Surveillance non invasive de la réponse neuroimmunitaire fœtale à l’infection

Introduction. In utero, l’infection des membranes maternelles et fœtales, la chorioamniotite, passe souvent inaperçue et, en particulier lorsque associée à une acidémie, due à l’occlusion du cordon ombilical (OCO), comme il se produirait au cours du travail, peut entrainer des lésions cérébrales et avoir des répercussions neurologiques péri - et postnatales à long terme chez le fœtus. Il n'existe actuellement aucun moyen de détecter précocement ces conditions pathologiques in utéro afin de prévenir ou de limiter ces atteintes. Hypothèses. 1)l’électroencéphalogramme (EEG) fœtal obtenu du scalp fœtal pourrait servir d’outil auxiliaire à la surveillance électronique fœtale du rythme cardiaque fœtal (RCF) pour la détection précoce d'acidémie fœtale et d'agression neurologique; 2) la fréquence d’échantillonnage de l’ECG fœtal (ECGf) a un impact important sur le monitoring continu de la Variabilité du Rythme Cardiaque (VRCf) dans la prédiction de l’acidémie fœtale ; 3) les patrons de la corrélation de la VRCf aux cytokines pro-inflammatoires refléteront les états de réponses spontanées versus inflammatoires de la Voie Cholinergique Anti-inflammatoire (VCA); 4) grâce au développement d’un modèle de prédictions mathématiques, la prédiction du pH et de l’excès de base (EB) à la naissance sera possible avec seulement une heure de monitoring d’ECGf. Méthodes. Dans une série d’études fondamentales et cliniques, en utilisant respectivement le mouton et une cohorte de femmes en travail comme modèle expérimental et clinique , nous avons modélisé 1) une situation d’hypoxie cérébrale résultant de séquences d’occlusion du cordon ombilical de sévérité croissante jusqu’à atteindre un pH critique limite de 7.00 comme méthode expérimentale analogue au travail humain pour tester les première et deuxième hypothèses 2) un inflammation fœtale modérée en administrant le LPS à une autre cohorte animale pour vérifier la troisième hypothèse et 3) un modèle mathématique de prédictions à partir de paramètres et mesures validés cliniquement qui permettraient de déterminer les facteurs de prédiction d’une détresse fœtale pour tester la dernière hypothèse. Résultats. Les séries d’OCO répétitives se sont soldés par une acidose marquée (pH artériel 7.35±0.01 à 7.00±0.01), une diminution des amplitudes à l'électroencéphalogramme( EEG) synchronisé avec les décélérations du RCF induites par les OCO accompagnées d'une baisse pathologique de la pression artérielle (PA) et une augmentation marquée de VRCf avec hypoxie-acidémie aggravante à 1000 Hz, mais pas à 4 Hz, fréquence d’échantillonnage utilisée en clinique. L’administration du LPS entraîne une inflammation systémique chez le fœtus avec les IL-6 atteignant un pic 3 h après et des modifications de la VRCf retraçant précisément ce profil temporel des cytokines. En clinique, avec nos cohortes originale et de validation, un modèle statistique basée sur une matrice de 103 mesures de VRCf (R2 = 0,90, P < 0,001) permettent de prédire le pH mais pas l’EB, avec une heure d’enregistrement du RCF avant la poussée. Conclusions. La diminution de l'amplitude à l'EEG suggère un mécanisme d'arrêt adaptatif neuroprotecteur du cerveau et suggère que l'EEG fœtal puisse être un complément utile à la surveillance du RCF pendant le travail à haut risque chez la femme. La VRCf étant capable de détecter une hypoxie-acidémie aggravante tôt chez le fœtus à 1000Hz vs 4 Hz évoque qu’un mode d'acquisition d’ECG fœtal plus sensible pourrait constituer une solution. Des profils distinctifs de mesures de la VRCf, identifiés en corrélation avec les niveaux de l'inflammation, ouvre une nouvelle voie pour caractériser le profil inflammatoire de la réponse fœtale à l’infection. En clinique, un monitoring de chevet de prédiction du pH et EB à la naissance, à partir de mesures de VRCf permettrait des interprétations visuelles plus explicites pour des prises de décision plus exactes en obstétrique au cours du travail.Introduction. In utero, the infection of maternal and fetal membranes, chorioamnionitis, goes frequently unnoticed and, especially when combined with acidemia due to occlusions of the umbilical cord as they occur during labour, can result in brain damage and long term neurological sequelae peri- and postnatally. Currently, there is no way to early detect these pathological conditions to prevent or limit lasting neurological deficits. Hypotheses. (1) the fetal electroencephalogram (EEG), obtained from the scalp could serve as a useful ancillary tool to the existing fetal heart rate (FHR) monitoring for early detection of fetal acidemia and neurological injury; (2) the sampling rate of fetal ECG has a significant impact on the continuous FHR monitoring in the prediction of fetal acidemia; 3) patterns of FHR variability will reflect fetal baseline and inflammatory states; (4) FHR variability analysis should permit prediction of pH and base excess (BE) at birth. Methods. In a series of studies using the chronically instrumented unanesthetized fetal sheep and clinical cohort, we modeled 1) worsening fetal acidemia with intermittent hypoxia resulting from umbilical cord occlusions (UCO) of increasing severity as experimental model of human labour to test the 1st and 2nd hypotheses; 2) moderate fetal inflammation by administering lipopolysaccharide (LPS) to test the 3rd hypothesis and 3) prediction of pH and BE status at birth using clinically validated FHR variability measures in a clinical cohort of laboring women to test the 4th hypothesis. Results. Repetitive UCO resulted in marked acidosis (pH arterial 7.35±0.01 to 7.00±0.01), decreased EEG amplitudes synchronized with UCO-induced FHR decelerations and pathological arterial blood pressure decreases; in addition, we detected a significant increase in FHR variability with worsening acidemia when sampled at 1000 but not at 4 Hz, the sampling rate used clinically. LPS administration resulted in systemic fetal inflammation with IL-6 peaking at 3 h and FHR variability changes tracking this temporal cytokine profile precisely. In the clinical cohort, a statistical model based on a matrix of 103 FHR variability measures predicted pH (R2 = 0.90, P < 0.001), but not BE, from one hour of FHR recording prior to pushing stage. Conclusions. The decrease in the EEG amplitude suggests an adaptive and neuroprotective brain shut-down; fetal EEG may complement the FHR monitoring during labour to improve early detection of incipient acidemia. FHR variability changes can detect early developing hypoxic-acidemia when sampled at 1000 Hz, but not when sampled at 4 Hz suggesting that a more sensitive mode of fetal ECG acquisition will improve early acidemia detection. Distinctive subsets of FHR variability measures permit online monitoring of fetal inflammation from ECG opening a new approach to characterizing the fetal inflammatory profile. Clinical bedside prediction of pH and BE monitoring at birth using FHR variability monitoring will allow more accurate decision making in obstetrics during labou

Studies on the assessment of the adequacy of anesthesia

Several hypnosis monitoring systems based on the processed electroencephalogram (EEG) have been developed for use during general anesthesia. The assessment of the analgesic component (antinociception) of general anesthesia is an emerging field of research. This study investigated the interaction of hypnosis and antinociception, the association of several physiological variables with the degree of intraoperative nociception, and aspects of EEG Bispectral Index Scale (BIS) monitoring during general anesthesia. In addition, EEG features and heart rate (HR) responses during desflurane and sevoflurane anesthesia were compared. A propofol bolus of 0.7 mg/kg was more effective than an alfentanil bolus of 0.5 mg in preventing the recurrence of movement responses during uterine dilatation and curettage (D C) after a propofol-alfentanil induction, combined with nitrous oxide (N2O). HR and several HR variability-, frontal electromyography (fEMG)-, pulse plethysmography (PPG)-, and EEG-derived variables were associated with surgery-induced movement responses. Movers were discriminated from non-movers mostly by the post-stimulus values per se or normalized with respect to the pre-stimulus values. In logistic regression analysis, the best classification performance was achieved with the combination of normalized fEMG power and HR during D C (overall accuracy 81%, sensitivity 53%, specificity 95%), and with the combination of normalized fEMG-related response entropy, electrocardiography (ECG) R-to-R interval (RRI), and PPG dicrotic notch amplitude during sevoflurane anesthesia (overall accuracy 96%, sensitivity 90%, specificity 100%). ECG electrode impedances after alcohol swab skin pretreatment alone were higher than impedances of designated EEG electrodes. The BIS values registered with ECG electrodes were higher than those registered simultaneously with EEG electrodes. No significant difference in the time to home-readiness after isoflurane-N2O or sevoflurane-N2O anesthesia was found, when the administration of the volatile agent was guided by BIS monitoring. All other early and intermediate recovery parameters were also similar. Transient epileptiform EEG activity was detected in eight of 15 sevoflurane patients during a rapid increase in the inspired volatile concentration, and in none of the 16 desflurane patients. The observed transient EEG changes did not adversely affect the recovery of the patients. Following the rapid increase in the inhaled desflurane concentration, HR increased transiently, reaching its maximum in two minutes. In the sevoflurane group, the increase was slower and more subtle. In conclusion, desflurane may be a safer volatile agent than sevoflurane in patients with a lowered seizure threshold. The tachycardia induced by a rapid increase in the inspired desflurane concentration may present a risk for patients with heart disease. Designated EEG electrodes may be superior to ECG electrodes in EEG BIS monitoring. When the administration of isoflurane or sevoflurane is adjusted to maintain BIS values at 50-60 in healthy ambulatory surgery patients, the speed and quality of recovery are similar after both isoflurane-N2O and sevoflurane-N2O anesthesia. When anesthesia is maintained by the inhalation of N2O and bolus doses of propofol and alfentanil in healthy unparalyzed patients, movement responses may be best avoided by ensuring a relatively deep hypnotic level with propofol. HR/RRI, fEMG, and PPG dicrotic notch amplitude are potential indicators of nociception during anesthesia, but their performance needs to be validated in future studies. Combining information from different sources may improve the discrimination of the level of nociception.Useita aivosähkökäyrään (EEG) perustuvia unen syvyyden valvontamenetelmiä on kehitetty yleisanestesian aikana käytettäväksi. Kudosvaurion aiheuttamia ärsykkeitä vaimentavan yleisanestesian osan arviointimenetelmien tutkimus on alkamassa. Tässä väitöskirjatyössä tutkittiin unen syvyyden ja kudosvaurion aiheuttamien ärsykkeiden vaimennuksen vuorovaikutusta, useiden elimistön toimintaa kuvaavien muuttujien ja kudosvaurion aiheuttaman ärsytyksen suhdetta sekä EEG:n bispektraali-indeksin (BIS) käyttöä yleisanestesian valvonnassa. Lisäksi verrattiin desfluraani- ja sevofluraanianestesiaan liittyviä EEG-muutoksia ja sykevasteita. Kun anestesia oli aloitettu propofolilla, alfentaniililla ja typpioksiduulilla (N2O), propofoliannos 0.7 mg/kg esti liikevasteiden toistumista kohdun kaavinnan aikana tehokkaammin kuin alfentaniiliannos 0.5 mg. Sydämen syke ja useat sykevaihtelusta, otsalihastoiminnasta, pulssiaallon mittauksesta ja EEG:sta johdetut muuttujat olivat yhteydessä leikkauksen aiheuttamiin liikevasteisiin. Pääsääntöisesti ärsykkeen jälkeen mitatut arvot sellaisenaan tai suhteutettuna ärsykettä edeltäviin arvoihin (normalisoituna) erottelivat liikkuvat potilaat liikkumattomista potilaista. Paras luokittelu saavutettiin kohdun kaavinnan aikana yhdistämällä tieto normalisoidusta otsalihastoiminnasta ja sykkeestä (herkkyys 53%, tarkkuus 95%), ja sevofluraanianestesian aikana yhdistämällä tieto normalisoidusta (otsalihastoimintaan liittyvästä) vaste-entropiasta, sykkeestä ja pulssiaallon muodosta (herkkyys 90%, tarkkuus 100%). Kun iho valmisteltiin vain pyyhkäisemällä alkoholilla, sydänsähkökäyrän (EKG) mittaukseen tarkoitettujen elektrodien sähköinen vastus oli suurempi kuin EEG:n mittaukseen tarkoitettujen elektrodien. EKG-elektrodeilla mitatut BIS-arvot olivat korkeampia kuin samanaikaisesti EEG-elektrodeilla mitatut BIS-arvot. Kun höyrystyviä anestesia-aineita annosteltiin BIS-arvojen mukaan, toipuminen oli yhtä nopeaa isofluraani-N2O-anestesian jälkeen kuin sevofluraani-N2O-anestesian jälkeen. Kun höyrystyvän anestesia-aineen pitoisuutta nostettiin nopeasti viiden minuutin ajaksi, ohimenevää epileptistä aivosähkötoimintaa havaittiin kahdeksalla viidestätoista sevofluraanipotilaasta, mutta ei yhdelläkään kuudestatoista desfluraanipotilaasta. Havaitut ohimenevät EEG-muutokset eivät vaikuttaneet haitallisesti potilaiden toipumiseen. Desfluraanipitoisuuden nopean noston jälkeen syke kiihtyi ohimenevästi ja saavutti huippunsa kahdessa minuutissa. Sevofluraaniryhmässä sykenousu oli hitaampi ja lievempi. Tulosten perusteella voidaan todeta, että desfluraani saattaa olla sevofluraania turvallisempi anestesia-aine potilailla joiden kouristuskynnys on alentunut. Nopeaan desfluraanipitoisuuden nostoon liittyvä sykenousu voi olla haitallinen sydänsairaille potilaille. EEG-elektrodit ovat BIS-mittauksessa parempia kuin halvemmat EKG-elektrodit. Kun höyrystyvä anestesia-aine annostellaan siten että BIS-arvo pysyy välillä 50-60, toipuminen on samankaltainen sekä isofluraani-N2O- että sevofluraani-N2O-anestesian jälkeen terveillä päiväkirurgisilla potilailla. Kun anestesiaa ylläpidetään N2O:lla sekä propofoli- ja alfentaniiliannoksilla terveillä potilailla, joiden lihastoimintaa ei ole lamattu, liikevasteita estetään mahdollisesti parhaiten pitämällä uni verrattain syvänä propofolin avulla. Sydämen syke, otsalihastoiminta ja pulssiaallon muoto saattavat soveltua kudosvaurion aiheut-taman ärsytyksen valvontaan anestesian aikana, mutta lisätutkimuksia aiheesta tarvitaan. Kudosvaurion aiheuttaman ärsytyksen arviointia voidaan mahdollisesti tarkentaa yhdistämällä tietoa useista elimistön toimintaa kuvaavista muuttujista

The Effects of Anesthetic Induced Loss of Consciousness on Quantitative Electroen Cephalogram, and Bispectral and Spectral Entropy Indices. Studies on Healthy Male

Changes in the electroencephalography (EEG) signal have been used to study the effects of anesthetic agents on the brain function. Several commercial EEG based anesthesia depth monitors have been developed to measure the level of the hypnotic component of anesthesia. Specific anesthetic related changes can be seen in the EEG, but still it remains difficult to determine whether the subject is consciousness or not during anesthesia. EEG reactivity to external stimuli may be seen in unconsciousness subjects, in anesthesia or even in coma. Changes in regional cerebral blood flow, which can be measured with positron emission tomography (PET), can be used as a surrogate for changes in neuronal activity. The aim of this study was to investigate the effects of dexmedetomidine, propofol, sevoflurane and xenon on the EEG and the behavior of two commercial anesthesia depth monitors, Bispectral Index (BIS) and Entropy. Slowly escalating drug concentrations were used with dexmedetomidine, propofol and sevoflurane. EEG reactivity at clinically determined similar level of consciousness was studied and the performance of BIS and Entropy in differentiating consciousness form unconsciousness was evaluated. Changes in brain activity during emergence from dexmedetomidine and propofol induced unconsciousness were studied using PET imaging. Additionally, the effects of normobaric hyperoxia, induced during denitrogenation prior to xenon anesthesia induction, on the EEG were studied. Dexmedetomidine and propofol caused increases in the low frequency, high amplitude (delta 0.5-4 Hz and theta 4.1-8 Hz) EEG activity during stepwise increased drug concentrations from the awake state to unconsciousness. With sevoflurane, an increase in delta activity was also seen, and an increase in alpha- slow beta (8.1-15 Hz) band power was seen in both propofol and sevoflurane. EEG reactivity to a verbal command in the unconsciousness state was best retained with propofol, and almost disappeared with sevoflurane. The ability of BIS and Entropy to differentiate consciousness from unconsciousness was poor. At the emergence from dexmedetomidine and propofol induced unconsciousness, activation was detected in deep brain structures, but not within the cortex. In xenon anesthesia, EEG band powers increased in delta, theta and alpha (8-12Hz) frequencies. In steady state xenon anesthesia, BIS and Entropy indices were low and these monitors seemed to work well in xenon anesthesia. Normobaric hyperoxia alone did not cause changes in the EEG. All of these results are based on studies in healthy volunteers and their application to clinical practice should be considered carefully.Siirretty Doriast

Statistical Frequency-Dependent Analysis of Trial-to-Trial Variability in Single Time Series by Recurrence Plots

International audienceFor decades, research in neuroscience has supported the hypothesis that brain dynamics exhibits recurrent metastable states connected by transients, which together encode fundamental neural information processing. To understand the system’s dynamics it is important to detect such recurrence domains, but it is challenging to extract them from experimental neuroscience datasets due to the large trial-to-trial variability. The proposed methodology extracts recurrent metastable states in univariate time series by transforming datasets into their time-frequency representations and computing recurrence plots based on instantaneous spectral power values in various frequency bands. Additionally, a new statistical inference analysis compares different trial recurrence plots with corresponding surrogates to obtain statistically significant recurrent structures. This combination of methods is validated by applying it to two artificial datasets. In a final study of visually-evoked Local Field Potentials in partially anesthetized ferrets, the methodology is able to reveal recurrence structures of neural responses with trial-to-trial variability. Focusing on different frequency bands, the delta-band activity is much less recurrent than alpha-band activity. Moreover, alpha-activity is susceptible to pre-stimuli, while delta-activity is much less sensitive to pre-stimuli. This difference in recurrence structures in different frequency bands indicates diverse underlying information processing steps in the brain

Trauma, Tumors, Spine, Functional Neurosurgery

This book is written for graduate students, researchers, and practitioners who are interested in learning how the knowledge from research can be implemented in clinical competences. The first section is dedicated to deep brain stimulation, a surgical procedure which is the paramount example of how clinical practice can take advantage from fundamental research. The second section gathers four chapters on four different topics and illustrates how significant is the challenge to translate scientific advances into clinical practice because the route from evidence to action is not always obvious. It is hoped that this book will stimulate the interest in the process of translating research into practice for a broader range of neurosurgical topics than the one covered by this book, which could result in a forthcoming more comprehensive publication

The Refinement and Assessment of a Technique for General Anaesthesia Maintenance by Feedback Control

The objectives are to improve the quality of control obtained in a previous work which developed a system to maintain anaesthesia by feedback control of systolic arterial pressure (SAP). The study also aims to further validate the anaesthetic state produced by this system. The relationship of arterial pressure (AP) on admission to hospital and in the anaesthetic room to resting values is examined in a preliminary study, bearing in mind the recognition of the phenomenon of "white coat hypertension". Resting SAP, measured by an automatic monitor (Dinamap 1846), is then used to determine target SAP, which is the controlled variable in the feedback control system. Also, fentanyl analgesia is substituted for morphine in 20 of the 64 patients undergoing anaesthesia in this way. This narcotic has a more rapid onset of action than morphine, and it was thought that this would smooth anaesthesia and improve the SAP control. There has been no conscious awareness in patients undergoing anaesthesia by this method, and in this work we aim to further investigate the level of cognitive function during anaesthesia. We use a sensitive technique based on homophone priming in 24 patients. The anaesthetic state is assessed by the quality of SAP control, the absence of conscious awareness, the safety of the recovery period, and by the value of physiological variables during anaesthesia

CEPS: An Open Access MATLAB Graphical User Interface (GUI) for the Analysis of Complexity and Entropy in Physiological Signals

Background: We developed CEPS as an open access MATLAB® GUI (graphical user interface) for the analysis of Complexity and Entropy in Physiological Signals (CEPS), and demonstrate its use with an example data set that shows the effects of paced breathing (PB) on variability of heart, pulse and respiration rates. CEPS is also sufficiently adaptable to be used for other time series physiological data such as EEG (electroencephalography), postural sway or temperature measurements. Methods: Data were collected from a convenience sample of nine healthy adults in a pilot for a larger study investigating the effects on vagal tone of breathing paced at various different rates, part of a development programme for a home training stress reduction system. Results: The current version of CEPS focuses on those complexity and entropy measures that appear most frequently in the literature, together with some recently introduced entropy measures which may have advantages over those that are more established. Ten methods of estimating data complexity are currently included, and some 28 entropy measures. The GUI also includes a section for data pre-processing and standard ancillary methods to enable parameter estimation of embedding dimension m and time delay τ (‘tau’) where required. The software is freely available under version 3 of the GNU Lesser General Public License (LGPLv3) for non-commercial users. CEPS can be downloaded at https://bitbucket.org/deepak_panday/ceps/src/pipeline_v2/. In our illustration on PB, most complexity and entropy measures decreased significantly in response to breathing at 7 breaths per minute, differentiating more clearly than conventional linear, time- and frequency-domain measures between breathing states. In contrast, Higuchi fractal dimension increased during paced breathing. Conclusions: We have developed CEPS software as a physiological data visualiser able to integrate state of the art techniques. The interface is designed for clinical research and has a structure designed for integrating new tools. The aim is to strengthen collaboration between clinicians and the biomedical community, as demonstrated here by using CEPS to analyse various physiological responses to paced breathing

EFFECTS OF NEUROMODULATION ON NEUROVASCULAR COUPLING

The communication between neurons within neural circuits relies on neurotransmitters (glutamate, γ-aminobutyric acid (GABA)) and neuromodulators (acetylcholine, dopamine, serotonin, etc.). However, despite sharing similar molecular elements, neurotransmitters and neuromodulators are distinct classes of molecules and mediate different aspects of neural activity and metabolism. Neurotransmitters on one hand are responsible for synaptic signal transmission (classical transmission) while neuromodulators exert their functions by mediating different postsynaptic events that result in changes to the balance between excitation and inhibition. Neuromodulation, while essential to nervous system function, has been significantly more difficult to study than neurotransmission. This is principally due to the fact that effects elicited by neuromodulators are usually of slow onset, long lasting, and are not simply excitation or inhibition. In contrast to the effects of neurotransmitters, neuromodulators enable neurons to be more flexible in their ability to encode different sorts of information (e.g. sensory information) on a variety of time scales. However, it is important to appreciate that one of the challenges in the study of neuromodulation is to understand the extent to which neuromodulators’ actions are coordinated at all levels of brain function. That is, from the cellular and metabolic level to network and cognitive control. Therefore, understanding the molecules that mediate brain networks interactions is essential to understanding the brain dynamic, and also helps to put the cellular and molecular processes in perspective. Functional magnetic resonance imaging (fMRI) is a technique that allows access to various cellular and metabolic aspects of network communication that are difficult to access when studying one neuron at the time. Its non-invasiveness nature allows the comparison of data and hypotheses of the primate brain to that of the human brain. Hence, understanding the effects of neuromodulation on local microcircuits is needed. Furthermore, given the massive projections of the neuromodulatory diffuse ascending systems, fMRI combined with pharmacological and neurophysiological methods may provide true insight into their organization and dynamics. However, little is known about how to interpret the effects of neuromodulation in fMRI and neurophysiological data, for instance, how to disentangle blood oxygenation level dependent (BOLD) signal changes relating to cognitive changes (presumably neuromodulatory influences) from stimulus-driven or perceptual effects. The purpose of this dissertation is to understand the causal relationship between neural activity and hemodynamic responses under the influence of neuromodulation. To this end we present the results of six studies. In the first study, we aimed to establish a mass-spectrometry-based technique to uncover the distribution of different metabolites, neurotransmitters and neuromodulators in the macaque brain. We simultaneously measured the concentrations of these biomolecules in brain and in blood. In a second study, we developed a multimodal approach consisting of fMRI (BOLD and cerebral blood flow or CBF), electrophysiological recording with a laminar probe and pharmacology to assess the effects of neuromodulation on neurovascular coupling. We developed a pharmacological injection delivery system using pressure-operated pumps to reliably apply drugs either systemically or intracortically in the NMR scanner. In our third study, we systemically injected lactate and pyruvate to explore whether the plasma concentration of either of these metabolites affects the BOLD responses. This is important given that both metabolites are in a metabolic equilibrium; if this equilibrium is disrupted, changes in the NAD and NADH concentrations would elicit changes in the CBF. In a fourth study, we explored the influence of dopaminergic (DAergic) neuromodulation in the BOLD, CBF and neurophysiological activity. Here we found that DAergic neuromodulation dissociated the BOLD responses from the underlying neural activity. Interestingly, the changes in the neural activity were tightly coupled to the effects seen in the CBF responses. In a subsequent study, we explored whether the effects of dopamine (DA) on the electrophysiological responses are cortical layer dependent and whether specific patterns of neural activity can be used to infer the effects of neuromodulation on the neural activity. This is important, given that different types of neural activity provide independent information about the amplitude and dynamics from BOLD responses, and studies have shown that these bands originate from different cortical layers. What this study revealed, is that local field potentials (LFPs) in the midrange frequencies can indeed provide indications about the sustained effects of neuromodulation on cortical sensory processing. Given the results from the previous study, in our sixth study, we aimed at understanding how different cortical layers may process incoming and outgoing information in the different LFP bands. These findings provide evidence that neuromodulation has profound effects on neurovascular coupling. By changing the excitation-inhibition balance of neural circuits, neuromodulators not only mediate the neural activity, but also adjust the metabolic demands. Therefore, understanding how the different types of neuromodulators affect the BOLD response is essential for an effective interpretation of fMRI-data, not only in tasks involving attentional and reward-related processes, but also for future diagnostic use of fMRI, since many psychiatric disorders are the result of alterations in neuromodulatory systems.Die Kommunikation zwischen den Neuronen innerhalb neuronalen Schaltkreise beruht auf Neurotransmitter (Glutamat, γ-Aminobuttersäure (GABA)) und Neuromodulatoren (Acetylcholin, Dopamin, Serotonin, etc.). Neurotransmitter und Neuromodulatoren sind jedoch unterschiedliche Klassen von Molekülen und verschiedenen Aspekte der neuronalen Aktivität und den Stoffwechsel vermitteln. Neurotransmitters sind einerseits verantwortlich für die synaptische Signalübertragung (klassische Übertragung), während ihre Funktionen ausüben, Neuromodulatoren durch verschiedene postsynaptischen Ereignisse zu vermitteln, die in Änderungen an der Balance zwischen Erregung und Hemmung führen. Neuromodulation , während wesentlich Funktion des Nervensystems hat sich als Neurotransmission wesentlich schwieriger gewesen, zu studieren. Dies ist hauptsächlich auf die Tatsache zurückzuführen, die durch Neuromodulatoren sind in der Regel von langsamen Beginn, langlebig, und sind nicht einfach Anregung oder Hemmung ausgelöst beeinflusst. Im Gegensatz zu den Wirkungen von Neurotransmittern, Neuromodulatoren ermöglichen Neuronen flexibler zu sein in ihrer Fähigkeit, verschiedene Arten von Informationen (beispielsweise sensorische Informationen) auf einer Vielzahl von Zeitskalen zu kodieren. Im Gegensatz zu den Wirkungen von Neurotransmittern, Neuromodulatoren ermöglichen Neuronen flexibler zu sein in ihrer Fähigkeit, verschiedene Arten von Informationen (beispielsweise sensorische Informationen) auf einer Vielzahl von Zeitskalen zu kodieren. Im Gegensatz zu den Wirkungen von Neurotransmittern, Neuromodulatoren ermöglichen Neuronen flexibler zu sein in ihrer Fähigkeit, verschiedene Arten von Informationen (beispielsweise sensorische Informationen) auf einer Vielzahl von Zeitskalen zu kodieren. Jedoch ist es wichtig, dass eine der Herausforderungen bei der Untersuchung von Neuromodulations zu schätzen ist, das Ausmaß, in dem Neuromodulatoren Aktionen koordiniert sind auf allen Ebenen der Gehirnfunktion zu verstehen. Das heißt, von der zellulären und metabolischen Ebene zu vernetzen und kognitive Kontrolle. Daher die Moleküle zu verstehen, die Gehirn Netzwerke Interaktionen vermitteln ist wesentlich für das Verständnis des Gehirns dynamisch, und hilft auch, die zellulären und molekularen Prozesse in Perspektive zu setzen. Funktionellen Kernspintomographie (fMRI) ist eine Technik, die Zugang zu verschiedenen zellulären und metabolischen Aspekte der Netzwerk-Kommunikation ermöglicht, die schwer zugänglich sind, wenn zu der Zeit eines Neurons zu studieren. Seine nicht-Invasivität Natur ermöglicht den Vergleich von Daten und Hypothesen des Primatengehirn zu der des menschlichen Gehirns. Somit wurde das Verständnis der Auswirkungen der Neuromodulation auf lokale Mikro benötigt. Darüber hinaus sind die massiven Projektionen der neuromodulatorischen diffuse Aufstiegsanlagen gegeben, kombiniert fMRI mit pharmakologischen und neurophysiologischen Methoden wahren Einblick in ihre Organisation und Dynamik liefern. Allerdings ist nur wenig darüber bekannt, wie die Auswirkungen der Neuromodulations in fMRI und neurophysiologische Daten zu interpretieren, zum Beispiel, wie Blutoxydation pegelabhängig (BOLD) Signaländerungen in Bezug auf kognitive Veränderungen (vermutlich neuromodulatorischen Einflüsse) von Stimulus-driven oder Wahrnehmungseffekte zu entwirren. Der Zweck dieser Arbeit ist es, die kausale Beziehung zwischen neuronaler Aktivität und hämodynamischen Reaktionen unter dem Einfluss der Neuromodulations zu verstehen. Zu diesem Zweck stellen wir die Ergebnisse von sechs Studien. In der ersten Studie wollten wir eine auf Massenspektrometrie basierende Technik einzurichten, um die Verteilung von verschiedenen Metaboliten, Neurotransmittern und Neuromodulatoren in Makakengehirn aufzudeckenWir maßen gleichzeitig die Konzentrationen dieser Biomoleküle im Gehirn und im Blut. In einer zweiten Studie entwickelten wir einen multimodalen Ansatz, bestehend aus fMRI (BOLD und zerebralen Blutflusses oder CBF), elektrophysiologische Aufzeichnung mit einer laminaren Sonde und Pharmakologie, die Auswirkungen der Neuromodulation auf neurovaskulären Kopplung zu beurteilen. Wir entwickelten eine pharmakologische Injektionsverabreichungssystem druckbetriebenen Pumpen mit zuverlässiger Medikamente gelten entweder systemisch oder intrakortikale im NMR-Scanner. In unserer dritten Studie injizierten wir systemisch Laktat und Pyruvat zu untersuchen, ob die Plasmakonzentration von entweder dieser Metaboliten die BOLD-Antworten beeinflusst. Dies ist wichtig, dass beide gegeben Metaboliten in einem Stoffwechselgleichgewicht sind; wenn dieses Gleichgewicht gestört ist, Veränderungen in den NAD und NADH-Konzentrationen würden Veränderungen in der CBF entlocken. In einer vierten Studie untersuchten wir den Einfluss von dopaminergen (DA-erge) -Neuromodulation im BOLD, CBF und neurophysiologische Aktivität. Hier fanden wir, dass DAerge -Neuromodulation die BOLD-Antworten von der zugrunde liegenden neuronalen Aktivität distanzierte. Interessanterweise waren verbunden, um die Veränderungen in der neuronalen Aktivität eng auf die in den CBF Reaktionen gesehen Wirkungen. In einer nachfolgenden Studie untersuchten wir, ob die Wirkungen von Dopamin (DA) auf die elektrophysiologischen Reaktionen sind Rindenschicht abhängig, und ob bestimmte Muster der neuronalen Aktivität verwendet werden kann, die Wirkungen von Neuromodulations auf die neurale Aktivität zu schließen. Dies ist wichtig, da verschiedene Arten von neuralen Aktivität liefern unabhängige Informationen über die Amplitude und die Dynamik von BOLD-Antworten, und Studien haben gezeigt, dass diese Bands aus verschiedenen kortikalen Schichten stammen. Was diese Studie ergab, dass lokale Feldpotentiale (LFP) in den mittleren Frequenzen in der Tat Hinweise über die nachhaltige Wirkung der Neuromodulation auf die kortikale sensorische Verarbeitung zur Verfügung stellen kann. In Anbetracht der Ergebnisse der früheren Studie, in unserer sechsten Studie wollten wir auf das Verständnis, wie die verschiedenen kortikalen Schichten verarbeiten kann ein- und ausgehenden Informationen in den verschiedenen LFP-Bands. Diese Ergebnisse belegen, dass -Neuromodulation profunde Auswirkungen auf die neurovaskulären Kopplung hat. Durch die Veränderung der Erregungs Hemmung Gleichgewicht neuronaler Schaltkreise vermitteln Neuromodulatoren nicht nur die neurale Aktivität, sondern auch die metabolischen Anforderungen anzupassen. Daher verstehen, wie die verschiedenen Arten von Neuromodulatoren beeinflussen die BOLD-Antwort für eine effektive Interpretation von fMRI-Daten notwendig ist, nicht nur in Aufgaben attentional und Belohnung bezogenen Prozessen mit, sondern auch für zukünftige diagnostische Verwendung von fMRI, da viele psychiatrische Störungen sind das Ergebnis von Veränderungen in neuromodulatorischen Systemen.La comunicación de las neuronas en los circuitos neuronales depende de los neurotransmisores (glutamato, acido γ-amino-butírico o GABA) y los neuromoduladores (acetilcolina, dopamina, serotonina, etc.). Sin embargo, tanto neurotransmisores como neuromoduladores son diferentes clases de moléculas y median diferentes aspectos de la actividad neuronal y del metabolismo, a pesar de compartir elementos moleculares muy similares. Los neurotransmisores, por una lado, son responsables de la transmisión sináptica de la información mientras que los neuromoduladores median diferentes eventos pos-sinápticos que resultan en cambios en el balance de la excitación e inhibición. La influencia de la neuromodulación es esencial para la función del sistema nerviosos, sin embargo es más difícil de estudiar que neurotransmisión. Esto se debe a que los efectos de los neuromoduladores suelen ser de un inicio lento, de larga duración, y no reflejan excitación o inhibición. En contraste a los efectos de los neurotransmisores, los neuromoduladores permiten que las neuronas sean más flexibles en su habilidad de codificar diferentes tipos de información (por ejemplo, información sensorial) en varias escalas temporales. Sin embargo, es importante darse cuenta que uno de objetivos primordiales en el estudio de neuromodulación es el de entender el grado en que la acción de los neuromoduladores está coordinada a todos los niveles de la función cerebral. Es decir, desde los aspectos celulares y metabólicos hasta los niveles de redes neuronales y control cognitivo. Por lo tanto, comprender los forma en la que diferentes moléculas median la interacción entre redes neuronal es esencial para el entendimiento de la dinámica cerebral, y también nos ayudara a comprender los procesos celulares y moleculares asociados a la percepción. La resonancia magnética funcional (fMRI, por sus siglas en inglés) es una técnica que permite acceder a varios aspectos celulares y metabólicos de la comunicación entre redes neuronales que suele ser de difícil acceso. Al mismo tiempo y debido que la fMRI es de naturaleza no invasiva, también permite comparar resultados e hipótesis entre humanos y primates. Por lo tanto, entender los efectos de la neuromodulación en la actividad de los circuitos neuronales es de alta relevancia. Dado que las proyecciones anatómicas de los sistemas de neuromoduladores, el uso de fMRI en combinación con farmacología y neurofisiología puede incrementar nuestro conocimiento sobre la estructura y dinámica de los sistemas de neuromoduladores. Sin embargo, poco se sabe sobre cómo interpretar los efectos de neuromodulation usando fMRI y neurofisiología, por ejemplo, como diferenciar los cambios en la señal BOLD que están relacionados a diferentes estados cognitivos (presumiblemente reflejando la influencia de neuromodulation). El propósito de esta disertación es la de comprender la relación causal que existe entre la actividad neural y la respuesta hemodinámica bajo la influencia de neuromodulación. Para tal fin presentamos los resultados de seis estudios que fueron producto de esta disertacion. En el primer estudio, desarrollamos una técnica basada en espectrometría de masa para detectar y medir la concentración de diferente metabolitos, neurotransmisores y neuromoduladores en el cerebro de primates. Dicha cuantificación se desarrollo simultáneamente tanto in sangre y cerebro. En un segundo estudio, utilizamos varias técnicas de fMRI (BOLD y flujo cerebral sanguíneo, CBF por sus siglas en ingles), registros electrofisiológicos con electrodos laminares y farmacología para acceder a los efectos de neuromodulation en el acople neurovascular. Para este fin, desarrollamos un sistema de inyecciones, basada en cambios de presión, para aplicar substancias sistémicamente o intracorticalmente dentro de un escáner de resonancia magnética. En nuestro tercer estudio, comparamos los efectos de lactato y piruvato para explorar como el desequilibrio metabólico de estas dos substancias afecta la respuesta BOLD. Esto es de gran importancia ya que ambas substancias metabólicas usualmente están en equilibrio. Sin embargo, cuando dicho equilibrio es interrumpido, los procesos metabólicos que acontecen en la mitocondria afectan las concentraciones de NAD y NADH causado cambios en el CBF. En un cuarto estudio, exploramos los efectos de las modulación dopaminergica (DAergic) en las señales BOLD, CBF y en la actividad neuronal. Encontramos que la modulación DAergic disocia las respuesta BOLD de la respuesta neuronal. Interesalmente, los cambios que observamos en la actividad de las neuronas estaba altamente acoplados a los efectos que observamos en la señal de CBF. En un estudio subsecuente, exploramos si los efectos de dopamina en la actividad neuronal es diferentes en las distintas capas de la corteza cerebral. Al mismo tiempo y ya que los neuromoduladores afectan la actividad de circuitos neuronales, exploramos si dichos efectos pueden usados como marcadores de la influencia de la neuromodulación . Esto es importante, ya que diferentes tipos de actividad neuronal brinda información sobre la amplitud y dinámica de la repuesta BOLD, y estudies han demostrado que estas bandas se originan de diferentes capas cortical. Este estudio revelo, que los potenciales de capo (LFPs, por sus siglas en ingles) en frecuencias intermedias puede ser indicativos sobre los efectos de neuromodulation en el procesamiento cortical. Dado los resultados en el estudio previo, en un sexto estudio, nos enfocamos a entender que tan diferentes las capas de la corteza procesan información entrante y saliente en diferentes frecuencias de los LFPs. Estos descubrimientos demuestran que los efectos de los neuromoduladores tiene una fuerte influencia en el acople neurovascular. Los neuromoduladores cambian el balance de excitación e inhibición de los circuitos neuronal, pero también median las demandas metabólicas. De esta manera, entender cómo interpretar los efectos de los neuromoduladores en la respuesta BOLD es esencial para una interpretación veraz y efectiva de los datos generados con fMRI. Estos resultados, no solo nos permiten comprender los procesos que están relacionados a la atención o de varios procesos cognitivos, sino que a su vez, nos permite comprender la señal de fMRI para su futuro uso en la medicina diagnostica, ya que muchas enfermedades psiquiátricas están asociadas a trastornos en el sistemas neuromoduladores

Endoscopy

Endoscopy is a fast moving field, and new techniques are continuously emerging. In recent decades, endoscopy has evolved and branched out from a diagnostic modality to enhanced video and computer assisting imaging with impressive interventional capabilities. The modern endoscopy has seen advances not only in types of endoscopes available, but also in types of interventions amenable to the endoscopic approach. To date, there are a lot more developments that are being trialed. Modern endoscopic equipment provides physicians with the benefit of many technical advances. Endoscopy is an effective and safe procedure even in special populations including pediatric patients and renal transplant patients. It serves as the tool for diagnosis and therapeutic interventions of many organs including gastrointestinal tract, head and neck, urinary tract and others