Study Aims
Space motion sickness (SMS) is a problem during the first 72 hours of spaceflight and during transitions from different gravity environments. To date, there are no effective drug countermeasures that are able to combat SMS while allowing an individual to retain cognitive integrity. This creates a dilemma for astronauts as full cognition is particularly important during gravity transitions, such as take-off and landing. SMS is generally believed to be caused by a sensory conflict due to unweighting of the otolithic organs (i.e., vestibular cues indicate the head is stable while visual cues indicate the head is moving). We hypothesized that the vestibular dysfunction due to over stimulation of the semicircular canals by the rotary chair can serve as a paradigm for SMS, thus enabling us to effectively test drug countermeasures while using test batteries to determine the effect of these countermeasures on cognition.

Specific aim one determined the effects of four drug countermeasures (lorazepam, meclizine, promethazine, and scopolamine) in alleviating motion sickness induced by vestibular stimulation with a rotary chair. These countermeasures were selected based on our extensive clinical experience with pharmacologic interventions for vertigo. Specific aim two determined the effects of these countermeasures on cognitive performance and in counteracting the effects of rotation (our SMS paradigm) using an Operant Test Battery (OTB) to assess effects on short-term memory, learning, and time perception, and measures of the P50 potential to assess effects on arousal and distractibility (ability to filter out extraneous information, or sensory gating). Specific aim three, conducted at the Vestibular Function Laboratory in Antwerp, used 3-D oculography and unilateral otolith testing to determine the extent of correlation between vestibular dysfunction induced by the rotary chair and unloading of otolithic organs due to 0 G.

Key Findings
We have shown that only scopolamine effected a statistically significant mean change in duration of rotation compared to placebo (p<0.008); scopolamine decreased the sensory gating deficit induced by rotation; scopolamine had one of the best cognitive profiles based on the OTB; and scopolamine exclusively affected the otolith organs (utricular system)

We have shown that over stimulation of the semicircular canals by rotation leads to decreased habituation to repetitive stimuli, as measured by the midlatency auditory evoked P50 potential, which may be at the root of a sensory gating deficit (an inability to appraise and filter out unwanted stimuli) present during SMS. In terms of alleviating the symptoms of rotation and the induced sensory gating deficit, our data in 72 subjects indicated scopolamine to be the countermeasure of choice. Scopolamine was the only countermeasure to effect a statistically significant mean change in duration of rotation compared to placebo (p<0.008), with >40% increase in rotation time. Results with promethazine, the current pharmacologic treatment for SMS, were not statistically significant, and meclizine and lorazepam were no more effective than placebo.

Scopolamine by itself did not affect amplitude or habituation of P50 potential measures, suggesting that, at the dose used, scopolamine did not dysregulate RAS function to a significant level. However, scopolamine did lead to a lower decrease in habituation after rotation (~22%); in other words, scopolamine decreased the sensory gating deficit induced by rotation. Although this decrease was numerical and not statistically significant, it is indicative of a trend by scopolamine toward amelioration of the sensory gating deficit induced by rotation.

The Operant Test Battery (OTB) indicated the Delayed Matching-to-Sample (DMTS) task, or short-term memory and attention task, to be the most sensitive measure of cognitive performance. The DMTS indicated SMS by itself had no discernible effects on accuracy or response rate and that, at the doses employed, the rank order of drugs with the best cognitive profiles are meclizine > scopolamine > promethazine > lorazepam.

Work performed by our co-investigators at the Vestibular Function Laboratory in Antwerp using 3-D oculography and unilateral centrifugation for otolith testing confirmed the ability of our paradigm to accurately assess the effects of countermeasures on the vestibular apparatus, from which the sensation of SMS may originate. These studies showed that the different components of the vestibular system (the semicircular canals vs. the otolith organs) react differently to the countermeasures and that scopolamine exclusively affected the utricular response, indicating a possible mechanism of action for scopolamine via a direct effect on the utricular system.

The distribution of spin time frequencies among our study subject population (N=75) demonstrated that, in terms of the ability of our study subjects to tolerate induced SMS, the population had significant outliers. The majority of the study population exhibited a fairly low tolerance for induced SMS; however, there was a group of outliers who could spin significantly longer, appearing to have a predisposition to SMS tolerance. This novel finding, combined with results of off-axis rotation (see below), has been proposed for further examination as we study means of screening for SMS susceptibility and subsequent prophylaxis.

As an extension of our NSBRI study, we attempted to assess the otolith organs using a new clinical paradigm involving off-axis rotation and measurement of the subjective visual vertical (SVV), the ability of an individual in darkness to adjust a luminous line to true vertical while at rest and during rotation. Clinical assessment of otolith organs is important to space medicine research due to the involvement of the utricle and saccule in SMS. Our objective was to assess otolith function in subjects with no vestibular complaints and in subjects with unilateral labyrinthine hypofunction. Subjects with no vestibular anomalies were able to set the SVV very close to vertical. However, certain subjects showed a mild asymmetry (vestibular dominance) of the otolith organs during on-axis rotation that was further accentuated during off-axis rotation. In the vestibular patients, the SVV deviated significantly toward the side of the lesion. Some subjects with dominant otolith organs were able to spin in the chair two and a half to three times longer than those without ear dominance, indicating less susceptibility to motion sickness. By screening for ear dominance using the SVV/rotational paradigm, pre-flight medication or compensation behaviors could be instituted in those individuals with an indicated susceptibility to SMS.

Impact
This study addressed one of the main exploration-mission risk areas set forth by NASA in the Critical Path Roadmap (Impaired cognitive and/or physical performance due to motion sickness symptoms or treatments, especially during/after G-level changes [Risk Type III, Risk Rank 3]) and had a countermeasure readiness level of 6. We have addressed critical question 9.12: How effective are other drugs in providing fast relief in mission critical situations and does the drug have unacceptable side effects, particularly the short term effects on cognitive function? (Aims one and two). In addition, through the completion of this study, we have standardized measures of oculomotor function, postural stability, and cognitive performance (Aims one, two and three). These standards are crucial for establishing the effectiveness and quantifying the side effects of potential drug countermeasures.

During our two-year grant period, we have obtained salient findings in completion of the objectives of the original proposal. The results of our study have clearly indicated scopolamine to be the countermeasure of choice, leading to an NSBRI renewal proposal that will investigate optimization of the dose and delivery of this countermeasure. Pursuant to this, Dr. Lakshmi Putcha, senior pharmacologist at the Johnson Space Center and a member of the Smart Medical Systems Team, will serve as a co-investigator on the new project. Dr. Putcha has shown the bioavailability of oral scopolamine to be poor and quite variable compared to IV or intranasal administration and that oral scopolamine may not be effective as rescue therapy due to the effects of SMS on gut absorption and gastric motility. Thus, our renewal focuses on optimizing drug delivery parameters for scopolamine, testing potential combination therapies, and examining the feasibility of scopolamine as rescue therapy.

The results of our study will also advance earth medical research by determining the extent of correlation between rotary-induced motion sickness (i.e., vertigo) and SMS and developing a testable model that integrates our current knowledge of both conditions. This may ultimately help physicians treat patients with balance disorders related to inner ear dysfunction. Our findings at the Antwerp site strongly suggest that there is a distinct difference in reaction to medication between the semi-circular canals and the utricular system. This can have a great impact on the pharmaceutical treatment of dizziness and vertigo since different management might be necessary depending on the site (canal- or otolith-related) of the vestibular lesion.

Our comprehensive CNS assessment is currently being used to evaluate patients with tinnitus and vertigo, in an effort to determine if a pre-existing cognitive deficit underlies some of the symptom complex associated with these conditions (particularly fatigue, inability to concentrate, and depression). If such is the case, the optimized scopolamine regimen obtained in future studies would be applied as therapy. Demonstrating links between vestibular dysfunction and cognitive difficulties would be an important discovery by allowing clinicians to better educate patients about how vestibular pathology may affect their ability to concentrate and retain information. Our findings could also lead to future research into different treatment modalities. Current treatment for peripheral vestibular dysfunction includes the use of vestibular suppressants whereas our results may indicate that research is also needed in the area of treating patients. cognitive difficulties, possibly via CNS stimulants. Funding for this application is currently pending as part of an NIH COBRE grant.

Proposed Research Plan
Over this final year of our two-year project, we have completed our enrollment and testing, to give a total of 75 subjects for which data is available. We have submitted an NSBRI renewal (Optimization of Scopolamine as a Countermeasure for Space Motion Sickness.; PI: John Dornhoffer, MD [UAMS]; Co-Is: Edgar Garcia-Rill, PhD [UAMS], Merle Paule, PhD [NCTR], Paul Van de Heyning, MD, PhD [Antwerp], Floris Wuyts, PhD [Antwerp], Lakshmi Putcha, PhD [JSC]) that will examine alternate doses and delivery methods (oral vs. intranasal) for scopolamine, combination therapy, and utility of scopolamine as rescue therapy. We plan to add the Psychomotor Vigilance Task (PVT) to our NSBRI protocol as a measure of basic attentional processes (behavioral alertness) in order to further validate our OTB findings and P50 results and to test for any learned behaviors. Studies conducted at the Antwerp study site will enable us to obtain better insight into the mechanism of action of scopolamine on the separate parts of the vestibular system as well as motion sickness and factors involved in SMS. We also plan to continue off-axis testing of the NSBRI study subjects in an effort to show a correlation between otolith symmetry and susceptibility to SMS, which could lead to a screening paradigm for astronauts and "tailored" SMS therapy.

Project Description
NASA Task Book