Medical monitoring during the NASA Artificial Gravity-Bed Rest Pilot Study

The NASA artificial gravity-bed rest pilot study (AGPS) was designed to investigate the efficacy of daily exposure to a +Gz acceleration gradient for counteracting the physiologic decrements induced by prolonged bed rest. Test subjects were continuously monitored by a physician for signs and symptoms of pre-syncope, motion sickness, and arrhythmias while on the centrifuge. In this article, we have summarized the medical monitoring observations that were made during the AGPS and included an assessment of the relative usefulness of the information provided by the various monitoring tools in making a decision to terminate a centrifuge spin.     

Susceptibility to motion sickness in fish: a parabolic aircraft flight study

Juvenile swordtail fish and larval cichlids were subjected to parabolic aircraft flights (PAFs) and individually observed. After the PAFs, inner ear otoliths and sensory epithelia were examined on the light microscopical level. Otolith asymmetry (differences in otolith size between the left and the right side) was especially pronounced in those fish, who exhibited a kinetotic behaviour (e.g., spinning movements) during microgravity. This speaks in favour of a theoretical concept according to which susceptibility to space motion sickness in humans may be based on asymmetric inner ear stones. The cell density of sensory epithelia was lower in kinetotic animals as compared to normally swimming fish. Thus, asymmetric otoliths can cause kinetosis in fish during PAFs, but susceptibility to kinetosis may also be based on an aberrative inner ear morphology.     

Demonstrating the Potential for Dynamic Auditory Stimulation to Contribute to Motion Sickness

Auditory cues can create the illusion of self-motion (vection) in the absence of visual or physical stimulation. The present study aimed to determine whether auditory cues alone can also elicit motion sickness and how auditory cues contribute to motion sickness when added to visual motion stimuli. Twenty participants were seated in front of a curved projection display and were exposed to a virtual scene that constantly rotated around the participant''s vertical axis. The virtual scene contained either visual-only, auditory-only, or a combination of corresponding visual and auditory cues. All participants performed all three conditions in a counterbalanced order. Participants tilted their heads alternately towards the right or left shoulder in all conditions during stimulus exposure in order to create pseudo-Coriolis effects and to maximize the likelihood for motion sickness. Measurements of motion sickness (onset, severity), vection (latency, strength, duration), and postural steadiness (center of pressure) were recorded. Results showed that adding auditory cues to the visual stimuli did not, on average, affect motion sickness and postural steadiness, but it did reduce vection onset times and increased vection strength compared to pure visual or pure auditory stimulation. Eighteen of the 20 participants reported at least slight motion sickness in the two conditions including visual stimuli. More interestingly, six participants also reported slight motion sickness during pure auditory stimulation and two of the six participants stopped the pure auditory test session due to motion sickness. The present study is the first to demonstrate that motion sickness may be caused by pure auditory stimulation, which we refer to as “auditorily induced motion sickness”.     

Use of Controlled Diaphragmatic Breathing for the Management of Motion Sickness in a Virtual Reality Environment

Evidence indicates that activation of the parasympathetic nervous system (PNS) suppresses physiological responses associated with motion sickness. Research also shows paced breathing increases PNS activation; the current study examines the use of paced diaphragmatic breathing (DB) training to quell motion sickness symptoms. Healthy participants (N = 60) were pre-screened for motion sickness susceptibility. Participants were then randomly assigned to either a control condition, focusing on environmental awareness, or to an experimental condition implementing paced DB. Following this, participants were exposed to a virtual reality (VR) motion sickness experience, while heart rate variability, breathing rate (RPM), and motion sickness ratings were collected. Results demonstrated participants in the DB condition had higher PNS activation and reported fewer motion sickness symptoms during the VR experience than the participants in the control condition. Results suggest that the DB protocol can be used to significantly increase PNS tone and decrease the development of motion sickness symptoms.     

Altered susceptibility to motion sickness as a function of subgravity level

Large interindividual differences among 74 normal subjects in the change in susceptibility to motion sickness with effective lifting of the normal g-load by parabolic flight maneuvers were recorded with high test-retest reliability. Most subjects, who were required to make standardized head movements while seated in a chair rotating at a constant speed, demonstrated either a substantial increase or a decrease in susceptibility, in confirmation of a previous study, while a few appeared to be more or less unaffected by the 1 g to 0 g gravitational change. A similar test procedure conducted with eighteen of the subjects at lunar- and Martian-gravity levels revealed further interindividual differences in susceptibility as a function of g-level. The subjects with gravity-dependent susceptibility revealed: (1) a progressive change in susceptibility as a function of g-load in either the positive or negative direction that was characteristic of the individual, (2) a susceptibility level that appeared to be maintained at the fractional g-load, and (3) immunity to motion sickness at all g-levels tested below the Earth standard. The case history as well as ground-based functional and provocative tests of normal subjects proved to be inadequate in predicting susceptibility to motion sickness under subgravity conditions.This research was conducted under the sponsorship of the Biomedical Research Office, Order T-81633, Manned Spacecraft Center, and the Office of Life Sciences, NASA, Washington, D. C., Order L-43518. Opinions or conclusions contained in this report are those of the authors and do not necessarily reflect the views and endorsement of the Navy Department.     

Effects of ginger on motion sickness and gastric slow-wave dysrhythmias induced by circular vection

Ginger has long been used as an alternative medication to prevent motion sickness. The mechanism of its action, however, is unknown. We hypothesize that ginger ameliorates the nausea associated with motion sickness by preventing the development of gastric dysrhythmias and the elevation of plasma vasopressin. Thirteen volunteers with a history of motion sickness underwent circular vection, during which nausea (scored 0-3, i.e., none to severe), electrogastrographic recordings, and plasma vasopressin levels were assessed with or without ginger pretreatment in a crossover-design, double-blind, randomized placebo-controlled study. Circular vection induced a maximal nausea score of 2.5 +/- 0.2 and increased tachygastric activity and plasma vasopressin. Pretreatment with ginger (1,000 and 2,000 mg) reduced the nausea, tachygastria, and plasma vasopressin. Ginger also prolonged the latency before nausea onset and shortened the recovery time after vection cessation. Intravenous vasopressin infusion at 0.1 and 0.2 U/min induced nausea and increased bradygastric activity; ginger pretreatment (2,000 mg) affected neither. Ginger effectively reduces nausea, tachygastric activity, and vasopressin release induced by circular vection. In this manner, ginger may act as a novel agent in the prevention and treatment of motion sickness.     

大鼠动情周期雌激素水平变化对晕动病易感性的影响

目的：众多的流行病学研究和动物实验表明,晕动病存在明显的性别差异,特别是雌激素对晕动病易感性可能存在某些易化的调节作用,本研究为探讨“异食癖”模型上大鼠动情周期雌激素水平的变化对晕动病易感性的影响。方法：大鼠在不同的动情周期,给予足够的旋转刺激以后,通过摄取高岭土量的变化评价大鼠的晕动病反应,同时测定血浆雌激素（E2和P）水平,观察雌激素水平的变化对晕动病易感性的影响。结果：大鼠体内的雌性激素（E2和P）水平随着动情周期而发生波动,在动情期时,E2水平达到最高,而在动情前期则达到最低。P水平在动情间期和动情前期较高而在动情期与动情后期较低。足够的旋转刺激之后,大鼠的摄取高岭土量显著增加,并且呈现与大鼠动情周期雌激素水平波动的一致性,即动情期时摄取高岭土量最多。结论：大鼠动情周期雌激素水平的升高可能在一定程度上会加重大鼠的晕动病反应。可为进一步探讨雌激素水平与晕动病易感性之间的关系提供参考,从而也可能为发现晕动病新病因的研究打下基础,还可能为晕动病预防策略和措施启发新的应用价值。     

Identification of Neural Networks That Contribute to Motion Sickness through Principal Components Analysis of Fos Labeling Induced by Galvanic Vestibular Stimulation

Motion sickness is a complex condition that includes both overt signs (e.g., vomiting) and more covert symptoms (e.g., anxiety and foreboding). The neural pathways that mediate these signs and symptoms are yet to identified. This study mapped the distribution of c-fos protein (Fos)-like immunoreactivity elicited during a galvanic vestibular stimulation paradigm that is known to induce motion sickness in felines. A principal components analysis was used to identify networks of neurons activated during this stimulus paradigm from functional correlations between Fos labeling in different nuclei. This analysis identified five principal components (neural networks) that accounted for greater than 95% of the variance in Fos labeling. Two of the components were correlated with the severity of motion sickness symptoms, and likely participated in generating the overt signs of the condition. One of these networks included neurons in locus coeruleus, medial, inferior and lateral vestibular nuclei, lateral nucleus tractus solitarius, medial parabrachial nucleus and periaqueductal gray. The second included neurons in the superior vestibular nucleus, precerebellar nuclei, periaqueductal gray, and parabrachial nuclei, with weaker associations of raphe nuclei. Three additional components (networks) were also identified that were not correlated with the severity of motion sickness symptoms. These networks likely mediated the covert aspects of motion sickness, such as affective components. The identification of five statistically independent component networks associated with the development of motion sickness provides an opportunity to consider, in network activation dimensions, the complex progression of signs and symptoms that are precipitated in provocative environments. Similar methodology can be used to parse the neural networks that mediate other complex responses to environmental stimuli.     

Rice germ oil as multifunctional excipient in preparation of self-microemulsifying drug delivery system (SMEDDS) of tacrolimus

Surmounting the constraints of limited solubilization efficiency and prime requisite of antioxidant for conventional lipid formulations, the research work explores an edge over formulation utilizing potential applicability of rice germ oil (RGO) as a multifunctional excipient. Self-microemulsifying drug delivery system (SMEDDS) of tacrolimus (TAC) was formulated with RGO, an indigenous source of gamma-oryzanol. Being the same biological source, RGO and rice bran oil (RBO) were compared and it was found that RGO have more solubilization potential for TAC (2.2-fold) as well as higher antioxidant activity (8.06-fold) than the RBO. TAC-SMEDDS was prepared using RGO/Capmul PG8 (2:3) as an oil phase, Cremophore EL as a surfactant, and Transcutol P as a cosurfactant. The approximate particle size of TAC-SMEDDS was found to be 38 nm by dynamic light scattering and 12 nm by small angle neutron scattering. The in vitro dissolution studies showed complete and rapid drug release in 30 min compared to a plain drug (<5%) and marketed capsule (<50%). AUC and C _max were found to be 45.05 ± 15.64 ng h/ml and 3.91 ± 1.2 ng/ml for TAC-SMEDDS, 12.59 ± 5.54 ng h/ml and 0.48 ± 0.12 ng/ml for plain TAC, and 30.23 ± 10.34 ng h/ml and 2.31 ± 0.68 ng/ml for marketed formulation, respectively. The improved pharmacokinetic profile of TAC-SMEDDS is correlating to the dissolution results. Thus, gamma-oryzanol-enriched RGO acts as a potential multifunctional excipient for lipid formulations.     

Factors influencing the susceptibility of anurans to motion sickness

We examined the propensity for motion sickness in five anuran species, concentrating our efforts on the treefrog Rhacophorus schlegelii, because it had shown the greatest susceptibility to motion sickness in a previous study. We used parabolic flight as our provocative stimulus and fed all specimens a known volume of food 1.5-3 h before flight. The presence of vomitus in a frog's cage was our indicator of motion sickness. Significantly more emesis was observed in flight-exposed than in control R. schlegelii (P < 0.05). There was no sex difference in susceptibility to motion sickness (P > 0.5). Individuals that vomited were significantly larger (P < 0.02) than those that did not. Among microgravity-treated frogs, those that vomited spent on average 85% more time airborne and tumbling in microgravity than those that did not vomit (P=0.031). Our data support the view that postural instability and sensory conflict are elements of motion sickness in anurans. Specifically, conflicts between tactile, vestibular and visual input seem essential for producing motion-induced emesis in anurans. Since the factors that induce motion sickness in R. schlegelii are the same ones that produce motion sickness in humans, arboreal frogs may be useful alternative models to mammals in motion sickness research.     

Assessment of the effect of pharmaceuticals used to treat motion sickness on adaptation to model conditions involving prolonged rotation

The pharmacological preparation P-4 administered according to a reduced scheme (the first dose, 1.5?C2 h before stimulation; the second dose, 2 h after stimulation) efficiently alleviated the main symptoms of motion sickness, accelerated the process of adaptation and increased its efficiency in persons prone to motion sickness upon exposure to slow rotation during four days. Administration of the preparation according to the scheme described above did not cause the abstinence syndrome.     

Expression of Calcitonin Gene-Related Peptide in Efferent Vestibular System and Vestibular Nucleus in Rats with Motion Sickness

Motion sickness presents a challenge due to its high incidence and unknown pathogenesis although it is a known fact that a functioning vestibular system is essential for the perception of motion sickness. Recent studies show that the efferent vestibular neurons contain calcitonin gene-related peptide (CGRP). It is a possibility that the CGRP immunoreactivity (CGRPi) fibers of the efferent vestibular system modulate primary afferent input into the central nervous system; thus, making it likely that CGRP plays a key role in motion sickness. To elucidate the relationship between motion sickness and CGRP, the effects of CGRP on the vestibular efferent nucleus and the vestibular nucleus were investigated in rats with motion sickness.

Methods

An animal model of motion sickness was created by subjecting rats to rotary stimulation for 30 minutes via a trapezoidal stimulation pattern. The number of CGRPi neurons in the vestibular efferent nucleus at the level of the facial nerve genu and the expression level of CGRPi in the vestibular nucleus of rats were measured. Using the ABC method of immunohistochemistry technique, measurements were taken before and after rotary stimulation. The effects of anisodamine on the expression of CGRP in the vestibular efferent nucleus and the vestibular nucleus of rats with motion sickness were also investigated.

Results and Discussion

Both the number of CGRPi neurons in the vestibular efferent nucleus and expression level in the vestibular nucleus increased significantly in rats with motion sickness compared to that of controls. The increase of CGRP expression in rats subjected to rotary stimulation 3 times was greater than those having only one-time stimulation. Administration of anisodamine decreased the expression of CGRP within the vestibular efferent nucleus and the vestibular nucleus in rats subjected to rotary stimulation. In conclusion, CGRP possibly plays a role in motion sickness and its mechanism merits further investigation.     

天香胶囊对晕动病模型大鼠前庭核NMDAR1信号通路的影响*

目的:观察天香胶囊对晕动病模型大鼠前庭核NMDAR1(N-甲基-D-天冬氨酸受体1,N-methyl-D-aspartate acid receptor 1)、P-CaMKⅡ (磷酸化钙调蛋白激酶Ⅱ-亚基,the phosphorylation of calmodulin protein kinase Ⅱ alpha subunit)、P-CREB(磷酸化cAMP反应元件结合蛋白,the phosphorylation of cAMP response element binding protein)表达的影响,探讨天香胶囊调节晕动病模型大鼠前庭核兴奋性的内在分子机制。方法:将36只雄性SD大鼠随机分为正常对照组、模型组、阳性药对照组(东莨菪碱)、天香胶囊低、中、高剂量组。灌胃预给药3天后,采用双轴旋转刺激法复制大鼠晕动病模型,通过Western blotting法检测各组大鼠前庭核NMDAR1、P-CaMKⅡ/CaMKⅡ、P-CREB/CREB的表达情况。结果:与正常组大鼠相比,模型组大鼠前庭核NMDAR1、P-CaMKⅡ、P-CREB蛋白表达水平显著增加;与模型组相比,中、高剂量天香胶囊可显著下调晕动病模型大鼠前庭核组织NMDAR1、P-CaMKⅡ、P-CREB蛋白表达。结论:天香胶囊可抑制晕动病模型大鼠前庭核NMDAR1信号通路的活化,这可能是其在治疗晕动病中降低前庭核兴奋性的内在分子机制之一。     

Vestibulo-protective properties of regulatory peptides

Endogenous opioid peptides take an active part in the pathogenesis of motion sickness (MS). Some regulatory peptides (substances P, gamma and des-tyr-gamma-endorphins) manifest antiemetic properties, unlike opioid peptides and morphine. Thus, we have examined the vestibulo-protective properties of some regulatory peptides during simulation of MS in cats. Vestibulo-protective properties have been discovered in some peptides: sweet water hydra undecapeptide, substances P, gamma and des-tyr-gamma-endorphins. It has been suggested that regulatory peptides take an active part in the genesis of vestibulo-protective disorders during motion sickness.     

How to Study Placebo Responses in Motion Sickness with a Rotation Chair Paradigm in Healthy Participants

Placebo responses occur in every medical intervention when patients or participants expect to receive an effective treatment to relieve symptoms. However, underlying mechanisms of placebo responses are not fully understood. It has repeatedly been shown that placebo responses are associated with changes in neural activity but for many conditions it is unclear whether they also affect the target organ, such as the stomach in motion sickness. Therefore, we present a methodology for the multivariate assessment of placebo responses by subjective, behavioral and objective measures in motion sickness with a rotation chair paradigm. The physiological correlate of motion sickness is a shift in gastric myoelectrical activity towards tachygastria that can be recorded with electrogastrography. The presented study applied the so-called balanced placebo design (BPD) to investigate the effects of ginger compared to placebo and the effects of expectations by verbal information. However, the study revealed no significant main or interactional effects of ginger (as a drug) or information on outcome measures but showed interactions when sex of participants and experimenters are taken into considerations. We discuss limitations of the presented study and report modifications that were used in subsequent studies demonstrating placebo responses when rotation speed was lowered. In general, future placebo studies have to identify the appropriate target organ for the studied placebo responses and to apply the specific methods to assess the physiological correlates.     

Suncus murinus as a new experimental model for motion sickness

Characteristics of motion sickness and effects of possible prophylactic drugs were studied using Suncus murinus (house musk shrew) for its potential use as an experimental model in motion sickness. Mild reciprocal shaking (amplitude: 10-40 mm; frequency: 0.5-3.0 Hz) induced vomiting in most of Suncus murinus within 2 min. Adaptation was observed when the motion stimulus was repeated with an interval of 2 to 3 days. During the repetitive motion training, both the ratio of sensitive animals and the number of vomiting episodes decreased, and the time from the start of shaking to the first vomiting was extended. Subcutaneous injection of scopolamine (100 mg/kg), chlorpromazine (8 mg/kg), promethazine (50 mg/kg), diphenhydramine (20 mg/kg), chlorphenylamine (20 mg/kg) and methamphetamine (2 mg/kg) decreased the emetic effect of motion sickness, but pyrilamine (20 mg/kg), meclizine (20 mg/kg) and dimenhydrinate (32 mg/kg) were not effective or very weak. These results indicate that the Suncus murinus is sensitive to the motion stimulus and antiemetic drugs are effective as prophylaxis. The Suncus murinus is useful as a new experimental animal model for motion sickness.     

Participation of endogenous opioid peptides in the pathogenesis of motion sickness

Investigations were performed with 19 healthy male volunteers to specify a possible role of endogenous opioid peptides in the pathogenesis of motion sickness. For this purpose the test subjects were administered naloxone, a specific antagonist of opiates and opioids, before rotation and during rotation in a BU-4 armchair at a rate of 30 rpm. In addition, the content of beta-endorphin in blood plasma was measured. It was discovered that naloxone exerts both prophylactic and therapeutic effects as regards the simulated motion sickness. In this respect it was more efficacious than the reference drug scopolamine. After rotation there was a significant increase in the beta-endorphin content in the blood plasma of the test subjects. It is assumed that endogenous opioid peptides (in particular beta-endorphin) may be directly involved in the genesis of vestibulo-vegetative disorders in motion sickness.     

实验性运动病大鼠神经细胞钙离子超微结构定位变化

本研究采用正负交变加速度旋转刺激法制备大鼠运动病模型,并用钙离子（Ｃａ２＋）超微结构定位法观察了运动病大鼠大脑皮质、小脑皮质和脑干前庭区神经细胞中的Ｃａ２＋变化。结果表明,运动病大鼠大脑皮质、小脑皮质和脑干前庭区神经细胞胞质基质、线粒体和内质网中Ｃａ２＋反应产物增多。提示运动病的发生与中枢神经细胞Ｃａ２＋内流有关。     

Rotation of subjective vertical is an important factor of visually-induced motion sickness

Motion of visual scene (optokinetic stimulus) projected on a wide screen frequently induces motion sickness. Rotational movements of 3D visual images were analyzed to examine what factors are effective in visually-induced motion sickness and how the gravity contributes to its inducement. While an angle of a rotational axis of 3D visual image from the gravitational direction and its angle from the subjective vertical which was perceived by viewers through 3D visual image were varied, the severity of visually-induced motion sickness was measured.