Our first specific aim was to evaluate the effect of timing on the administration of our non-pharmaceutical treatment to motion sickness. While we have previously demonstrated that our approach can mitigate motion sickness if introduced prior to the provocative stimuli, one of the goals of this study is to determine the efficacy if we administer the treatment following the onset of symptoms. Validating the efficacy following symptom onset would alleviate the need for certifying the device to be worn within the landing suit and greatly enhance flexibility to implement this treatment during recovery operations. Our first hypothesis was that efficacy of galvanic vestibular reduction to reduce motion sickness severity will depend on the timing of the administration. We tested this hypothesis by exposing subjects to provocative Coriolis cross-coupling stimuli on a rotating chair using a repeated measures counter-balanced design to compare motion sickness severity across three treatment interventions: prior to stimulus onset (Prevention), following symptom onset (Rescue), and without GVR (Control). Symptom severity was assessed using both subjective reports and objective autonomic measures (electrogastrography). We expected that the most effective administration will be GVR delivered prior to the onset of symptoms, but that it will continue to be more effective relative to placebo control even if delivered following symptom onset.

Our second specific aim was to evaluate the effect of GVR amplitude on functional fitness task performance. One disadvantage of pharmaceutical approaches is that increased drug dosage is often accompanied by sedative side effects that impact functional ability. In order to leverage our non-pharmaceutical technique that allows continuous adjustments in “dosage” level throughout recovery, we must map changes in GVR level with functional performance. Our second hypothesis is that functional task performance will decline with increasing levels of galvanic vestibular reduction. We will test this hypothesis by measuring performance on a sensorimotor and cognitive test battery in steps ranging from 0mA (control) to the level of GVR thought to provide maximal motion sickness protection (2.25mA). The test battery, conducted on the same subjects as specific aim 1, will include posturography, mobility (modified Timed Up and Go) as well as other oculo-cognitive metrics. The combined deliverable from both specific aims will be to validate the efficacy of GVR when customizing the stimulus level and introducing it following symptom onset, and to understand the effects of this non-pharmaceutical approach on crew performance on functional task performance.

Galvanic vestibular reduction stimulation: Galvanic vestibular reduction was delivered using a proprietary system developed at the Mayo clinic laboratory. This utilizes a multi-channel commercial galvanic stimulator (Good Vibrations Engineering Ltd, King City, ON) with custom software. The stimulator bidirectionally delivered a sinusoidal profile (2.5 Hz) with variable amplitudes from ±1.75 to ±2.25 mA to provide matching cathodal or anodal currents simultaneously to each mastoid.

Motion sickness stressor: Each of the three sessions involved a series of trapezoid velocity profiles with acceleration (6 º/s2) up constant velocity of 60 º/s for 2.5 min during which 7 forward (chin to chest) and backward (return to upright) head movements were cued every 10 seconds. Although the head position was not measured, the typical range of motion for head flexion in young healthy adults is 60º. Subjects were tested in a dark room with their eyes closed and audio cueing over a chair-fixed speaker to pace the head movements and allow operator-subject communications throughout the protocol. Since the GVR stimulus was chair mounted and needed to be turned on manually, the 2 min pause between rotations was required to allow the operator to turn on the GVR during the rescue sessions. This pause also allowed time for symptom recovery and in part led to a higher-than-expected number of subjects who did not reach the symptom endpoint during the control session.

Symptom reporting: During the 2 min pause between head movement sets, symptom scoring was obtained using the Pensacola Diagnostic Index (PDI) and a Subjective Discomfort Rating (SDR). The PDI provides an acute score derived using diagnostic criteria introduced by Graybiel et al. (1968) by obtaining the subjective intensity of eight different modalities of symptoms and signs reported on a “slight/moderate/severe” basis used to derive a weighted “malaise index”. The symptom endpoint for stopping the test was a PDI score of 8 pts, considered severe malaise. We also used the PDI to determine when to initiate the GVR during the Rescue session. During these sessions, the GVR was initiated with a moderate malaise (PDI = 3), or following 4 sets of head movements, whichever came first. The SDR used a subjective magnitude estimation scale of 0-20, with 20 indicating vomiting (Oman et al. 1986), similar to what has been used for Field Tests and Spaceflight Standard Measures. If GVR effectively suppresses vestibular sensitivity, we hypothesized subjects would experience lower symptom scores, and be able to perform more head movements before reaching the endpoint. An objective measure of sickness was also obtained using the physiological response of gastric myoelectric activity, known as the electrogastrogram (EGG). These EGG recordings were analyzed to derive the dominant power instability coefficient (DPIC) as an index for motion sickness. DPIC quantifies the stability of the power of the dominant frequency – higher DPIC values indicate higher gastric dysrhythmia, presumably in this case due to motion sickness.

Motion perception reporting: A chair-mounted joystick was used to obtain objective measures of motion perception in three-dimensions during the pitch head movements. During the head movements, subjects experienced a combination of yaw rotation from the persisting horizontal canal response to the angular acceleration of the chair rotation, pitch tilt from canal, otolith and cervical cues associated with alternating the head between upright and chin-to-chest positions, and Coriolis cross-coupled roll canal cues associated with aligning the roll plane of the head relative to plane of rotation. As the horizontal canal response decays, the conflicting cues from the cross-coupled roll canal cues and otolith cues of pitch head tilt give rise to the nauseogenic effects. Subjects were trained to indicate the direction and magnitude of perceived pitch and roll tilt using the joystick so that the maximum deflection represented the magnitude of the pitch forward and backward movement. If GVR effectively suppresses vestibular sensitivity, we hypothesized subjects would experience reduced pitch and roll tilt sensation during GVR versus the control condition without GVR.

Sensorimotor cognitive test battery: Our second specific aim was to evaluate the effect of GVR amplitude on functional fitness task performance. This aim was important to understand how GVR may impair performance over the range of stimulus amplitudes (0 to 2.25 mA) used to treat motion sickness. This test battery utilizes both dynamic posturography as well as a modified timed up and go (TUG) locomotion task. A third test in the battery was designed to measure cognitive performance indicators during variable workload through eye movement features. The Oculo-Cognitive Addition Test (OCAT, Pradhan et al. 2022) tracks eye movements as the subject sums three consecutive single-digit numbers displayed at various positions around an infinity-loop pattern to elicit saccades in horizontal, vertical, and diagonal directions.

RESULTS: Fifteen of the 27 subjects were not susceptible to the motion stressor (i.e., did not reach an endpoint in the control condition). While the time to endpoint, or number of head movements, did not significantly vary across the three GVR conditions in the remaining subjects, the symptom levels were significantly delayed during the Prevention session when GVR was on throughout the testing. Initiating GVR following symptom onset did not appear to alter the symptom progression nor time to motion sickness endpoint. Based on the joystick measures, GVR significantly modified the perceived roll and pitch sensation during head movements, reducing the amplitude of tilt in most subjects. It is important to note that comparable levels of GVR did not impair performance on the functional test battery including mobility, balance, and oculometric tasks.

DISCUSSION: Our findings suggest GVR may be useful in reducing disorienting roll and pitch illusions and delaying the onset of motion sickness. Further enhancements will be required to individualize the stimulation amplitude and optimize the waveform delivery. Adapting this non-pharmaceutical countermeasure approach to allow self-administered titration of current amplitude during recovery would enable transfer to post-flight treatment, perhaps combined with a pharmaceutical approach to mitigate G-transitional induced motion sickness.

REFERENCES:

Graybiel A, Wood CD, Miller EF et al. (1968) Diagnostic criteria for grading the severity of acute motion sickness. Aerosp Med 39:453-455.

Oman CM, Lichtenberg BK, Money KE et al. (1986) M.I.T./Canadian vestibular experiments on the Spacelab-1 mission: 4. Space motion sickness: symptoms, stimuli, and predictability. Exp Brain Res 64:316-334.

Pradhan GN, Hagen KM, Cevette MJ et al. (2022) Oculo-Cognitive Addition Test: Quantifying cognitive performance during variable cognitive workload through eye movement features. In: 2022 IEEE 10th International Conference on Healthcare Informatics (ICHI), June 11-14, 2022. pp 422-430. doi:10.1109/ICHI54592.2022.00064

Motion sickness stressor: During the three rotating chair sessions, subjects are accelerated (10 deg/s/s) to a constant velocity. Subjects then perform up to 10 sets of head movements. For each set, a head movement is cued every 10 seconds, alternating between pitch forward (chin resting to chest) and pitch backward (head upright). During each head movement subjects are asked to use a joystick to record the amplitude of their rotation sensation (yaw, pitch and/or roll). There were total of 7 forward and 7 backward movements per set lasting 2.5 mins. During the 2 min pause between head movement sets, symptom scoring is obtained using the Pensacola Diagnostic Index and a subject discomfort (0-20) ratings. If GVR effectively suppresses vestibular sensitivity, subjects should experience low symptom scores, be able to perform more head movements before reaching the endpoint, and have reduced motion illusions as quantified by the joystick.

There have been no adverse effects or dermal discomfort due to GVR stimulation. The rotation speed was 30 deg/s for the first 9 subjects. Subjects are tested until they reach the motion sickness endpoint of 8 symptom points or a maximum set of 10 head movements. Since several subjects did not reach a motion sickness endpoint, the rotation speed was increased to 60 deg/s to increase motion sickness stressor for the remaining 21 subjects. Given the repeated measures design, we do not plan to recruit replacement subjects for those reaching motion sickness endpoints at the lower speed.

Sensorimotor cognitive test battery: The purpose of this test battery is to assess how GVR may impair performance over the range of stimulus amplitudes used to treat motion sickness. This test battery utilizes both dynamic posturography as well as a modified timed up and go (TUG) locomotion task. The dynamic posturography is known as the modified Clinical Test of Sensory Integration on Balance (mCTSIB) measuring sway velocity during two 10-second trials for each of the following conditions: Standard -- eyes open on firm surface (EO-FI), Proprioception -- eyes closed on firm surface (EC-FI), vision -- eyes open on foam surface (EO-FO), and vestibular -- eye closed on foam surface (EC-FO). The modified TUG involved standing up upon on command, walking 4 meters, turning around, walking back to the chair, and sitting down. The subject is required to step over an obstacle (30 cm high, 10 cm wide) positioned midway between the chair and the turning point, once on the way toward the turning point and again on the return back. The time stops when the patient is seated.

We also conducted flight simulator performance in Virtual Reality (VR) and cognitive tasks in the form of the Oculo-Cognitive Addition Test (OCAT), which requires participants to look for numbers on a screen and add these numbers together. OCAT includes eye-tracking, and currently, we are analyzing cognitive and oculomotor performance measures. VR Flight performance provides simulator immersion and visuomotor function during flight. Data collection and analysis is still ongoing through the remainder of the calendar year.