The aims of our laboratory studies include evaluation of intranasal scopolamine and sensory augmentation to mitigate motion sickness and enhance crew performance. The intranasal form of scopolamine has the advantage of rapid bioavailability (i.e., therapeutic plasma concentration) with minimal side effects. This formulation allows crewmembers to self-medicate in a suited environment either before or after the onset of symptoms. Water landings may involve provocative wave motion during which crewmembers are deprived of a stable Earth reference inside the crew capsule. Sensory augmentation, e.g., vibrotactile feedback of Earth vertical, has been effective as a spatial awareness and balance aid with vestibular impairment. We hypothesize that both intranasal scopolamine and sensory augmentation of Earth vertical, either administered separately or combined, will be effective to mitigate motion sickness and improve task performance.

The initial pilot ground study involved validation of a wave motion stressor to induce sickness, and evaluation of sensory augmentation in this simulated wave motion environment. A multi-degree of freedom platform with the subject seated in an enclosed cabin mockup was utilized to simulate the provocative capsule motion during water landings. Performance on a series of functional tasks (tilt motion tracking with and without a paced auditory serial addition test (PASAT) dual-task, eye-head-hand target acquisition, psychomotor vigilance test) was measured pre, during, after capsule wave motion. The capsule motion consisted of three 15 min periods of combined pseudorandom pitch, roll and heave that continued until the subject reached a motion sickness endpoint representing severe malaise on the Pensacola Diagnostic Index (up to 45 min maximum duration).

The first study aim (1a) focused on prevention of motion sickness using intranasal scopolamine using a double-blinded repeated measures design in 30 subjects. Intranasal scopolamine was provided by Defender Pharmaceuticals, Inc. (DPI-386 Nasal Gel, referred to as Inscop) self-administered by a nasal pump (Aptar Pharma) that delivers 0.4 mg dose (0.2 mg / nostril). Motion sickness symptom onset, severity, and recovery were compared across treatment and placebo control sessions counterbalanced across subjects and separated by at least one week. The bioavailability of scopolamine for each session will be estimated from plasma concentrations obtained every 15 min. Cognition (psychomotor vigilance task) and subjective reports of drug side effects were obtained. Based on the pilot study, operational performance was assessed during the capsule wave motion using tilt motion tracking and a tablet-based eye-hand target acquisition task. The second part of this laboratory aim (1b) will be to evaluate sensory augmentation with and without intranasal scopolamine to prevent motion sickness during simulated capsule wave motion. For specific aim 2, a laboratory-based study will be used to evaluate the efficacy of intranasal scopolamine to provide treatment (“rescue”) of symptoms following motion sickness onset during simulated capsule wave motion. We are currently evaluating utilizing the advanced capsule wave motion capabilities of the Disorientation Research Device (aka Kraken) at the Naval Medical Research Unit – Dayton for aim 1B and/or aim 2.

Specific aim 3 will evaluate the feasibility and efficacy of administering the intranasal scopolamine in operational field settings using both astronaut and ground-control subjects that are exposed to provocative motion as part of their assigned duties. For the ground-control subjects, these may involve a number of operational environments including motion simulations (e.g., high-g profile simulations during centrifugation), parabolic flights and/or Orion capsule recovery operations at sea. For the astronaut participants, we are recruiting from free-flier missions (e.g., Polaris Dawn), and both Private Astronaut Missions (PAM) and United States Orbital Segment (USOS) crewmembers assigned to the missions to the International Space Station (ISS). Astronaut participants may choose to test Inscop during provocative preflight training exercises (e.g., centrifugation), and can choose to take the medication prophylactically to prevent symptoms or after symptom onset to treat motion sickness during the launch and/or landing mission phases. Both ground-control and astronaut participants will be required to test the medication during a training session to monitor for adverse side effects. Participants will complete a short debrief questionnaire to capture motion sickness symptoms, side effects, and feasibility comments each time they take the medication. We will also include astronaut “control” subjects who do not take Inscop to comment on motion sickness severity within the initial early inflight and postflight periods, what countermeasures they did use and rate their effectiveness. While this study aim is not blinded, the inclusion of both active and control subjects will provide a more complete characterization of the impacts of motion sickness on crew activities during and following g-transitions, and the effectiveness of motion sickness countermeasures to improve inflight and postflight recovery. In addition, we are conducting a retrospective review of medical records from both the Shuttle and ISS programs to include a more comprehensive characterization of the motion sickness risks during missions with different vehicles and mission durations.

As described in the Task Description, we plan to explore how the combination of Inscop with non-pharmaceutical sensory aids, e.g., vibrotactile feedback of Earth vertical, may further mitigate motion sickness and improve task performance. Our pilot study (Bollinger et al., 2023) demonstrated that sensory augmentation (SA) alone appeared to delay symptom onset, with no subjects receiving sensory augmentation reaching the endpoint prior to the end of 45 min (PDI after 15 min = 6.0 ± 2.5 in the control group versus 3.4 ± 2.5 in the SA group, mean ±std). Aim 1a and/or Aim 2 may be conducted at the Naval Medical Research Unit – Dayton (NAMRU-D) Disorientation Research Device (aka Kraken) which would include increased heave for simulated wave motion.

Aim 3 Field Testing: Notable progress has been made for the Aim 3 measurements to test the feasibility of intranasal scopolamine during spaceflight, and to better characterize the effectiveness of other motion sickness countermeasures (control subjects). Following the successful implementation of Inspiration 4 (Ericson et al., 2022), we are now prepared to continue data collection this next year on additional free-flier missions (3 control and 1 active on SpaceX Polaris Dawn), private astronaut missions to the International Space Station (ISS) (4 control subjects on Axiom 3), and during nominal long duration ISS increments (starting with 1 active and 1 control on Crew 8).

Retrospective Data Mining: In addition to our prospective study, we have been summarizing medical reports of both inflight space motion sickness and reentry motion sickness following landing using data from both Shuttle and ISS missions. This data was obtained from the Longitudinal Study of Astronaut Health (LSAH) data archive and was reviewed as part of a SpaceX symposium to prepare the medical teams involved in postflight recovery operations (Wood, 2023). This data set is being used to evaluate different risk factors such as sex, prior flight experience, body mass index, flight duration, and launch/landing vehicles.

As part of this retrospective analysis of the flight motion sickness data, we also re-evaluated the data from all nine Skylab crewmembers to determine asymmetry of each astronaut’s ocular counter-rolling (OCR) response and their OCR slope from sigmoid fits during static leftward and rightward body tilts, which we then compared with their Coriolis sickness susceptibility index (CSSI) on the ground, their motion sickness symptom scores during 0 g maneuvers in parabolic flight, and the severity of the symptoms of space motion sickness (SMS) they reported during their spaceflights (see Clément et al., Front Physiol, 2023). We arranged the astronauts in rank order for SMS severity based on the SMS symptoms they reported during spaceflight and the amount of anti-motion sickness medication they used. As previously reported, the OCR amplitudes of these astronauts were within the normal range. We determined that the OCR amplitudes were not correlated with SMS severity ranking, CSSI, or motion sickness symptoms experienced during parabolic flight. Indices of asymmetry in the OCR reflex were generally small and poorly correlated with SMS scores; however, the only subject with a high index of asymmetry also ranked highly for SMS. Although OCR slope, CSSI, and motion sickness symptoms induced during parabolic flight were each only moderately correlated with SMS severity ranking (rho = 0.41–0.44), a combined index that included all three parameters with equal weighting was significantly correlated with SMS severity ranking (rho = 0.71, p = 0.015). These results demonstrate the challenge of predicting an individual’s susceptibility to SMS by measuring a single test parameter in a terrestrial environment and from a limited sample size.

The aims of our laboratory studies include evaluation of intranasal scopolamine and sensory augmentation to mitigate motion sickness and enhance crew performance. The intranasal form of scopolamine has the advantage of rapid bioavailability (i.e., therapeutic plasma concentration) with minimal side effects. This formulation allows crewmembers to self-medicate in a suited environment either before or after the onset of symptoms. Water landings may involve provocative wave motion during which crewmembers are deprived of a stable Earth reference inside the crew capsule. Sensory augmentation, e.g., vibrotactile feedback of Earth vertical, has been effective as a spatial awareness and balance aid with vestibular impairment. We hypothesize that both intranasal scopolamine and sensory augmentation of Earth vertical, either administered separately or combined, will be effective to mitigate motion sickness and improve task performance.

The initial pilot ground study involved validation of a wave motion stressor to induce sickness, and evaluation of sensory augmentation in this simulated wave motion environment. A multi-degree of freedom platform with the subject seated in an enclosed cabin mockup was utilized to simulate the provocative capsule motion during water landings. Performance on a series of functional tasks (tilt motion tracking with and without a paced auditory serial addition test (PASAT) dual-task, eye-head-hand target acquisition, psychomotor vigilance test) was measured pre, during, after capsule wave motion. The capsule motion consisted of three 15 min periods of combined pseudorandom pitch, roll and heave that continued until the subject reached a motion sickness endpoint representing severe malaise on the Pensacola Diagnostic Index (up to 45 min maximum duration).

The first study aim (1a) focused on prevention of motion sickness using intranasal scopolamine using a double-blinded repeated measures design in 30 subjects. Intranasal scopolamine was provided by Defender Pharmaceuticals, Inc. (DPI-386 Nasal Gel, referred to as Inscop) self-administered by a nasal pump (Aptar Pharma) that delivers 0.4 mg dose (0.2 mg / nostril). Motion sickness symptom onset, severity, and recovery were compared across treatment and placebo control sessions counterbalanced across subjects and separated by at least one week. The bioavailability of scopolamine for each session will be estimated from plasma concentrations obtained every 15 min. Cognition (psychomotor vigilance task) and subjective reports of drug side effects were obtained. Based on the pilot study, operational performance was assessed during the capsule wave motion using tilt motion tracking and a tablet-based eye-hand target acquisition task. The second part of this laboratory aim (1b) will be to evaluate sensory augmentation with and without intranasal scopolamine to prevent motion sickness during simulated capsule wave motion. For specific aim 2, a laboratory-based study will be used to evaluate the efficacy of intranasal scopolamine to provide treatment (“rescue”) of symptoms following motion sickness onset during simulated capsule wave motion. We are currently evaluating utilizing the advanced capsule wave motion capabilities of the Disorientation Research Device (aka Kraken) at the Naval Medical Research Unit – Dayton for aim 1B and/or aim 2.

Specific aim 3 will evaluate the feasibility and efficacy of administering the intranasal scopolamine in operational field settings using both astronaut and ground-control subjects that are exposed to provocative motion as part of their assigned duties. For the ground-control subjects, these may involve a number of operational environments including motion simulations (e.g., high-g profile simulations during centrifugation), parabolic flights and/or Orion capsule recovery operations at sea. For the astronaut participants, we are recruiting from free-flier missions (e.g., Polaris Dawn), and both Private Astronaut Missions (PAM) and United States Orbital Segment (USOS) crewmembers assigned to the missions to the International Space Station (ISS). Astronaut participants may choose to test Inscop during provocative preflight training exercises (e.g., centrifugation), and can choose to take the medication prophylactically to prevent symptoms or after symptom onset to treat motion sickness during the launch and/or landing mission phases. Both ground-control and astronaut participants will be required to test the medication during a training session to monitor for adverse side effects. Participants will complete a short debrief questionnaire to capture motion sickness symptoms, side effects, and feasibility comments each time they take the medication. We will also include astronaut “control” subjects who do not take Inscop to comment on motion sickness severity within the initial early inflight and postflight periods, what countermeasures they did use and rate their effectiveness. While this study aim is not blinded, the inclusion of both active and control subjects will provide a more complete characterization of the impacts of motion sickness on crew activities during and following g-transitions, and the effectiveness of motion sickness countermeasures to improve inflight and postflight recovery. In addition, we are conducting a retrospective review of medical records from both the Shuttle and ISS programs to include a more comprehensive characterization of the motion sickness risks during missions with different vehicles and mission durations.

All ten subjects reported varying levels of motion sickness with 6 of 10 reaching a symptom endpoint. The PDI and SDR, motion sickness scores, were highly correlated (Spearman’s rho = 0.70, p<0.001). This was important since we are using the simpler 0-20 SDR scale in our field testing. Interestingly, subjects anecdotally reported that engagement in some tasks (e.g., joystick tracking) was less provocative than others. During the first block, the cabin-fixed target acquisition task appeared to be more provocative, especially for the control group. Sensory augmentation appeared to delay symptom onset, with 2 of 5 reaching an endpoint within the first 15-minute trial in the CN group versus none in the SA group (PDI after 15 min = 6.0 ± 2.5 in the CN group versus 3.4 ± 2.5 in the SA group, mean ±std). For the purposes of statistical comparison and plotting across timepoints, the highest symptom value was carried forward for subjects who reached a motion sickness endpoint. Independent samples of Mann-Whitney U tests indicated the SDR symptom score was significantly lower for the SA group at minute 10 (U=2.5, p=0.032) and remained lower through the remainder of the initial 15-minute block.

In addition to delaying motion sickness onset, sensory augmentation also improved performance on the joystick tracking task at lower stimulus frequencies (0.1 Hz in roll and 0.2 Hz in pitch). While the magnitude of the tilt motion was cued by pulsing the tactors more during greater amplitudes of tilt, this was of limited value based on anecdotal reports. During the pilot testing, this task was repeated with a dual task involving paced auditory serial addition test. There were no differences in performance detected with the dual task in this pilot study. Both CN and SA groups maintained a consistent level of performance on the eye-hand target acquisition and PVT throughout the baseline (no motion) and wave motion periods. Our pilot study results validated that the simulated capsule wave motion paradigm provides an effective motion stressor and is currently being used to investigate the effects of intranasal scopolamine to prevent motion sickness. Sensory augmentation using vibrotactile feedback appears to improve spatial awareness and delay symptom onset during complex passive motion. One advantage of this portable belt design is that it incorporates all tactor drive and IMU circuitry and, therefore could continue to be worn by crewmembers and serve as a balance aid during egress and ambulation with recovery operations. These results from this pilot study will be presented at the 2023 Investigators’ Workshop (Bollinger et al., 2023).

Aim 1a Lab Study: Plans for our laboratory testing were highlighted during the 2022 Investigators’ Workshop (Beltran et al., 2022). Due to delays in testing related to COVID, and based on the pilot study results described above, we elected to limit our initial Aim 1 laboratory data collection to a comparison of intranasal scopolamine (0.4 mg) and placebo control conditions using a repeated measures double-blinded design, postponing the combination of Inscop and sensory augmentation. We completed data collection on all thirty subjects during two sessions, each separated by at least one week. The joystick used during the pilot testing exhibited differential spring resistance and therefore was replaced with a hand-held board using an IMU to measure roll and pitch movements. The subject instruction was modified to maintain the board level, i.e., parallel to the perceived horizon (Clément et al., 2002), thus accomplishing a similar spatial tracking task. The dual tasking was also omitted in favor of increasing the duration of the joystick tracing task. Otherwise, all of the functional tasks were identical to the pilot testing. Data processing is ongoing at this time while the study remains blinded.

Plasma concentrations of scopolamine will be measured by a modified liquid chromatography with a tandem mass spectrometry (LC-MS/MS) method similar to that reported previously (Wu et al., 2015). During this past year, Dr. Wang has been standing up this refined methodology in the Nutritional Biochemistry laboratory using a LC-MS/MS process published by Waters Corporation to complete this analysis. Importantly, the previous internal standard (Hyoscyamine) has been replaced with a stable isotope-labeled scopolamine-d3 (Swaminathan et al., 2019). This improved the analytical range to 25 to 5000 pg/mL with correlation coefficients =0.99. The previous lower limit of quantitation of scopolamine was 50 pg/mL using the previous standard. Unfortunately, the plasma concentration analysis has been delayed due to repairs needed for the LC-MS/MS equipment. The repairs were completed at the end of the year and should be completed during FY23.

The Interagency Agreement with the Naval Medical Research Unit – Dayton (NAMRU-D) was approved this past year and includes the use of the DRD Kraken for simulated wave motion. We anticipate Aim 1b and/or Aim 2 to be conducted following the implementation of this motion with increased heave motion.

Aim 3 Field Testing: During this past year, the initial field test results on the first private commercial orbital flight were highlighted during the 2022 Investigators’ Workshop (Ericson et al., 2022). Two of four crewmembers utilized intranasal scopolamine effectively mitigated immediate symptoms of nausea and was easily self-administered by crewmembers with minimal training and did not impede flight operations by requiring unscheduled suit doffing or medical equipment access. Three ground-control subjects were also tested during the National Aerospace Training and Research (NASTAR) g-profile training with similar results. The augmentation for additional astronauts and retrospective analysis was processed, and four crewmembers of the SpaceX Polaris Dawn mission were recruited. This implementation will require all participants to record motion sickness history, including those that choose not to take Inscop. The Select for Flight process for United States Operational Segment (USOS) crewmembers was submitted for out-of-board approval, and we anticipate recruiting additional crewmembers in the near future. The retrospective data mining was initiated with the Life Sciences Data Archive to summarize the medical records from Shuttle and the International Space Station (ISS). These results will be published in a new edition of Principles of Clinical Medicine for Space Flight. A review of the existing data was provided this year at a motion sickness conference in Caen, France (Wood et al., 2022).

During this ground-based study, we will evaluate combining intranasal scopolamine and sensory augmentation as an integrated countermeasure on a multi-degree of freedom platform simulating capsule motion during water landings. We hypothesize that exposure to simulated capsule wave motion will induce motion sickness and impair performance on functional tasks. We also hypothesize that the combination of intranasal scopolamine and sensory augmentation of Earth vertical will be more effective to mitigate motion sickness and improve task performance than when administered separately. We will compare motion sickness symptom onset, severity, and recovery across four conditions: intranasal scopolamine (0.4 mg) and placebo control with and without sensory augmentation. Performance on a series of functional tasks (tilt motion tracking with and without a paced auditory serial addition test (PASAT) dual-task, eye-head-hand target acquisition)) will be performed pre, during, after capsule wave motion. The motion will continue until the subject reaches a motion sickness endpoint representing severe malaise on the Pensacola Diagnostic Index up to 45 min. The bioavailability of scopolamine for each session will be estimated from plasma concentrations every 15 min. Cognition (psychomotor vigilance task) and subjective reports of drug side effects will be obtained.

Two additional specific aims are also proposed to further evaluate the efficacy of intranasal scopolamine to provide treatment (“rescue”) of symptoms following motion sickness onset. For specific aim 2, a laboratory-based study will be used to compare motion sickness symptom severity and recovery for intranasal scopolamine (0.4 mg) and placebo control subjects will self-administer during the simulated capsule wave motion following symptom onset. Finally, specific aim 3 will involve an operational clinical field study in which flight surgeons will administer intranasal scopolamine to astronauts and/or recovery operations personnel during SpaceX landings or Orion splashdown recovery simulations.

Specific Aim 2: This aim will compare motion sickness symptom severity and recovery for intranasal scopolamine (0.4 mg) and placebo control subjects will self-administer during the simulated capsule wave motion following symptom onset. We are currently evaluating moving this study arm to utilize the Disorientation Research Device (Kraken) located at the Naval Medical Research Unit – Dayton (NAMRU-D) at the Wright-Patterson Air Force Base in Ohio. This device has the capability to provide a greater range in levels of sea states for the capsule wave motion.

Specific Aim 3: This aim is a clinical field study to examine the efficacy of intranasal scopolamine in various operational settings including SpaceX missions, Orion splashdown recovery simulations, and centrifuge training. The field test aim was initiated during the 3-day orbital free-flyer mission (Inspiration4) onboard the SpaceX Crew Dragon capsule this past year. Commercial crewmembers were trained in standardized self-administration of intranasal scopolamine for mild-to-moderate motion sickness (0.2 mg per nostril, 0.4 mg total dose). Each crewmember was supplied with one scopolamine nasal applicator, stowed in an accessible pocket of the IVA (intravehicular activity) suit. No restriction was placed upon the use of prophylactic anti-emetics, with decision for prophylactic use for each crewmember based on observed motion sickness susceptibility during training. Nausea levels (1 = no nausea, 20 = severe nausea) were recorded as a standard part of regularly scheduled Private Medical Conferences (PMCs). PMCs occurred shortly after initial orbital insertion, nightly prior to crew sleep, and post-splashdown. Two of four crewmembers utilized intranasal scopolamine during the hours of the spaceflight. Both Crewmembers reported a peak nausea level of 8 on the 0-20 scale prior to INSCOP (Intranasal Scopolamine) self-administration, reducing to 5 after 15 minutes. Side effects reported included drowsiness, dry mouth, and nasal irritation (n=1 for each). Duration of reported relief was 2.5 hrs. and 3.5 hrs. for each crewmember, respectively, later requiring more aggressive treatment for higher symptom scores. Nausea resolved by mission day 1, resulting in no further use of anti-emetics in flight. Despite the later need for anti-emetics, this novel tool effectively mitigated immediate symptoms of nausea and was easily self-administered by crewmembers with minimal training and did not impede flight operations by requiring unscheduled suit doffing or medical equipment access.

Water landings are expected to exacerbate reentry motion sickness severity. In addition to the unstable support surface, crewmembers will be deprived of a stable Earth visual reference inside the crew capsule. Sensory augmentation, e.g., vibrotactile feedback of an Earth vertical reference, has been effective as a spatial awareness and balance aid with vestibular impairment. We hypothesize that the combination of intranasal scopolamine and sensory augmentation of Earth vertical will be more effective to mitigate motion sickness and improve task performance than when administered separately.

During this ground-based study, we will evaluate combining intranasal scopolamine and sensory augmentation as an integrated countermeasure on a multi-degree of freedom platform simulating capsule motion during water landings. We hypothesize that exposure to simulated capsule wave motion will induce motion sickness and impair performance on functional tasks. We also hypothesize that the combination of intranasal scopolamine and sensory augmentation of Earth vertical will be more effective to mitigate motion sickness and improve task performance than when administered separately. We will compare motion sickness symptom onset, severity, and recovery across four conditions: intranasal scopolamine (0.4 mg) and placebo control with and without sensory augmentation. Performance on a series of functional tasks (dual-task tracking, eye-head-hand target acquisition, sit-to-stand) will be performed pre, during, immediately post and following 15 min of recovery of each test. The bioavailability of scopolamine for each session will be estimated from plasma concentrations. Cognition and alertness assessments and subjective reports of drug side effects will be obtained.

Two additional specific aims are also proposed to further evaluate the efficacy of intranasal scopolamine to provide treatment (“rescue”) of symptoms following motion sickness onset. For specific aim 2, a laboratory-based study will be used to compare motion sickness symptom severity and recovery for intranasal scopolamine (0.4 mg) and placebo control that subjects self-administer during the simulated capsule wave motion following symptom onset. Finally, specific aim 3 will involve an operational clinical field study in which flight surgeons will administer intranasal scopolamine to astronauts and/or recovery operations personnel during SpaceX landings or Orion splashdown recovery simulations.

The significance of treating motion sickness with intranasal scopolamine is the ability to self-administer real-time dosage adjustments during crew landing and recovery operations. The combination of non-pharmaceutical sensory augmentation approach with intranasal scopolamine has the benefit to not only mitigate motion sickness but enhance crew performance of landing and egress tasks.