NOTE: End date changed to 8/31/2023 per NSSC information (Ed., 8/22/22)

NOTE: End date changed to 8/31/2022 per NSSC information (Ed., 8/13/21)

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) for both male and female subjects. During this past year, we have focused on refining our data analysis from experiment 1 and 2, and on preparing the many publications we expect to have from this project. Thus, in 2024 we have already published 2 journal papers related to this project (Hall et al. 2024 and Fois et al 2024), and we have several more in preparation and/or in review. We also continue to work on the Aerospace Engineering centrifuge and expect to have it ready soon, so we can conduct our third experiment.

In addition, in 2024 we received an augmentation grant to investigate cardiovascular and ocular adaptation during 60 minutes of exposure to simulated microgravity (6° HDT). In the last few months, we completed the testing of 24 subjects and data analysis is underway.

In the next few paragraphs, we provide a summary of what has been completed in this project to date.

EXPERIMENTAL WORK

Data from experiment 1 (male subjects) have been captured in the following peer-reviewed publications:

• Whittle R.S. and Diaz-Artiles A. “Gravitational effects on jugular and carotid hemodynamics in graded head up and head down tilt”. Journal of Applied Physiology 2023, 134: 217–229. doi: 10.1152/japplphysiol.00248.2022

• Whittle R.S., Keller N., Hall E.A., Vellore H.S., Stapleton L.M., Findlay K.H., Dunbar B.J., and Diaz-Artiles A. “Gravitational dose response curves for acute cardiovascular hemodynamics in a tilt paradigm”. Journal of the American Heart Association 2022, 11: e024175. doi: 10.1161/JAHA.121.024175 Data analysis of female subjects has also been completed and a journal article is in preparation.

Data analysis from experiment 2 (LBNP) has also been completed and our first peer-reviewed article has been published: • Hall E., Whittle R.S., Diaz-Artiles A. (2024) “Ocular Perfusion Pressure is not Reduced in Response to Lower Body Negative Pressure” npj Microgravity 10, 67. Several journal articles related to our LBNP results are currently in preparation

The complete data are captured in the following dissertation with several journal articles in preparation:

• Whittle R.S., "Quantifying the effects of altered-gravity and spaceflight countermeasures of acute cardiovascular and ocular hemodynamics". Ph.D. Dissertation, Texas A&M University, August 2023.

For experiment 3 (centrifugation), 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 further delays since year 2, but we expect to have the centrifuge operational soon.

Further, during the course of our data collection for experiments 1 and 2, we published a manuscript covering the differences observed in measurement of cardiac output in altered gravity conditions using inert gas rebreathing and pulse contour analysis. These data are captured in the following peer-reviewed publication:

• Whittle R.S., Stapleton L.M., Petersen L.G., and Diaz-Artiles A. “Indirect measurement of absolute cardiac output during exercise in simulated altered gravity is highly dependent on the method”. Journal of Clinical Monitoring and Computing 2021, 1-12. doi: 10.1007/s10877-021-00769-y

MODELING WORK

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 the results are captured in the following peer-reviewed publication:

• Petersen L.G., Whittle R.S., Lee J.H., Sieker J., Carlson J., Finke C., Shelton C.M., Petersen J.C.G., and Diaz-Artiles A. “Gravitational effects on intraocular pressure and ocular perfusion pressure”. Journal of Applied Physiology 2022, 132: 24-35. doi: 10.1152/japplphysiol.00546.2021

We have extended our full-body model to include a detailed simulation of the head incorporating multiple cranial venous drainage pathways. We have also improved the simulation of the decrease in intravascular volume as a result of transcapillary flow to the dependent vasculature during head-down tilt, as well as the effects of body weight. Validation of these changes has been completed with data from experiments 1 and 2, and the model has also been used to simulate additional scenarios, such as centrifugation, and changes in gravity. Results are being prepared for publication in a peer-reviewed journal and will be shared with the research community.

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.

2024 AUGMENTATION GRANT

Finally, as part of the 2024 augmentation grant, we tested 24 subjects to characterize cardiovascular and ocular responses during the first 60 min of 6° HDT. Testing has been finalized and data analysis is underway. In addition, an additional cardiovascular modeling work associated with this research effort was published in npj Microgravity (this work was done in collaboration with our colleagues from the Univeristy of Torino, Italy):

• Fois M., Diaz-Artiles A., Zaman S.Y., Ridolfi L., Scarsoglio S. (2024) “Linking cerebral hemodynamics and ocular microgravity-induced alterations through an in-silico/in-vivo head-down tilt framework”. npj Microgravity 10, 22.

NOTE: End date changed to 8/31/2023 per NSSC information (Ed., 8/22/22)

NOTE: End date changed to 8/31/2022 per NSSC information (Ed., 8/13/21)

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) for both male and female subjects. Data from experiment 1 (male subjects) have been captured in the following peer reviewed publications:

• Whittle R.S. and Diaz-Artiles A. “Gravitational effects on jugular and carotid hemodynamics in graded head up and head down tilt”. Journal of Applied Physiology 2023, 134: 217–229. doi: 10.1152/japplphysiol.00248.2022

• Whittle R.S., Keller N., Hall E.A., Vellore H.S., Stapleton L.M., Findlay K.H., Dunbar B.J., and Diaz-Artiles A. “Gravitational dose response curves for acute cardiovascular hemodynamics in a tilt paradigm”. Journal of the American Heart Association 2022, 11: e024175. doi: 10.1161/JAHA.121.024175

Data analysis of female subjects in tilt and both male and female subjects in the LBNP experiment has also been completed. The complete data are captured in the following dissertation with several journal articles in preparation:

• Whittle R.S., "Quantifying the effects of altered gravity and spaceflight countermeasures of acute cardiovascular and ocular hemodynamics". Ph.D. Dissertation, Texas A&M University, August 2023.

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 further delays since year 2, but we expect to have the centrifuge operational later this year.

Further, during the course of our data collection for experiments 1 and 2, we published a manuscript covering the differences observed in measurement of cardiac output in altered gravity conditions using inert gas rebreathing and pulse contour analysis. These data are captured in the following peer-reviewed publication:

• Whittle R.S., Stapleton L.M., Petersen L.G., and Diaz-Artiles A. “Indirect measurement of absolute cardiac output during exercise in simulated altered gravity is highly dependent on the method”. Journal of Clinical Monitoring and Computing 2021, 1-12. doi: 10.1007/s10877-021-00769-y.

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; the results are captured in the following peer-reviewed publication:

• Petersen L.G., Whittle R.S., Lee J.H., Sieker J., Carlson J., Finke C., Shelton C.M., Petersen J.C.G., and Diaz-Artiles A. “Gravitational effects on intraocular pressure and ocular perfusion pressure”. Journal of Applied Physiology 2022, 132: 24-35. doi: 10.1152/japplphysiol.00546.2021.

We have extended our full body model to include a detailed simulation of the head incorporating multiple cranial venous drainage pathways. We have validated the results of this addition to the full body model, the results of which will be published and shared with the research community. The complete model will be validated with data from all three experiments (i.e., tilt, lower body negative pressure/LBNP, and short radius centrifugation). This will 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.

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.

NOTE: End date changed to 8/31/2023 per NSSC information (Ed., 8/22/22)

NOTE: End date changed to 8/31/2022 per NSSC information (Ed., 8/13/21)

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) for male subjects. It was necessary to recollect the data from the LBNP experiment (originally collected in year 1) due to a hardware issue with the LBNP chamber identified in early 2022. Data collection is currently in progress for female subjects. Data analysis has been completed for experiment 1 (male subjects) and the results have been captured in the following peer reviewed publications:

• Whittle R.S. and Diaz-Artiles A. “Gravitational effects on jugular and carotid hemodynamics in graded head up and head down tilt”. [in review].

• Whittle R.S., Keller N., Hall E.A., Vellore H.S., Stapleton L.M., Findlay K.H., Dunbar B.J., and Diaz-Artiles A. “Gravitational dose response curves for acute cardiovascular hemodynamics in a tilt paradigm”. Journal of the American Heart Association 2022, [in press]. doi: 10.1161/JAHA.121.024175

Data analysis of the LBNP experiment is currently underway (for male and female subjects in parallel). 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 further delays since year 1, but we expect to have the centrifuge operational later this year.

Further, during the course of our data collection for experiments 1 and 2, we published a manuscript covering the differences observed in measurement of cardiac output in altered gravity conditions using inert gas rebreathing and pulse contour analysis. These data are captured in the following peer-reviewed publication:

• Whittle R.S., Stapleton L.M., Petersen L.G., and Diaz-Artiles A. “Indirect measurement of absolute cardiac output during exercise in simulated altered gravity is highly dependent on the method”. Journal of Clinical Monitoring and Computing 2021, 1-12. doi: 10.1007/s10877-021-00769-y

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; the results are captured in the following peer-reviewed publication:

• Petersen L.G., Whittle R.S., Lee J.H., Sieker J., Carlson J., Finke C., Shelton C.M., Petersen J.C.G., and Diaz-Artiles A. “Gravitational effects on intraocular pressure and ocular perfusion pressure”. Journal of Applied Physiology 2022, 132: 24-35. doi: 10.1152/japplphysiol.00546.2021

We have extended our full body model to include a detailed simulation of the head incorporating multiple cranial venous drainage pathways. We are currently validating the results of this addition to the full body model, and anticipate incorporating our eye model into the full body simulation later this year. This complete model will be validated with data from all three experiments (i.e., tilt, LBNP, and short radius centrifugation). This will 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.

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.

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.

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.