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 cardiorespiratory network in healthy first-degree relatives of schizophrenic patients

Impaired heart rate- and respiratory regulatory processes as a sign of an autonomic dysfunction seems to be obviously present in patients suffering from schizophrenia. Since the linear and non-linear couplings within the cardiorespiratory system with respiration as an important homeostatic control mechanism are only partially investigated so far for those subjects, we aimed to characterize instantaneous cardiorespiratory couplings by quantifying the casual interaction between heart rate (HR) and respiration (RESP). Therefore, we investigated causal linear and non-linear cardiorespiratory couplings of 23 patients suffering from schizophrenia (SZO), 20 healthy first-degree relatives (REL) and 23 healthy subjects, who were age-gender matched (CON). From all participants’ heart rate (HR) and respirations (respiratory frequency, RESP) were investigated for 30 min under resting conditions. The results revealed highly significant increased HR, reduced HR variability, increased respiration rates and impaired cardiorespiratory couplings in SZO in comparison to CON. SZO were revealed bidirectional couplings, with respiration as the driver (RESP → HR), and with weaker linear and non-linear coupling strengths when RESP influencing HR (RESP → HR) and with stronger linear and non-linear coupling strengths when HR influencing RESP (HR → RESP). For REL we found only significant increased HR and only slightly reduced cardiorespiratory couplings compared to CON. These findings clearly pointing to an underlying disease-inherent genetic component of the cardiac system for SZO and REL, and those respiratory alterations are only clearly present in SZO seem to be connected to their mental emotional states

Altered causal coupling pathways within the central-autonomic-network in patients suffering from schizophrenia

The multivariate analysis of coupling pathways within physiological (sub)systems focusing on identifying healthy and diseased conditions. In this study, we investigated a part of the central-autonomic-network (CAN) in 17 patients suffering from schizophrenia (SZO) compared to 17 age–gender matched healthy controls (CON) applying linear and nonlinear causal coupling approaches (normalized short time partial directed coherence, multivariate transfer entropy). Therefore, from all subjects continuous heart rate (successive beat-to-beat intervals, BBI), synchronized maximum successive systolic blood pressure amplitudes (SYS), synchronized calibrated respiratory inductive plethysmography signal (respiratory frequency, RESP), and the power PEEG of frontal EEG activity were investigated for 15 min under resting conditions. The CAN revealed a bidirectional coupling structure, with central driving towards blood pressure (SYS), and respiratory driving towards PEEG. The central-cardiac, central-vascular, and central-respiratory couplings are more dominated by linear regulatory mechanisms than nonlinear ones. The CAN showed significantly weaker nonlinear central-cardiovascular and central-cardiorespiratory coupling pathways, and significantly stronger linear central influence on the vascular system, and on the other hand significantly stronger linear respiratory and cardiac influences on central activity in SZO compared to CON, and thus, providing better understanding of the interrelationship of central and autonomic regulatory mechanisms in schizophrenia might be useful as a biomarker of this diseas

Joint symbolic dynamics for the assessment of cardiovascular and cardiorespiratory interactions

Beat-to-beat variations in heart period provide information on cardiovascular control and are closely linked to variations in arterial pressure and respiration. Joint symbolic analysis of heart period, systolic arterial pressure and respiration allows for a simple description of their shared short-term dynamics that are governed by cardiac baroreflex control and cardiorespiratory coupling. In this review, we discuss methodology and research applications. Studies suggest that analysis of joint symbolic dynamics provides a powerful tool for identifying physiological and pathophysiological changes in cardiovascular and cardiorespiratory control.Mathias Baumert, Michal Javorka and Muammar Kabi

Investigating the neuroprotective effect of exercise; the role of redox homeostasis

The balance between oxidant production and the antioxidant defence system is essential to brain health. First-episode psychosis (FEP) and schizophrenia (SZ) are psychiatric disorders that affect the patients’ contact with reality, with unique presentation of symptoms and experiences. Both FEP and SZ can be characterised by perturbed redox status, notably via antioxidant depletion. Previous research, undertaken in healthy populations, has highlighted the ability of exercise training to regulate redox balance. One particular biomarker of redox status is the antioxidant glutathione (GSH), which has a principal role of removing toxic substances from the cell, especially in the brain. This thesis presents novel data investigating the drawbacks of exercise study design in youth mental health, the efficacy of a training intervention in ‘normalising’ measures of antioxidant capacity, oxidative stress, inflammation and functionality in FEP. Studies presented go on to interrogate some of the redox-related mechanisms of the neurodevelopmental aspect of psychosis pathophysiology. Assessment of GSH in the brain, blood and in patient-derived cell models offers significant gateways into elucidating the pathological mechanisms of mental ill-health. In order to address some of the principle weaknesses in previous study design which have aimed to provide exercise to a FEP cohort, chapter 2 of this thesis used personalised heart rate zones (50-70% VO2max) to standardise bouts of activity across a range of exercise modalities, in a healthy but sedentary group of young people. The study was successful in provoking a redox response 2 during each acute bout, which typically initiates the stimulation of adaptive processes. This study achieved 100% retention, which also demonstrated that engagement in an exercise intervention is possible in a sedentary group, when choice of activity and variety of exercise mode are offered to the participant. Chapters 3 and 4 highlight the therapeutic benefits of regular exercise training (12 weeks, 3-4 times/week, 40-60 minutes) for FEP patients in a randomised trial. The study highlighted the positive impact of increased physical activity on peripheral and brain indices of GSH, markers of oxidative stress, and patient- centred measures of psychotic symptomology and daily function. In a more in- depth assessment of the GSH cycle and indices of cell damage, chapter 5 describes the characterisation and generation of mature astrocytes and neurons from SZ patient-derived induced pluripotent stem cells (iPSCs), as a model of the neurodevelopmental aspect of disease pathogenesis. It was found that the de-toxifying ability of GSH is impaired in SZ cerebral cells, offering a cogent target for further investigation in this novel approach to assessing the mechanisms of mental ill-health, in the brain

Untersuchung zur Prävalenz kardialer autonomer Dysfunktion bei unmedizierten schizophrenen Patienten

Die schizophrene Erkrankung geht mit einer verkürzten Lebenserwartung von 15 bis 20 Jahren einher, die vor allem auf kardiovaskuläre Erkrankungen zurückzuführen ist. Ziel dieser Arbeit war es eine Bewertungsskala zu entwickeln, die die individuelle Ausprägung kardial autonomer Dysfunktion (CADF), als maßgeblichen Faktor für die erhöhte kardial bedingte Mortalität quantifiziert, um dann in einem weiteren Schritt zu untersuchen, wie häufig verschiedene Ausprägungen in einem großen Kollektiv unmedizierter Patienten vorkommen. Indem für jeden der 112 Patienten jeder einzelne der 13 ausgewählten Indices der Herzratenvariabilität, die aus 30-minütigen EKG-Ableitungen unter Ruhebedingungen generiert wurden, in Bezug zur ersten, eineinhalbfachen und zweiten Standardabweichung vom jeweiligen Mittelwert des gesunden Kontrollkollektivs (N=112) gesetzt wurde, wurden Bewertungspunkte vergeben, deren Gesamtpunktzahl die Zuordnung in eine der Gruppen keine, moderate und schwere CADF festlegte. Wir konnten zeigen, dass ein Drittel der Patienten von einer schwerwiegenden kardialen autonomen Dysfunktion betroffen ist, die vor allem durch erhöhte Herzfrequenzen und eine verminderte vagale Modulation charakterisiert ist. Ein Viertel zeigte keine autonomen Auffälligkeiten und die restlichen Patienten hatten moderate autonome Abweichungen. In unserer Arbeit hatten nur wenige psychopathologische und epidemiologische Indices einen geringen Einfluss auf die CADF, einen eindeutigen Zusammenhang konnten wir mit der Chronizität der schizophrenen Erkrankung zeigen. Zukünftige Untersuchungen sollten die Frage klären, wie Gesundheit und Lebensqualität der disponierten Patienten mit den moderaten und schweren kardial autonomen Veränderungen besser geschützt werden können

Respuesta emocional de ira y alteraciones del lenguaje en pacientes con esquizofrenia

Los pacientes con esquizofrenia presentan alteraciones en el procesamiento emocional especialmente en la expresión, y en el reconocimiento de emociones. Sin embargo, se ha investigado poco cómo experimentan las emociones los pacientes con esquizofrenia y en concreto existe una literatura muy escasa sobre la respuesta cardiovascular, hormonal o de la activación asimétrica cerebral. Por otro lado, la ira es clave en la conducta agresiva, y en el caso de la esquizofrenia parece estar mediada por síntomas psicóticos como las alucinaciones y los delirios. Basándonos, pues, en la respuesta emocional anómala que pueden presentar las personas con esquizofrenia en general, y los pacientes con alucinaciones en particular, para estudiar la respuesta emocional de ira en esquizofrenia hemos seleccionado una muestra de 34 pacientes con esquizofrenia, de los cuales la mitad presenta alucinaciones auditivas persistentes y la otra mitad nunca las ha experimentado y los hemos comparado con un grupo de 30 sujetos sanos. Los resultados muestran como las personas con esquizofrenia después de la inducción emocional se sienten más enfadados aunque no al mismo nivel que los sujetos sanos. Sin embargo la respuesta psicobiológica de los pacientes ante la ira es muy similar a los sujetos sanos: aumentan la tensión arterial y la testosterona y disminuyen el cortisol. De hecho, cuanto más se enfadan más aumentan el nivel de testosterona en saliva. Respecto a la actividad asimétrica cerebral, encontramos, como en sujetos sanos, una mayor activación del hemisferio izquierdo (medido a través de la técnica de la escucha dicótica), presumiblemente del lóbulo frontal izquierdo, lo que apoyaría el modelo de dirección motivacional. Aunque no hemos encontrado diferencias entre alucinadores y no alucinadores respecto a la respuesta emocional de ira y la ira rasgo no se relacionaba con la gravedad de las voces, sí hemos encontrado una clara relación de la ira con los delirios y la paranoia lo que refuerza la importancia de estudiar más esta emoción en esquizofrenia como se ha hecho en la presente tesis

Improving somatic health for outpatients with severe mental illness: the development of an intervention

Objective: Patients with severe mental illness (SMI) suffer from more somatic illness than the general population. Possible causes are side effects of neuropsychiatric medication, genetic vulnerability, insufficient health care and lifestyle. This co-morbidity is potentially reversible and augments the costs for health care and diminishes quality of life. Screening on symptoms and risks of somatic diseases and coordination of care are proposed to improve SMI-patients' somatic health status. Methods: A clinical facility was started to improve the somatic health status of patients in an outpatient centre in southern Netherlands. This outpatient centre was added to the specialized care for severe and enduring SMI. The intervention consisted of the inventarisation of side-effects and the detection of gaps in health care provision for 72 patients. This was based on interviewing the patients, laboratory screening, collecting information from their general practitioner and pharmacy. A list was compiled of possible diagnosis and health risks, and a plan of action was made for the treatment. Healthcare consumption, quality of life and general functioning were assessed to analyze cost-effectiveness. Evaluations were performed with the psychiatric care team on the process. Results: Mean annual cost of GP's and medical specialist's consultations were E492. There existed a negative relation between EQ5D VAS and the number of self reported chronic diseases. Conclusion: The authors conclude that the procedure is well feasible, but should be set up in close collaboration with all health care professionals of these patients to make tailor made solutions possible

Primate Ventromedial Prefrontal Cortex and the Physiological and Behavioural Dysfunction Characteristic of Mood and Anxiety Disorders

The heterogeneity intrinsic to the ventromedial prefrontal cortex (vmPFC) is evidenced in both its anatomy and implicated function: vmPFC subregions have roles in positive affect, negative affect and autonomic/endocrine regulation. Whether different subregions serve fundamentally different functions, or whether they perform similar computations on different inputs, remains unclear. Nevertheless, the role of the vmPFC in psychopathology is widely appreciated – in mood and anxiety disorders, over-activity within constituent regions of the vmPFC is consistently implicated in symptomatology, together with its normalisation following successful treatment. However, the precise locus of change varies between studies. The work presented in this thesis investigates the causal contributions of over-activity within two key subregions of the vmPFC – the subgenual anterior cingulate cortex (sgACC, area 25) and perigenual anterior cingulate cortex (pgACC, area 32) – in discrete dimensions of behaviour and physiology affected in psychiatric disorders. Specifically, the impact of over-activity is assessed on (i) baseline physiological function; (ii) the regulation of anticipatory, motivational and consummatory aspects of reward-related behaviour; and (iii) negative affect including fear learning, stress recovery and the intolerance of uncertainty. To provide further insight into the mechanism of action of antidepressants, the efficacy of selected treatments is tested on changes induced by over-activity of these regions. Beyond the direct relevance of the results presented here to psychiatric disorders and their treatment, the thesis aims to emphasise the importance of broader themes associated with the measurement and quantification of emotion in preclinical animal studies. First, a multi-faceted approach is utilised enabling quantification of both the autonomic and behavioural aspects of emotion. In so doing, the experiments maintain relevance to studies which assess these correlates in isolation, both in humans (which typically measure subjective responses and physiology) and in rodents (which frequently assess behaviour in isolation). The assessment of more than one dimension of emotion confers these studies with improved power to detect maladaptive changes. Second, the experiments described were conducted in the marmoset, a new-world primate. The extensive anatomical homology between marmoset and human prefrontal cortex facilitates the forward-translation of functional results. In combination with the appropriate assays, this renders marmosets as an invaluable species to study the causal contributions of vmPFC subregions to symptoms of psychiatric disorders. I believe that the results of these experiments provide important insights into the causal role primate vmPFC has in relation to the behavioural and physiological aspects of psychiatric symptomatology. Most importantly, I hope that they serve as the foundation for future work to further elucidate the neuropathological processes underlying mental disorders.MRC DTP Studentshi