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Assessment of Programs in Space Biology and Medicine 1991 3 Human Physiology Physiology is the science of normal vital processes of animal organisms. It is a fundamental science in its own right, but it is also the bridge to the practical problems of human health and performance in space. Problems produced by disordered physiology in space include a steady loss of bone and muscle, the cause of which has yet to be determined; abnormalities of the cardiovascular system related to pooling of blood in the chest and head; and motion sickness and the difficulties it causes not only in terms of astronaut discomfort but also in their performance in handling spacecraft. The committee has had, over the years, access to anecdotal data from the Soviet space program. This anecdotal information is, while interesting, not sufficiently reliable for drawing conclusions or in planning the U.S. program for a number of reasons. There are differences in experimental protocols and controls in laboratory equipment, and the Soviets do not publish their results in refereed scientific journals. However, increased recent cooperative activities between the Soviets and the United States suggest promise for the future in standardized experimental procedures and data exchange: In some areas of physiology, there has been appreciable progress. Much remains to be done before we can be certain that humans can stay healthy and perform well for extended periods in space. The physiological problems of concern are divided into three main topics in order of priority regarding their importance to extended human space travel. First and of greatest concern is bone, muscle, and mineral metabolism; second, cardiovascular and homeostatic functions; and third; sensorimotor integration. BONE, MUSCLE, AND MINERAL METABOLISM Status of the Discipline The bone and muscle atrophy that occurs in the microgravity environment is a severe hurdle to an extended human presence in space. Although astronauts

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are subject to elevated urinary calcium and increased risk of kidney stones, the most significant risk to the musculoskeletal system may only be realized on return to normal gravitational fields. As emphasized in both the 1987 and 1988 CSBM reports, very little regarding the etiology of space-induced osteopenia (bone loss) or muscle atrophy is understood. While countermeasures to inhibit or prevent this bone loss are imperative, this goal will only be realized following an improved understanding of the basic cellular mechanisms responsible for the maintenance of muscle and bone mass. As importantly, the interaction of microgravity with various risk factors (e.g., age, gender, race, nutrition) must be established to ensure that the musculoskeletal integrity of payload specialists of diverse backgrounds will not be compromised by extended spaceflight. Major Goals As recommended in the Goldberg Strategy, eight major goals have been defined for the science of bone and mineral metabolism. In brief, they are as follows: (1) determine the temporal sequence of bone remodeling in response to microgravity; (2) establish the reversibility of this process on return to 1 g; (3) establish the relationship between muscle activity and bone function; (4) investigate countermeasures to prevent bone loss; (5) study the cellular mechanisms responsible for bone loss; (6) study the interdependence of calcium homeostasis and bone remodeling; (7) determine the etiology of pathologic calcification; and (8) establish the biomechanics of the skeleton under microgravity conditions. Given these goals, it is clear that it will be difficult to separate operational considerations (astronaut health, safety, and performance) from the basic scientific questions. In light of these goals, it must be emphasized that understanding the etiology of osteopenia is the focus of an enormous research program within the National Institutes of Health. The extent of NIH programs, which include Centers of Excellence (COE) and Specialized Centers of Research (SCOR), underscores our nation's commitment to improving an understanding of these disease processes. Multidisciplinary studies address issues such as promotion of bone formation, inhibition of resorption, biomechanics of skeletal modeling and remodeling. Also under development are treatment modalities such as diphosphonates, fluorides, estrogen, calcitonin, calcium, electrical and mechanical intervention, and exercise, with the aim of inhibiting or reversing bone destruction. These studies range from the structural organization of the bone mineral to human clinical trials of these novel treatment prophylaxes, and have had a great impact on the way we perceive the musculoskeletal problems that parallel aging, menopause, hyperparathyroidism, a diabetes, poor nutrition, immobilization, and extended bedrest. Every effort should be made to ensure that the goal-oriented NASA mission concerning musculoskeletal science exploits the knowledge base derived from the scientific advances of other agencies.

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Progress Significant progress has been achieved by NASA scientists over the past five years. The initial mandates of the Goldberg committee have been addressed, and the animal models developed by NASA personnel and their colleagues have provided some insight into the skeletal tissue response to decreased functional stimuli. Whole animal studies have been performed that demonstrate the compromising effects of microgravity, and some information has been generated regarding the temporal sequence of tissue response to disuse. Additionally, human studies correlating inactivity (bedrest) to factors such as diminished bone mass and increased urinary calcium have proven useful models to understanding the risks of skeletal fracture or mineral disorders during extended spaceflight. Lack of Progress While significant work has been done, and NASA investigators have established collaborations with superb musculoskeletal and connective tissue scientists at a number of university centers, it must also be emphasized that the directions for future programs are not yet clear. Aside from the general hypothesis that gravity serves as a signal to the regulation of bone mass, it is not clear if NASA investigators have constructed a series of basic testable hypotheses regarding the cellular mechanisms that regulate this response. Nor is it clear whether the models currently used will be appropriate to deal with the next phase of study, i.e., countermeasures to prevent bone loss. Of the eight major scientific goals of the Goldberg Strategy, only the first has been addressed. Unfortunately, even this information is limited by the dissimilarities between the animal model chosen and normal human physiology. Considering the current focus on singular methodologies, it is unclear how NASA will investigate the remaining seven research objectives. Specifically, it is not clear if the principal animal model of NASA scientists, the rat tail suspension model of osteopenia, has demonstrated either a repeatable bone loss or how this skeletal response correlates to that experienced in microgravity. Nor is it clear how this model will be developed to address issues such as a minimum strain environment capable of retaining bone mass, or the correlation of sites of bone formation and resorption to specific aspects of the bone's mechanical environment (i.e., what are the changes in the lower limbs' stress/strain environment following suspension?). Complementary analytical/experimental models should be developed immediately which can test (and validate) proposed hypotheses of bone remodeling. In addition, the limitations of the rat as a model, which responds to microgravity by inhibited growth, should be contrasted with the human condition of accelerated resorption. It must be determined whether commitment to a singular animal model is an efficient and effective means of addressing the range of scientific goals within the Goldberg Strategy. Simultaneously, a realistic and reasonable time frame for addressing the

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scientific issues of the Goldberg Strategy must be implemented. If certain scientific criteria are not met within these temporal constraints, new avenues should be established immediately; the risk of overcommitting to a single model must be diminished. Indeed, despite the extreme efforts by NASA investigators regarding their models for osteopenia, a great reluctance remains within the general scientific community to accept the extrapolations to the human condition. Importantly, the research program must move to beyond the phenomenologic (i.e., bone tissue response to microgravity) to issues of mechanism. A commitment to in vitro studies of bone cells, to study mechanisms of perception and response to physical factors (e.g., mechanical/electrical), should be implemented immediately. Additional alternative strategies and technologies (i.e., molecular biology and structural biology) within the musculoskeletal system should also be considered. Before reasonable prophylaxes for bone loss can be developed, the basic cell and subcellular mechanisms responsible for this osteopenia must be understood. Finally, it is clear that this work will provide important spinoff technology for the treatment of earth-based musculoskeletal disorders. CARDIOVASCULAR AND OTHER HOMEOSTATIC SYSTEMS This section describes the problems, goals, and recommendations for space-related and in-flight studies of four broad areas of adaptive and protective physiology. The cardiovascular and neuroendocrine elements of the circulatory system are addressed in two areas, focusing respectively on basic cardiovascular functions and the influences of regulatory systems on these functions. The third area includes immunology, hematopoiesis, and wound healing, which share cellular constituents and the recognition of regulatory proteins. The fourth area, nutrition and gastroentology, describes the lack of major problems and discusses the absence of a relationship to serious problems with other systems. Circulatory Adjustments Cardiovascular physiology is a high-priority area for NASA. To a large; extent, gravitational forces determine the distribution of intravascular and intracardiac pressures and volumes. The cardiovascular system appears to function normally during short-term exposure to microgravity. However, clinically significant dysfunction is often apparent during readaptation to 1 g and is likely amplified with prolonged spaceflight. In addition, prolonged exposure to the altered loading conditions of microgravity is considered to be a potential cause of irreversible functional and structural changes. Status of the Discipline

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Many important features of cardiovascular adaptation in microgravity and re-adaptation at I g have been identified during the past 20 years. There is an early shift of body fluids toward the head, followed by a loss of intravascular and interstitial fluid volume with decreased heart size. A fall in blood pressure on changing from a supine to an erect posture with consequent light headedness or fainting (orthostatic intolerance) and decreased exercise capacity are usually evident after return to Earth. Simple descriptive observations have been made in many subjects, but our understanding of the mechanisms responsible for adaptation to microgravity and readaptation to 1 g is incomplete. Major Goals The 1988 Life Sciences Task Group report states very clearly that biological and medical research in space should include different species and be performed at all levels of integration. This approach requires the development of a set of animal holding facilities, experiment modules, and work stations for Shuttle use and a wide range of facilities for the Space Station, including a large variable force centrifuge (VFC). This same report also makes the point that all crew members should contribute to a life sciences/ space medicine data base by serving as subjects in biomedical studies. The report defines several important cardiovascular research areas including (1) cardiovascular and systemic responses to the initial fluid shift and their interactions; (2) mechanisms responsible for postflight orthostatic intolerance; (3) the long-term, possibly irreversible, effects of the altered loading conditions in microgravity, e.g., atrophy of heart muscle, chronic orthostatic hypotension; and (4) maintenance of reflex control of blood pressure. Specific high-priority areas of investigation include (1) the role of exercise and physical fitness before, during, and after flight; (2) countermeasures against cardiovascular abnormal function and rehabilitation after long flights; (3) validation of ground-based models of microgravity for short-term and long-term studies, and (4) characterization of drug actions and metabolism in microgravity. The Goldberg Strategy also defines a series of scientific goals: (1) to understand acute (0 to 2 weeks), medium-term (2 weeks to 3 months), and long- term (3 months to several years) cardiovascular and pulmonary adaptation to microgravity; (2) to examine the validity of ground-based models of microgravity and to determine whether actual microgravity offers any unique advantages for cardiovascular studies; and (3) to define measures that will hasten human adaptation to microgravity and return to a 1-g environment. Progress Studies performed by Johnson Space Center investigators before, during, and after several Shuttle flights have provided echocardiographic data on cardiac

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dimensions and function and also explored the use of oral saline loading as a countermeasure against postflight orthostatic hypotension. Studies in progress deal with reflex regulation of blood pressure (baroreceptor reflex). A series of more detailed and comprehensive cardiovascular and pulmonary experiments will occur on future Spacelab flights to meet many of the objectives listed in the Goldberg Strategy for short-term flights, ranging from direct measurement of central venous pressure and cardiac output during maximal and minimal exercise, characterization of the baroreceptor reflex, and detailed study of the effects of microgravity on body fluid volumes and their regulation. The validity of head-down tilt as a method of simulation of microgravity will also be explored. SLS-1 will also initiate the use of animals (rats) for the study of cardiovascular physiology. The SLS-1 experiments are also an important component in a unique NASA pilot program in which experiments planned for a Spacelab life sciences (SLS) flight will be discussed as a means of enhancing elementary and secondary school science classes. With joint participation by NASA, ESA, and the German Space Program, the D-2 flight will extend the range of measurements and interventions with detailed observations during intravenous fluid load and lower body negative pressure. Lack of Progress The number of subjects available for physiological and medical studies is generally fewer than would be desired. The Life Sciences Task Group of the Space Science of the Twenty-First Century study noted that increased participation by the crew in biomedical studies during all flights is an important objective. A better understanding of cardiovascular and pulmonary physiology at all levels of investigation is still a major science goal and a requirement for a significant rational approach to space medicine, including the development of scientifically sound countermeasures against, and adaptation to, changing gravitational forces. There are only limited Soviet data on the cardiovascular consequences of prolonged exposure to microgravity. The U.S. data are limited to the Skylab exposure, which produced data on medium-term exposure. Much more information is needed on cardiovascular and pulmonary responses to the changing loading conditions in space, and on the interactions between the cardiovascular system and its control mechanisms. Potential interactions between the space environment and cardiovascular and pulmonary physiology modified by disease processes or pharmacological

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agents have not been addressed and also need attention. Hormones and Stress Hormones that affect the cardiovascular system are of great importance to NASA and should be considered in the context of the cardiovascular changes that occur in space cardiovascular deconditioning. Progress Recommended measurements of many hormones have already been made in astronauts who made the 28-, 59-, and 84-day flights in Skylab in 1973 and 1974. Two comments are relevant in terms of these observations. First, it would be beneficial to repeat them to increase the number of subjects studied in order to get a better idea of biological variations. Second, it would be wise to repeat them using the more refined methods that have been developed since 1974. A controlled study of blood and urinary levels of the relevant hormones is planned for SLS-1. Experiments are planned for mission specialists who will be concerned with laboratory experiments and will not be involved in flying the spacecraft. Consequently, better data should be obtained. Lack of Progress The observations planned to be made on SLS-1 are still far from ideal. Even if the best data are obtained, it remains only descriptive. It is important that ongoing ground-based investigations of the fundamental mechanisms involved in producing the hormonal responses observed in space be carried out in humans and animals. One concern not specifically addressed in either the 1979 or the 1987 report is the hormonal response to stress. For instance, the adrenal hormone, cortisol, was measured in Skylab and was found to be elevated from time to time during spaceflight. It would be appropriate to carry out a more detailed, better controlled study of the pituitary hormone ACTH (that stimulates the release of cortisol from the adrenal cortex) and cortisol secretion on a future SLS mission and on the Space Station. Measurements of ACTH and cortisol are also relevant to investigation of circadian rhythms in space. This topic is covered in detail in another part of this report (see Chapter 4 discussion regarding circadian rhythms). Many experiments that have examined physiological and behavioral variables in space have failed to take into account the rhythmic nature of these factors. For example, it is not possible to accurately determine the overall pattern of adrenal cortisol secretion (a stress-related hormone) by simply taking a single blood sample on a daily basis. However, NASA has carried out such studies with the result that contradictory findings have been obtained within and between

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different missions. All experimental protocols that propose to use single point measurements for variables that show pronounced pulsatile and/or circadian variations need to be reexamined to insure that the data, which will be collected at enormous costs, are valid and will not be meaningless to the scientific community. Immunology, Hematopoiesis, and Wound Healing Status of Discipline Immune cells in mammalian bone marrow and lymphoid organs, such as the thymus and spleen, provide integrated and adaptive host defense against infections, other external environmental challenges, and deviations in host cellular growth and differentiation. Many of the cells and proteins of the immune system, which initiate and regulate lymphocyte and antibody responses, also control the production and functions of cells in the blood and connective tissues. Major Problems and Goals The importance of investigations of immunology and related systems in space was suggested initially by the findings of abnormalities in human lymphocytes, red blood cells, and other blood cells on Spacelab Mission D1, and rat immunity on unmanned Soviet spaceflights, as well as by a few anecdotal reports of an increased incidence of cutaneous, gastrointestinal, and renal infections in humans on Russian and U.S. spaceflights. Progress Most studies of immunity in space have been directed to the detection of abnormalities in human and animal lymphocyte numbers and morphology, their proliferation and synthesis of immunological proteins in response to bacterial products, and the serum concentrations of gamma globulins important in immunity. Other human white blood cells prepared prior to launch also showed impaired function after spaceflight, relative to ground controls, when studied after landing. Spaceflight results in significant reductions in both plasma volume and red blood cell mass within days, and reversal of both after a few weeks. Although some reports have cited minor abnormalities in red blood cell biochemistry, no major primary metabolic or structural defects have been documented. There are plans to measure aspects of iron uptake and storage in bone marrow. Lack of Progress

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The very uncommon occurrence of serious infections during spaceflight, despite the apparently profound laboratory defects in some immune functions in vitro, casts some doubt on the preliminary findings of alterations of immune responses. However, the grave consequences of any attenuation of adaptive host defense during spaceflight and the important roles of immune proteins as regulators of non-immune blood cells and connective tissue cell generation and functions, such as wound healing, mandate recommendations for more investigations of immune system functions. Our current understanding of immunity in space is not commensurate with the goals proposed in Space Science in the Twenty-First Century—Imperatives for the Decades 1995-2015, Life Sciences and earlier sets of recommendations. Above all else in practical importance are in vivo studies designed to elucidate any abnormalities in integrated immune, hematopoietic, and tissue- healing responses of humans. The critical need for 1-g in-flight controls cannot be overemphasized, if the resultant data are to be analyzed rigorously for specific mechanisms and to provide unequivocal clinical guidelines for countering any abnormalities. The availability now of stimuli and inhibitors of immune and bone marrow cell functions, derived from genetic techniques, provides an opportunity to detect and possibly correct any excesses or deficiencies of activity or any regulatory abnormalities. Studies of the mechanisms for reduction in red blood cell mass with spaceflight and of effective countermeasures for attenuated compensation to bleeding and blood clot formation are recommended. Gastrointestinal System and Nutrition Major Goals A Strategy for Space Biology and Medical Science for the 1980s and 1990s recommends studies of caloric needs, nitrogen balance, supplements to the basic diet during spaceflight, and the energetic requirements of work in space. Space Science in the Twenty-First Century—Life Sciences discusses nutritional requirements in the context of integrated functions and closed ecological life support systems (CELSS). Progress Appreciable data are available on energy expenditures and motor performance. In experiments carried out to date, nitrogen balance in space has been negative, probably because dietary intake was often inadequate in view of space motion sickness and crowded schedules and because of muscle wasting. The amounts of vitamins and minerals provided to the astronauts more than meet the Recommended Dietary Allowances, (Tenth edition, National Academy Press, Washington, D.C., 1991), and there is no evidence indicating any additional

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special needs in space. Little is known of possible minor changes in bowel, liver, pancreatic, and salivary functions during spaceflight, although there are plans to study gastric emptying and gastrointestinal motility and their relationship to movement of body fluids. Lack of Progress Very few significant problems have been encountered in space with nutrition or the gastrointestinal system to date. However, NASA has plans to conduct investigations on areas that may be potential problems on future Shuttle flights. SENSORIMOTOR INTEGRATION Status of Discipline The changes in the gravito-inertial environment that inevitably occur during a space mission lead to disturbances of sensorimotor function including impaired spatial orientation, instability of posture and gaze, and motion sickness. Fortunately the central nervous system (CNS) adapts to those environmental changes within a few days so that the problems are of relatively short duration provided a constant environment is maintained. There are two caveats to this assessment of relative risk. One is that gravito-inertial changes occur at the most critical parts of a mission—during takeoff or landing. For instance, sensorimotor problems could impair crew effectiveness for several days after landing on Mars. The second caveat is that the use of a spinning spacecraft to eliminate problems of prolonged microgravity would entail repeated changes in gravito-inertial environment when it was necessary to change spin rates or to service different parts of the craft. To deal with these concerns, A Strategy for Space Biology and Medical Science for the 1980s and 1990s recommends experimentation in five areas: spatial orientation, postural mechanisms, vestibuloocular reflex (VOR), neural processing in the vestibular system, and motion sickness. Both in-flight and ground-based experiments were proposed in each area. Because the otolith organs of the vestibular labyrinth are the primary sensors informing the brain of the linear accelerations induced by gravity, the research recommended focuses on neural mechanisms that transform vestibular sensory inputs (especially those from otolith organs) into sensations, movements, and changes in homeostatic state (i.e., space adaptation sickness). Major Goals As indicated in the Goldberg Strategy, the neuronal mechanisms underlying a sense of spatial orientation are complex, as yet relatively poorly

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understood, and directly relevant to assuring effective functioning of humans involved in space missions. Accordingly, the strategy recommends a vigorous program of both ground-based and flight research aimed at better understanding these mechanisms as they operate on Earth, in space, and on return from low- gravity to high-gravity environments. The report also recommends that the adaptation of the posture control system to microgravity be investigated by studying its input/output behavior before, during, and after flight. The VOR, which converts head motion into compensatory eye movement, is both well understood and important in maintaining stable vision. However, it is not known how this reflex is affected by microgravity. Accordingly, the 1987 strategy report recommends that it be studied in microgravity. The Goldberg Strategy concludes that neural processing mechanisms in the vestibular system must be investigated both in normal gravity and microgravity if NASA is to achieve its goal of controlling for sensorimotor changes and space adaptation sickness. These studies would focus on the vestibular nuclei of the brainstem, which serve both as the point at which vestibular signals from receptors of the vestibular labyrinth in the inner ear enter the brain and as a primary processing center for all signals—vestibular, visual, and proprioceptive (sense of body position)—that relate to orientation in space and to motor responses that maintain a stable orientation. In addition to their potential for solving operational problems, studies of vestibular nuclei in microgravity provide unique opportunities for understanding basic vestibular function since microgravity is the only environment in which certain aspects of semicircular canal and otolith function can be studied in isolation. The report further concludes that one focus of sensorimotor studies must be upon the adaptive mechanisms that alter vestibular processing in response to altered feedback from the environment. Present knowledge indicates that it is these mechanisms that both allow an astronaut to adapt to microgravity conditions and then raise problems during return to normal gravity when the adapted responses are no longer appropriate. Further, space adaptation sickness may be a side effect of the adaptive process. The Goldberg Strategy reviews uncertainties about the etiology of motion sickness and stresses the importance of vigorous research on this subject, with the shorter term objective of mitigating associated operational difficulties. Longer- term objectives include eliminating such difficulties as well as enhancing understanding of the function of the nervous system. Progress Overall, NASA has made a concerted effort to stimulate appropriate,

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quality research in the sensorimotor area. Space adaptation sickness (SAS) has clearly been perceived as an important problem that can only be solved by a combination of basic and more applied research. In the area of basic research, NASA has supported an array of external studies, which have included contributions by a number of leading vestibular physiologists. These have generated useful information in the areas of spatial sensation, vestibular processing, posture and gaze control, and vestibular-autonomic interactions. A promising development is the establishment of the Vestibular Research Facility (VRF) at Ames Research Center (ARC), which is becoming a focal point for state- of-the-art studies of the vestibular system in animals, involving investigators from many universities and other research institutions. If this facility can become a national resource and a site of projects with joint funding from NASA and NIH, its impact will be even greater. Whereas in some cases microgravity is a singular point so that behavior on-orbit cannot be extrapolated from measurements at various g levels on the ground, it is likely that some of the vestibular changes in going from 1 g to microgravity could be extrapolated from changes between a range of gravitational forces. Therefore, parallel development of the ARC centrifuge or other similar facilities as centers for vestibular studies could contribute to solving some of the outstanding questions. Given the limited number of flight opportunities, considerable progress has also been made in studying human sensorimotor performance in microgravity. A great deal of this progress has resulted from the well-planned experiments conducted by groups at MIT as well as in Canada and Europe. Tantalizing preliminary results and interesting new concepts have resulted from their studies on the Spacelab and D-1 missions. Follow-up studies on SLS1, IML- 1 and D-2 missions should be very productive, but it must be emphasized that extensive replications will be needed before any of these preliminary results can be accepted with confidence. As set forth in the Goldberg Strategy, what is needed now in vestibuloocular studies are 3-dimensional analysis and modeling of the VOR to account for changes in microgravity and investigation of the effects of conflict between visual, vestibular, and proprioceptive stimuli on gaze stability and on the adaptive systems that regulate the VOR. Studies of vestibuloocular and optokinetic (visually induced) reflexes scheduled for SLS-1 will address these issues as will planned ground-based studies of adaptive changes in otolith-ocular reflex. Thus work in this area is on track. Progress in meeting the objectives set forth in the 1987 report regarding neural processing can be summarized as follows: Studies of structural changes in labyrinthine receptors in microgravity are under way and will be continued on SLS-1. In the future, it will be necessary to perform control experiments in which some animals are maintained at 1 g on orbit using the centrifuge so that we can be confident that any changes observed are due to exposure to microgravity rather than other factors. Studies of vestibular afferent signals (i.e., those nerves that transmit

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impulses to the CNS) in microgravity and studies of the role of gravity in neonatal development of sensorimotor functions will require periods of a month or more in orbit. Plans should be formulated to perform these studies on Space Station Freedom and prerequisite ground-based development should be initiated. The CSBM is not aware of any such activities at the present time. The Goldberg Strategy recommends "a vigorous, ground-based program of research involving the use of modern physiological methods" to investigate the central processing of vestibular sensory information, especially that from the gravity-sensitive otolith organs. NASA is to be commended for establishing the VRF Program and a good series of university-based studies to address this goal. Further emphasis on single neuron recordings will be needed to attain the goal of understanding those elements of vestibular processing that are related to sensorimotor changes in microgravity. Even more important is the development of neural models of the vestibular system that could both generate hypotheses for experimental testing and assist in the interpretation of experimental results. If properly managed, the nascent modeling effort at the ARC could provide a national resource for such theoretical studies of vestibular systems. As appropriate, NASA appears to have been pursuing an active multidimensional research program in understanding motion sickness. Lack of Progress Within this generally positive context, NASA might consider some fine tuning of its program related to spatial orientation along the following lines. The Goldberg report stresses that vestibular signals are only one of the inputs influencing spatial orientation, with other kinds of inputs certainly involved and perhaps determinative under particular sets of circumstances. The issue of whether observed instances of sensorimotor difficulties are, or are not, entirely a function of disturbed vestibular processing has become of operational importance in connection with ongoing and projected increases in mission duration (letter to Administrator Truly, NASA, regarding extended duration orbiter medical program, December 20, 1989). In this connection, both increased attention to possible nonvestibular influences on spatial orientation, and improved monitoring of astronaut performance (as recommended in that letter), would seem desirable. It also appears that these and other observed disturbances may relate not so much to steady-state conditions as to fluctuating environments, such as the changing gravity loads associated with return from orbit. This suggests that in the ground- based program increased attention might profitably be given to the program of spatial orientation in fluctuating environments. Finally, the breadth of the problem of spatial orientation is such that efforts in this area will probably be most productive when considered in connection with those in possibly related areas, including, for example, not only other sensorimotor subareas but also chronobiology and human behavior generally. NASA might want to explore ways to assure effective interactions along these lines, possibly by way of organizing a meeting focused on the spatial orientation problem but involving investigators

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from a number of different relevant areas. NASA should consider increasing its support of ground-based studies of postural mechanisms to complement the flight studies since significant changes in eye-hand coordination and in postural responses to applied perturbations are being found. When a sufficient level of understanding has been reached, it may become possible to train astronauts to adopt postural strategies that will be useful in altered gravity environments as suggested by the Goldberg Strategy. The problem of VOR has already been discussed and NASA appears to be headed in the correct direction. Similarly, issues related to neural processing are being dealt with properly, although a great deal of work remains to be done. It remains the case that no single hypothesis as to the origin of space motion sickness fits all existing observations, and no single therapeutic regime with assured effectiveness has yet been developed. While existing lines of research may yet achieve one or both of these objectives, it may be that the time has come to take a fresh look at whether the syndrome, with individual variations in the expression and intensity of components, is actually several distinguishable syndromes. A recognition of this fact could accelerate both therapeutic and basic research. When viewed in the light of resources required to develop new therapeutic drugs, the amount of funding for this key area is clearly inadequate. If NASA requires a solution to this problem, ways need to be found to mobilize a much larger joint NASA/ university initiative in the area.