Aims: Previous work provided indirect evidence that the neurotrophic factor neurturin (NRTN) is required for normal cholinergic innervation of the heart. This study used nrtn knockout (KO) and wild-type (WT) mice to determine the effect of nrtn deletion on cardiac cholinergic innervation and function in the adult heart. Methods and results: Immunohistochemistry, confocal microscopy, and quantitative image analysis were used to directly evaluate intrinsic cardiac neuronal development. Atrial acetylcholine (ACh) levels were determined as an indirect index of cholinergic innervation. Cholinergic function was evaluated by measuring negative chronotropic responses to right vagal nerve stimulation in anaesthetized mice and responses of isolated atria to muscarinic agonists. KO hearts contained only 35% the normal number of cholinergic neurons, and the residual cholinergic neurons were 15% smaller than in WT. Cholinergic nerve density at the sinoatrial node was reduced by 87% in KOs, but noradrenergic nerve density was unaffected. Atrial ACh levels were substantially lower in KO mice (0.013 ± 0.004 vs. 0.050 ± 0.011 pmol/μg protein; P < 0.02) as expected from cholinergic neuron and nerve fibre deficits. Maximum bradycardia evoked by vagal stimulation was reduced in KO mice (38 ± 6% vs. 69 ± 3% decrease at 20 Hz; P < 0.001), and chronotropic responses took longer to develop and fade. In contrast to these deficits, isolated atria from KO mice had normal post-junctional sensitivity to carbachol and bethanechol. Conclusion: These findings demonstrate that NRTN is essential for normal cardiac cholinergic innervation and cholinergic control of heart rate. The presence of residual cardiac cholinergic neurons and vagal bradycardia in KO mice suggests that additional neurotrophic factors may influence this system.

The presence of vasoactive intestinal polypeptide (VIP) has been analyzed in fibers and neurons within the guinea pig intrinsic cardiac ganglia and in fibers innervating cardiac tissues. In whole-mount preparations, VIP-immunoreactive (IR) fibers were present in about 70% of the cardiac ganglia. VIP was co-localized with neuronal nitric oxide synthase (nNOS) in fibers innervating the intrinsic ganglia but was not present in fibers immunoreactive for pituitary adenylate cyclase-activating polypeptide, choline acetyltransferase (ChAT), tyrosine hydroxylase, or substance P. A small number of the intrinsic ChAT-IR cardiac ganglia neurons (approximately 3%) exhibited VIP immunoreactivity. These few VIP-IR cardiac neurons also exhibited nNOS immunoreactivity. After explant culture for 72 h, the intraganglionic VIP-IR fibers degenerated, indicating that they were axons of neurons located outside the heart. In cardiac tissue sections, VIP-IR fibers were present primarily in the atria and in perivascular connective tissue, with the overall abundance being low. VIP-IR fibers were notably sparse in the sinus node and conducting system and generally absent in the ventricular myocardium. Virtually all VIP-IR fibers in tissue sections exhibited immunoreactivity to nNOS. A few VIP-IR fibers, primarily those located within the atrial myocardium, were immunoreactive for both nNOS and ChAT indicating they were derived from intrinsic cardiac neurons. We suggest that, in the guinea pig, the majority of intraganglionic and cardiac tissue VTP-IR fibers originate outside of the heart. These extrinsic VIP-IR fibers are also immunoreactive for nNOS and therefore most likely are a component of the afferent fibers derived from the vagal sensory ganglia.

The pathological conse-quences of ischemic heart disease involve signaling through the autonomic nervous system. Although early activation may serve to maintain hemodynamic stability, persistent aberrant sympathoexcitation contributes to the development of lethal arrhythmias and heart failure. We hypothesized that as the myocardium reacts and remodels to ischemic injury over time, there is an analogous sequence of gene expression changes in the thoracic spinal cord dorsal horn, the processing center for incoming afferent fibers from the heart to the central nervous system. Acute and chronic myocardial ischemia (MI) was induced in a large animal model of Yorkshire pigs, and the thoracic dorsal horn of treated pigs, along with control nonischemic pigs, was harvested for transcriptome analysis. We identified 32 differentially expressed genes between healthy and acute ischemia cohorts and 46 differentially expressed genes between healthy and chronic ischemia cohorts. The canonical immediate-early gene c-fos was upregulated after acute MI, along with fosB, dual specificity phosphatase 1 and 2 (dusp1 and dusp2), and early growth response 2 (egr2). After chronic MI, there was a persistent yet unique activation of immediate-early genes, including fosB, nuclear receptor subfamily 4 group A members 1±3 (nr4a1, nr4a2, and nr4a3), egr3, and TNF-β-induced protein 3 (tnfaip3). In addition, differentially expressed genes from the chronic MI signature were enriched in pathways linked to apoptosis, immune regulation, and the stress response. These findings support a dynamic progression of gene expression changes in the dorsal horn with maturation of myocardial injury, and they may explain how early adaptive autonomic nervous system responses can maintain hemodynamic stability, whereas prolonged maladaptive signals can predispose patients to arrhythmias and heart failure. NEW & NOTEWORTHY Activation of the autonomic nervous system after myocardial injury can provide early cardiovascular support or prolonged aberrant sympathoexcitation. The later response can lead to lethal arrhythmias and heart failure. This study provides evidence of ongoing changes in the gene expression signature of the spinal cord dorsal horn as myocardial injury progresses over time. These changes could help explain how an adaptive nervous system response can become maladaptive over time.

As software systems have grown in size and complexity, the costs of maintaining such systems increases steadily. In the early 2000's, IBM launched the autonomic computing initiative to mitigate this problem by injecting feedback control mechanisms into software systems to enable them to observe their health and self-heal without human intervention and thereby cope with certain changes in their requirements and environments. Self-healing is one of several fundamental challenges addressed and includes software systems that are able to recover from failure conditions. There has been considerable research on software architectures with feedback loops that allow a multi-component system to adjust certain parameters automatically in response to changes in its environment. However, modifying the components' source code in response to failures remains an open and formidable challenge. Automatic program repair techniques aim to create and apply source code patches autonomously. These techniques have evolved over the years to take advantage of advancements in programming languages, such as reflection. However, these techniques require mechanisms to evaluate if a candidate patch solves the failure condition. Some rely on test cases that capture the context under which the program failed---the patch applied can then be considered as a successful patch if the test result changes from failing to passing. Although test cases are an effective mechanism to govern the applicability of potential patches, the automatic generation of test cases for a given scenario has not received much attention. ReCrash represents the only known implementation to generate test cases automatically with promising results through the use of low-level instrumentation libraries. The work reported in this thesis aims to explore this area further and under a different light. It proposes the use of Aspect-Oriented Programming (AOP)---and in particular of AspectJ---as a higher-level paradigm to express the code elements on which monitoring actions can be interleaved with the source code, to create a representation of the context at the most relevant moments of the execution, so that if the code fails, the contextual representation is retained and used at a later time to automatically write a test case. By doing this, the author intends to contribute to fill the gap that prevents the use of automatic program repair techniques in a self-healing architecture. The prototype implementation engineered as part of this research was evaluated along three dimensions: memory usage, execution time and binary size. The evaluation results suggest that (1) AspectJ introduces significant overhead with respect to execution time, (2) the implementation algorithm causes a tremendous strain on garbage collection, and (3) AspectJ incorporates tens of additional lines of code, which account for a mean size increase to every binary file of a factor of ten compared to the original size. The comparative analysis with ReCrash shows that the algorithm and data structures developed in this thesis produce more thorough test cases than ReCrash. Most notably, the solution presented here mitigates ReCrash's current inability to reproduce environment-specific failure conditions derived from on-demand instantiation. This work can potentially be extended to apply in less-intrusive frameworks that operate at the same level as AOP to address the shortcomings identified in this analysis. / Graduate

L’autonomicité - la capacité des systèmes à se gérer eux-mêmes - est une qualité nécessaire pour parvenir à contrôler des systèmes complexes, c’est à dire des systèmes ouverts, à grande échelle, dynamiques, composés de sous-systèmes tiers hétérogènes et suivant de multiples objectifs, éventuellement en conflit. Dans cette thèse, nous cherchons à fournir des supports génériques et réutilisables pour la conception de tels systèmes autonomiques complexes. Nous proposons une formalisation des objectifs de gestion, une architecture générique pour la conception de systèmes autonomiques multi-objectifs et adaptables, et des organisations génériques pour l’intégration de tels systèmes autonomiques. Nous appliquons nôtre approche au cas d’utilisation des réseaux électriques intelligents, qui sont un parfait exemple de complexité. Nous présentons une plateforme de simulation que nous avons développée et via laquelle nous illustrons nôtre approche, au travers de plusieurs scénarios de simulation. / Autonomic features, i.e. the capability of systems to manage themselves, are necessary to control complex systems, i.e. systems that are open, large scale, dynamic, comprise heterogeneous third-party sub-systems and follow multiple, sometimes conflicting objectives. In this thesis, we aim to provide generic reusable supports for designing complex autonomic systems. We propose a formalisation of management objectives, a generic architecture for designingadaptable multi-objective autonomic systems, and generic organisations integrating such autonomic systems.We apply our approach to the concrete case of smart micro-grids which is a relevant example of such complexity. We present a simulation platform we developped and illustrate our approach via several simulation scenarios.

The purpose of this dissertation was to test the significance of objective l y measured imagery ability on the learning of self-controled relaxation of autonomic nervous system activity. Imagery is discussed in terms of its interaction with Autogenic vs. Jacobsonian methods of training clinical relaxation. Thirty-six female subjects from a college population, representing extreme highs and lows on "spatial ability" tests were given a series of three six-session sequences of Baseline, Treatment 1, and Treatment 2, which contained silent relaxation as a control, plus Jacobsonian and Autogenic relaxation. High and low spatial ability subjects were divided into split groups (A & B) which were given Jacobsonian and Autogenic relaxation treatment in different sequence orders. Skin temperature biofeedback was used to monitor the little fingers on both hands as a general indicator of autonomic clinical relaxation. Mean temperature; temperature change within sessions; and temperature change between sessions, were analyzed by different treatment periods and spatial ability groups. The data from these groups were analyzed using an ANOVA design. There were no significant differences in mean temperature data. A nearly significant two-way interaction was found between imagery ability and treatment order during Autogenic training. Also a significant interaction was found in skin temperature change between sessions for, "Sensory" vs. "Intuitive" personality types, and a nearly significant difference for Autogenic vs. Jacobsonian treatment. It was concluded that Jacobsonian training was generally more effective than Autogenic training for inducing vascular relaxation in both high and low imagery subjects. Also it was found that Sensory perceptual types are significantly more stable in terms of day to day skin temperature variation during relaxation training, than are Intuitive perceptual types.

To test this a three part study would be required. First, it should be determined if there is a difference between the threshold for perception of increased heart rate in psychopaths and normals in order to see if the problem is an attentional one. If such a difference were not found the next step would be to compare psychopaths and normals on the strength of the cognitive fear reaction to Sarm the source of which in this case is increased heart rate. Finally, if results show no cognitive fear attached to the awareness of their increased heart rate, an attempt would be made to condition fear to the physiological stimulus of increased heart rate. The following study was concerned with completion of the initial phase of this three part study.

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Background. Although treatments for dizziness as a result of visual-vestibular mismatch (VVM) exist, the lack of prognostic information about this population affects the quality of their rehabilitation care. Despite numerous studies showing that individuals presenting with non-specific dizziness are likely to have VVM, and despite VVM being recognized by to the international classification of vestibular disorders by the Bárány Society, it remains unknown how prevalent this condition is. The VVM diagnostic questionnaire has not yet been generally accepted as a useful tool for diagnosis. There are inadequate criteria for prescribed vestibular rehabilitation for individuals with VVM, and little evidence to support the selection of treatment programs among this population. Treatment outcomes are not particularly successful because of a lack of guidelines. Studies have been performed that address dizziness severity, but no reliable biometric measurement has been developed yet. A potential measure of VVM could be responses of the autonomic nervous system (ANS) during vestibulo-visual challenges given the anatomical relationship between the vestibular system and the ANS. Individuals with both peripheral and central vestibular dysfunction exhibit symptoms and signs of autonomic dysfunction as a result of vestibulo-autonomic interactions. Moreover, changes in postural sway are a tangible indicator of the balance during any disturbance to the vestibular system. In this dissertation the use of measures of electrodermal activity (EDA) of the ANS and postural acceleration are explored in vestibular migraine (VM) individuals both with and without VVM. Purpose. The aims of this dissertation were to examine, in VM adults: 1) the presence of VVM and visual dependency in individuals presenting with complaints of dizziness using the VVM questionnaire and the Rod and Frame protocol, respectively; 2) the potential of EDA activity and postural responses to differentiate between VM and healthy individuals when accommodating for postural instability and visual-vestibular conflict; and 3) the effect of exposure to different visual contexts of VR environments on EDA phasic and tonic responses and postural responses in identified VM adults with VVM. Participants. Seventy-four participants with dizziness were enrolled in Aim 1 (70% female, mean age 45.4 ± 14.8 years), and a total of 45 participants (23 healthy, 45.5% female, mean age 34± 9 years) and (22 VM adults, 61% female, mean age 34.4 ± 8, including 12 VM adults with VVM, 77% female, mean age 34±9) were enrolled in the experimental studies for Aims 2 and 3. Methods. In Aim 1, the VVM questionnaire and the Rod and Frame protocol were used to test the presence of VVM and visual dependency, respectively. In Aims 2 and 3, a Shimmer 3 IMU sensor accelerometer was used to assess trunk acceleration in the anterior-posterior, medial-lateral, and vertical directions with different VR environments (STREET and SPACE). EDA measurements were assessed with a wireless wearable Shimmer 3 GSR+. Clinical measures of dizziness and mobility were concurrently tested. A linear mixed model was used to examine the effect of VM with and without VVM on standing balance and EDA activity. Results. The presence of VVM, headache, and visual dependency demonstrated a strong association. EDA activity and postural acceleration significantly differed between VM and healthy individuals. Specific subjective reporting tools, including ABC, VSS-SF, VVAS, and DHI, were reliable for distinguishing between VM and healthy individuals. Lastly, VM individuals with VVM exhibited significantly greater NPL of trunk accelerations in the vertical plane than VM individuals without VVM with the STREET environment compared to the SPACE environment. Conclusion. VVM and visual dependency could be risk factors for developing vestibular migraine and should be included in the examination protocol of those populations. Combining measures of EDA and trunk acceleration may provide objective measures of the severity of dizziness related to VVM. Results of this dissertation suggest that the use of EDA measures combined with NPL-Vert could provide potential neurophysiological biomarkers in identifying VVM in adults with vestibular migraines. Further, the correlation between the characteristics of the visual environment and the subjective dizziness outcome measure may contribute to establishing a threshold-tolerance basis for designing a vestibular rehabilitation program that will more precisely target symptom severity. / Physical Therapy