Based on the current knowledge and hypotheses, countermeasures focused on producing hydrostatic gradients or reducing the microgravity-induced fluid shift, such as lower body negative pressure (LBNP) or centrifugation, become particularly interesting. LBNP shifts fluids from the head to the lower body is expected to reduce the translaminar pressure across the eye and thus, might prevent some of the ocular changes and remodeling associated with SANS. LBNP is also a promising countermeasure to enhance venous flow in the upper body. Similarly, head-to-foot (Gz) centrifugation also produces a fluid shift and induces hydrostatic gradients within the vessels in the body, which may also reduce intraocular pressure (IOP), reduce the translaminar pressure, and enhance venous flow. However, at present, it is not possible to estimate the overall physiological response (neither acute nor long term) of a particular “dose” of artificial gravity (AG) or LBNP, and more specifically and relevant to our purposes, the response in the upper body and around the eye. As a first step and in the context of this short project, we propose to focus on acute responses. Our objective is to generate acute gravitational dose-response curves of cardiovascular (CV) and ocular variables due to changes in the gravitational vector, with and without countermeasures. We propose to conduct a series of experimental studies (using tilt table, LBNP, and centrifugation), and combine the results with numerical modeling to leverage the advantages of both experimental and computational methodologies. Then, we propose to exert the full flexibility of the numerical framework to investigate CV and ocular responses in additional configurations where data collection is difficult, expensive, or infeasible.

A short-description of the experiments is shown below:

- Experiment 1: Tilt table. Subjects will be exposed to multiple tilt angles, from 45° HUT (head up tilt) to 45° HDT (head down tilt), in both prone and supine configurations. CV and ocular measures will be collected and used to generate gravitational dose-response curves as a function of tilt angle.

- Experiment 2: LBNP. Subjects will be exposed to multiple levels of negative pressure (from 0 to -50 mmHg), in both supine and 15° HDT. Similarly, CV and ocular measures will be collected and used to generate gravitational dose-response curves as a function of external pressure.

- Experiment 3: Centrifugation. Subjects will be exposed to multiple levels of artificial gravity on the human short-radius NASA centrifuge that is being relocated and installed at Texas A&M University (TAMU). CV and ocular measures will be collected and used to generate gravitational dose-response curves as a function of g-level.

In addition to the experiments, we will develop a numerical model from two different but complementary lumped-parameter models that have been previously validated and published in the literature: 1) A full-body model that provides an accurate simulation of short-term CV regulatory changes during changes in the gravitational vector (i.e., different tilt angles, centrifugation) and countermeasures (i.e., LBNP, exercise). This model features a more accurate body representation, including a cardiac pacemaker (i.e., pulsatile waveform), baroreceptor and cardiopulmonary feedback control of heart and arterial parameters, and a large number of compartments, particularly in the Gz direction, allowing for an improved representation of hydrostatic gradients in this direction and overall body hemodynamics. 2) An eye model that simulates volume/pressure alterations in the eye during gravitational changes. We will combine both approaches leveraging the advantages of each one of them into a unique more powerful and versatile model to study SANS, the cranial venous system, and other fluid shifts mechanisms and the effects of potential countermeasures. The model will be validated with the experimental data generated during the experiments.

Results from this investigation will inform current and future countermeasure development and in-flight prescriptions.

To date, we have successfully completed the first two experiments (i.e., tilt and LBNP), and data analysis is underway. For experiment 3, we are planning to use the Aerospace Human Centrifuge at TAMU, which is a NASA-funded facility that was formerly at the University of Texas Medical Branch (UTMB) in Galveston (TX). The final installation and check-out of the centrifuge are currently underway. This process has experienced important delays due to COVID, but we expect to have the centrifuge operational later this year.

We are also investigating gravitational dose responses using modeling approaches. We are developing a comprehensive numerical framework capable of predicting the expected acute cardiovascular responses and ocular changes when exposed to different types of orthostatic stress. We will use our own experimental data to validate the model.

To date, we modified an existing numerical model of the eye (Nelson et al., 2017) to model Intraocular Pressure (IOP) during a full range of tilt positions (360°, which covers both prone and supine positions). Experimental data collected in 13 subjects supported the hypothesis that IOP is statistically significantly higher in prone position than in supine position due to the extra hydrostatic column between the eye globe and the coronal plane, and this is true at most of the tilt angles investigated. Our modified version of the model successfully reproduced these results and a manuscript is currently in preparation. Additionally, we have conducted a comprehensive sensitive analysis in a “full body” numerical model (Diaz Artiles et al. 2019) to investigate individual differences in cardiovascular responses to orthostatic stress (Whittle and Diaz-Artiles 2021). Conditions simulated include constant gravity conditions (from 0g to 1g, in increments of 0.25g), and gravitation stress generated by a short-radius centrifuge, which induce a strong gravity gradient in the head-to-toe direction (from 0g to 1g, in increments of 0.25g, measured at the center of mass). Results from the constant gravity conditions show that model parameters related to the length, resistance, and compliance of the large veins and parameters related to right ventricular function have the most influence on model outcomes. For most outcome measures considered, parameters related to the heart are dominant. Results highlight which model parameters to accurately value in simulations of individual subjects’ CV response to gravitational stress, improving the accuracy of predictions. Influential parameters remain largely similar across gravity levels, highlighting that accurate model fitting in 1 g can increase the accuracy of predictive responses in reduced gravity. These research efforts have been captured in the following peer-reviewed publication:

- Whittle R.S. and Diaz-Artiles A. “Modeling individual differences in cardiovascular response to gravitational stress using a sensitivity analysis.” Journal of Applied Physiology 2021, 130: 1983-2001

Similar analysis is currently being conducted in the centrifugation conditions and a manuscript is in preparation. Future modeling efforts include the integration of the “full body model” and “the eye model” to leverage the advantages of each one of them into a unique more powerful and versatile model to study SANS, the cranial venous system, and other fluid shifts mechanisms and the effects of potential countermeasures.

References

Nelson ES, Mulugeta L, Feola A, Raykin J, Myers JG, Samuels BC, Ethier CR. The impact of ocular hemodynamics and intracranial pressure on intraocular pressure during acute gravitational changes. J Appl Physiol 123: 352–363, 2017.

Diaz-Artiles A, Heldt T, Young LR. Computational Model of Cardiovascular Response to Centrifugation and Lower-body Cycling Exercise. J Appl Physiol 127: 1453–1468, 2019.

Whittle R.S. and Diaz-Artiles A. Modeling individual differences in cardiovascular response to gravitational stress using a sensitivity analysis. Journal of Applied Physiology 130: 1983-2001, 2021.

AsMA 2021 Proceedings, in press as of July 2021. , Jul-2021

ISGP 2021 Proceedings. International Society for Gravitational Physiology (ISGP) 2021 Meeting, Virtual, May 24-27, 2021. , May-2021

ISGP 2021 Proceedings. International Society for Gravitational Physiology (ISGP) 2021 Meeting, Virtual, May 24-27, 2021. , May-2021

Abstracts. 2021 NASA Human Research Program Investigators’ Workshop, Virtual, February 1-4, 2021. , Feb-2021

IEEE Conference on Aerospace, March 2020. https://doi.org/10.1109/AERO47225.2020.9172582 , Mar-2020

Based on the current knowledge and hypotheses, countermeasures focused on producing hydrostatic gradients or reducing the microgravity-induced fluid shift, such as lower body negative pressure (LBNP) or centrifugation, become particularly interesting. LBNP shifts fluids from the head to the lower body and is expected to reduce the translaminar pressure across the eye and thus, might prevent some of the ocular changes and remodeling associated with SANS. LBNP is also a promising countermeasure to enhance venous flow in the upper body. Similarly, head-to-foot (Gz) centrifugation also produces a fluid shift and induces hydrostatic gradients within the vessels in the body, which may also reduce intraocular pressure (IOP), reduce the translaminar pressure, and enhance venous flow. However, at present, it is not possible to estimate the overall physiological response (both acute or long term) of a particular “dose” of artificial gravity (AG) or LBNP, and more specifically and relevant to our purposes, the response in the upper body and in the eye.

The objective of this ground-based research effort is to generate acute gravitational dose-response curves of cardiovascular (CV) and ocular variables due to changes in the gravitational vector, with and without countermeasures. We propose to use both experimental and computational approaches to leverage the advantages of each one of these research methodologies. We propose to conduct a set of three human experiments to generate the desired dose-response curves experimentally. The experiments will include exposure to multiple tilt angles (360° spectrum) in prone and supine postures, LBNP, and centrifugation. We also propose to develop a numerical model capable of predicting the expected acute CV and ocular changes in those conditions. The model will be validated with the experimental data generated during the experiments, and then will be used to simulate additional conditions where data collection is difficult, expensive, or infeasible. Results from this investigation will inform current and future countermeasure development and in-flight prescriptions.