Brachial artery peak velocity variation to predict fluid responsiveness in mechanically ventilated patients

INTRODUCTION Although several parameters have been proposed to predict the hemodynamic response to fluid expansion in critically ill patients, most of them are invasive or require the use of special monitoring devices. The aim of this study is to determine whether noninvasive evaluation of respiratory variation of brachial artery peak velocity flow measured using Doppler ultrasound could predict fluid responsiveness in mechanically ventilated patients. METHODS We conducted a prospective clinical research in a 17-bed multidisciplinary ICU and included 38 mechanically ventilated patients for whom fluid administration was planned due to the presence of acute circulatory failure. Volume expansion (VE) was performed with 500 mL of a synthetic colloid. Patients were classified as responders if stroke volume index (SVi) increased >or= 15% after VE. The respiratory variation in Vpeakbrach (DeltaVpeakbrach) was calculated as the difference between maximum and minimum values of Vpeakbrach over a single respiratory cycle, divided by the mean of the two values and expressed as a percentage. Radial arterial pressure variation (DeltaPPrad) and stroke volume variation measured using the FloTrac/Vigileo system (DeltaSVVigileo), were also calculated. RESULTS VE increased SVi by >or= 15% in 19 patients (responders). At baseline, DeltaVpeakbrach, DeltaPPrad and DeltaSVVigileo were significantly higher in responder than nonresponder patients [14 vs 8%; 18 vs. 5%; 13 vs 8%; P < 0.0001, respectively). A DeltaVpeakbrach value >10% predicted fluid responsiveness with a sensitivity of 74% and a specificity of 95%. A DeltaPPrad value >10% and a DeltaSVVigileo >11% predicted volume responsiveness with a sensitivity of 95% and 79%, and a specificity of 95% and 89%, respectively. CONCLUSIONS Respiratory variations in brachial artery peak velocity could be a feasible tool for the noninvasive assessment of fluid responsiveness in patients with mechanical ventilatory support and acute circulatory failure. TRIAL REGISTRATION ClinicalTrials.gov ID: NCT00890071.

Cardiovascular patterns associated with appetitive and defensive activation during affective picture viewing

In this study we assessed blood pressure (BP), heart rate (HR), stroke volume (SV), cardiac output (CO), and total peripheral resistance (TPR) in response to 13 picture series in 37 participants in order to investigate their hemodynamic response associated with activation of the appetitive and defensive motivational systems underlying emotional experience. BP and SV, but not TPR, increased with increasing self-rated arousal, whereas HR decelerated more in response to negative than positive and neutral pictures. These findings suggest that modulation of the cardiovascular response to pictures is primarily myocardial. The observed response pattern is consistent with a configuration of cardiac sympathetic-parasympathetic coactivation. The relationships between self-rated arousal, BP, and SV were mainly exhibited by men, suggesting that increases in the sympathetic inotropic effect to the heart with self-rated arousal may be larger in men than in women.

The PPARgamma agonist pioglitazone modifies the vascular sodium-angiotensin II relationship in insulin-resistant rats.

Glitazones are efficient insulin sensitizers that blunt the effects of angiotensin II (ANG II) in the rat. Sodium chloride is another important modulator of the systemic and renal effects of ANG II. Whether glitazones interfere with the interaction between sodium and the response to ANG II is not known. Therefore, we investigated the effects of pioglitazone on the relationship between sodium and the systemic and renal effects of ANG II in rats. Pioglitazone, or vehicle, was administered for 4 wk to 8-wk-old obese Zucker rats. Animals were fed a normal-sodium (NS) or a high-sodium (HS) diet. Intravenous glucose tolerance tests, systemic and renal hemodynamic responses to ANG II, and the renal ANG II binding and expression of ANG II type 1 (AT(1)) receptors were measured. The results of our study were that food intake and body weight increased, whereas blood pressure, heart rate, filtration fraction, and insulin levels decreased significantly with pioglitazone in obese rats on both diets. Pioglitazone blunted the systemic response to ANG II and abolished the increased responsiveness to ANG II induced by a HS diet. Pioglitazone modified the renal hemodynamic response to changes in salt intake while maintaining a lower filtration fraction with ANG II perfusion. These effects were associated with a decrease in the number and expression of the AT(1) receptor in the kidney. In conclusion, these data demonstrate that the peroxisome proliferator-activated receptor-gamma agonist pioglitazone modifies the physiological relationship between sodium chloride and the response to ANG II in insulin-resistant rats.

Multimodal MRI analysis of structural and functional networks in the human brain : application to two clinical studies : driving abilities under THC intoxication and early white matter changes in FXTAS

Les approches multimodales dans l'imagerie cérébrale non invasive sont de plus en plus considérées comme un outil indispensable pour la compréhension des différents aspects de la structure et de la fonction cérébrale. Grâce aux progrès des techniques d'acquisition des images de Resonance Magnetique et aux nouveaux outils pour le traitement des données, il est désormais possible de mesurer plusieurs paramètres sensibles aux différentes caractéristiques des tissues cérébraux. Ces progrès permettent, par exemple, d'étudier les substrats anatomiques qui sont à la base des processus cognitifs ou de discerner au niveau purement structurel les phénomènes dégénératifs et développementaux. Cette thèse met en évidence l'importance de l'utilisation d'une approche multimodale pour étudier les différents aspects de la dynamique cérébrale grâce à l'application de cette approche à deux études cliniques: l'évaluation structurelle et fonctionnelle des effets aigus du cannabis fumé chez des consommateurs réguliers et occasionnels, et l'évaluation de l'intégrité de la substance grise et blanche chez des jeunes porteurs de la prémutations du gène FMR1 à risque de développer le FXTAS (Fragile-X Tremor Ataxia Syndrome). Nous avons montré que chez les fumeurs occasionnels de cannabis, même à faible concentration du principal composant psychoactif (THC) dans le sang, la performance lors d'une tâche visuo-motrice est fortement diminuée, et qu'il y a des changements dans l'activité des trois réseaux cérébraux impliqués dans les processus cognitifs: le réseau de saillance, le réseau du contrôle exécutif, et le réseau actif par défaut (Default Mode). Les sujets ne sont pas en mesure de saisir les saillances dans l'environnement et de focaliser leur attention sur la tâche. L'augmentation de la réponse hémodynamique dans le cortex cingulaire antérieur suggère une augmentation de l'activité introspective. Une investigation des ef¬fets au niveau cérébral d'une exposition prolongée au cannabis, montre des changements persistants de la substance grise dans les régions associées à la mémoire et au traitement des émotions. Le niveau d'atrophie dans ces structures corrèle avec la consommation de cannabis au cours des trois mois précédant l'étude. Dans la deuxième étude, nous démontrons des altérations structurelles des décennies avant l'apparition du syndrome FXTAS chez des sujets jeunes, asymptomatiques, et porteurs de la prémutation du gène FMR1. Les modifications trouvées peuvent être liées à deux mécanismes différents. Les altérations dans le réseau moteur du cervelet et dans la fimbria de l'hippocampe, suggèrent un effet développemental de la prémutation. Elles incluent aussi une atrophie de la substance grise du lobule VI du cervelet et l'altération des propriétés tissulaires de la substance blanche des projections afférentes correspondantes aux pédoncules cérébelleux moyens. Les lésions diffuses de la substance blanche cérébrale peu¬vent être un marquer précoce du développement de la maladie, car elles sont liées à un phénomène dégénératif qui précède l'apparition des symptômes du FXTAS. - Multimodal brain imaging is becoming a leading tool for understanding different aspects of brain structure and function. Thanks to the advances in Magnetic Resonance imaging (MRI) acquisition schemes and data processing techniques, it is now possible to measure different parameters sensitive to different tissue characteristics. This allows for example to investigate anatomical substrates underlying cognitive processing, or to disentangle, at a pure structural level degeneration and developmental processes. This thesis highlights the importance of using a multimodal approach for investigating different aspects of brain dynamics by applying this approach to two clinical studies: functional and structural assessment of the acute effects of cannabis smoking in regular and occasional users, and grey and white matter assessment in young FMR1 premutation carriers at risk of developing FXTAS. We demonstrate that in occasional smokers cannabis smoking, even at low concentration of the main psychoactive component (THC) in the blood, strongly decrease subjects' performance on a visuo-motor tracking task, and globally alters the activity of the three brain networks involved in cognitive processing: the Salience, the Control Executive, and the Default Mode networks. Subjects are unable to capture saliences in the environment and to orient attention to the task; the increase in Hemodynamic Response in the Anterior Cingulate Cortex suggests an increase in self-oriented mental activity. A further investigation on long term exposure to cannabis, shows a persistent grey matter modification in brain regions associated with memory and affective processing. The degree of atrophy in these structures also correlates with the estimation of drug use in the three months prior the participation to the study. In the second study we demonstrate structural changes in young asymptomatic premutation carriers decades before the onset of FXTAS that might be related to two different mechanisms. Alteration of the cerebellar motor network and of the hippocampal fimbria/ fornix, may reflect a potential neurodevelopmental effect of the premutation. These include grey matter atrophy in lobule VI and modification of white matter tissue property in the corresponding afferent projections through the Middle Cerebellar Peduncles. Diffuse hemispheric white matter lesions that seem to appear closer to the onset of FXTAS and be related to a neurodegenerative phenomenon may mark the imminent onset of FXTAS.

Quantitative functional neuroimaging of cerebral physiology in healthy aging

Les études d’imagerie par résonance magnétique fonctionnelle (IRMf) ont pour prémisse générale l’idée que le signal BOLD peut être utilisé comme un succédané direct de l’activation neurale. Les études portant sur le vieillissement cognitif souvent comparent directement l’amplitude et l’étendue du signal BOLD entre des groupes de personnes jeunes et âgés. Ces études comportent donc un a priori additionnel selon lequel la relation entre l’activité neurale et la réponse hémodynamique à laquelle cette activité donne lieu restent inchangée par le vieillissement. Cependant, le signal BOLD provient d’une combinaison ambiguë de changements de métabolisme oxydatif, de flux et de volume sanguin. De plus, certaines études ont démontré que plusieurs des facteurs influençant les propriétés du signal BOLD subissent des changements lors du vieillissement. L’acquisition d’information physiologiquement spécifique comme le flux sanguin cérébral et le métabolisme oxydatif permettrait de mieux comprendre les changements qui sous-tendent le contraste BOLD, ainsi que les altérations physiologiques et cognitives propres au vieillissement. Le travail présenté ici démontre l’application de nouvelles techniques permettant de mesurer le métabolisme oxydatif au repos, ainsi que pendant l’exécution d’une tâche. Ces techniques représentent des extensions de méthodes d’IRMf calibrée existantes. La première méthode présentée est une généralisation des modèles existants pour l’estimation du métabolisme oxydatif évoqué par une tâche, permettant de prendre en compte tant des changements arbitraires en flux sanguin que des changements en concentrations sanguine d’O2. Des améliorations en terme de robustesse et de précisions sont démontrées dans la matière grise et le cortex visuel lorsque cette méthode est combinée à une manipulation respiratoire incluant une composante d’hypercapnie et d’hyperoxie. Le seconde technique présentée ici est une extension de la première et utilise une combinaison de manipulations respiratoires incluant l’hypercapnie, l’hyperoxie et l’administration simultanée des deux afin d’obtenir des valeurs expérimentales de la fraction d’extraction d’oxygène et du métabolisme oxydatif au repos. Dans la deuxième partie de cette thèse, les changements vasculaires et métaboliques liés à l’âge sont explorés dans un groupe de jeunes et aînés, grâce au cadre conceptuel de l’IRMf calibrée, combiné à une manipulation respiratoire d’hypercapnie et une tâche modifiée de Stroop. Des changements de flux sanguin au repos, de réactivité vasculaire au CO2 et de paramètre de calibration M ont été identifiés chez les aînés. Les biais affectant les mesures de signal BOLD obtenues chez les participants âgés découlant de ces changements physiologiques sont de plus discutés. Finalement, la relation entre ces changements cérébraux et la performance dans la tâche de Stroop, la santé vasculaire centrale et la condition cardiovasculaire est explorée. Les résultats présentés ici sont en accord avec l’hypothèse selon laquelle une meilleure condition cardiovasculaire est associée à une meilleure fonction vasculaire centrale, contribuant ainsi à l’amélioration de la santé vasculaire cérébrale et cognitive.

fNIRS-EEG study of focal interictal epileptiform discharges

Functional near-infrared spectroscopy (fNIRS) acquired with electroencephalography (EEG) is a relatively new non-invasive neuroimaging technique with potential for long term monitoring of the epileptic brain. Simultaneous EEG-fNIRS recording allows the spatio-temporal reconstruction of the hemodynamic response in terms of the concentration changes in oxy-hemoglobin (HbO) and deoxy-hemoglobin (HbR) associated with recorded epileptic events such as interictal epileptic discharges (IEDs) or seizures. While most previous studies investigating fNIRS in epilepsy had limitations due to restricted spatial coverage and small sample sizes, this work includes a sufficiently large number of channels to provide an extensive bilateral coverage of the surface of the brain for a sample size of 40 patients with focal epilepsies. Topographic maps of significant activations due to each IED type were generated in four different views (dorsal, frontal, left and right) and were compared with the epileptic focus previously identified by an epileptologist. After excluding 5 patients due to the absence of IEDs and 6 more with mesial temporal foci too deep for fNIRS, we report that significant HbR (respectively HbO) concentration changes corresponding to IEDs were observed in 62% (resp. 38%) of patients with neocortical epilepsies. This HbR/HbO response was most significant in the epileptic focus region among all the activations in 28%/21% of patients.

Comparación del tiempo de despertar y tiempo de descarga entre dos técnicas de anestesia total intravenosa manual : Remifentanil vs Fentanil.

Introducción: A pesar de que las combinaciones de Propofol y opioides son ampliamente usadas para inducir y mantener una adecuada anestesia y analgesia, disminuir la dosis del inductor, incrementar la estabilidad hemodinámica y suprimir la respuesta a la laringoscopia y la intubación; no existen estudios que comparen el uso de Anestesia Total Intravenosa manual con Remifentanil - Propofol versus Fentanil - Propofol. Objetivo: Comparar el tiempo de despertar y el tiempo de descarga entre dos técnicas de Anestesia Total Intravenosa manual empleadas en el Hospital Occidente de Kennedy, una basada en Propofol y Remifentanil y otra basada en Propofol y Fentanil controlado por Stangraf. Metodología: Estudio de corte transversal, en 43 pacientes llevados a cirugía bajo Anestesia Total Intravenosa en el Hospital Occidente de Kennedy. Se analizó la información mediante las pruebas de Shapiro-Wilks, t de Student y U de Mann Withney y los coeficientes de correlación de Spearman y de Pearson, usando SPSS versión 20 para Windows. Un valor de p < 0.05 fue aceptado como estadísticamente significativo. Resultados: Al comparar las dos técnicas, no se encontraron diferencias estadísticamente significativas en los tiempos evaluados. El tiempo de despertar promedio fue 10,1 minutos para Fentanil y 10,2 minutos para Remifentanil. El tiempo de descarga para Fentanil fue 11,9 minutos y para Remifentanil fue 11,5 minutos. Conclusiones: El uso de Fentanil - Propofol guiado por Stangraf es equivalente al uso de Remifentanil – Propofol en cuanto a los tiempos de despertar y de descarga. Se requieren nuevos estudios para corroborar estos hallazgos.

Comparación de la anestesia espinal con anestesia general endovenosa para legrado uterino obstétrico

Introducción: La elección de la técnica anestésica para cualquier procedimiento quirúrgico debe estar basada en su seguridad, la rapidez para su aplicación, la recuperación óptima para el paciente y minimización de los efectos secundarios, la anestesia raquídea es una técnica anestésica que puede ser utilizada con buenos resultados clínicos y minimas complicaciones . Materiales y métodos: Se realizó un estudio observacional con recolección prospectiva en mujeres clasificadas como ASA I - II y que posteriormente fueron llevadas a la realización de legrado uterino obstétrico por embarazo no viable durante las primeras 12 semanas de gestación, las técnicas anestésicas fueron anestesia espinal o anestesia general endovenosa dependiendo de la elección hecha por el anestesiólogo previo al procedimiento. Se midieron variables hemodinámicas, control del dolor postoperatorio, tiempo de recuperación y complicaciones perioperatorias con el fin de determinar si se presentaban diferencias significativas entre estas dos técnicas anestésicas. Resultados: Se incluyeron un total de 110 pacientes, 63.6% (n=70) con anestesia general y 36.4% (n40) con anestesia espinal. Ambas poblaciones fueron comparables. Se presentaron menos efectos secundarios con la técnica espinal, hay una diferencia estadísticamente significativa en cuanto al dolor a favor de la anestesia espinal (p0,000) Discusión: La anestesia raquídea es una opción viable, sencilla , fácil y eficaz para la realización de legrados obstétricos, se puede realizar con monitorización básica y las complicaciones son mínimas. Se requieren estudios más amplios para determinar el papel de cual es la mejor técnica. Palabras claves: legrado uterino instrumentado, anestesia espinal, anestesia general endovenosa

Efficient modeling and inference for event-related fMRI data

Event-related functional magnetic resonance imaging (efMRI) has emerged as a powerful technique for detecting brains' responses to presented stimuli. A primary goal in efMRI data analysis is to estimate the Hemodynamic Response Function (HRF) and to locate activated regions in human brains when specific tasks are performed. This paper develops new methodologies that are important improvements not only to parametric but also to nonparametric estimation and hypothesis testing of the HRF. First, an effective and computationally fast scheme for estimating the error covariance matrix for efMRI is proposed. Second, methodologies for estimation and hypothesis testing of the HRF are developed. Simulations support the effectiveness of our proposed methods. When applied to an efMRI dataset from an emotional control study, our method reveals more meaningful findings than the popular methods offered by AFNI and FSL. (C) 2008 Elsevier B.V. All rights reserved.

Epoch-specific functional networks involved in working memory

Working memory (WM) is not a unitary construct. There are distinct processes involved in encoding information, maintaining it on-line, and using it to guide responses. The anatomical configurations of these processes are more accurately analyzed as functionally connected networks than collections of individual regions. In the current study we analyzed event-related functional magnetic resonance imaging (fMRI) data from a Sternberg Item Recognition Paradigm WM task using a multivariate analysis method that allowed the linking of functional networks to temporally-separated WM epochs. The length of the delay epochs was varied to optimize isolation of the hemodynamic response (HDR) for each task epoch. All extracted functional networks displayed statistically significant sensitivity to delay length. Novel information extracted from these networks that was not apparent in the univariate analysis of these data included involvement of the hippocampus in encoding/probe, and decreases in BOLD signal in the superior temporal gyrus (STG), along with default-mode regions, during encoding/delay. The bilateral hippocampal activity during encoding/delay fits with theoretical models of WM in which memoranda held across the short term are activated long-term memory representations. The BOLD signal decreases in the STG were unexpected, and may reflect repetition suppression effects invoked by internal repetition of letter stimuli. Thus, analysis methods focusing on how network dynamics relate to experimental conditions allowed extraction of novel information not apparent in univariate analyses, and are particularly recommended for WM experiments for which task epochs cannot be randomized.

Does neural input or processing play a greater role in the magnitude of neuroimaging signals?

An important constraint on how hemodynamic neuroimaging signals such as fMRI can be interpreted in terms of the underlying evoked activity is an understanding of neurovascular coupling mechanisms that actually generate hemodynamic responses. The predominant view at present is that the hemodynamic response is most correlated with synaptic input and subsequent neural processing rather than spiking output. It is still not clear whether input or processing is more important in the generation of hemodynamics responses. In order to investigate this we measured the hemodynamic and neural responses to electrical whisker pad stimuli in rat whisker barrel somatosensory cortex both before and after the local cortical injections of the GABAA agonist muscimol. Muscimol would not be expected to affect the thalamocortical input into the cortex but would inhibit subsequent intra-cortical processing. Pre-muscimol infusion whisker stimuli elicited the expected neural and accompanying hemodynamic responses to that reported previously. Following infusion of muscimol, although the temporal profile of neural responses to each pulse of the stimulus train was similar, the average response was reduced in magnitude by ∼79% compared to that elicited pre-infusion. The whisker-evoked hemodynamic responses were reduced by a commensurate magnitude suggesting that, although the neurovascular coupling relationships were similar for synaptic input as well as for cortical processing, the magnitude of the overall response is dominated by processing rather than from that produced from the thalamocortical input alone.

A model of the dynamic relationship between blood flow and volume changes during brain activation

The temporal relationship between changes in cerebral blood flow (CBF) and cerebral blood volume (CBV) is important in the biophysical modeling and interpretation of the hemodynamic response to activation, particularly in the context of magnetic resonance imaging and the blood oxygen level-dependent signal. Grubb et al. (1974) measured the steady state relationship between changes in CBV and CBF after hypercapnic challenge. The relationship CBV proportional to CBFPhi has been used extensively in the literature. Two similar models, the Balloon (Buxton et al., 1998) and the Windkessel (Mandeville et al., 1999), have been proposed to describe the temporal dynamics of changes in CBV with respect to changes in CBF. In this study, a dynamic model extending the Windkessel model by incorporating delayed compliance is presented. The extended model is better able to capture the dynamics of CBV changes after changes in CBF, particularly in the return-to-baseline stages of the response.

Nonlinear estimation of neural processing time from BOLD signal with application to decision-making

The extraction of information about neural activity timing from BOLD signal is a challenging task as the shape of the BOLD curve does not directly reflect the temporal characteristics of electrical activity of neurons. In this work, we introduce the concept of neural processing time (NPT) as a parameter of the biophysical model of the hemodynamic response function (HRF). Through this new concept we aim to infer more accurately the duration of neuronal response from the highly nonlinear BOLD effect. The face validity and applicability of the concept of NPT are evaluated through simulations and analysis of experimental time series. The results of both simulation and application were compared with summary measures of HRF shape. The experiment that was analyzed consisted of a decision-making paradigm with simultaneous emotional distracters. We hypothesize that the NPT in primary sensory areas, like the fusiform gyrus, is approximately the stimulus presentation duration. On the other hand, in areas related to processing of an emotional distracter, the NPT should depend on the experimental condition. As predicted, the NPT in fusiform gyrus is close to the stimulus duration and the NPT in dorsal anterior cingulate gyrus depends on the presence of an emotional distracter. Interestingly, the NPT in right but not left dorsal lateral prefrontal cortex depends on the stimulus emotional content. The summary measures of HRF obtained by a standard approach did not detect the variations observed in the NPT. Hum Brain Mapp, 2012. (C) 2010 Wiley Periodicals, Inc.

Parameters and algorithms to evaluate cardiac mechanics by conductance catheter

This work is structured as follows: In Section 1 we discuss the clinical problem of heart failure. In particular, we present the phenomenon known as ventricular mechanical dyssynchrony: its impact on cardiac function, the therapy for its treatment and the methods for its quantification. Specifically, we describe the conductance catheter and its use for the measurement of dyssynchrony. At the end of the Section 1, we propose a new set of indexes to quantify the dyssynchrony that are studied and validated thereafter. In Section 2 we describe the studies carried out in this work: we report the experimental protocols, we present and discuss the results obtained. Finally, we report the overall conclusions drawn from this work and we try to envisage future works and possible clinical applications of our results. Ancillary studies that were carried out during this work mainly to investigate several aspects of cardiac resynchronization therapy (CRT) are mentioned in Appendix. -------- Ventricular mechanical dyssynchrony plays a regulating role already in normal physiology but is especially important in pathological conditions, such as hypertrophy, ischemia, infarction, or heart failure (Chapter 1,2.). Several prospective randomized controlled trials supported the clinical efficacy and safety of cardiac resynchronization therapy (CRT) in patients with moderate or severe heart failure and ventricular dyssynchrony. CRT resynchronizes ventricular contraction by simultaneous pacing of both left and right ventricle (biventricular pacing) (Chapter 1.). Currently, the conductance catheter method has been used extensively to assess global systolic and diastolic ventricular function and, more recently, the ability of this instrument to pick-up multiple segmental volume signals has been used to quantify mechanical ventricular dyssynchrony. Specifically, novel indexes based on volume signals acquired with the conductance catheter were introduced to quantify dyssynchrony (Chapter 3,4.). Present work was aimed to describe the characteristics of the conductancevolume signals, to investigate the performance of the indexes of ventricular dyssynchrony described in literature and to introduce and validate improved dyssynchrony indexes. Morevoer, using the conductance catheter method and the new indexes, the clinical problem of the ventricular pacing site optimization was addressed and the measurement protocol to adopt for hemodynamic tests on cardiac pacing was investigated. In accordance to the aims of the work, in addition to the classical time-domain parameters, a new set of indexes has been extracted, based on coherent averaging procedure and on spectral and cross-spectral analysis (Chapter 4.). Our analyses were carried out on patients with indications for electrophysiologic study or device implantation (Chapter 5.). For the first time, besides patients with heart failure, indexes of mechanical dyssynchrony based on conductance catheter were extracted and studied in a population of patients with preserved ventricular function, providing information on the normal range of such a kind of values. By performing a frequency domain analysis and by applying an optimized coherent averaging procedure (Chapter 6.a.), we were able to describe some characteristics of the conductance-volume signals (Chapter 6.b.). We unmasked the presence of considerable beat-to-beat variations in dyssynchrony that seemed more frequent in patients with ventricular dysfunction and to play a role in discriminating patients. These non-recurrent mechanical ventricular non-uniformities are probably the expression of the substantial beat-to-beat hemodynamic variations, often associated with heart failure and due to cardiopulmonary interaction and conduction disturbances. We investigated how the coherent averaging procedure may affect or refine the conductance based indexes; in addition, we proposed and tested a new set of indexes which quantify the non-periodic components of the volume signals. Using the new set of indexes we studied the acute effects of the CRT and the right ventricular pacing, in patients with heart failure and patients with preserved ventricular function. In the overall population we observed a correlation between the hemodynamic changes induced by the pacing and the indexes of dyssynchrony, and this may have practical implications for hemodynamic-guided device implantation. The optimal ventricular pacing site for patients with conventional indications for pacing remains controversial. The majority of them do not meet current clinical indications for CRT pacing. Thus, we carried out an analysis to compare the impact of several ventricular pacing sites on global and regional ventricular function and dyssynchrony (Chapter 6.c.). We observed that right ventricular pacing worsens cardiac function in patients with and without ventricular dysfunction unless the pacing site is optimized. CRT preserves left ventricular function in patients with normal ejection fraction and improves function in patients with poor ejection fraction despite no clinical indication for CRT. Moreover, the analysis of the results obtained using new indexes of regional dyssynchrony, suggests that pacing site may influence overall global ventricular function depending on its relative effects on regional function and synchrony. Another clinical problem that has been investigated in this work is the optimal right ventricular lead location for CRT (Chapter 6.d.). Similarly to the previous analysis, using novel parameters describing local synchrony and efficiency, we tested the hypothesis and we demonstrated that biventricular pacing with alternative right ventricular pacing sites produces acute improvement of ventricular systolic function and improves mechanical synchrony when compared to standard right ventricular pacing. Although no specific right ventricular location was shown to be superior during CRT, the right ventricular pacing site that produced the optimal acute hemodynamic response varied between patients. Acute hemodynamic effects of cardiac pacing are conventionally evaluated after stabilization episodes. The applied duration of stabilization periods in most cardiac pacing studies varied considerably. With an ad hoc protocol (Chapter 6.e.) and indexes of mechanical dyssynchrony derived by conductance catheter we demonstrated that the usage of stabilization periods during evaluation of cardiac pacing may mask early changes in systolic and diastolic intra-ventricular dyssynchrony. In fact, at the onset of ventricular pacing, the main dyssynchrony and ventricular performance changes occur within a 10s time span, initiated by the changes in ventricular mechanical dyssynchrony induced by aberrant conduction and followed by a partial or even complete recovery. It was already demonstrated in normal animals that ventricular mechanical dyssynchrony may act as a physiologic modulator of cardiac performance together with heart rate, contractile state, preload and afterload. The present observation, which shows the compensatory mechanism of mechanical dyssynchrony, suggests that ventricular dyssynchrony may be regarded as an intrinsic cardiac property, with baseline dyssynchrony at increased level in heart failure patients. To make available an independent system for cardiac output estimation, in order to confirm the results obtained with conductance volume method, we developed and validated a novel technique to apply the Modelflow method (a method that derives an aortic flow waveform from arterial pressure by simulation of a non-linear three-element aortic input impedance model, Wesseling et al. 1993) to the left ventricular pressure signal, instead of the arterial pressure used in the classical approach (Chapter 7.). The results confirmed that in patients without valve abnormalities, undergoing conductance catheter evaluations, the continuous monitoring of cardiac output using the intra-ventricular pressure signal is reliable. Thus, cardiac output can be monitored quantitatively and continuously with a simple and low-cost method. During this work, additional studies were carried out to investigate several areas of uncertainty of CRT. The results of these studies are briefly presented in Appendix: the long-term survival in patients treated with CRT in clinical practice, the effects of CRT in patients with mild symptoms of heart failure and in very old patients, the limited thoracotomy as a second choice alternative to transvenous implant for CRT delivery, the evolution and prognostic significance of diastolic filling pattern in CRT, the selection of candidates to CRT with echocardiographic criteria and the prediction of response to the therapy.

Funktionelle Magnetresonanztomographie mittels simultaner EEG-Registrierung interiktaler Spikes bei fokaler Epilepsie: Vergleich der on-, off- mit der häufigkeitskorrelierten Datenanalyse

Obwohl die funktionelle Magnetresonanztomographie (fMRI) interiktaler Spikes mit simultaner EEG-Ableitung bei Patienten mit fokalen Anfallsleiden seit einigen Jahren zur Lokalisation beteiligter Hirnstrukturen untersucht wird, ist sie nach wie vor eine experimentelle Methode. Um zuverlässig Ergebnisse zu erhalten, ist insbesondere die Verbesserung des Signal-zu-Rausch-Verhältnisses in der statistischen Bilddatenauswertung von Bedeutung. Frühere Untersuchungen zur sog. event-related fMRI weisen auf einen Zusammenhang zwischen Häufigkeit von Einzelreizen und nachfolgender hämodynamischer Signalantwort in der fMRI hin. Um einen möglichen Einfluss der Häufigkeit interiktaler Spikes auf die Signalantwort nachzuweisen, wurden 20 Kinder mit fokaler Epilepsie mit der EEG-fMRI untersucht. Von 11 dieser Patienten konnten die Daten ausgewertet werden. In einer zweifachen Analyse mit dem Softwarepaket SPM99 wurden die Bilddaten zuerst ausschließlich je nach Auftreten interiktaler Spikes der „Reiz“- oder „Ruhe“-Bedingung zugeordnet, unabhängig von der jeweiligen Anzahl der Spikes je Messzeitpunkt (on/off-Analyse). In einem zweiten Schritt wurden die „Reiz“- Bedingungen auch differenziert nach jeweiliger Anzahl einzelner Spikes ausgewertet (häufigkeitskorrelierte Analyse). Die Ergebnisse dieser Analysen zeigten bei 5 der 11 Patienten eine Zunahme von Sensitivität und Signifikanzen der in der fMRI nachgewiesenen Aktivierungen. Eine höhere Spezifität konnte hingegen nicht gezeigt werden. Diese Ergebnisse weisen auf eine positive Korrelation von Reizhäufigkeit und nachfolgender hämodynamischer Antwort auch bei interiktalen Spikes hin, welche für die EEG-fMRI nutzbar ist. Bei 6 Patienten konnte keine fMRI-Aktivierung nachgewiesen werden. Mögliche technische und physiologische Ursachen hierfür werden diskutiert.