Computational model of cardiovascular response to centrifugation and lower body cycling exercise.

Short-radius centrifugation combined with exercise has been suggested as a potential countermeasure against spaceflight deconditioning. Both the long-term and acute physiological responses to such a combination are incompletely understood. We developed and validated a computational model to study the acute cardiovascular response to centrifugation combined with lower body ergometer exercise. The model consisted of 21 compartments, including the upper body, renal, splanchnic, and leg circulation, as well as a four-chamber heart and pulmonary circulation. It also included the effects of gravity gradient and ergometer exercise. Centrifugation and exercise profiles were simulated and compared with experimental data gathered on 12 subjects exposed to a range of gravitational levels (1 and 1.4G measured at the feet) and workload intensities (25-100 W). The model was capable of reproducing cardiovascular changes (within ± 1 SD from the group-averaged behavior) due to both centrifugation and exercise, including dynamic responses during transitions between the different phases of the protocol. The model was then used to simulate the hemodynamic response of hypovolemic subjects (blood volume reduced by 5-15%) subjected to similar gravitational stress and exercise profiles, providing insights into the physiological responses of experimental conditions not tested before. Hypovolemic results are in agreement with the limited available data and the expected responses based on physiological principles, although additional experimental data are warranted to further validate our predictions, especially during the exercise phases. The model captures the cardiovascular response for a range of centrifugation and exercise profiles, and it shows promise in simulating additional conditions where data collection is difficult, expensive, or infeasible.NEW & NOTEWORTHY Artificial gravity combined with exercise is a potential countermeasure for spaceflight deconditioning, but the long-term and acute cardiovascular response to such gravitational stress is still largely unknown. We provide a novel mathematical model of the cardiovascular system that incorporates gravitational stress generated by centrifugation and lower body cycling exercise, and we validate it with experimental measurements from human subjects. Simulations of experimental conditions not used for model development corroborate the model's predictive capabilities.

Short-Term Cardiovascular Response to Short-Radius Centrifugation With and Without Ergometer Exercise.

Artificial gravity (AG) has often been proposed as an integrated multi-system countermeasure to physiological deconditioning associated with extended exposure to reduced gravity levels, particularly if combined with exercise. Twelve subjects underwent short-radius centrifugation along with bicycle ergometry to quantify the short-term cardiovascular response to AG and exercise across three AG levels (0 G or no rotation, 1 G, and 1.4 G; referenced to the subject's feet and measured in the centripetal direction) and three exercise intensities (25, 50, and 100 W). Continuous cardiovascular measurements were collected during the centrifugation sessions using a non-invasive monitoring system. The cardiovascular responses were more prominent at higher levels of AG and exercise intensity. In particular, cardiac output, stroke volume, pulse pressure, and heart rate significantly increased with both AG level (in most of exercise group combinations, showing averaged increments across exercise conditions of 1.4 L/min/g, 7.6 mL/g, 5.22 mmHg/g, and 2.0 bpm/g, respectively), and workload intensity (averaged increments across AG conditions of 0.09 L/min/W, 0.17 mL/W, 0.22 mmHg/W, and 0.74 bpm/W respectively). These results suggest that the addition of AG to exercise can provide a greater cardiovascular benefit than exercise alone. Hierarchical regression models were fitted to the experimental data to determine dose-response curves of all cardiovascular variables as a function of AG-level and exercise intensity during short-radius centrifugation. These results can inform future studies, decisions, and trade-offs toward potential implementation of AG as a space countermeasure.

Human manual control precision depends on vestibular sensory precision and gravitational magnitude.

Precise motion control is critical to human survival on Earth and in space. Motion sensation is inherently imprecise, and the functional implications of this imprecision are not well understood. We studied a "vestibular" manual control task in which subjects attempted to keep themselves upright with a rotational hand controller (i.e., joystick) to null out pseudorandom, roll-tilt motion disturbances of their chair in the dark. Our first objective was to study the relationship between intersubject differences in manual control performance and sensory precision, determined by measuring vestibular perceptual thresholds. Our second objective was to examine the influence of altered gravity on manual control performance. Subjects performed the manual control task while supine during short-radius centrifugation, with roll tilts occurring relative to centripetal accelerations of 0.5, 1.0, and 1.33 GC (1 GC = 9.81 m/s2). Roll-tilt vestibular precision was quantified with roll-tilt vestibular direction-recognition perceptual thresholds, the minimum movement that one can reliably distinguish as leftward vs. rightward. A significant intersubject correlation was found between manual control performance (defined as the standard deviation of chair tilt) and thresholds, consistent with sensory imprecision negatively affecting functional precision. Furthermore, compared with 1.0 GC manual control was more precise in 1.33 GC (-18.3%, P = 0.005) and less precise in 0.5 GC (+39.6%, P < 0.001). The decrement in manual control performance observed in 0.5 GC and in subjects with high thresholds suggests potential risk factors for piloting and locomotion, both on Earth and during human exploration missions to the moon (0.16 G) and Mars (0.38 G). NEW & NOTEWORTHY The functional implications of imprecise motion sensation are not well understood. We found a significant correlation between subjects' vestibular perceptual thresholds and performance in a manual control task (using a joystick to keep their chair upright), consistent with sensory imprecision negatively affecting functional precision. Furthermore, using an altered-gravity centrifuge configuration, we found that manual control precision was improved in "hypergravity" and degraded in "hypogravity." These results have potential relevance for postural control, aviation, and spaceflight.

Human perception of whole body roll-tilt orientation in a hypogravity analog: underestimation and adaptation.

Overestimation of roll tilt in hypergravity ("G-excess" illusion) has been demonstrated, but corresponding sustained hypogravic conditions are impossible to create in ground laboratories. In this article we describe the first systematic experimental evidence that in a hypogravity analog, humans underestimate roll tilt. We studied perception of self-roll tilt in nine subjects, who were supine while spun on a centrifuge to create a hypogravity analog. By varying the centrifuge rotation rate, we modulated the centripetal acceleration (GC) at the subject's head location (0.5 or 1 GC) along the body axis. We measured orientation perception using a subjective visual vertical task in which subjects aligned an illuminated bar with their perceived centripetal acceleration direction during tilts (±11.5-28.5°). As hypothesized, based on the reduced utricular otolith shearing, subjects initially underestimated roll tilts in the 0.5 GC condition compared with the 1 GC condition (mean perceptual gain change = -0.27, P = 0.01). When visual feedback was given after each trial in 0.5 GC, subjects' perceptual gain increased in approximately exponential fashion over time (time constant = 16 tilts or 13 min), and after 45 min, the perceptual gain was not significantly different from the 1 GC baseline (mean gain difference between 1 GC initial and 0.5 GC final = 0.16, P = 0.3). Thus humans modified their interpretation of sensory cues to more correctly report orientation during this hypogravity analog. Quantifying the acute orientation perceptual learning in such an altered gravity environment may have implications for human space exploration on the moon or Mars. NEW & NOTEWORTHY Humans systematically overestimate roll tilt in hypergravity. However, human perception of orientation in hypogravity has not been quantified across a range of tilt angles. Using a centrifuge to create a hypogravity centripetal acceleration environment, we found initial underestimation of roll tilt. Providing static visual feedback, perceptual learning reduced underestimation during the hypogravity analog. These altered gravity orientation perceptual errors and adaptation may have implications for astronauts.

A Case Study of Human Roll Tilt Perception in Hypogravity.

BACKGROUND: Increased gravito-inertial acceleration, or hypergravity, such as produced in a centrifuge or in an aircraft coordinated turn, causes humans to systematically overestimate their roll tilt in the dark. This is known as the "G-excess" illusion. We have previously modified a mathematical observer model of dynamic orientation perception to replicate these illusory tilt perceptions. This modified model also made a novel, previously untested, prediction that humans would underestimate acute roll tilt in reduced gravitational environments (hypogravity). CASE REPORT: In the current study, we used aircraft parabolic flight to test this prediction in a single subject. Roll tilt perception was reported using a subjective visual vertical task in which the subject aligned an illuminated line, presented in a head mounted display, with their perceived direction of down. The same subject made reports during hypogravity parabolas (0.165 G and 0.38 G, corresponding to lunar and Martian gravity, respectively), hypergravity maneuvers (1.6 G during a pull out maneuver and 1.2 G during a coordinated turn), and 1-G control conditions (both on the ground and in straight and level flight). As hypothesized, the subject significantly underestimated roll tilt in the hypogravity environments by approximately 40% compared to 1-G reports while overestimating roll tilt in the hypergravity environments. DISCUSSION: The amount of underestimation observed was quantitatively consistent with that predicted a priori by the modified observer model. We propose the term "G-shortage" illusion for the underestimation of roll tilt in hypogravity. This illusion may have implications for aircraft pilots and astronauts.Clark TK, Young LR. A case study of human roll tilt perception in hypogravity. Aerosp Med Hum Perform. 2017; 88(7):682-687.

The Impact of Oral Promethazine on Human Whole-Body Motion Perceptual Thresholds.

Despite the widespread treatment of motion sickness symptoms using drugs and the involvement of the vestibular system in motion sickness, little is known about the effects of anti-motion sickness drugs on vestibular perception. In particular, the impact of oral promethazine, widely used for treating motion sickness, on vestibular perceptual thresholds has not previously been quantified. We examined whether promethazine (25 mg) alters vestibular perceptual thresholds in a counterbalanced, double-blind, within-subject study. Thresholds were determined using a direction recognition task (left vs. right) for whole-body yaw rotation, y-translation (interaural), and roll tilt passive, self-motions. Roll tilt thresholds were 31 % higher after ingestion of promethazine (P = 0.005). There were no statistically significant changes in yaw rotation and y-translation thresholds. This worsening of precision could have functional implications, e.g., during driving, bicycling, and piloting tasks. Differing results from some past studies of promethazine on the vestibulo-ocular reflex emphasize the need to study motion perception in addition to motor responses.

Vestibular stimulation interferes with the dynamics of an internal representation of gravity.

The remembered vanishing location of a moving target has been found to be displaced downward in the direction of gravity (representational gravity) and more so with increasing retention intervals, suggesting that the visual spatial updating recruits an internal model of gravity. Despite being consistently linked with gravity, few inquiries have been made about the role of vestibular information in these trends. Previous experiments with static tilting of observers' bodies suggest that under conflicting cues between the idiotropic vector and vestibular signals, the dynamic drift in memory is reduced to a constant displacement along the body's main axis. The present experiment aims to replicate and extend these outcomes while keeping the observers' bodies unchanged in relation to physical gravity by varying the gravito-inertial acceleration using a short-radius centrifuge. Observers were shown, while accelerated to varying degrees, targets moving along several directions and were required to indicate the perceived vanishing location after a variable interval. Increases of the gravito-inertial force (up to 1.4G), orthogonal to the idiotropic vector, did not affect the direction of representational gravity, but significantly disrupted its time course. The role and functioning of an internal model of gravity for spatial perception and orientation are discussed in light of the results.

Modeling human perception of orientation in altered gravity.

Altered gravity environments, such as those experienced by astronauts, impact spatial orientation perception, and can lead to spatial disorientation and sensorimotor impairment. To more fully understand and quantify the impact of altered gravity on orientation perception, several mathematical models have been proposed. The utricular shear, tangent, and the idiotropic vector models aim to predict static perception of tilt in hyper-gravity. Predictions from these prior models are compared to the available data, but are found to systematically err from the perceptions experimentally observed. Alternatively, we propose a modified utricular shear model for static tilt perception in hyper-gravity. Previous dynamic models of vestibular function and orientation perception are limited to 1 G. Specifically, they fail to predict the characteristic overestimation of roll tilt observed in hyper-gravity environments. To address this, we have proposed a modification to a previous observer-type canal-otolith interaction model based upon the hypothesis that the central nervous system (CNS) treats otolith stimulation in the utricular plane differently than stimulation out of the utricular plane. Here we evaluate our modified utricular shear and modified observer models in four altered gravity motion paradigms: (a) static roll tilt in hyper-gravity, (b) static pitch tilt in hyper-gravity, (c) static roll tilt in hypo-gravity, and (d) static pitch tilt in hypo-gravity. The modified models match available data in each of the conditions considered. Our static modified utricular shear model and dynamic modified observer model may be used to help quantitatively predict astronaut perception of orientation in altered gravity environments.

Human manual control performance in hyper-gravity.

Hyper-gravity provides a unique environment to study how misperceptions impact control of orientation relative to gravity. Previous studies have found that static and dynamic roll tilts are perceptually overestimated in hyper-gravity. The current investigation quantifies how this influences control of orientation. We utilized a long-radius centrifuge to study manual control performance in hyper-gravity. In the dark, subjects were tasked with nulling out a pseudo-random roll disturbance on the cab of the centrifuge using a rotational hand controller to command their roll rate in order to remain perceptually upright. The task was performed in 1, 1.5, and 2 G's of net gravito-inertial acceleration. Initial performance, in terms of root-mean-square deviation from upright, degraded in hyper-gravity relative to 1 G performance levels. In 1.5 G, initial performance degraded by 26 % and in 2 G, by 45 %. With practice, however, performance in hyper-gravity improved to near the 1 G performance level over several minutes. Finally, pre-exposure to one hyper-gravity level reduced initial performance decrements in a different, novel, hyper-gravity level. Perceptual overestimation of roll tilts in hyper-gravity leads to manual control performance errors, which are reduced both with practice and with pre-exposure to alternate hyper-gravity stimuli.

Human perceptual overestimation of whole body roll tilt in hypergravity.

Hypergravity provides a unique environment to study human perception of orientation. We utilized a long-radius centrifuge to study perception of both static and dynamic whole body roll tilt in hypergravity, across a range of angles, frequencies, and net gravito-inertial levels (referred to as G levels). While studies of static tilt perception in hypergravity have been published, this is the first to measure dynamic tilt perception (i.e., with time-varying canal stimulation) in hypergravity using a continuous matching task. In complete darkness, subjects reported their orientation perception using a haptic task, whereby they attempted to align a hand-held bar with their perceived horizontal. Static roll tilt was overestimated in hypergravity, with more overestimation at larger angles and higher G levels, across the conditions tested (overestimated by ∼35% per additional G level, P < 0.001). As our primary contribution, we show that dynamic roll tilt was also consistently overestimated in hypergravity (P < 0.001) at all angles and frequencies tested, again with more overestimation at higher G levels. The overestimation was similar to that for static tilts at low angular velocities but decreased at higher angular velocities (P = 0.006), consistent with semicircular canal sensory integration. To match our findings, we propose a modification to a previous Observer-type canal-otolith interaction model. Specifically, our data were better modeled by including the hypothesis that the central nervous system treats otolith stimulation in the utricular plane differently than stimulation out of the utricular plane. This modified model was able to simulate quantitatively both the static and the dynamic roll tilt overestimation in hypergravity measured experimentally.

Postural performance of vestibular loss patients under increased postural threat.

The effects of increasing postural task difficulty on balance control was investigated in 9 compensated vestibular loss patients whose results were compared to 11 healthy adults. Subjects were tested in static (stable support) and dynamic (sinusoidal translation of the support) conditions, both at floor level and at height (62 cm above the floor), and with and without vision, to create an additional postural threat. Wavelet analysis of the center of foot pressure displacement and motion analysis of the body segments were used to evaluate the postural performance. Evaluation questionnaires were used to examine the compensation level of the patients (DHI test), their general anxiety level (SAST), fear of height (subjective scale), and workload (NASA TLX test). (Vestibular loss patients rely more on vision and spend more energy maintaining balance than controls, but they use the same postural strategy as normals in both static and dynamic conditions.) Questionnaire data all showed differences in behavior and perceptions between the controls and the patients. However, at height and without vision, a whole body strategy leading to rigid posture replaces the head stabilization strategy found for standing at floor level. The effects of height on postural control can be attributable to an increase in postural threat and attention changes resulting from modifications in perception.

Squat exercise biomechanics during short-radius centrifugation.

INTRODUCTION: Centrifuge-induced artificial gravity (AG) with exercise is a promising comprehensive countermeasure against the physiological de-conditioning that results from exposure to weightlessness. However, body movements onboard a rotating centrifuge are affected by both the gravity gradient and Coriolis accelerations. The effect of centrifugation on squat exercise biomechanics was investigated, and differences between AG and upright squat biomechanics were quantified. METHODS: There were 28 subjects (16 male) who participated in two separate experiments. Knee position, foot reaction forces, and motion sickness were recorded during the squats in a 1-G field while standing upright and while supine on a horizontally rotating 2 m radius centrifuge at 0, 23, or 30 rpm. RESULTS: No participants terminated the experiment due to motion sickness symptoms. Total mediolateral knee deflection increased by 1.0 to 2.0 cm during centrifugation, and did not result in any injuries. There was no evidence of an increased mediolateral knee travel "after-effect" during postrotation supine squats. Peak foot reaction forces increased with rotation rate up to approximately 200% bodyweight (iRED on ISS provides approximately 210% bodyweight resistance). The ratio of left-to-right foot force throughout the squat cycle on the centrifuge was nonconstant and approximately sinusoidal. Total foot reaction force versus knee flexion-extension angles differed between upright and AG squats due to centripetal acceleration on the centrifuge. DISCUSSION: A brief exercise protocol during centrifugation can be safely completed without significant after-effects in mediolateral knee position or motion sickness. Several recommendations are made for the design of future centrifuge-based exercise protocols for in-space applications.

Optimal estimator models for spatial orientation and vestibular nystagmus.

Mathematical models have played an important role in research on the vestibular system over the past century, from the torsion pendulum analogies of the semicircular canal to the optimal estimator "observer" models of multisensory interaction and adaptation. This short review is limited to our own contributions in bringing the technology of feedback control theory to bear on the understanding of human spatial orientation, eye movements, and nystagmus, both on Earth and in space. It points to the importance of the "internal model" concept for treatment of the manner in which the brain constantly makes predictions about future sensory feedback, adjusts the weightings of sensors according to their signal-to-noise ratios, and adapts control according to the motion environment, and availability of sensory cues.

Asymmetry in vestibular responses to cross-coupled stimulus.

Head turns performed while rotating about another axis result in a cross-coupled stimulus (CCS) to the vestibular system. The CCS causes a tumbling sensation, and the magnitude of the tumbling sensation is dependent on the type of head turn (HT) that is performed. Asymmetric CCS responses to different rotational directions are widely acknowledged, yet poorly understood. The objective of this study was to: 1) correctly describe the asymmetries in responses to different configurations of CCS stimulation and 2) test two previously proposed hypotheses for explaining the asymmetries, dominant direction, and dominant end position. The dominant direction hypothesis states that the tumbling sensations evoked by the CCS will be more intense for certain directions of the tumbling sensation than for others. The dominant end position hypothesis states that head turns ending in the nose-up position result in more intense sensations than those ending on the side positions. Subjects performed four types of 60-degree yaw head turns while lying horizontally on a centrifuge. Subjects were either supine or prone, while rotating clockwise or counterclockwise. Three experimental conditions were tested: clockwise supine (n = 33); counterclockwise supine (n = 10); and clockwise prone (n = 10). Subjective tumbling intensity scores were recorded for each head turn. Head turns to the left are dominant for clockwise supine centrifugation (P < 0.0001) and head turns to the right are dominant for counterclockwise supine centrifugation (P = 0.0020), matching what is expected from previous studies. However, for prone centrifugation, head turns to the left are more intense than head turns to the right (P = 0.0078), refuting the dominant direction hypothesis. The dominant end position effect is small in magnitude and cannot by itself explain the asymmetries. For every test condition, there is a dominant direction, but the dominant direction is not just a function of the HT and centrifuge rotation directions, instead it is also dependent on the subject's orientation on the centrifuge. An alternative perceived danger hypothesis that matches the data from all three experiments is proposed.

Partial weight suspension: a novel murine model for investigating adaptation to reduced musculoskeletal loading.

We developed a new model of hypodynamic loading to support mice in chronic conditions of partial weight bearing, enabling simulations of reduced gravity environments and related clinical conditions. The novel hardware allows for reduced loading between 10 and 80% of normal body weight on all four limbs and enables characteristic quadrupedal locomotion. Ten-week-old female BALB/cByJ mice were supported for 21 days under Mars-analog suspension (38% weight bearing) and compared with age-matched and jacketed (100% weight bearing) controls. After an initial adaptation, weight gain did not differ between groups, suggesting low levels of animal stress. Relative to age-matched controls, mice exposed to Mars-analog loading had significantly lower muscle mass (-23% gastrocnemius wet mass, P < 0.0001); trabecular and cortical bone morphology (i.e., trabecular bone volume: -24% at the distal femur, and cortical thickness: -11% at the femoral midshaft, both P < 0.001); and biomechanical properties of the femoral midshaft (i.e., -27% ultimate moment, P < 0.001). Bone formation indexes were decreased compared with age-matched full-weight-bearing mice, whereas resorption parameters were largely unchanged. Singly housed, full-weight-bearing controls with forelimb jackets were largely similar to age-matched, group-housed controls, although a few variables differed and warrant further investigation. Altogether, these data provide strong rationale for use of our new model of partial weight bearing to further explore the musculoskeletal response to reduced loading environments.

The effect of head turn velocity on cross-coupled stimulation during centrifugation.

Short-radius centrifugation (SRC) provides a practical means of producing artificial gravity for long duration space flights, though perceptual side-effects could limit its operational feasibility. Head turns (HT) during SRC, other than those about the centrifugation axis, produce Cross-Coupled Stimulation (CCS), perceived as a tumbling sensation. CCS can be nauseagenic, though adaptation can minimize this detrimental effect over time. The force environment of CCS suggests that the head turn velocity plays a role in determining the stimulus magnitude, though its degree has not been characterized. Twenty-three subjects performed right quadrant head turns of 8 different velocities while spinning at 19 and 23 RPMs on the SRC over two consecutive days. The perceptual effects were characterized by subjective metrics, investigating the acute differences between velocities as well as the chronic effects on adaptation. It was found that the perceived CCS magnitude can be regulated by modulating HT velocity. Further, a threshold of HT velocity exists above which an asymptotic perceptual response is observed, and below which the perceptual response diminishes at an exponential rate relative to head turn velocity. Finally, the effects of HT velocity are independent of HT direction, though the differing head turn directions likely produce contextually specific stimuli. These results suggest that HT velocity modulation could provide a practical means of incremental adaptation to CCS during SRC.

Vestibular adaptation to centrifugation does not transfer across planes of head rotation.

Out-of-plane head movements performed during fast rotation produce non-compensatory nystagmus, sensations of illusory motion, and often motion sickness. Adaptation to this cross-coupled Coriolis stimulus has previously been demonstrated for head turns made in the yaw (transverse) plane of motion, during supine head-on-axis rotation. An open question, however, is if adaptation to head movements in one plane of motion transfers to head movements performed in a new, unpracticed plane of motion. Evidence of transfer would imply the brain builds up a generalized model of the vestibular sensory-motor system, instead of learning a variety of individual input/output relations separately. To investigate, over two days 9 subjects performed pitch head turns (sagittal plane) while rotating, before and after a series of yaw head turns while rotating. A Control Group of 10 subjects performed only the pitch movements. The vestibulo-ocular reflex (VOR) and sensations of illusory motion were recorded in the dark for all movements. Upon comparing the two groups we failed to find any evidence of transfer from the yaw plane to the pitch plane, suggesting that adaptation to cross-coupled stimuli is specific to the particular plane of head movement. The findings have applications for the use of centrifugation as a possible countermeasure for long duration spaceflight. Adapting astronauts to unconstrained head movements while rotating will likely require exposure to head movements in all planes and directions.

Incremental adaptation to yaw head turns during 30 RPM centrifugation.

A 3-day incremental protocol was conducted with the aim of adapting human subjects to make head movements comfortably during 30 RPM centrifugation. With motion sickness as a potentially limiting factor, the protocol was designed using a quantitative motion sickness model based upon the neural mismatch sensory conflict theory. Centrifuge velocity was incremented from 14 RPM on day 1, to 23 RPM on day 2, to 30 RPM on day 3, with subjects making a total of 42 head movements on each day. Twenty-four subjects completed the experiment with average motion sickness levels below five (out of 20). Four subjects aborted due to motion sickness. Adaptation of non-compensatory vertical nystagmus was observed through an 18% decrease in the vertical aVOR time constant over the 3 days. Subjective intensity ratings for the head movements decreased by approximately 40% over the 3 days, while illusory motion duration decreased by 18%. Feasibility of head movements during 30 RPM rotation was demonstrated with only 3 days of incremental training.