Chronic refractory gastrointestinal (GI) motility disorders are a significant burden on the healthcare system, acting as a large public health issue with significant impact on the quality of life in both the pediatric and adult population. Control systems of gastrointestinal motility are complex and involve coordination of smooth muscle contraction and relaxation, which the autonomic nervous system is largely responsible for. Gaps in the diagnosis process, such as overlooking autonomic function, has left patients with diminished quality of life and limited treatment options. Many patients in the clinic have experienced injury within the spinal cord and we hypothesized that GI symptoms might be related to spinal injury causing disruption of sensory and/or motor nerves of the autonomic nervous system. Our objective became to better understand the specific location and nature of spinal injuries and GI symptoms, as completed through the development of a self-report questionnaire. Main findings suggest symptoms indicative of T3-T9 and T10-L2 spinal pathology. COVID-19 did not allow for in-clinic neuromodulation with autonomic assessments, resulting in experiments remotely assessing at-home neuromodulation treatment for GI symptoms with suspected spinal autonomic dysfunction. At-home neuromodulation was not suitable for many patients, but those who were able to manage it showed highly promising results. After years of suffering, transcutaneous electrical nerve stimulation alleviated symptoms, particularly postprandial abdominal pain, constipation, vomiting and nausea. I discuss what we learned to set us up for successful at-home treatment, and we will use all information to design randomized controlled trials to prove the benefit of TENS. The present work offers significant information on the relationship of thoracolumbar spinal pathology and complex GI symptoms, which is now used in the clinic in the diagnosis process of GI dysmotility. In addition, we have learned how to conduct at-home treatment using TENS, which allows us to execute future studies. / Thesis / Master of Science (MSc) / There are gaps in the diagnosis process of complex gastrointestinal (GI) dysmotility disorders, including lack of testing of autonomic function, leaving patients suffering with diminished quality of life with unsuccessful treatment attempts. As many patients also experience injury or conditions of the spine, I have hypothesized that GI symptoms may be related to spinal injury-induced dysfunction of the autonomic nervous system. Experimental models aim to understand the location and nature of spinal pathology with GI symptoms for future diagnoses, as well as potential treatment options such as neuromodulation. Findings of this thesis suggest symptoms indicative of particular thoracolumbar spinal pathology and promising results of transcutaneous electrical nerve stimulation (TENS) to alleviate GI symptoms, including T3-T9 and T10-L2 spinal pathology-related postprandial abdominal pain, constipation, nausea, and vomiting. This work offers information for the diagnostic process of GI dysmotility and the future design of clinical trials of neuromodulation therapies.

The ability to sense the internal state of one's body is the process of interoception and is a marker for positive emotional outcomes. The last five years have seen burgeoning research interest in interoception, including a call for more integrative and predictive biomarkers for interoceptive ability. While there is a robust literature purporting to measure interoception, there is also significant research challenging the content validity of the current methodology. Beyond these published challenges, I offer a broader critique that suggests that the current reductionist approach fails to capture the integrative nature of interoception. I introduce an alternate methodology to assess interoceptive ability that leverages the integrative nature of the autonomic nervous system. Thirty-four undergraduates provided real-time feedback about their subjective state of arousal while watching three videos of varying intensity. Across subjects, arousal feedback did not positively correlate with physiological indices of sympathetic arousal including electrodermal activity and the inverse of pre-ejection period. However, each subject appeared to have an idiographic pattern of physiological variables that correlated strongly, although often negatively, with the subjective slider feedback. These physiological patterns provide the foundation for investigating a new biomarker for interoception that relies on the autonomic nervous system to surmise interoceptive states. / Doctor of Philosophy / A person's sense of their body is called interoception. Research has shown that people who are good at interoception tend to live happier and more fulfilling lives. But current research techniques don't do a great job measuring whether someone is good at interoception. These techniques have faced a lot of criticism for the errors they are known to make. I add my concerns that the current techniques don't reflect how we naturally sense into our bodies when we're not in a lab. I explain why I think we need a new way of measuring interoception that captures how holistic this process is. I introduce a new measure that is based on the energy in our body. I believe that people use this energy system naturally and will also be better able to reflect this is a lab setting. The people in this study used a slider dial to indicate how much energy they felt while they watched videos with different excitement levels. While they watched the videos and moved the dial, we measured their bodily readings from their heart, breathing, and sweat to see if these readings matched their dial ratings. We were surprised that the typical body readings for excitement were not directly related to the slider movements when we averaged across people, but we did find that each person had their own unique way of responding that was similar in both mind and body. This research is the basis for a new way to understand how people read their own body, and how accurate this reading is.

The autonomic nervous system (ANS) controls most involuntary functions of the body. Dysfunctions of the ANS can be life-threatening. However, several critical questions related to cardiovascular and breathing regulations remain unclear. One of the open questions is how the system lose control of the vascular tones under certain circumstances. Using the septic shock model induced by lipopolysaccharide (LPS) in isolated and perfused mesenteric arterial rings, we found the vascular hyporeactivity is attributed to the decreased vasoconstriction to α-adrenoceptor agonists. The endotoxin-induced vasodilation can be intervened with endothelin-1 (ET-1), serotonin (5-HT) or vasopressin, which have never been used in clinical treatment. It is unclear how the excitability of endothelium affects vascular tones. Using optogenetics and transgenic mice with channelrhodopsin expression in endothelial cells (ECs), we found selective activation of the ECs induces a fast, robust, reproducible and long-lasting vasoconstriction in isolated and perfused hearts and kidneys. Breathing control by the ANS within the brain becomes abnormal in certain genetic diseases, such as Rett syndrome with defected norepinephrine (NE) system in locus coeruleus (LC). The LC neurons are hyperexcitable while NE release is deficient. Using optogenetics and double transgenic mice with Mecp2 null and channelrhodopsin expression in LC neurons, we found the NE-ergic modulation of hypoglossal neurons was impaired in transgenic mice, which cannot be improved with optostimulation, suggesting that LC neuronal hyperexcitability may not benefit the NE modulation in Rett syndrome. Collectively, our results provide insight into the autonomic dysfunctions using experimental interventions that have barely been used before.

The enteric nervous system (ENS) is derived from neural crest cells (NCCs). Once these NCCs reach the foregut, they are recognized as enteric NCCs(ENCCs) which subsequently colonize the gastrointestinal track. The proliferation, migration and neuronal versusglial differentiation of ENCCs are tightly controlled by multiple signaling pathways and transcription factors. Impaired ENS development may result in various human congenital disorders such as Hirschsprung disease(HSCR). Hedgehog (Hh) signaling is a key element in ENS development. Patched-1 (Ptch1) is a negatively regulated receptor for Hh. Binding to Hh or deletion of Ptch1releases its inhibitory function and activates the Hh signaling cascade. Our group has previously revealedPTCH1as a susceptibility gene for HSCR. In particular, NCC-specific deletionofPtch1in mice led to premature glial differentiation and depletion of proliferative ENCC pool, but the molecular mechanisms are still not very clear. Sox10, a member of SRY-related HMG-box family transcription factor, is implicated in these two processes of ENS development. It prompted us to hypothesis that Ptch1 may interact with Sox10 to control ENCC proliferation and glial lineage differentiation. In this study, I generated compound mouse mutants to i) investigate the potential functional interaction between Ptch1 and Sox10 in ENCC differentiation and proliferation, and ii) examine the link between the perturbed NCC differentiation and aberrant proliferation of ENS progenitors, to determine how interruption of these processes may lead to intestinal hypoganglionosis of Ptch1mutants. I found that persistent Hh activation through deletionofPtch1causes a differentiation bias toward glial lineage. Ptch1mutants consistently contained more Sox10expressing glial committed ENCCs and exhibited premature gliogenesis. To test whether elevated Sox10expressing cells contribute in the ENS phenotypes of Ptch1 mutants, 〖Sox10〗^(NGFP/+); Ptch1 compound mutants were generated, where one copy of Sox10 was deleted. Immunohistochemical analysis revealed that 〖Sox10〗^(NGFP/+) mutants exhibitpremature neurogenesis as reported previously, while the proliferation and glial differentiation of ENCCs are not affected.On the other hand, in the compound mutants, heterozygous deletion of Sox10 markedly rescued premature gliogenesis caused by deletion of Ptch1. These data suggest that Ptch1 regulates gliogenesis of ENCCs through maintaining Sox10 expression. To delineate how premature glial differentiation of ENCCs leads to hypoganglionosis, I further investigated whether the differentiation defect perturbs the proliferation capacities of ENCCs. Correction of glial differentiation defect in Ptch1 mutant by heterogeneous deletion of Sox10 could significantly restore the pool size of the proliferative ENCCs of the compound mutant. This observation implies that proliferation defects in Ptch1 mutant represents a secondary consequence of premature gliogenesis, highlighting the close link between these two developmental processes. In summary, the current study provides evidence that Sox10 works coordinately with Ptch1 to mediate ENS development. Loss of Ptch1 favors glial differentiation and formation ofSox10 expressing glial progenitors, leading to intestinal hypoganglionosis as seen in Hirschsprung’s disease. / published_or_final_version / Surgery / Master / Master of Philosophy

<p>Autonomic computing is a paradigm that aims at reducing administrative overhead by using autonomic managers to make applications self-managing. To better deal with large-scale dynamic environments; and to improve scalability, robustness, and performance; we advocate for distribution of management functions among several cooperative autonomic managers that coordinate their activities in order to achieve management objectives. Programming autonomic management in turn requires programming environment support and higher level abstractions to become feasible.</p><p>In this thesis we present an introductory part and a number of papers that summaries our work in the area of autonomic computing. We focus on enabling and achieving self-management for large scale and/or dynamic distributed applications. We start by presenting our platform, called Niche, for programming self-managing component-based distributed applications. Niche supports a network-transparent view of system architecture simplifying designing application self-* code.  Niche provides a concise and expressive API for self-* code. The implementation of the framework relies on scalability and robustness of structured overlay networks. We have also developed a distributed file storage service, called YASS, to illustrate and evaluate Niche.</p><p>After introducing Niche we proceed by presenting a methodology and design space for designing the management part of a distributed self-managing application in a distributed manner. We define design steps, that includes partitioning of management functions and orchestration of multiple autonomic managers. We illustrate the proposed design methodology by applying it to the design and development of an improved version of our distributed storage service YASS as a case study.</p><p>We continue by presenting a generic policy-based management framework which has been integrated into Niche. Policies are sets of rules that govern the system behaviors and reflect the business goals or system management objectives. The policy based management is introduced to simplify the management and reduce the overhead, by setting up policies to govern system behaviors. A prototype of the framework is presented and two generic policy languages (policy engines and corresponding APIs), namely SPL and XACML, are evaluated using our self-managing file storage application YASS as a case study.</p><p>Finally, we present a generic approach to achieve robust services that is based on finite state machine replication with dynamic reconfiguration of replica sets. We contribute a decentralized algorithm that maintains the set of resource hosting service replicas in the presence of churn. We use this approach to implement robust management elements as robust services that can operate despite of churn.</p><p> </p> / QC 20100520

The rapid growth and deployment of network technologies and Internet services has made security and management of networks a challenging research problem. This growth is accompanied by an exponential growth in the number of network attacks, which have become more complex, more organized, more dynamic, and more severe than ever. Current network protection techniques are static, slow in responding to attacks, and inefficient due to the large number of false alarms. Attack detection systems can be broadly classified as being signature-based, classification-based, or anomaly-based. In this dissertation, I present a multi-level anomaly based autonomic network defense system which can efficiently detect both known and unknown types of network attacks with a high detection rate and low false alarms. The system uses autonomic computing to automate the control and management of multi-level intrusion detection system and integrate the different components of the system. The system defends the network by detecting anomalies in network operations that may have been caused by network attacks. Like other anomaly detection systems, AND captures a profile of normal network behavior.In this dissertation, I introduce experimental results that evaluate the effectiveness and performance of the multi-level anomaly based autonomic network intrusion detection system in detecting network attacks. The system consist of monitoring modules, feature aggregation and correlation modules, behavior analysis modules, decision fusion module, global visualization module, risk and impact analysis module, action module, attack classification module, and the adaptive learning module. I have successfully implemented a prototype system based on my multi-level anomaly based approach. The experimental results and evaluation of our prototype show that our multi-level intrusion detection system can efficiently and effectively detect and protect against any type of network attacks known or unknown in real-time. Furthermore, the overhead of our approach is insignificant on the normal network operations and services.

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Ces dernières années ont vu le développement du cloud computing. Le principe fondateur est de déporter la gestion des services informatique des entreprises dans des centres d'hébergement gérés par des entreprise tiers. Ce déport a pour principal avantage une réduction des coûts pour l'entreprise cliente, les moyens nécessaires à la gestion de ces services étant mutualisés entre clients et gérés par l'entreprise hébergeant ces services. Cette évolution implique la gestion de structures d'hébergement à grande échelle, que la dimension et la complexité rendent difficiles à administrer. Avec le développement des infrastructures de calcul de type cluster ou grille ont émergé des système fournissant un support pour l'administration automatisée de ces environnements. Ces systèmes sont désignés sous le terme Systèmes d'Administration Autonomes (SAA). Ils visent à fournir des services permettant d'automatiser les tâches d'administration comme le déploiement des logiciels, la réparation en cas de panne ou leur dimensionnement dynamique en fonction de la charge. Ainsi, il est naturel d'envisager l'utilisation des SAA pour l'administration d'une infrastructure d'hébergement de type clouds. Cependant, nous remarquons que les SAA disponibles à l'heure actuelle ont été pour la plupart conçus pour répondre aux besoins d'un domaine applicatif particulier. Un SAA doit pouvoir être adapté en fonction du domaine considéré, en particulier celui de l'administration d'un cloud. De plus, dans le domaine du cloud, différents besoins doivent être pris en compte : ceux de l'administrateur du centre d'hébergement et ceux de l'utilisateur du centre d'hébergement qui déploie ses applications dans le cloud. Ceci implique qu'un SAA doit pouvoir être adapté pour répondre à ces besoins divers. Dans cette thèse, nous étudions la conception et l'implantation d'un SAA adaptable. Un tel SAA doit permettre d'adapter les services qu'il offre aux besoins des domaines dans lesquels il est utilisé. Nous montrons ensuite comment ce SAA adaptable peut être utilisé pour l'administration autonome d'un environnement de cloud. / Last years have seen the development of cloud computing. The main underlying principle of to externalize the management of companies' IT services in hosting centers which are managed by third party companies. This externalization allows saving costs for the client company, since the resources required to manage these services are mutualized between clients and managed by the hosting company. This orientation implies the management of large scale hosting centers, whose dimension and complexity make them difficult to manage. With the developement of computing infrastructures such as clusters or grids, researchers investigated the design of systems which provides support of an automatized management of these environments. We refer to these system as Autonomic Management Systems (AMS). They aim at providing services which automate administration tasks such as software deployment, fault repair or dynamic dimensioning according to a load. Therefore, in this context, it is natural to consider the use of AMS for the administration of a cloud infrastructure. However, we observe that currently available AMS have been designed to address the requirements of a particular application domain. It should be possible to adapt an AMS according to the considered domain, in particular that of the cloud. Moreover, in the cloud computing area, different requirements have to be accounted : those of the administrator of the hosting center and those of the user of the hosting center (who deploys his application in the cloud). Therefore, an AMS should be adaptable to fulfill such various needs. In this thesis, we investigate the design and implementation of an adaptable AMS. Such an AMS must allow adaptation of all the services it provides, according to the domains where it is used. We next describe the application of this adaptable AMS for the autonomic management of a cloud environment.

Research on the various subtypes of aggression has documented differences in the experience of anger and the expression of angry aggression. Mixed proactive and reactive aggressive individuals exhibit reactive aggression but, unlike reactive aggressive individuals, fail to exhibit angry expressions or physiological arousal. Similar to the proactive group, individuals with psychopathic traits have been found to exhibit emotional underreactivity, and physiological underarousal, while still exhibiting reactive aggression. The present study examined 85 boys (ages 13 to 18) from a detention center. Three groups of aggressive boys were identified via cluster analysis based on the self-report of types of aggressive behavior: a primarily reactive aggressive group (n=29), a mixed reactive and proactive group (n=16), and a low aggressive group (n=40). The three groups were compared on aggressive responding (during a computerized provocation task with low and high provocation trials), on callous and unemotional traits (CU) and on psychophysiological indices of emotional reactivity. All aggressive groups showed greater aggressive responding to high provocation than to low provocation. The mixed aggressive group showed high aggressive responding across all provocation levels, including the no provocation condition, while the reactive aggressive group only showed high levels similar to the mixed aggressive group during low provocation. Unexpectedly, the reactive and mixed aggressive groups reported higher levels of CU traits than the other group. Although the groups did not differ on psychophysiological activity/reactivity, higher levels of CU traits were related to lower skin conductance responses to provocation. Thus, the contribution of high and low CU traits in the three groups to psychophysiological activity/reactivity was examined. Interestingly, the low and mixed aggressive groups who were high on CU traits had lower sympathetic arousal (indexed by skin conductance) and lower sympathetic reactivity to provocation. Thus, the mixed aggressive group showed a general disconnect between their angry aggression (on the provocation task) and their sympathetic reactivity to provocation. However, this was true only if they also showed high rates of CU traits. These results suggest that interventions targeted toward individuals who exhibit particular subtypes of aggression may be more beneficial if the presence of CU traits is also considered.

Much of the research examining emotion induction, regulation, and suppression considers solely the visual modality (e.g., pictures of faces) for emotion elicitation. In reality, emotions are cued, expressed, and interpreted through multiple modalities by employing the extensive use of auditory stimuli in addition to visual stimuli. There have been some recent efforts to offset this imbalance in modality preference by using emotional auditory stimuli alone or in addition to visual stimuli. This project aims to further investigate emotional and autonomic responding to auditory stimuli with the added component of examining differential responding across social (nonlinguistic vocal expression) and non-social auditory (music) emotional stimuli. We found mixed support indicating that our auditory stimuli induced physiological changes compared to a neutral condition. We also found that participants reported experiencing emotions congruent with those expressed by the stimuli. Most interestingly, increased autonomic activation was found in vocalizations compared to music possibly indicating more salient emotional responding to voices expressing nonverbal emotions compared to other types of less social emotional stimuli such as music. We discuss these findings through a lens that is not only interested in these potential differences as being driven by vocalizations, but also the unique nature of musical stimuli. This project presents a novel way to further our scientific understanding of the salience of auditory emotional information and the possible differences and similarities in processing more instinctive vocalizations and instrumental music.