsThe number of RBCs contaminating the final cell product significantly correlated with reduced recovery of left ventricular ejection fraction 4 months after BMC therapy (p = 0.007). Higher numbers of RBCs in the BMC preparation were associated with reduced BMC viability (r = −0.23, p = 0.001), CFU capacity (r = −0.16, p = 0.03), and invasion capacity (r = −0.27, p < 0.001). To assess a causal role for RBC contamination, we coincubated isolated BMCs with RBCs for 24 h in vitro. The addition of RBCs dose-dependently abrogated migratory capacity (p = 0.003) and reduced CFU capacity (p < 0.05) of isolated BMCs. Neovascularization capacity was significantly impaired after infusion of BMCs contaminated with RBCs, compared with BMCs alone (p < 0.05). Mechanistically, the addition of RBCs was associated with a profound reduction in mitochondrial membrane potential of BMCs.ConclusionsContaminating RBCs affects the functionality of isolated BMCs and determines the extent of left ventricular ejection fraction recovery after intracoronary BMC infusion in patients with acute myocardial infarction. These results suggest a bioactivity response relationship very much like a dose–response relationship in drug trials. (Reinfusion of Enriched Progenitor cells and Infarct Remodeling in Acute Myocardial Infarction [REPAIR-AMI]; NCT00279175

Clinical Characterization of Symptomatic Microangiopathic Brain Lesions

Background: Microangiopathic brain lesions can be separated in diffuse lesions – leukoaraiosis – and focal lesions – lacunes. Leukoaraiosis and lacunes are caused by common cerebrovascular risk factors, but whether they represent a common entity is not sufficiently investigated. The present study aimed to determine the clinical profiles associated with the extent of leukoaraiosis and lacunes. Methods: Sixty-four consecutive patients with acute microangiopathic stroke were studied. Leukoaraiosis and lacunes were stratified according to their MRI-based extent. Standardized clinical assessment included clinical syndromes, cerebrovascular risk factors, cognitive performance, retinal imaging, ultrasonography, blood, and urine parameters. Results: Different clinical profiles for leukoaraiosis and lacunes were found. Regarding leukoaraiosis, the cognitive scores (SISCO, mini mental score examination, mental examination) and the presence of hyperlipidemia decreased as the severity of leukoaraiosis increased. Univariate and multivariate analysis revealed that these cognitive score values as well as the presence of hyperlipidemia correlated significantly with no or only mild leukoaraiosis. Regarding lacunes, the percentage of migraine, previous stroke events, hydrocephalus, left ventricular hypertrophy, and a higher National Institutes of Health Stroke Scale increased as the number of lacunar lesions increased. Statistical analysis revealed that these parameters correlated not significantly with the number of lacunes. Conclusions: The findings suggests that leukoaraiosis and lacunes are different microangiopathic entities potentially requiering different treatment concepts

magnetoencephalography and near-infrared spectroscopy

Die Möglichkeit einer nicht-invasiven Erfassung von DC-Signalen ist in der klinischen Neurologie von großem Interesse. Neben der physiologischen Charakterisierung von funktions-gebundener DC-Aktivität und von funktionellen kortikalen Netzwerken ist auch die Erfassung pathologischer DC-Aktivität bedeutsam. Bisher sind nicht-invasive Verfahren zum Erfassen und Monitoren von DC-Signalen klinisch nicht etabliert. In Kooperation mit der Physikalisch- Technischen Bundesanstalt wurde eine innovative, weltweit einzigartige Messtechnologie verwendet. Ziel der Arbeit war es, die Signalqualität der nicht-invasiven DC-Magnetenzephalographie über dem primär motorischen Kortex während motorischer Stimulation bei gesunden Probanden und nachfolgend bei Patienten mit Hirninfarkt zu validieren. Darauf aufbauend wurde die erweiterte kombinierte Messtechnologie mit zusätzlicher zeitaufgelöster Nahinfrarot- Spektroskopie verwendet, um das neuro-vaskuläre Antwortverhalten nicht-invasiv zu untersuchen. Im Ergebnis konnten mittels DC-Magnetenzephalographie stabile und reproduzierbare DC-Signale sowohl quantitativ als auch qualitativ nicht- invasiv erfasst und hinsichtlich Amplitudenstärke, Dynamik und räumlichem Feldmuster charakterisiert werden. Die DC-Signale konnten über Zeiträume von 30 bzw. 60 Minuten direkt und ohne Mittelung von Reiz- oder Aktivierungsantworten aufgezeichnet werden. Bei Verwendung differenter Stimulusmodalitäten konnten die analysierten DC-Signale mit Stimulus-bezogenen differenten Signalcharakteristika dargestellt werden und damit die neuronale Genese der gemessenen Signale unterstreichen. Die kombinierte nicht-invasive Messtechnologie von DC-Magnetenzephalographie und zeitaufgelöster Nahinfrarot- Spektroskopie erlaubte ebenfalls eine reproduzierbare quantitative und qualitative Analyse stimulus-bezogener neuronaler und vaskulärer Signale von 30 Minuten Aufzeichnungsdauer. Der Einsatz der zeitlich hochaufgelösten Breitband-Magnetenzephalographie mit zeitaufgelöster Nahinfrarot-Spektroskopie zeigte darüber hinaus weitgehende Linearitäten des neuro-vaskulären Signalverhaltens sowie Hinweise für Nicht-Linearitäten. So führten beispielhaft komplexe Fingerbewegungen im Vergleich zu einfachen Fingerbewegungen bei älteren Probanden nur zu einer signifikanten vaskulären Amplitudenzunahme, nicht aber zu einer neuronalen Amplitudenzunahme. In allen kombinierten MEG-NIRS-Arbeiten zeigte sich eine im Sekundenbereich verzögerte vaskuläre Signalantwort im Vergleich zur neuronalen Signalantwort. Dieses war besonders ausgeprägt am Ende einer motorischen Stimulationsperiode. Der Aktivierungsanstieg verlief weitgehend parallel zwischen neuronaler und vaskulärer Antwort. In den anwendungsorientierten Untersuchungen der Messtechnik am Patienten mit subakutem Hirninfarkt zeigte sich, dass auch klinisch schwer betroffene und eingeschränkt lagerungsfähige Patienten mit hinreichender Signalqualität über mindestens 15 Minuten untersuchbar waren. Das Signal-Rausch-Verhalten erlaubte bei etwa 60 Prozent der Patienten eine quantitative und qualitative Signalauswertung ohne Notwendigkeit einer Mittelung. Dabei zeigte sich ein Amplitudenverlust des neuronalen DC-Signales über den betroffenen Hemisphären sowohl bei kortikalen Infarkten, aber auch -schwächer ausgeprägt- bei rein subkortikalen Läsionen als Zeichen des betroffenen Funktionssystemes einschließlich seiner kortiko-subkortikalen Bahnen. Zusammenfassend konnte die Methode der DC-Magnetenzephalographie, aber auch der kombinierten DC-Magnetenzephalographie und Nahinfrarot-Spektroskopie als zuverlässig für die Erfassung von neuronalen Signalen bzw. vaskulären Signalen gezeigt werden. Im Ausblick soll die etablierte Messtechnologie beim gesunden Probanden zur weiteren Charakterisierung linearer bzw. nicht-linearer Komponenten der neuro-vaskulären Kopplung verwendet werden, was insbesondere für die valide Auswertung funktioneller Bildgebungsstudien bedeutsam ist. Potentiell ist die Messtechnologie auch am Patienten einsetzbar, um akute pathologische DC-Aktivität nach Hirninfarkt zu erfassen oder um funktionelle zerebrale Erholung besser zu charakterisieren.In cooperation with the Physikalisch-Technische Bundesanstalt Berlin we used combined dc-magnetoencephalography (MEG) and near-infrared spectroscopy (NIRS) to study the cerebral motor network. The non-invasive 'dual' setup with broadband MEG and NIRS was elaborated and tested to be capable of characterizing simultaneously the complementary aspects of the 'hemodynamic inverse problem', i.e., the coupling of neuronal and vascular/metabolic signals with a time resolution of milliseconds in healthy subjects and in subacute stroke patients. Basic physiological signals, such as heart rate, respiration, and electromyographical activity were correlated with the DC-MEG and tr-NIRS signals. We were able to monitor the time course of motor-related neuronal and vascular signals up to 60 minutes. The signals were visible even in a single trial mode without the need of averaging. In conclusion we confirmed that the combined MEG and NIRS technique provides a clinically feasible, non-invasive 'dual' measuring tool to examine physiological and pathophysiological cerebral coupling concepts of the motor network

Ischemia time impacts on respiratory chain functions and Ca2+-handling of cardiac subsarcolemmal mitochondria subjected to ischemia reperfusion injury

Abstract Background Mitochondrial impairment can result from myocardial ischemia reperfusion injury (IR). Despite cardioplegic arrest, IR-associated cardiodepression is a major problem in heart surgery. We determined the effect of increasing ischemia time on the respiratory chain (RC) function, the inner membrane polarization and Ca2+ homeostasis of rat cardiac subsarcolemmal mitochondria (SSM). Methods Wistar rat hearts were divided into 4 groups of stop-flow induced warm global IR using a pressure-controlled Langendorff system: 0, 15, 30 and 40 min of ischemia with 30 min of reperfusion, respectively. Myocardial contractility was determined from left ventricular pressure records (dP/dt, dPmax) with an intraventricular balloon. Following reperfusion, SSM were isolated and analyzed regarding electron transport chain (ETC) coupling by polarography (Clark-Type electrode), membrane polarization (JC1 fluorescence) and Ca2+-handling in terms of Ca2+-induced swelling and Ca2+-uptake/release (Calcium Green-5 N® fluorescence). Results LV contractility and systolic pressure during reperfusion were impaired by increasing ischemic times. Ischemia reduced ETC oxygen consumption in IR40/30 compared to IR0/30 at complex I-V (8.1 ± 1.2 vs. 18.2 ± 2.0 nmol/min) and II-IV/V (16.4 ± 2.6/14.8 ± 2.3 vs. 2.3 ± 0.6 nmol/min) in state 3 respiration (p < 0.01). Relative membrane potential revealed a distinct hyperpolarization in IR30/30 and IR40/30 (171.5 ± 17.4% and 170.9 ± 13.5%) compared to IR0/30 (p < 0.01), wearing off swiftly after CCCP-induced uncoupling. Excess mitochondrial permeability transition pore (mPTP)-gated Ca2+-induced swelling was recorded in all groups and was most pronounced in IR40/30. Pyruvate addition for mPTP blocking strongly reduced SSM swelling in IR40/30 (relative AUC, ± pyruvate; IR0/30: 1.00 vs. 0.61, IR15/30: 1.68 vs. 1.00, IR30/30: 1.42 vs. 0.75, IR40/30: 1.97 vs. 0.85; p < 0.01). Ca2+-uptake remained unaffected by previous IR. Though Ca2+-release was delayed for ≥30 min of ischemia (p < 0.01), Ca2+ retention was highest in IR15/30 (RFU; IR0/30: 6.3 ± 3.6, IR 15/30 42.9 ± 5.0, IR30/30 15.9 ± 3.8, IR40/30 11.5 ± 6.6; p ≤ 0.01 for IR15/30 against all other groups). Conclusions Ischemia prolongation in IR injury gradually impaired SSM in terms of respiratory chain function and Ca2+-homeostasis. Membrane hyperpolarization appears to be responsible for impaired Ca2+-cycling and ETC function. Ischemia time should be considered an important factor influencing IR experimental data on subsarcolemmal mitochondria. Periods of warm global ischemia should be minimized during cardiac surgery to avoid excessive damage to SSMs

The role of neuromuscular ultrasound in diagnostics of peripheral neuropathies induced by cytostatic agents or immunotherapies

Abstract A relevant number of cancer patients who receive potentially neurotoxic cytostatic agents develop a chemotherapy-induced peripheral neuropathy over time. Moreover, the increasing use of immunotherapies and targeted agents leads to a raising awareness of treatment-associated peripheral neurotoxicity, e.g., axonal and demyelinating neuropathies such as Guillain–Barré-like syndromes. To date, the differentiation of these phenomena from concurrent neurological co-morbidities or (para-)neoplastic nerve affection as well as their longitudinal monitoring remain challenging. Neuromuscular ultrasound (NMUS) is an established diagnostic tool for peripheral neuropathies. Performed by specialized neurologists, it completes clinical and neurophysiological diagnostics especially in differentiation of axonal and demyelinating neuropathies. No generally approved biomarkers of treatment-induced peripheral neurotoxicity have been established so far. NMUS might significantly extend the repertoire of diagnostic and neuromonitoring methods in this growing patient group in short term. In this article, we present enlargements of the dorsal roots both in cytostatic and in immunotherapy-induced neurotoxicity for the first time. We discuss related literature regarding new integrative applications of NMUS for cancer patients by reference to two representative case studies. Moreover, we demonstrate the integration of NMUS in a diagnostic algorithm for suspected peripheral neurotoxicity independently of a certain cancer treatment regimen emphasizing the emerging potential of NMUS for clinical routine in this interdisciplinary field and prospective clinical trials

Secondary Prevention after Minor Stroke and TIA - Usual Care and Development of a Support Program

Background: Effective methods of secondary prevention after stroke or TIA are available but adherence to recommended evidence-based treatments is often poor. The study aimed to determine the quality of secondary prevention in usual care and to develop a stepwise modeled support program. Methods: Two consecutive cohorts of patients with acute minor stroke or TIA undergoing usual outpatient care versus a secondary prevention program were compared. Risk factor control and medication adherence were assessed in 6-month follow-ups (6M-FU). Usual care consisted of detailed information concerning vascular risk factor targets given at discharge and regular outpatient care by primary care physicians. The stepwise modeled support program additionally employed up to four outpatient appointments. A combination of educational and behavioral strategies was employed. Results: 168 patients in the observational cohort who stated their openness to participate in a prevention program (mean age 64.7 y, admission blood pressure (BP): 155/84 mmHg) and 173 patients participating in the support program (mean age 67.6 y, BP: 161/84 mmHg) were assessed at 6 months. Proportions of patients with BP according to guidelines were 50% in usual-care and 77% in the support program (p<0.01). LDL<100 mg/dl was measured in 62 versus 71% (p = 0.12). Proportions of patients who stopped smoking were 50 versus 79% (p<0.01). 72 versus 89% of patients with atrial fibrillation were on oral anticoagulation (p = 0.09). Conclusions: Risk factor control remains unsatisfactory in usual care. Targets of secondary prevention were met more often within the supported cohort. Effects on (cerebro-)vascular recurrence rates are going to be assessed in a multicenter randomized trial