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A brief review of the compensatory-adjusting body changes observed during and after human exposure to prolonged spaceflight is given. Pathological disturbances caused by increased functional hypokinesia and weightlessness loads affect the cardiovascular system, the nervous and hormonal systems, and the state of the skeletal musculo apparatus.
To date, in our research we have focused on the use of normal human neuronal progenitor (NHNP) cells because of their importance in human nervous system regeneration, development and maintenance, but we have developed 2-D and 3-D bioreactors that can accommodate any cell line. In this Project, we will include the use of tissues important for physiological regeneration: Human osteoblasts or chondrocytes, and vascular cells. Our initial results with the NHNP cells were quite startling using extremely low-level electromagnetic fields (5 microtesla at 10Hz; 6mA). The low-amplitude, rapidly time-varying electromagnetic fields exert a very potent effect on the proliferation, morphology, and gene expression of the cells in culture, both in standard 2-dimensional culture plates as well as cells organized into 3-dimensional tissue-like assemblies (TLAs) in a 3D bioreactor. We have replicated our preliminary results many, many times, have analyzed the gene expression using gene arrays (followed by Luminex analysis for protein production), and have monitored cell proliferation, orientation, morphology, and glucose metabolism, and we are confident that we have a stable and reliable model to study the control of high-level cellular processes by application of low-amplitude, time varying electromagnetic fields (TVEMF) (1, 2). In additional studies at the University of Michigan, we have been able to generate functional in vitro engineered mammalian skeletal muscle, and have employed nerve-muscle co-culture techniques to promote axonal sprouting. We believe that nearly all tissues, in particular, neural, are susceptible to the influences of low-level TVEMF.
Bone mass is maintained constant between puberty and menopause by the balance between osteoblast and osteoclast activity. The existence of a hormonal control of osteoblast activity has been speculated for years by analogy to osteoclast biology. Through the search for such humoral signal(s) regulating bone formation, leptin has been identified as a strong inhibitor of bone formation. Furthermore, intracerebroventricular infusion of leptin has shown that the effect of this adipocyte-derived hormone on bone is mediated via a brain relay. Subsequent studies have led to the identification of hypothalamic groups of neurons involved in leptin's antiosteogenic function. In addition, those neurons or neuronal pathways are distinct from neurons responsible for the regulation of energy metabolism. Finally, the peripheral mediator of leptin's antiosteogenic function has been identified as the sympathetic nervous system. Sympathomimetics administered to mice decreased bone formation and bone mass. Conversely, beta-blockers increased bone formation and bone mass and blunted the bone loss induced by ovariectomy.
The timing of cell generation (onset and duration) in the developing rat vestibular and proprioceptive systems is investigated. The results clearly indicate a defined time-span for generation of all neurons in the central nervous system nuclei studied. This cytogenetic period in both vestibular and proprioceptive sensory nuclei is determined to occur during and immediately after placentation, a potentially critical period for spaceflight exposure due to alterations in maternal physiology.
The purpose of this report is to describe how changes in autonomic nervous system responses may be used as an index of individual differences in adaptational capacity to space flight. During two separate Spacelab missions, six crewmembers wore an ambulatory monitoring system which enabled continuous recording of their physiological responses for up to twelve hours a day for 3 to 5 mission days. The responses recorded were electrocardiography, respiration wave form, skin conductance level, hand temperature, blood flow to the hands and triaxial accelerations of the head and upper body. Three of these subjects had been given training, before the mission, in voluntary control of these autonomic responses as a means of facilitating adaptation to space. Three of these subjects served as Controls, i.e., did not receive this training but took anti-motion sickness medication. Nearly 300 hours of flight data are summarized. These data were examined using time-series analyses, spectral analyses of heart rate variability, and analyses of variance. Information was obtained on responses to space motion sickness, inflight medications, circadian rhythm, workload and fatigue. Preliminary assessment was made on the effectiveness of self-regulation training as a means of facilitating adaptation, with recommendations for future flights.
Post-flight orthostatic intolerance is a dramatic physiological consequence of human adaptation to microgravity made inappropriate by a sudden return to 1-G. The immediate mechanism is almost always a failure to maintain adequate tissue perfusion, specifically perfusion of the central nervous system, but vestibular dysfunction may occasionally be the primary cause. Orthostatic intolerance is present in a wide range of clinical disorders of the nervous and cardiovascular systems. The intolerance that is produced by spaceflight and 1-G analogs (bed rest, head-down tilt at a moderate angle, water immersion) is different from its clinical counterparts by being only transiently present in subjects who otherwise have normal cardiovascular and regulatory systems. However, the same set of basic pathophysiological elements should be considered in the analysis of any form of orthostatic intolerance.
Thriving In DEep Space (TIDES) initiative aims to comprehensively understand how hostile environments such as the Moon and Mars affect human physiology. Here we present two NASA-selected spaceflight experiments under the TIDES portfolio, iGCE (Integrated Gravity Continuum Experiment) and MitoFlyght (Mitochondrial Investigation of Oxidative Stress in Flies). We hypothesize that exposure to spaceflight conditions induces oxidative stress responses that negatively impact physiology. The iGCE mission employs two well-established spaceflight models, Drosophila melanogaster and C.elegans, using Redwire’s Multi-use Variable-g Platform (MVP) hardware to assess changes in cardiac, muscle, and nervous systems across five different gravities: Hypergravity (2g), Earth (1g), Mars (0.37g), Moon (0.16g), and microgravity (ug). This mission focuses on uncovering alterations in protein homeostasis, autophagy, and mitochondrial function conserved across species. In the MitoFlyght mission to the ISS, Drosophila will be housed in the Vented Fly Box (VFB). This mission evaluates the oxidative stress response and autophagic pathway in muscle, heart, and nervous system. Additionally, we will (a) use the genetic mutant, Tor7/P to test whether increased autophagy is beneficial or a maladaptive response to the spaceflight stressors, and (b) utilize fly lines with tissue-specific expression (neuronal, muscle, and cardiac) of an antioxidant gene, SOD2 (superoxide dismutase) as a potential countermeasure. Data from these missions will be compared with previous LEO-based datasets to identify shared signatures. Furthermore, cross-species analysis of the transcriptomic data from other invertebrate and vertebrate spaceflight studies will help determine evolutionarily conserved pathways perturbed by space stressors. Overall, both these missions aim to provide crucial insights into the mechanisms underlying oxidative stress responses, synaptic changes, and heart and muscle deficits, facilitating the identification of diagnostic and therapeutic targets to mitigate the adverse health effects of long-duration space habitation. Ultimately, this research will enhance our ability to thrive in deep space and inform future missions.
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.
Future deep space exploration to the Moon and Mars and beyond are currently major goals of NASA. Space flight presents unique challenges to the human physiology from the combined effects of microgravity, social isolation, altered circadian rhythm and radiation. Oxidative stress has been implicated as a crucial factor in space environment induced injury. Elucidating these detrimental effects on the central nervous system and brain is a primary objective, as they may result in adverse changes in astronaut behavior, mood and performance of critical tasks. We were recently funded by HRP Human Factors Behavioral Performance (HFBP) Element to test the hypothesis that Galactic Cosmic Ray Simulation (GCRsim) Ionizing Radiation (IR), microgravity and social isolation combine synergistically to trigger an oxidative stress response that alters immune homeostasis, brain structure and function, and neurobehavioral and cognitive performance. This project will identify potential biomarkers for, and mechanisms underlying, structural and functional changes in the immune and nervous systems leading to behavioral/cognitive performance deficits, and its potential application to develop effective countermeasures to mitigate negative health effects of long duration space habitation. Countermeasures to offset neurological damaged and cognitive deficits are paramount for protecting astronauts during deep space transits, but many countermeasures have been found to be unsuitable in ground-based model studies. We have developed a multi targeted dietary supplement (MTDS) designed to simultaneously ameliorate oxidative stress, inflammatory processes, energetic shortfalls, and membrane and mitochondrial deterioration. Administration of this MTDS has improved cognition and longevity in age accelerated and normal aging mice. Specifically, the MTDS was found to prevent a decline in mitochondrial complex III activity and cell loss, as well as prevent an increase in protein carbonyls and mitochondrial 3-nitrotyrosine in the brain of these mice. Further, administration of the MTDS was also found to reduce bone marrow chromosomal aberrations, DNA damage, lymphocyte apoptosis after whole body exposure of 2 Gy γ radiation. Mice exposed to a high dose cranially (10 Gy) had decreased cognitive responses (seen as increased latency time to uncover buried food and decreased novel object recognition), increased plasma 8-OHdG levels, increased markers of cell stress in the brain, decreased hippocampal brain-derived neurotrophic factor (BDNF) protein and decreased plasma levels of cytokines, all of which were ameliorated with treatment of the MTDS. As we have shown the supplement is protective in models of cognitive damage similar space environment stressors, particularly increased oxidative stress, we propose it may be a suitable countermeasure for upcoming deep space exploration.
As part of a program to develop a treatment for motion sickness based on self-regulation of autonomic nervous system (ANS) activity, this study examined the stability of an individual's pattern of ANS responses to motion sickness stimulation on repeated occasions. Motion sickness symptoms were induced in 58 people during two rotating chair test. Physiological responses measured were heart rate, finger pulse volume, respiration rate, and skin conductance. Using standard scores, stability of responses of specific magnitudes across both tests is as examined. Correlational analyses, analysis of variance, and a components of variance analysis all revealed marked, but quite stable, individual differences in ANS responses to both mild and severe motion sickness. These findings confirm the prior observation that people are sufficiently unique in their ANS responses to motion sickness provocation to make it nesessary to individually tailor self-regulation training. Further, these data support the contention that individual ANS patterns are sufficiently consistent from test to test so as to serve as an objective indicator of individual motion sickness malaise levels.
The purpose of this paper is to present a detailed description of the physiological and performance responses of two military pilots undergoing a treatment for motion sickness. The treatment used, Autogenic-Feedback Training (AFT), is an operant conditioning procedure where subjects are taught to control several of their autonomic responses and thereby suppress their motion sickness symptoms. Two male, active duty military pilots (U.S. Navy and U. S. Marine Corps), ages 30 and 35, were each given twelve 30-minute training sessions. The primary criterion for success of training was the subject's ability to tolerate rotating chair motion sickness tests for progressively longer periods of time and at higher rotational velocities. A standardized diagnostic scale was used during motion sickness to assess changes in the subject's perceived malaise. Physiological data were obtained from one pilot during tactical maneuvers in an F-18 aircraft after completion of his training. A significant increase in tolerance to laboratory-induced motion sickness tests and a reduction in autonomic nervous system (ANS) response variability was observed for both subjects after training. Both pilots were successful in applying AFT for controlling their airsickness during subsequent qualification tests on F-18 and T-38 aircraft and were returned to active duty flight status.
The acute radiation syndrome in man is clinically bounded by death at high dose levels and by the prodromal syndrome of untoward physiological effects at minimal levels of clinically effective exposure. As in lower animals, man experiences principally three acute modes of death from radiation exposure (Bond et al., 1965). These are known collectively as the lethal radiation syndromes: central nervous system death, gastrointestinal death, and hematopoietic death. The effect of multiple exposure on lethality, the effect of multiple exposure on hematopoietic recovery, and quantitative aspects of cell and tissue repair are discussed.
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.
The autonomic nervous system can now be studied quantitatively, noninvasively, and reproducibly in a clinical autonomic laboratory. The approach at the Mayo Clinic is to study the postganglionic sympathetic nerve fibers of peripheral nerve (using the quantitative sudomotor axon reflex test [QSART]), the parasympathetic nerves to the heart (cardiovagal tests), and the regulation of blood pressure by the baroreflexes (adrenergic tests). Patient preparation is extremely important, since the state of the patient influences the results of autonomic function tests. The autonomic technologist in this evolving field needs to have a solid core of knowledge of autonomic physiology and autonomic function tests, followed by training in the performance of these tests in a standardized fashion. The range and utilization of tests of autonomic function will likely continue to evolve.
Extravehicular activity (EVA) is at the core of a manned space exploration program. Some elements of exploration may be safely and effectively performed by robots, but certain critical elements will require the trained, assertive, and reasoning mind of a human crewmember. To effectively use these skills, NASA needs a safe, effective, and efficient EVA component integrated into the human exploration program. The EVA preparation time should be minimized and the suit pressure should be low to accommodate EVA tasks without causing undue fatigue, physical discomfort, or suit-related trauma. Commissioned in 2005, the Exploration Atmospheres Working Group (EAWG) had the primary goal of recommending to NASA an internal environment that allowed efficient and repetitive EVAs for missions that were to be enabled by the former Constellation Program. At the conclusion of the EAWG meeting, the 8.0 psia and 32% oxygen (O2) environment were recommended for EVA-intensive phases of missions. After re-evaluation in 2012, the 8/32 environment was altered to 8.2 psia and 34% O2 to reduce the hypoxic stress to a crewmember. These two small changes increase alveolar O2 pressure by 11 mmHg, which is expected to significantly benefit crewmembers. The 8.2/34 environment (inspired O2 pressure = 128 mmHg) is also physiologically equivalent to the staged decompression atmosphere of 10.2 psia / 26.5% O2 (inspired O2 pressure = 127 mmHg) used on 34 different shuttle missions for approximately a week each flight. As a result of selecting this internal environment, NASA gains the capability for efficient EVA with low risk of decompression sickness (DCS), but not without incurring the additional negative stimulus of hypobaric hypoxia to the already physiologically challenging spaceflight environment. This report provides a review of the human health and performance risks associated with the use of the 8.2 psia / 34% O2 environment during spaceflight. Of most concern are the potential effects on the central nervous system (CNS), including increased intracranial pressure, visual impairment, sensorimotor dysfunction, and oxidative damage. Other areas of focus include validation of the DCS mitigation strategy, incidence and treatment of transient acute mountain sickness (AMS), development of new exercise countermeasure protocols, effective food preparation at 8.2 psia, assurance of quality sleep, and prevention of suit-induced injury. Although missions proposing to use an 8.2/34 environment are still years away, it is recommended that these studies begin early enough to ensure that the correct decisions pertaining to vehicle design, mission operational concepts, and human health countermeasures are appropriately informed.
To further validate the Pellet Gastric Emptying Test (PGET) as a marker of gastric emptying, a randomized, four-way crossover study was conducted with 12 healthy subjects. The study consisted of oral co-administration of enteric coated caffeine (CAFF) and acetaminophen (APAP) pellets in four treatment phases: Same Size (100 kcal), Fasted, Small Liquid Meal (100 kcal), and Standard Meal (847 kcal). The time of first appearance of measurable drug marker in plasma, t(initial), was taken as the emptying time for the markers. Co-administration of same size enteric coated pellets of CAFF and APAP (0.7 mm in diameter) revealed no statistically significant differences in t(initial) values indicating that emptying was dependent only on size and not on chemical make-up of the pellets. Co-administration of different size pellets indicated that the smaller 0.7-mm diameter (CAFF) pellets were emptied and absorbed significantly earlier than the larger 3.6-mm diameter (APAP) pellets with both the Small Liquid Meal (by 35 min) and the Standard Meal (by 33 min) (P<0.05). The differences in emptying of the pellets were not significant in the Fasted Phase. The results suggest that the pellet gastric emptying test could prove useful in monitoring changes in transit times in the fasted and fed states and their impact on drug absorption.
In space exploration outside the Earth s geomagnetic field, radiation exposure from solar particle events (SPE) presents a health concern for astronauts, that could impair their performance and result in possible failure of the mission. Acute risks are of special concern during extra-vehicular activities because of the rapid onset of SPE. However, most SPEs will not lead to acute risks but can lead to mission disruption if accurate projection methods are not available. Acute Radiation Sickness (ARS) is a group of clinical syndromes developing acutely (within several seconds to 3 days) after high dose whole-body or significant partial-body ionizing radiation exposures. The manifestation of these syndromes reflects the disturbance of physiological processes of various cellular groups damaged by radiation. Hematopoietic cells, skin, epithelium, intestine, and vascular endothelium are among the most sensitive tissues of human body to ionizing radiation. Most ARS symptoms are directly related to these tissues and other systems (nervous, endocrine, and cardiovascular, etc.) with coupled regulations. Here we report the progress in bio-mathematical models to describe the dose and time-dependent early human responses to ionizing radiation. The responses include lymphocyte depression, granulocyte modulation, fatigue and weakness syndrome, and upper gastrointestinal distress. The modest dose and dose-rates of SPEs are predicted to lead to large sparing of ARS, however detailed experimental data on a range of proton dose-rates for organ doses from 0.5 to 2 Gy is needed to validate the models. We also report on the ARRBOD code that integrates the BRYNTRN and SUMDOSE codes, which are used to estimate the SPE organ doses for astronauts under various space travel scenarios, with our models of ARS. The more recent effort is to provide easy web access to space radiation risk assessment using the ARRBOD code.
Brown adipose tissue serves as a model system for nonshivering thermogenesis (NST) since a) it has as a primary physiological function the conversion of chemical energy to heat; and b) preliminary data from other tissues involved in NST (e.g., muscle) indicate that parallel mechanisms may be involved. Now that biochemical pathways have been proposed for brown fat thermogenesis, cellular models consistent with a thermodynamic representation can be formulated. Stated concisely, the thermogenic mechanism in a brown fat cell can be considered as an energy converter involving a sequence of cellular events controlled by signals over the autonomic nervous system. A thermodynamic description for NST is developed in terms of a nonisothermal system under steady-state conditions using network thermodynamics. Pathways simulated include mitochondrial ATP synthesis, a Na+/K+ membrane pump, and ionic diffusion through the adipocyte membrane.