Acute cardiovascular responses to slow and deep breathing

This thesis was submitted for the award of Doctor of Philosophy and was awarded by Brunel University LondonSlow and deep breathing (SDB) has long been regarded as a nonpharmacological method for dealing with several physiological and emotional imbalances, and widely used for relaxation purposes. There is, however, limited understanding of the putative mechanisms by which SDB acutely impacts the cardiovascular and autonomic systems to elicit chronic adaptations. The present thesis explored how the manipulation of breathing pattern and intrathoracic pressure during SDB could further the understanding of the regulatory mechanisms that underpin the acute cardiovascular response to SDB. This thesis makes an original contribution to the existing knowledge by reporting a previously undescribed inversion of normal within-breath (inspiration vs. expiration) left ventricular stroke volume (LVSV) pattern for breathing frequencies < 8 breaths∙min-1. This finding might reflect the influence of a lag between enhanced right atrial filling and right ventricular stroke volume during inspiration, and its expression in left ventricular stroke volume; this lag results from the time required for blood to transit the pulmonary circulation. Furthermore, blood pressure variability (BPV) was reduced significantly at the lowest breathing frequencies, likely due to the involvement of baroreflex mediated responses. The pattern of responses was consistent with the buffering of respiratory-driven fluctuations in left ventricular cardiac output (Q̇) and arterial blood pressure (ABP) by within breath fluctuations in heart rate (fc), i.e., respiratory sinus arrhythmia (RSA) (Chapter 4). Chapter 5 demonstrated that magnifying negative intrathoracic pressure with inspiratory loading during SDB increased inspiratory pressure-driven fluctuations in LVSV and fc, and enhanced Q̇, independently of changes in VT and fR. The data support an important contribution to the amplification of RSA, during SDB, of previously underappreciated reflex, and/or ‘myogenic’, cardiac response mechanisms. The findings in Chapter 6 confirmed that inspiratory loading during SDB amplified the effects observed with un-loaded SDB (reported in chapter 5). In contrast, expiratory loading increased ABP and attenuated RSA, LVSV and Q̇ during SDB. A lower RSA for higher ABP, supports the presence of a formerly underappreciated contribution of sinoatrial node stretch to RSA, and throws into question the clinical benefits of expiratory resisted SDB, particularly in hypertensive populations. In conclusion, the findings of the present thesis provide novel information regarding the mechanisms contributing to acute cardiovascular response to SDB. These new insights may contribute to the development of more effective SDB interventions, geared towards maximising the perturbation to the cardiovascular control systems

Superpressure Stratospheric Vehicle

Our need for wide-band global communications, earth imaging and sensing, atmospheric measurements and military reconnaissance is extensive, but growing dependence on space-based systems raises concerns about vulnerability. Military commanders require space assets that are more accessible and under local control. As a result, a robust and low cost access to space-like capability has become a national priority. Free floating buoyant vehicles in the middle stratosphere can provide the kind of cost effective access to space-like capability needed for a variety of missions. These vehicles are inexpensive, invisible, and easily launched. Developments in payload electronics, atmospheric modeling, and materials combined with improving communications and navigation infrastructure are making balloon-borne concepts more attractive. The important milestone accomplished by this project was the planned test flight over the continental United States. This document is specifically intended to review the technology development and preparations leading up to the test flight. Although the test flight experienced a payload failure just before entering its assent altitude, significant data were gathered. The results of the test flight are presented here. Important factors included in this report include quality assurance testing of the balloon, payload definition and characteristics, systems integration, preflight testing procedures, range operations, data collection, and post-flight analysis. 41 figs., 5 tabs

Word sense discovery and disambiguation

The work is based on the assumption that words with similar syntactic usage have similar meaning, which was proposed by Zellig S. Harris (1954,1968). We study his assumption from two aspects: Firstly, different meanings (word senses) of a word should manifest themselves in different usages (contexts), and secondly, similar usages (contexts) should lead to similar meanings (word senses). If we start with the different meanings of a word, we should be able to find distinct contexts for the meanings in text corpora. We separate the meanings by grouping and labeling contexts in an unsupervised or weakly supervised manner (Publication 1, 2 and 3). We are confronted with the question of how best to represent contexts in order to induce effective classifiers of contexts, because differences in context are the only means we have to separate word senses. If we start with words in similar contexts, we should be able to discover similarities in meaning. We can do this monolingually or multilingually. In the monolingual material, we find synonyms and other related words in an unsupervised way (Publication 4). In the multilingual material, we ?nd translations by supervised learning of transliterations (Publication 5). In both the monolingual and multilingual case, we first discover words with similar contexts, i.e., synonym or translation lists. In the monolingual case we also aim at finding structure in the lists by discovering groups of similar words, e.g., synonym sets. In this introduction to the publications of the thesis, we consider the larger background issues of how meaning arises, how it is quantized into word senses, and how it is modeled. We also consider how to define, collect and represent contexts. We discuss how to evaluate the trained context classi?ers and discovered word sense classifications, and ?nally we present the word sense discovery and disambiguation methods of the publications. This work supports Harris' hypothesis by implementing three new methods modeled on his hypothesis. The methods have practical consequences for creating thesauruses and translation dictionaries, e.g., for information retrieval and machine translation purposes. Keywords: Word senses, Context, Evaluation, Word sense disambiguation, Word sense discovery

Magnetoencephalography for the investigation and diagnosis of Mild Traumatic Brain Injury

Mild Traumatic Brain Injury (mTBI), (or concussion), is the most common type of brain injury. Despite this, it often goes undiagnosed and can cause long term disability—most likely caused by the disruption of axonal connections in the brain. Objective methods for diagnosis and prognosis are needed but clinically available neuroimaging modalities rarely show structural abnormalities, even when patients suffer persisting functional deficits. In the past three decades, new powerful techniques to image brain structure and function have shown promise in detecting mTBI related changes. Magnetoencephalography (MEG), which measures electrical brain activity by detecting magnetic fields outside the head generated by neural currents, is particularly sensitive and has therefore gained interest from researchers. Numerous studies are proposing abnormal low-frequency neural oscillations and functional connectivity—the statistical interdependency of signals from separate brain regions—as potential biomarkers for mTBI. However, typically small sample sizes, the lack of replication between groups, the heterogeneity of the cohorts studied, and the lack of longitudinal studies impedes the adoption of MEG as a clinical tool in mTBI management. In particular, little is known about the acute phase of mTBI. In this thesis, some of these gaps will be addressed by analysing MEG data from individuals with mTBI, using novel as well as conventional methods. The potential future of MEG in mTBI research will also be addressed by testing the capabilities of a wearable MEG system based on optically pumped magnetometers (OPMs). The thesis contains three main experimental studies. In study 1, we investigated the signal dynamics underlying MEG abnormalities, found in a cohort of subjects scanned within three months of an mTBI, using a Hidden Markov Model (HMM), as growing evidence suggests that neural dynamics are (in part) driven by transient bursting events. Applying the HMM to resting-state data, we show that previously reported findings of diminished intrinsic beta amplitude and connectivity in individuals with mTBI (compared to healthy controls) can be explained by a reduction in the beta-band content of pan-spectral bursts and a loss in the temporal coincidence of bursts respectively. Using machine learning, we find the functional connections driving group differences and achieve classification accuracies of 98%. In a motor task, mTBI resulted in reduced burst amplitude, altered modulation of burst probability during movement and decreased connectivity in the motor network. In study 2, we further test our HMM-based method in a cohort of subjects with mTBI and non-head trauma—scanned within two weeks of injury—to ensure specificity of any observed effects to mTBI and replicate our previous finding of reduced connectivity and high classification accuracy, although not the reduction in burst amplitude. Burst statistics were stable over both studies—despite data being acquired at different sites, using different scanners. In the same cohort, we applied a more conventional analysis of delta-band power. Although excess low-frequency power appears to be a promising candidate marker for persistently symptomatic mTBI, insufficient data exist to confirm this pattern in acute mTBI. We found abnormally high delta power to be a sensitive measure for discriminating mTBI subjects from healthy controls, however, similarly elevated delta amplitude was found in the cohort with non-head trauma, suggesting that excess delta may not be specific to mTBI, at least in the acute stage of injury. Our work highlights the need for longitudinal assessment of mTBI. In addition, there appears to be a need to investigate naturalistic paradigms which can be tailored to induce activity in symptom-relevant brain networks and consequently are likely to be more sensitive biomarkers than the resting state scans used to date. Wearable OPM-MEG makes naturalistic scanning possible and may offer a cheaper and more accessible alternative to cryogenic MEG, however, before deploying OPMs clinically, or in pitch-side assessment for athletes, for example, the reliability of OPM-derived measures needs to be verified. In the third and final study, we performed a repeatability study using a novel motor task, estimating a series of common MEG measures and quantifying the reliability of both activity and connectivity derived from OPM-MEG data. These initial findings—presently limited to a small sample of healthy controls—demonstrate the utility of OPM-MEG and pave the way for this technology to be deployed on patients with mTBI

References, Appendices & All Parts Merged

Includes: Appendix MA: Selected Mathematical Formulas; Appendix CA: Selected Physical Constants; References; EGP merged file (all parts, appendices, and references)https://commons.library.stonybrook.edu/egp/1007/thumbnail.jp

Magnetoencephalography for the investigation and diagnosis of Mild Traumatic Brain Injury

Mild Traumatic Brain Injury (mTBI), (or concussion), is the most common type of brain injury. Despite this, it often goes undiagnosed and can cause long term disability—most likely caused by the disruption of axonal connections in the brain. Objective methods for diagnosis and prognosis are needed but clinically available neuroimaging modalities rarely show structural abnormalities, even when patients suffer persisting functional deficits. In the past three decades, new powerful techniques to image brain structure and function have shown promise in detecting mTBI related changes. Magnetoencephalography (MEG), which measures electrical brain activity by detecting magnetic fields outside the head generated by neural currents, is particularly sensitive and has therefore gained interest from researchers. Numerous studies are proposing abnormal low-frequency neural oscillations and functional connectivity—the statistical interdependency of signals from separate brain regions—as potential biomarkers for mTBI. However, typically small sample sizes, the lack of replication between groups, the heterogeneity of the cohorts studied, and the lack of longitudinal studies impedes the adoption of MEG as a clinical tool in mTBI management. In particular, little is known about the acute phase of mTBI. In this thesis, some of these gaps will be addressed by analysing MEG data from individuals with mTBI, using novel as well as conventional methods. The potential future of MEG in mTBI research will also be addressed by testing the capabilities of a wearable MEG system based on optically pumped magnetometers (OPMs). The thesis contains three main experimental studies. In study 1, we investigated the signal dynamics underlying MEG abnormalities, found in a cohort of subjects scanned within three months of an mTBI, using a Hidden Markov Model (HMM), as growing evidence suggests that neural dynamics are (in part) driven by transient bursting events. Applying the HMM to resting-state data, we show that previously reported findings of diminished intrinsic beta amplitude and connectivity in individuals with mTBI (compared to healthy controls) can be explained by a reduction in the beta-band content of pan-spectral bursts and a loss in the temporal coincidence of bursts respectively. Using machine learning, we find the functional connections driving group differences and achieve classification accuracies of 98%. In a motor task, mTBI resulted in reduced burst amplitude, altered modulation of burst probability during movement and decreased connectivity in the motor network. In study 2, we further test our HMM-based method in a cohort of subjects with mTBI and non-head trauma—scanned within two weeks of injury—to ensure specificity of any observed effects to mTBI and replicate our previous finding of reduced connectivity and high classification accuracy, although not the reduction in burst amplitude. Burst statistics were stable over both studies—despite data being acquired at different sites, using different scanners. In the same cohort, we applied a more conventional analysis of delta-band power. Although excess low-frequency power appears to be a promising candidate marker for persistently symptomatic mTBI, insufficient data exist to confirm this pattern in acute mTBI. We found abnormally high delta power to be a sensitive measure for discriminating mTBI subjects from healthy controls, however, similarly elevated delta amplitude was found in the cohort with non-head trauma, suggesting that excess delta may not be specific to mTBI, at least in the acute stage of injury. Our work highlights the need for longitudinal assessment of mTBI. In addition, there appears to be a need to investigate naturalistic paradigms which can be tailored to induce activity in symptom-relevant brain networks and consequently are likely to be more sensitive biomarkers than the resting state scans used to date. Wearable OPM-MEG makes naturalistic scanning possible and may offer a cheaper and more accessible alternative to cryogenic MEG, however, before deploying OPMs clinically, or in pitch-side assessment for athletes, for example, the reliability of OPM-derived measures needs to be verified. In the third and final study, we performed a repeatability study using a novel motor task, estimating a series of common MEG measures and quantifying the reliability of both activity and connectivity derived from OPM-MEG data. These initial findings—presently limited to a small sample of healthy controls—demonstrate the utility of OPM-MEG and pave the way for this technology to be deployed on patients with mTBI

Employment in Europe 2004: Recent Trends and Prospects

[Excerpt] The sixteenth edition of the Employment in Europe appears just after the European Union\u27s enlargement to twenty-five Member States in May 2004. This unprecedented enlargement is a milestone in the history of European integration and has led to a united European continent sharing common values, fostering economic growth and social cohesion and strengthening Europe\u27s role in a globalised world. The most fundamental objective of the European Union, however, remains unchanged: to help raise the living standards and the quality of life of its citizens. This implies improving the growth performance of the EU economy on a sustainable basis; pursuing the way back to full employment in Europe; enhancing productivity and quality in work ( better jobs ); and fostering social cohesion and inclusion. Achieving full employment and reinforcing social cohesion will largely depend on an appropriate macroeconomic policy-mix and on effective employment and social policies. First, an appropriate policy setting would ensure high levels of business and consumer confidence and thus help maintain buoyant demand levels throughout the economic cycle. Second, effective employment and social policies are key to reducing poverty, social exclusion and regional imbalances, in turn helping to manage properly the social consequences of economic change. The parallel development of economic and social prosperity is central to the European Social Model. In its diverse forms in the Union, the model has played a crucial role in helping to lift productivity and living standards across Europe. It has also helped to ensure that the benefits are widely shared, recognising that we cannot make our economies stronger by making sections of society poorer. Against this background, the current report shows that the EU25 is potentially well placed to take advantage of the opportunities provided by enlargement. Following the economic slowdown of recent years, the report also documents some encouraging signs of a global economic recovery which may eventually help put Europe back on track towards the ambitious Lisbon objective for the EU “to become the most competitive and dynamic knowledge-based economy in the world, capable of sustainable economic growth with more and better jobs and greater social cohesion”

The Architecture Underlying Syntactic Processing

In this thesis, I report five eyetracking experiments that tested current sentence processing theories. So far, most research has attempted to discriminate between various sentence processing theories by investigating whether non-syntactic sources of information can be employed immediately in syntactic ambiguity resolution. Two-stage theories such as the garden-path theory claim that the use of non-syntactic information is delayed, whereas interactive or constraint-based theories claim that all sources of information can be employed immediately. The experiments in this thesis focussed on a different aspect of current sentence processing theories, which has been largely ignored. They investigated whether the architecture of the sentence processor involves reanalysis or competition. Two-stage theories claim that processing difficulty occurs when an initially adopted syntactic analysis has to be revised, whereas most current constraint-based theories stipulate that competition between two or more syntactic analyses that are activated in parallel makes a sentence difficult to process. The experiments in this thesis investigated reanalysis and competition by testing globally ambiguous syntactic structures and contrasting them with structures that are disambiguated (either to one analysis or the other). Constraint-based competition theories predict that competition occurs in globally ambiguous sentences which do not have a bias for one structure over another, because two syntactic analyses are about equally activated. No such competition should occur in disambiguated sentences, because only one analysis is supported by the disambiguating information. In contrast, traditional two-stage theories such as the garden-path theory predict that the processor initially adopts the structurally preferred analysis. When the disambiguation is inconsistent with this analysis, reanalysis should occur. Reanalysis should not occur when a sentence is disambiguated toward its preferred analysis, or when a sentence is globally ambiguous. The eyetracking experiments in this thesis showed that disambiguated sentences are more difficult to read than globally ambiguous sentences. These results are incompatible with competition as a mechanism of syntactic ambiguity resolution, and therefore disconfirm the predictions of most current constraint-based theories. They are also problematic for some two-stage theories, because processing difficulty occurred in sentences where the disambiguation was toward the structurally preferred analysis. In this thesis an alternative model, the unrestricted race model, is proposed, which explains the results in a straightforward manner. The unrestricted race model claims that the alternative analyses of a syntactically ambiguous sentence are engaged in a race. The analysis that is constructed fastest is adopted. The model stipulates that the analysis that receives most support from both syntactic and non-syntactic sources of information usually wins the race. When two analyses are about equally supported, as in balanced ambiguities, each analysis is adopted about half the time. Consequently, when the sentence is disambiguated (toward one analysis or the other), it is inconsistent with the analysis on half the trials, and therefore reanalysis should occur on those trials. Thus, the disambiguated sentences are more difficult than the ambiguous sentences, where reanalysis does not occur. Balanced ambiguities contrast with biased ambiguities, where there is a preference for one analysis. The unrestricted race model predicts that in such ambiguities, the processor adopts the preferred analysis on nearly all trials. Therefore, reanalysis should occur on very few trials when the disambiguation is consistent with this preference

Mechanisms of epithelial branching, nephrogenesis, and the role of the Rho-GTPase family in kidney development

The metanephric kidney consists of two types of epithelia; the Wolffian duct-derived ureteric bud and the nephrogenic components that originate from mesenchymal-toepithelial transitions in the metanephric mesenchyme. The ureteric bud forms when inductive signals from the metanephric mesenchyme stimulates the evagination of an epithelial tube from the Wolffian duct into the mesenchyme. Reciprocal signalling between the ureteric bud and the metanephric mesenchyme regulates the branching of the ureteric bud and the induction of nephron formation. Inductive and inhibitory signalling of ureteric bud growth and branching has been shown by several protein families, however, the mechanical aspects of ureteric bud branching and nephrogenesis are largely unknown. I investigated the roles of Rac1-GTPase and Rho-kinase during kidney development. These proteins are important regulators of the cytoskeleton where Rac1 is a promoter of actin filament polymerisation and Rho-kinase directly stimulates the formation and contraction of actin-myosin stress fibres. Using a cell-permeable inhibitor, Rac1 was inhibited with no effects on nephron formation or subsequent segmentation and patterning. Inhibition of active Rac1 significantly reduced the level of ureteric bud branching and also resulted in lower proliferation rates. Rho-kinase was similarly targeted using two inhibitors. Rho-kinase inhibition had important effects on nephron formation and nephron maturation. Inhibition of Rhokinase resulted in decreased levels of nephron formation and severely morphologically abnormal nephrons. The formation of apical-basal polarity was disturbed as was the development of the visceral and parietal epithelia; precursors of the renal corpuscle. Inhibition of Rho-kinase led to abnormal formation of the proximal-distal axis and abnormal segmentation of the nephron. The effects of Rho-kinase inhibition were partially mimicked by direct targeting of actin-myosin contractions using a myosin-ATPase inhibitor. This demonstrated that Rho-kinase is necessary during multiple stages of nephrogenesis and maturation, at least in part, as a result of its ability to regulate actin-myosin contraction. These results show that Rac1 and Rho-kinase play important roles during several aspects of kidney development and highlights the significance of further investigating the mechanisms involved during kidney organogenesis