Post spaceflight orthostatic intolerance is an important NASA safety concern with as many as 60% of returning astronauts experiencing symptoms of cerebral hypoperfusion. While the mechanisms underlying this problem are likely multifactorial, the goal of this research is to examine the role of vestibular inputs in cerebral blood flow regulation and the effect of these inputs on orthostatic tolerance. Our general hypothesis is that otolith mediated vestibular inputs act as a feed forward mechanism causing cerebral vasodilation to compensate for the decrease in cerebral perfusion pressure caused by the upright posture. We proposed four specific aims to address this hypothesis.

Specific Aim 1: Determine the effect of orthostatic stress (tilts) on cerebral blood flow and cerebral autoregulation in elderly subjects with intact and impaired vestibular function. The purpose of this aim was to determine whether the vestibular system plays an important role in the changes in cerebral blood flow when you go from a supine to upright.

Major Finding: Loss of vestibular function in both younger and older subjects is associated with greater decreases in cerebral blood flow when upright.

Implications for Human Spaceflight: 1) Sensorimotor disturbances related to adaptation to microgravity are common among astronauts and may result in greater drops in cerebral blood flow when astronauts are upright upon returning to a 1-G environment

Specific Aim 2: Determine the effect of static otolith stimulation on cerebral blood flow. The purpose of this aim was to determine whether continual stimulation of the otoliths without associated canal or other sensorimotor cues affects cerebral blood flow. This aim was accomplished by performing centrifugation to selectively stimulate the otoliths.

Major Finding: Changes in cerebral blood flow were consistent during otolith stimulation, even in the absence of other cues of tilt.

Implications for Human Spaceflight: 1) Vestibular adaptations that occur during spaceflight could result in reduced otolith inputs and maladaptive cerebral blood flow responses. Since cerebral blood flow changes occur during otolith stimulation in the absence of other cues of tilt, astronauts may be at greatest risk for orthostatic intolerance post spaceflight if other sensory cues of upright are missing to replace impaired otolith cues.

Specific Aim 3: Determine the effect of dynamic canal plus otolith vs otolith stimulation on cerebral blood flow. This aim was accomplished by examining cerebral blood during both centrifugation (otolith stimulation) vs dynamic pitch tilt (otolith and canal stimulation) in a group of young subjects with intact vestibular function.

Major Finding: Changes in cerebral blood flow were mediated primarily by otolith activation.

Implications for Human Spaceflight: 1) Since vestibular adaptation to microgravity involves changes in interpretation of otolith and not canal cues, this further supports the possibility that changes in otolith inputs could cause problems in cerebral blood flow regulation

Specific Aim 4: Determine the effect of training subjects to associate otolith input as tilt on cerebral blood flow during orthostatic stress in elderly subjects with intact and impaired vestibular function. The goal of this aim is to determine if enhancing vestibular function could be used as a countermeasure to improve cerebral blood flow when upright.

Major Finding: Stimulation of the vestibular nerve with subsensory stochastic noise causes improvement in both vestibular function and cerebral blood flow responses to tilt.

Implications for Human Spaceflight: 1) Greater reductions in cerebral blood flow associated with reduced vestibular function post spaceflight could be reduced by stimulation of the vestibular nerve

In addition, we found a strong relationship between sway parameters and otolith function. Thus, individuals with the worst otolith function tended to show the greatest sway. These increased levels of sway suggested they were also at greater risk for falls. Thus, elderly individuals with impaired vestibular function may be at even greater risk for falls. Testing a group of elderly subjects with normal and impaired vestibular function found that the group with impaired function demonstrated a significantly greater drop in brain blood flow when upright. In addition this greater drop only occurred when they were blindfolded and had no visual information. This would suggest that individuals with loss of vestibular function may have problems maintaining brain blood flow when upright. In addition, this impairment only occurs when they are unable to use vision in place of vestibular information to tell them about whether they are upright or not. Finally, we have tested a group of young subjects with and without impairment, but not yet analyzed the data.

We have already completed specific aim 2 by performing variable-radius centrifugation on a group of healthy subjects. While rotation on center did not cause any changes in brain blood flow, movement forward, causing the perception of forward tilt, and resulted in a significant decrease in brain blood flow. This decrease in brain blood flow could not be explained by any other physiological responses, indicating that vestibular inputs were likely the cause. To complete Specific Aim 3 we used a combination of dynamic tilt and variable radius centrifugation to separate the roles of otoliths vs canals in the brain blood flow response to vestibular stimulation. Brain blood flow oscillated with the frequency of motion, again suggesting an important role for vestibular inputs in this response. In addition, changes at higher and lower frequencies were similar between tilt and centrifugation. Since centrifugation at low frequencies has minimal canal inputs, these data suggest that the response was primarily driven by otolith inputs.

In addition, during the previous year we were able to develop a new method of stimulating the vestibular system to increase performance. In the last year of the grant we plan to test our stimulator to determine if it could be used as a new treatment paradigm for vestibular loss with the intention of working towards a countermeasure.

1) Complete screening of elderly and young to determine normal and impaired vestibular function 2) Testing the first cohort of subjects for Specific Aim 1 and 2 while preparing for completion of Aims 1, 2 and 3 in year 3 of the grant 3) Beginning data collection in Portland, Oregon for centrifugation studies

During this past year we have continued to collect screening data and reached 160 subjects (80% of the total number expected to be enrolled). From this we have found several interesting findings already. In addition our initial data indicates that vestibular function has a direct effect on the initial response to orthostatic stress and thus may be implicated in the orthostatic intolerance problem seen in astronauts. We plan to complete specific aim 1 within the first 3 months of the current funding cycle. We anticipate we will be able to complete Specific Aim 3 by the end of August using the same group of subjects used for the tilt study.

We have begun centrifuge testing at Legacy Health Systems in Portland, Oregon (Specific Aim 2) and have present data on 10 subjects to date. As can be seen, these data further support a connection between the vestibular system and cerebrovascular regulation. We plan to complete Specific Aim 2 by the end of the current funding period.

1) Establishing a population of elderly with normal and impaired vestibular function 2) Ensuring testing for the tilt table testing and head rotation experiments could be achieved in year 3 3) Preparing to begin data collection in Portland, Oregon

Since this is a first grant for the PI, significant equipment purchases and lab setup time was required. During the first 6 months the PI was able to successfully set up a complete vestibular screening and physiology testing lab. In addition the PI was able to have several custom pieces of equipment designed to meet the screening needs of the studies. Following set-up, the subsequent time has been used to recruit and screen 108 subjects (54% of the total number expected to be enrolled).

An important piece of equipment that has been developed is the ocular counterroll chair that allows for assessment of ocular torsion. Since the primary goal of the vestibular screening is to stratify subjects by otolith function, which is the vestibular component primarily affected by spaceflight, measuring ocular torsion is essential to assessing otolith function. Dr. Wood has previously shown that using slow oscillations (+/-20 degrees @ 0.01 Hz) provides an accurate estimate of otolith function as compared to other current assessment techniques (Merfeld et al. J Neurophys 2005; 94: 199-205; Merfeld et al. J Neurophys 2005; 94: 206-218). In a recent study Dr. Wood compared ocular torsion gain during earth horizontal axis (EHA) rotation (i.e. ocular counterroll) and variable radius centrifugation (VRC). Since VRC provides an otolith specific stimulation, torsion produced by this stimulus should be solely of otolith origin. In contrast, during EHA both otolith and canal organs are activated. However, at very low frequencies, response from VRC and EHA are virtually identical. This demonstrates that ocular torsion during ocular counterroll can be used as a good measure of otolith function. In addition with the assistance of Dr. Wood, we have been able to duplicate his ocular torsion analysis system in the PI’s lab allowing us to obtain continuous ocular torsion during our screening tilt test (+/-20 degrees @ 0.01 Hz).

To address the concern of obtaining an adequate sample of elderly subjects that will allow stratification into impaired and normal vestibular function, recruitment of elderly began within the first 6 months of the grant. Ads were placed in the print publications; Harvard Cooperative Program on Aging and Boston Seniority. Recruitment flyers were also posted at the Harvard Institute for Learning in Retirement. Recruitment has subsequently increased in the past year to 50 subjects, 50% of our target population for elderly subjects. We thus believe we will not have a problem meeting our recruitment goals over the second year of the grant.