Multivariate assessment of linear and non-linear causal coupling pathways within the central-autonomic-network in patients suffering from schizophrenia

Im Bereich der Zeitreihenanalyse richtet sich das Interesse zunehmend darauf, wie Einblicke in die Interaktions- und Regulationsprozesse von pathophysiologischen- und physiologischen Zuständen erlangt werden können. Neuste Fortschritte in der nichtlinearen Dynamik, der Informationstheorie und der Netzwerktheorie liefern dabei fundiertes Wissen über Kopplungswege innerhalb (patho)physiologischer (Sub)Systeme. Kopplungsanalysen zielen darauf ab, ein besseres Verständnis dafür zu erlangen, wie die verschiedenen integrierten regulatorischen (Sub)Systeme mit ihren komplexen Strukturen und Regulationsmechanismen das globale Verhalten und die unterschiedlichen physiologischen Funktionen auf der Ebene des Organismus beschreiben. Insbesondere die Erfassung und Quantifizierung der Kopplungsstärke und -richtung sind wesentliche Aspekte für ein detaillierteres Verständnis physiologischer Regulationsprozesse. Ziel dieser Arbeit war die Charakterisierung kurzfristiger unmittelbarer zentral-autonomer Kopplungspfade (top-to-bottom und bottom to top) durch die Kopplungsanalysen der Herzfrequenz, des systolischen Blutdrucks, der Atmung und zentraler Aktivität (EEG) bei schizophrenen Patienten und Gesunden. Dafür wurden in dieser Arbeit neue multivariate kausale und nicht-kausale, lineare und nicht-lineare Kopplungsanalyseverfahren (HRJSD, mHRJSD, NSTPDC) entwickelt, die in der Lage sind, die Kopplungsstärke und -richtung, sowie deterministische regulatorische Kopplungsmuster innerhalb des zentralen-autonomen Netzwerks zu quantifizieren und zu klassifizieren. Diese Kopplungsanalyseverfahren haben ihre eigenen Besonderheiten, die sie einzigartig machen, auch im Vergleich zu etablierten Kopplungsverfahren. Sie erweitern das Spektrum neuartiger Kopplungsansätze für die Biosignalanalyse und tragen auf ihre Weise zur Gewinnung detaillierter Informationen und damit zu einer verbesserten Diagnostik/Therapie bei. Die Hauptergebnisse dieser Arbeit zeigen signifikant schwächere nichtlineare zentral-kardiovaskuläre und zentral-kardiorespiratorische Kopplungswege und einen signifikant stärkeren linearen zentralen Informationsfluss in Richtung des Herzkreislaufsystems auf, sowie einen signifikant stärkeren linearen respiratorischen Informationsfluss in Richtung des zentralen Nervensystems in der Schizophrenie im Vergleich zu Gesunden. Die detaillierten Erkenntnisse darüber, wie die verschiedenen zentral-autonomen Netzwerke mit paranoider Schizophrenie assoziiert sind, können zu einem besseren Verständnis darüber führen, wie zentrale Aktivierung und autonome Reaktionen und/oder Aktivierung in physiologischen Netzwerken unter pathophysiologischen Bedingungen zusammenhängen.In the field of time series analysis, increasing interest focuses on insights gained how the coupling pathways of regulatory mechanisms work in healthy and ill states. Recent advances in non-linear dynamics, information theory and network theory lead to a new sophisticated body of knowledge about coupling pathways within (patho)physiological (sub)systems. Coupling analyses aim to provide a better understanding of how the different integrated physiological (sub)systems, with their complex structures and regulatory mechanisms, describe the global behaviour and distinct physiological functions at the organism level. In particular, the detection and quantification of the coupling strength and direction are important aspects for a more detailed understanding of physiological regulatory processes. This thesis aimed to characterize short-term instantaneous central-autonomic-network coupling pathways (top-to-bottom and bottom to top) by analysing the coupling of heart rate, systolic blood pressure, respiration and central activity (EEG) in schizophrenic patients and healthy participants. Therefore, new multivariate causal and non-causal linear and non-linear coupling approaches (HRJSD, mHRJSD, NSTPDC) that are able to determine the coupling strength and direction were developed. Whereby, the HRJSD and mHRJSD approaches allow the quantification and classification of deterministic regulatory coupling patterns within and between the cardiovascular- the cardiorespiratory system and the central-autonomic-network were developed. These coupling approaches have their own unique features, even as compared to well-established coupling approaches. They expand the spectrum of novel coupling approaches for biosignal analysis and thus contribute in their own way to detailed information obtained, and thereby contribute to improved diagnostics/therapy. The main findings of this thesis revealed significantly weaker non-linear central-cardiovascular and central-cardiorespiratory coupling pathways, and significantly stronger linear central information flow in the direction of the cardiac- and vascular system, and a significantly stronger linear respiratory information transfer towards the central nervous system in schizophrenia in comparison to healthy participants. This thesis provides an enhanced understanding of the interrelationship of central and autonomic regulatory mechanisms in schizophrenia. The detailed findings on how variously-pronounced, central-autonomic-network pathways are associated with paranoid schizophrenia may enable a better understanding on how central activation and autonomic responses and/or activation are connected in physiology networks under pathophysiological conditions

The Impact of Alcoholic Beverages on Human Health

Alcohol is often perceived as an under-rated risk factor for human health. This book corrects these misperceptions and misinformation by providing up to date reviews and publications that consider the impact of alcoholic beverages on human health in the domains of toxicity, carcinogenicity, genotoxicity, foetal toxicity, neurotoxicity, impacts of alcohol on the gastro-intestinal system (including nutrient deficiencies), cardiovascular system, injuries, body weight and communicable diseases. The reprint considers how the impact of alcohol on human health can be mitigated – through, for example, improved labelling on nutrients and health warnings, better policy measures, and actions by alcohol producers on their products through reformulation to lower alcoholic strength

11th European Headache Federation Congress jointly with 31st Congress of the Italian Society for the Study of Headaches : Rome, Italy. 01-03 December 2017

. Aims of the study were explore the relationship between peripheral chromatic and central visual dysfunction evaluating also the presence of functional receptor impairment in patients with migraine, with and without aura examined interictally

Neurophysiological mechanisms of chronic primary spine pain relief by chiropractic spinal manipulation = Mécanismes neurophysiologiques du soulagement de la douleur vertébrale chronique primaire par les manipulations vertébrales chiropratiques

La chiropratique est une profession de la santé qui s’intéresse au diagnostic, au traitement, et à la prévention des troubles musculosquelettiques. L’intervention la plus communément utilisée en chiropratique est la manipulation vertébrale (dite « ajustement chiropratique »). D’ailleurs, les consultations en chiropratique sont principalement pour des douleurs vertébrales, particulièrement dans la région lombaire. La lombalgie est la principale cause d'incapacité à travers le monde. Elle engendre des coûts considérables pour la société et les individus atteints. Chez environ un tiers des individus, la lombalgie persiste et devient chronique, entraînant une incapacité et une diminution de la qualité de vie. Chez ces individus, aucun processus pathologique affectant les tissus vertébraux ne peut être mis en évidence. En effet, cette douleur, dite nociplastique, serait plutôt causée par des mécanismes pathologiques du système nociceptif. La lombalgie chronique, dite primaire chez ces individus, est ainsi considérée comme le diagnostic en soi, et non un symptôme secondaire à une pathologie sous-jacente. Chez certains individus, les manipulations vertébrales peuvent soulager la lombalgie chronique primaire. Cependant, leur efficacité comme intervention de première ligne et leurs mécanismes hypoalgésiques restent à démontrer. L'objectif général de cette thèse est d’examiner les mécanismes hypoalgésiques des manipulations vertébrales. Le premier objectif spécifique est d’examiner les mécanismes hypoalgésiques d’une manipulation vertébrale à l’aide d’un modèle expérimental de douleur persistante chez des individus en santé. Le deuxième objectif spécifique est d’examiner les mécanismes du soulagement de la douleur lombaire chronique primaire par une intervention chiropratique de quatre semaines, qui comprend douze séances de manipulations vertébrales. La thèse comprend deux études empiriques, soit une étude expérimentale et une étude clinique, qui sont précédées d’une revue de littérature ciblée. Le premier article est une revue narrative explorant les mécanismes neurophysiologiques de la manipulation vertébrale pour soulager la douleur vertébrale. Le deuxième article décrit les résultats d’une étude expérimentale chez des individus en santé. Dans cette étude, nous avons examiné les mécanismes d'inhibition de la douleur en réponse à une manipulation vertébrale ciblant un segment vertébral dont la peau a été sensibilisée par une application topique de capsaïcine. Le troisième article est une revue narrative examinant l'efficacité des manipulations vertébrales pour le traitement des douleurs vertébrales. Le quatrième article décrit les résultats d’un essai contrôlé randomisé avec groupe placebo chez des individus atteints de lombalgie chronique primaire. Dans cette étude, nous avons examiné si le soulagement de la lombalgie chronique primaire par une intervention chiropratique s’accompagne d’une atténuation de processus pathologiques contribuant à la douleur nociplastique. Les résultats indiquent qu’une manipulation vertébrale peut atténuer l’hyperalgésie mécanique secondaire observée avec le modèle expérimental de douleur persistante. Ceci suggère qu’une manipulation vertébrale pourrait agir sur des processus pathologiques qui mènent à la douleur chronique. Ces résultats sont cohérents avec la réduction de la douleur observée chez les patients atteints de lombalgie chronique primaire recevant des manipulations vertébrales. De plus, la réduction de la lombalgie chronique était accompagnée d’une réduction de l’hyperalgésie mécanique lombaire et de la dramatisation de la douleur. Dans l’ensemble, ces résultats suggèrent qu’une intervention chiropratique comprenant des manipulations vertébrales est efficace pour réduire la lombalgie chronique primaire, et que cet effet pourrait découler en partie d’une réduction de processus contribuant à la douleur nociplastique. Ceci renforce les recommandations cliniques sur l’utilisation de la chiropratique pour le soulagement de la lombalgie chronique primaire. D’autres études seront nécessaires pour clarifier les mécanismes neurophysiologiques et anti-inflammatoires des manipulations vertébrales.Chiropractic is a health profession focused on the diagnosis, treatment, and prevention of musculoskeletal disorders, mainly through spinal manipulation (also known as "chiropractic adjustment"). The majority of patients consult a chiropractor seeking spine pain relief, primarily in the lower back. Low back pain is the leading cause of global disability, generating considerable costs for society and affected individuals. At least one third of people with low back pain experience persistent pain, leading to chronic disability and a decrease in quality of life. In affected individuals, no pathological process affecting the spinal tissues can be identified. Instead, this pain, called nociplastic, is presumed to be caused by pathological mechanisms within the nociceptive system. Thus, in these individuals, low back pain is considered as chronic primary pain, and not the symptom of an underlying disease. In some individuals, spinal manipulations can relieve chronic primary low back pain. However, their effectiveness as a first-line intervention and their hypoalgesic mechanisms remain to be demonstrated. The overarching aim of this thesis is to examine the hypoalgesic mechanisms of chiropractic spinal manipulations. The first specific objective is to investigate the hypoalgesic mechanisms of a spinal manipulation using an experimental model of persistent back pain in healthy individuals. The second specific objective is to investigate the mechanisms of relief of chronic primary low back pain by a four-week chiropractic intervention, including twelve sessions of spinal manipulations. The thesis includes two empirical studies: an experimental study and a clinical study, both preceded by a targeted literature review. The first study is a narrative review exploring the neurophysiological mechanisms of spinal manipulation to relieve spine pain. The second article describes the results of an experimental trial on healthy individuals, where we examined the mechanisms of pain inhibition following a spinal manipulation targeting a spinal segment sensitized by the topical application of capsaicin The third article is a narrative review examining the effectiveness of spinal manipulation for the treatment of spine pain. The fourth article describes the results of a randomized placebo-controlled trial with individuals suffering from chronic primary low back pain. In this study, we examined whether the relief of chronic primary low back pain by a chiropractic intervention is accompanied by an attenuation of pathological processes contributing to nociplastic pain. The results indicate that a single spinal manipulation can mitigate segmental mechanical hyperalgesia observed with the experimental model of persistent pain. This suggests that spinal manipulations could act on pathological processes that lead to chronic pain. These results are consistent with the pain reduction observed in patients with chronic primary low back pain receiving spinal manipulations. Furthermore, low back pain relief was accompanied by a reduction in mechanical hyperalgesia and in pain catastrophizing. Overall, these results indicate that a chiropractic intervention including spinal manipulations is efficacious in reducing chronic primary low back pain, and that this effect could in part stem from a reduction in processes contributing to nociplastic pain. This reinforces clinical recommendations on the use of chiropractic for the relief of chronic primary low back pain. Further studies will be needed to clarify the neurophysiological and anti-inflammatory mechanisms of spinal manipulations

On Bayesian Methods in Network Regression

There has been a growing interest during recent years in connectomics, which is the study of interconnections or networks within the human brain. This interest has been spurred by the development of new imaging technologies, which allow researchers to peer non-invasively into the human brain and obtain data on connections. Motivated by these datasets, this dissertation develops a novel class of Bayesian regression models which study the relationships between neuro-scientific phenotypes and brain connectome networks of individuals.First, we introduce a novel approach that develops a regression framework of the brain network (represented in the form of a symmetric matrix) on a continuous phenotypic response. We propose a novel network shrinkage prior on the network predictor coefficient matrix. The proposed framework is able to identify nodes or functional regions in the brain network and interconnections between different regions, significantly related to the phenotypic response. To the best of our knowledge, our framework is the first principled Bayesian framework that enables identification of network nodes and edges significantly relatedto the response. The performance of the proposed model is evaluated with respect to a wide range of existing competitors available in the high dimensional frequentist and Bayesian literature using a variety of simulation studies. The proposed model identifies important brain regions and interconnections significantly associated with creativity for a group of subjects.Next, we extend our model to build network classifiers when a brain connectome network along with a binary response is provided for a group of individuals. Here we develop a broader class of global-local network shrinkage priors which includes the novel prior distribution specified earlier as a special case. We specifically consider two different global-local network shrinkage priors from this class of priors and investigate them using simulation studies. In particular, we assess their performance in terms of network classification and identifying influential network nodes and edges for the purpose of classification. We also demonstrate superior performance of our proposed network classifiers over state-of-the-art high dimensional classification techniques. Another major contribution remains developing theoretical conditions to guarantee asymptotically consistent classification for the proposed framework. In particular, we derive conditions on the number of network nodes, sparsity in the network coefficient matrix as a function of the sample size to achieve asymptotically optimal classification. While theoretical results on high dimensional binary regression with ordinary shrinkage priors have emerged recently, developing theory for our network classifier model involves several additional challenges due to the complex nature of the global local shrinkage prior developed here. The framework is used to classify individuals into high and low IQ groups based on their brain connectomes.Notably, the work discussed in the last two paragraphs tacitly assumes that all nodes and edges have similar impact on a phenotype for every individual. In our next project, we study a brain connectome data where this assumption is violated. In fact, there is a relatively less developed literature in neuroscience that argues for different groups of individuals having shared relationships between brain networks and phenotypes, though this literature lacks a principled Bayesian approach that takes into account different relationships of nodes and edges with the response for different groups of individuals and facilitates clustering of individuals. Motivated by this problem and our dataset, we have developed a Bayesian network mixture regression model. Simulation studies and analysis of the brain connectome dataset demonstrate superior performance of the proposed approach over the approach described earlier. Simulation studies are also used to evaluate the performance of the proposed approach by varying the true and fitted number of clusters, size of the network and sample size.For these projects, computationally efficient Bayesian sampling algorithms are developed to enable computations even for reasonably large networks in presence of moderately large sample size

On the Origin of Dementia : a Population Perspective on Risk and Aetiology

Recent years have seen a surge in dementia research, with increasing awareness that preventive strategies are key to curbing the dementia epidemic. Drawing from long-term population-based studies, this thesis describes the burden of dementia in terms of (healthy) life years lost, lifetime risk of developing disease, and the past and potential effects of preventive interventions on dementia incidence. Furthermore, the role of (disturbances in) cerebral blood flow, for instance due to carotid artery stenosis, and that of cerebral autoregulatory mechanisms in the onset of dementia is extensively discussed. In the subsequent chapter, a literature review that ties coronary heart disease and heart failure to the risk of dementia is followed by exploration of potential underlying mechanisms, including thromboembolic disease (e.g. Von Willebrand factor and ADAMTS13), (vascular) amyloid-β, and aortic valve calcification. Finally, the heritability of dementia and Alzheimer’s disease is yielded for both aetiological and predictive purposes. In particular, the role of the Apolipoprotein E (APOE) gene is described in mortality and for clinical trial design, followed by the use of parental family history and common genetic variants for risk prediction. This thesis concludes with methodological considerations and recommendations – or rather a wish list – for future research to strive and take dementia into the realm of forgotten diseases

Childhood Trauma And Emotion Processing Neurocircuitry

Childhood trauma is one of the strongest risk factors for a range of common and debilitating neuropsychiatric disorders, including anxiety, depression, and posttraumatic stress disorder (PTSD). These emotion-related disorders have their roots in childhood and adolescence, underscoring a critical need to understand their biological bases in early life. In this dissertation, we evaluate how childhood trauma impacts emotion processing neurocircuitry in a sample of high-risk urban youth, ages 7-15. In four inter-related studies, we test neural function and functional connectivity of core emotion processing regions, including the amygdala, insula, and pregenual/subgenual anterior cingulate cortex (pgACC/sgACC). To examine the relevance of observed neurological changes, we evaluate behavioral performance on emotion processing neuropsychological tasks, as well as specific dimensions of subjective affective experience. Results indicate that, relative to matched comparison youth, trauma-exposed youth have (1) increased neural response to salient emotional cues in amygdala and insula, (2) reduced functional connectivity between amygdala and pgACC/sgACC, a pathway critical for emotion regulation, and (3) altered within- and between-network connectivity of the salience network, involved in detecting and orienting attention to salient emotional stimuli. These neurological changes are accompanied by behavioral alterations: trauma-exposed youth have a lower ability to ignore distracting emotional information, and to automatically regulate emotion. Additionally, observed neurobehavioral changes relate to a specific dimension of affective experience – reward sensitivity (RS), rather than negative affect. Moreover, trauma-exposed youth with the greatest neurobehavioral impairment report lower RS, suggesting reduced positive environmental engagement. These results suggest that RS may be a marker of stress susceptibility, a notion supported by emerging basic and clinical research. Based on our neurobehavioral findings, we discuss potential implications for intervention, and relay an emerging framework that dissociates neurological effects of different trauma types (i.e., threat/victimization vs. deprivation/neglect). In closing, we discuss future directions, including longitudinal research and evaluating the modulation of learned fear – a neurobehavioral mechanism that depends on emotion processing neurocircuitry, but has yet to be tested in trauma-exposed youth