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Influence of cigarette smoking on human autonomic function
BACKGROUND. Although cigarette smoking is known to lead to widespread augmentation of sympathetic nervous system activity, little is known about the effects of smoking on directly measured human sympathetic activity and its reflex control. METHODS AND RESULTS. We studied the acute effects of smoking two research-grade cigarettes on muscle sympathetic nerve activity and on arterial baroreflex-mediated changes of sympathetic and vagal neural cardiovascular outflows in eight healthy habitual smokers. Measurements were made during frequency-controlled breathing, graded Valsalva maneuvers, and carotid baroreceptor stimulation with ramped sequences of neck pressure and suction. Smoking provoked the following changes: Arterial pressure increased significantly, and RR intervals, RR interval spectral power at the respiratory frequency, and muscle sympathetic nerve activity decreased. Plasma nicotine levels increased significantly, but plasma epinephrine, norepinephrine, and neuropeptide Y levels did not change. Peak sympathetic nerve activity during and systolic pressure overshoots after Valsalva straining increased significantly in proportion to increases of plasma nicotine levels. The average carotid baroreceptor-cardiac reflex relation shifted rightward and downward on arterial pressure and RR interval axes; average gain, operational point, and response range did not change. CONCLUSIONS. In habitual smokers, smoking acutely reduces baseline levels of vagal-cardiac nerve activity and completely resets vagally mediated arterial baroreceptor-cardiac reflex responses. Smoking also reduces muscle sympathetic nerve activity but augments increases of sympathetic activity triggered by brief arterial pressure reductions. This pattern of autonomic changes is likely to influence smokers' responses to acute arterial pressure reductions importantly.
Instrumentation for Non-Invasive Assessment of Cardiovascular Regulation
It is critically important to be able to assess alterations in cardiovascular regulation during and after space flight. We propose to develop an instrument for the non-invasive assessment of such alterations that can be used on the ground and potentially during space flight. This instrumentation would be used by the Cardiovascular Alterations Team at multiple sites for the study of the effects of space flight on the cardiovascular system and the evaluation of countermeasures. In particular, the Cardiovascular Alterations Team will use this instrumentation in conjunction with ground-based human bed-rest studies and during application of acute stresses e.g., tilt, lower body negative pressure, and exercise. In future studies, the Cardiovascular Alterations Team anticipates using this instrumentation to study astronauts before and after space flight and ultimately, during space flight. The instrumentation may also be used by the Bone Demineralization/Calcium Metabolism Team, the Neurovestibular Team and the Human Performance Factors, Sleep and Chronobiology Team to measure changes in autonomic nervous function. The instrumentation will be based on a powerful new technology - cardiovascular system identification (CSI) - which has been developed in our laboratory. CSI provides a non-invasive approach for the study of alterations in cardiovascular regulation. This approach involves the analysis of second-to-second fluctuations in physiologic signals such as heart rate and non-invasively measured arterial blood pressure in order to characterize quantitatively the physiologic mechanisms responsible for the couplings between these signals. Through the characterization of multiple physiologic mechanisms, CSI provides a closed-loop model of the cardiovascular regulatory state in an individual subject.
Regulation of sympathetic nervous system function after cardiovascular deconditioning
Humans subjected to prolonged periods of bed rest or microgravity undergo deconditioning of the cardiovascular system, characterized by resting tachycardia, reduced exercise capability, and a predisposition for orthostatic intolerance. These changes in cardiovascular function are likely due to a combination of factors, including changes in control of body fluid balance or cardiac alterations resulting in inadequate maintenance of stroke volume, altered arterial or venous vascular function, reduced activation of cardiovascular hormones, and diminished autonomic reflex function. There is evidence indicating a role for each of these mechanisms. Diminished reflex activation of the sympathetic nervous system and subsequent vasoconstriction appear to play an important role. Studies utilizing the hindlimb-unloaded (HU) rat, an animal model of deconditioning, evaluated the potential role of altered arterial baroreflex control of the sympathetic nervous system. These studies indicate that HU results in blunted baroreflex-mediated activation of both renal and lumbar sympathetic nerve activity in response to a hypotensive stimulus. HU rats are less able to maintain arterial pressure during hemorrhage, suggesting that diminished ability to increase sympathetic activity has functional consequences for the animal. Reflex control of vasopressin secretion appears to be enhanced following HU. Blunted baroreflex-mediated sympathoexcitation appears to involve altered central nervous system function. Baroreceptor afferent activity in response to changes in arterial pressure is unaltered in HU rats. However, increases in efferent sympathetic nerve activity for a given decrease in afferent input are blunted after HU. This altered central nervous system processing of baroreceptor inputs appears to involve an effect at the rostral ventrolateral medulla (RVLM). Specifically, it appears that tonic GABAA-mediated inhibition of the RVLM is enhanced after HU. Augmented inhibition apparently arises from sources other than the caudal ventrolateral medulla. If similar alterations in control of the sympathetic nervous system occur in humans in response to cardiovascular deconditioning, it is likely that they play an important role in the observed tendency for orthostatic intolerance. Combined with potential changes in vascular function, cardiac function, and hypovolemia, the predisposition for orthostatic intolerance following cardiovascular deconditioning would be markedly enhanced by blunted ability to reflexly activate the sympathetic nervous system.
STS-90 Day 12 Highlights
On this twelth day of the STS-90 mission, the flight crew, Cmdr. Richard A. Searfoss, Pilot Scott D. Altman, and Mission Specialists Richard M. Linnehan, Dafydd Rhys Williams and Kathryn P. Hire, and Payload Specialists Jay C. Buckey and James A. Pawelczyk continue their investigations into how the human nervous system adapts to the weightlessness of space. Buckey and Pawelczyk take part in a variety of autonomic experiments designed to examine blood pressure regulation in microgravity. The test uses a special device resembling a hi-tech sack to place a stress on the cardiovascular system similar to that experienced when standing in Earth's gravity.
Immobile Robots: AI in the New Millennium
A new generation of sensor rich, massively distributed, autonomous systems are being developed that have the potential for profound social, environmental, and economic change. These include networked building energy systems, autonomous space probes, chemical plant control systems, satellite constellations for remote ecosystem monitoring, power grids, biosphere-like life support systems, and reconfigurable traffic systems, to highlight but a few. To achieve high performance, these immobile robots (or immobots) will need to develop sophisticated regulatory and immune systems that accurately and robustly control their complex internal functions. To accomplish this, immobots will exploit a vast nervous system of sensors to model themselves and their environment on a grand scale. They will use these models to dramatically reconfigure themselves in order to survive decades of autonomous operations. Achieving these large scale modeling and configuration tasks will require a tight coupling between the higher level coordination function provided by symbolic reasoning, and the lower level autonomic processes of adaptive estimation and control. To be economically viable they will need to be programmable purely through high level compositional models. Self modeling and self configuration, coordinating autonomic functions through symbolic reasoning, and compositional, model-based programming are the three key elements of a model-based autonomous systems architecture that is taking us into the New Millennium.
Non-invasive ventral cervical magnetoneurography as a proxy of in vivo lipopolysaccharide-induced inflammation
Maintenance of autonomic homeostasis is continuously calibrated by sensory fibers of the vagus nerve and sympathetic chain that convey compound action potentials (CAPs) to the central nervous system. Lipopolysaccharide (LPS) intravenous challenge reliably elicits a robust inflammatory response that can resemble systemic inflammation and acute endotoxemia. Here, we administered LPS intravenously in nine healthy subjects while recording ventral cervical magnetoneurography (vcMNG)-derived CAPs at the rostral Right Nodose Ganglion (RNG) and the caudal Right Carotid Artery (RCA) with optically pumped magnetometers (OPM). We observed vcMNG RNG and RCA neural firing rates that tracked changes in TNF-α levels in the systemic circulation. Further, endotype subgroups based on high and low IL-6 responders segregate RNG CAP frequency (at 30-120 min) and based on high and low IL-10 response discriminate RCA CAP frequency (at 0-30 min). These vcMNG tools may enhance understanding and management of the neuroimmune axis that can guide personalized treatment based on an individual’s distinct endophenotype.
Cardiac and Vascular Function in Bedrested Volunteers: Effects of Artificial Gravity Training
Cardiovascular effects of an artificial gravity (AG) countermeasure on deconditioned male volunteers were studied. In two groups of men we measured cardiovascular parameters at rest and in response to 30 minutes of 80 deg. head up tilt (HUT) before, at the end of, and four days following 21 days of 6 deg. head down bed rest (HDBR). One group (N=7) underwent no countermeasure while the other (N=8) received a daily, one hour, dose (2.5 gz at the foot, decreasing to 1.0 gz at the heart) of AG training on the Johnson Space Center short radius centrifuge. Cardiovascular parameters measured included heart rate, blood pressure, stroke volume, cardiac output, peripheral vascular resistance, plasma volume shifts, and vasoactive hormones. Untrained subjects exhibited shorter tilt survival (on average 8 minutes shorter) compared to trained subjects. By the end of bed rest, mean heart rate (MHR) was elevated in both groups (both supine and during tilt). In addition, treated subjects demonstrated lower, tilt-induced, increases in MHR four days following HDBR, indicating a more rapid return to pre bed rest conditions. Results from an index of autonomic balance (percentage of MHR spectral power in the respiratory frequency range) in control of heart rate are consistent with the interpretation that parasympathetic nervous system withdrawal was responsible for both tilt- and bed rest-induced increases in MHR. Our data support our pre-study hypothesis that AG treatment would lessen cardiovascular effects of deconditioning in bed rested men and suggest that AG should be further pursued as a space flight countermeasure.
Mechanisms of postspaceflight orthostatic hypotension: low alpha1-adrenergic receptor responses before flight and central autonomic dysregulation postflight
Although all astronauts experience symptoms of orthostatic intolerance after short-duration spaceflight, only approximately 20% actually experience presyncope during upright posture on landing day. The presyncopal group is characterized by low vascular resistance before and after flight and low norepinephrine release during orthostatic stress on landing day. Our purpose was to determine the mechanisms of the differences between presyncopal and nonpresyncopal groups. We studied 23 astronauts 10 days before launch, on landing day, and 3 days after landing. We measured pressor responses to phenylephrine injections; norepinephrine release with tyramine injections; plasma volumes; resting plasma levels of chromogranin A (a marker of sympathetic nerve terminal release), endothelin, dihydroxyphenylglycol (DHPG, an intracellular metabolite of norepinephrine); and lymphocyte beta(2)-adrenergic receptors. We then measured hemodynamic and neurohumoral responses to upright tilt. Astronauts were separated into two groups according to their ability to complete 10 min of upright tilt on landing day. Compared with astronauts who were not presyncopal on landing day, presyncopal astronauts had 1). significantly smaller pressor responses to phenylephrine both before and after flight; 2). significantly smaller baseline norepinephrine, but significantly greater DHPG levels, on landing day; 3). significantly greater norepinephrine release with tyramine on landing day; and 4). significantly smaller norepinephrine release, but significantly greater epinephrine and arginine vasopressin release, with upright tilt on landing day. These data suggest that the etiology of orthostatic hypotension and presyncope after spaceflight includes low alpha(1)-adrenergic receptor responsiveness before flight and a remodeling of the central nervous system during spaceflight such that sympathetic responses to baroreceptor input become impaired.
Effect of neurovestibular stimulation on autonomic regulation
Conditions associated with nausea and vomiting, such as motion sickness or side effects of medications, are commonly associated with a clinical picture consistent with parasympathetic activation and sympathetic withdrawal. It can be postulated, therefore, that vestibular stimulation contributes to sympathetic withdrawal. To test this hypothesis five normal volunteers, 24-33 years old, were studied during caloric vestibular stimulation while monitoring muscle sympathetic nerve activity directly through a needle electrode placed in a peroneal nerve. The ear was irrigated with water at a flow rate of 450 ml/min and 37 degrees C. The water temperature was sequentially lowered by 7 degree C intervals until intolerable side effects developed or a temperature of 16 degrees C was reached. Nystagmus was induced in all subjects, but heart rate, blood pressure, muscle sympathetic nerve activity and plasma norepinephrine levels did not change significantly during or after caloric stimulation, even when the subjects felt dizzy and nauseated. No evidence of sympathetic withdrawal was observed in any subject either by muscle sympathetic nerve activity or plasma norepinephrine measurements. In conclusion, we have found that selective vestibular stimulation is not accompanied by significant changes in the sympathetic nervous system function. In particular, no sympathetic withdrawal was observed. It could be argued that lack of sympathetic stimulation is an inadequate response to the symptoms associated with caloric stimulation.
Semi-Autonomous Rodent Habitat for Deep Space Exploration
NASA has flown animals to space as part of trailblazing missions and to understand the biological responses to spaceflight. Mice traveled in the Lunar Module with the Apollo 17 astronauts and now mice are frequent research subjects in LEO on the ISS. The ISS rodent missions have focused on unravelling biological mechanisms, better understanding risks to astronaut health, and testing candidate countermeasures. A critical barrier for longer-duration animal missions is the need for humans-in-the-loop to perform animal husbandry and perform routine tasks during a mission. Using autonomous or telerobotic systems to alleviate some of these tasks would enable longer-duration missions to be performed at the Deep Space Gateway. Rodent missions performed using the Gateway as a platform could address a number of critical risks identified by the Human Research Program (HRP), as well as Space Biology Program questions identified by NRC Decadal Survey on Biological and Physical Sciences in Space, (2011). HRP risk areas of potentially greatest relevance that the Gateway rodent missions can address include those related to visual impairment (VIIP) and radiation risks to central nervous system, cardiovascular disease, as well as countermeasure testing. Space Biology focus areas addressed by the Gateway rodent missions include mechanisms and combinatorial effects of microgravity and radiation. The objectives of the work proposed here are to 1) develop capability for semi-autonomous rodent research in cis-lunar orbit, 2) conduct key experiments for testing countermeasures against low gravity and space radiation. The hardware and operations system developed will enable experiments at least one month in duration, which potentially could be extended to one year in duration. To gain novel insights into the health risks to crew of deep space travel (i.e., exposure to space radiation), results obtained from Gateway flight rodents can be compared to ground control groups and separate groups of mice exposed to simulated Galactic Cosmic Radiation (at the NASA Space Radiation Lab). Results can then be compared to identical experiments conducted on the ISS. Together results from Gateway, ground-based, and ISS rodent experiments will provide novel insight into the effects of space radiation.
Mutations in the dopamine beta-hydroxylase gene are associated with human norepinephrine deficiency
Norepinephrine (NE), a key neurotransmitter of the central and peripheral nervous systems, is synthesized by dopamine beta-hydroxylase (DBH) that catalyzes oxidation of dopamine (DA) to NE. NE deficiency is a congenital disorder of unknown etiology, in which affected patients suffer profound autonomic failure. Biochemical features of the syndrome include undetectable tissue and circulating levels of NE and epinephrine, elevated levels of DA, and undetectable levels of DBH. Here, we report identification of seven novel variants including four potentially pathogenic mutations in the human DBH gene (OMIM 223360) from analysis of two unrelated patients and their families. Both patients are compound heterozygotes for variants affecting expression of DBH protein. Each carries one copy of a T-->C transversion in the splice donor site of DBH intron 1, creating a premature stop codon. In patient 1, there is a missense mutation in DBH exon 2. Patient 2 carries missense mutations in exons 1 and 6 residing in cis. We propose that NE deficiency is an autosomal recessive disorder resulting from heterogeneous molecular lesions at DBH. Copyright 2002 Wiley-Liss, Inc.
A forward model-based validation of cardiovascular system identification
We present a theoretical evaluation of a cardiovascular system identification method that we previously developed for the analysis of beat-to-beat fluctuations in noninvasively measured heart rate, arterial blood pressure, and instantaneous lung volume. The method provides a dynamical characterization of the important autonomic and mechanical mechanisms responsible for coupling the fluctuations (inverse modeling). To carry out the evaluation, we developed a computational model of the cardiovascular system capable of generating realistic beat-to-beat variability (forward modeling). We applied the method to data generated from the forward model and compared the resulting estimated dynamics with the actual dynamics of the forward model, which were either precisely known or easily determined. We found that the estimated dynamics corresponded to the actual dynamics and that this correspondence was robust to forward model uncertainty. We also demonstrated the sensitivity of the method in detecting small changes in parameters characterizing autonomic function in the forward model. These results provide confidence in the performance of the cardiovascular system identification method when applied to experimental data.
Interactive Materials for Bidirectional Redox-Based Communication
Emerging research indicates that biology routinely uses diffusible redox-active molecules to mediate communication that can span biological systems (e.g., nervous and immune) and even kingdoms (e.g., a microbiome and its plant/animal host). This redox modality also provides new opportunities to create interactive materials that can communicate with living systems. Here in this paper, it is reported that the fabrication of a redox-active hydrogel film can autonomously synthesize a H 2 O 2 signaling molecule for communication with a bacterial population. Specifically, a catechol-conjugated/crosslinked 4-armed thiolated poly(ethylene glycol) hydrogel film is electrochemically fabricated in which the added catechol moieties confer redox activity: the film can accept electrons from biological reductants (e.g., ascorbate) and donate electrons to O 2 to generate H 2 O 2 . Electron-transfer from an Escherichia coli culture poises this film to generate the H 2 O 2 signaling molecule that can induce bacterial gene expression from a redox-responsive operon. Overall, this work demonstrates that catecholic materials can participate in redox-based interactions that elicit specific biological responses, and also suggests the possibility that natural phenolics may be a ubiquitous biological example of interactive materials.
Holarchical Systems and Emotional Holons : Biologically-Inspired System Designs for Control of Autonomous Aerial Vehicles
The BEES (Bio-inspired Engineering for Exploration Systems) for Mars project at NASA Ames Research Center has the goal of developing bio-inspired flight control strategies to enable aerial explorers for Mars scientific investigations. This paper presents a summary of our ongoing research into biologically inspired system designs for control of unmanned autonomous aerial vehicle communities for Mars exploration. First, we present cooperative design considerations for robotic explorers based on the holarchical nature of biological systems and communities. Second, an outline of an architecture for cognitive decision making and control of individual robotic explorers is presented, modeled after the emotional nervous system of cognitive biological systems. Keywords: Holarchy, Biologically Inspired, Emotional UAV Flight Control
Mechanisms of selective attention and space motion sickness
The neural mismatch theory of space motion sickness asserts that the central and peripheral autonomic sequelae of discordant sensory input arise from central integrative processes falling to reconcile patterns of incoming sensory information with existing memory. Stated differently, perceived novelty reaches a stress level as integrative mechanisms fail to return a sense of control to the individual in the new environment. Based on evidence summarized here, the severity of the neural mismatch may be dependent upon the relative amount of attention selectively afforded to each sensory input competing for control of behavior. Components of the limbic system may play important roles in match-mismatch operations, be therapeutically modulated by antimotion sickness drugs, and be optimally positioned to control autonomic output.
Heart rate and respiratory rhythm dynamics on ascent to high altitude
OBJECTIVE--To investigate the alterations in autonomic control of heart rate at high altitude and to test the hypothesis that hypoxaemic stress during exposure to high altitude induces non-linear, periodic heart rate oscillations, similar to those seen in heart failure and the sleep apnoea syndrome. SUBJECTS--11 healthy subjects aged 24-64. MAIN OUTCOME MEASURES--24 hour ambulatory electrocardiogram records obtained at baseline (1524 m) and at 4700 m. Simultaneous heart rate and respiratory dynamics during 2.5 hours of sleep by fast Fourier transform analysis of beat to beat heart rate and of an electrocardiographically derived respiration signal. RESULTS--All subjects had resting hypoxaemia at high altitude, with an average oxyhaemoglobin saturation of 81% (5%). There was no significant change in mean heart rate, but low frequency (0.01-0.05 Hz) spectral power was increased (P < 0.01) at high altitude. Time series analysis showed a complex range of non-linear sinus rhythm dynamics. Striking low frequency (0.04-0.06 Hz) heart rate oscillations were observed during sleep in eight subjects at high altitude. Analysis of the electrocardiographically derived respiration signal indicated that these heart rate oscillations correlated with low frequency respiratory oscillations. CONCLUSIONS--These data suggest (a) that increased low frequency power during high altitude exposure is not simply attributable to increased sympathetic modulation of heart rate, but relates to distinctive cardiopulmonary oscillations at approximately 0.05 Hz and (b) that the emergence of periodic heart rate oscillations at high altitude is consistent with an unstable cardiopulmonary control system that may develop on acute exposure to hypoxaemic stress.
Linear and nonlinear system identification of autonomic heart-rate modulation
No abstract available