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Project Title:  Bed Rest Combined with 0.5% CO2 as a Spaceflight Analog to Study Neurocognitive Changes: Extent, Longevity, and Neural Bases Reduce
Fiscal Year: FY 2023 
Division: Human Research 
Research Discipline/Element:
HRP HFBP:Human Factors & Behavioral Performance (IRP Rev H)
 Start Date: 06/29/2017  
End Date: 06/30/2023  
Task Last Updated: 11/01/2023 		 Download report in PDF pdf
Principal Investigator/Affiliation:   Seidler, Rachael D. Ph.D. / University of Florida 
Address:  Applied Physiology & Kinesiology 
FLG 142, P.O. Box 118205 
Gainesville , FL 32611-8205 		 Email: rachaelseidler@ufl.edu 
Phone: 352-294-1722  
Congressional District: 3 
Web:  
 Organization Type: UNIVERSITY 
Organization Name: University of Florida 
Joint Agency:  
Comments: NOTE: PI moved to University of Florida in July 2017; previous affiliation was University of Michigan.  
Co-Investigator(s)
Affiliation: 
Bloomberg, Jacob  Ph.D. NASA Johnson Space Center 
Mulavara, Ajitkumar  Ph.D. Universities Space Research Association 
Kernagis, Dawn  Ph.D. University of North Carolina 
Key Personnel Changes / Previous PI: April 2021 report: For the augmentation study, Dr. Dawn Kernagis of University of North Carolina is a co investigator.
Project Information: Grant/Contract No. 80NSSC17K0021 
Responsible Center: NASA JSC 
Grant Monitor: Whitmire, Alexandra  
Center Contact:  
alexandra.m.whitmire@nasa.gov 
Unique ID: 11455  		Solicitation / Funding Source: 2014-15 HERO NNJ14ZSA001N-MIXEDTOPICS. Appendix E: Behavioral Health & Human Health Countermeasures Topics 
Grant/Contract No.: 80NSSC17K0021 
Project Type: GROUND 
Flight Program:  
TechPort: No  		No. of Post Docs: 3 
No. of PhD Candidates: 4 
No. of Master's Candidates:  
No. of Bachelor's Candidates:   		No. of PhD Degrees:  
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) HFBP:Human Factors & Behavioral Performance (IRP Rev H)
Human Research Program Risks: (1) BMed:Risk of Adverse Cognitive or Behavioral Conditions and Psychiatric Disorders
(2) Sensorimotor:Risk of Altered Sensorimotor/Vestibular Function Impacting Critical Mission Tasks
Human Research Program Gaps: (1) BMed-101:We need to identify, quantify, and validate the key selection factors for astronaut cognitive and behavioral strengths (e.g., resiliency) and operationally-relevant performance threats for increasingly Earth independent, long-duration, autonomous, and/or long-distance exploration missions.
(2) BMed-108:Given each crewmember will experience multiple spaceflight hazards simultaneously, we need to identify and characterize the potential additive, antagonistic, or synergistic impacts of multiple stressors (e.g., space radiation, altered gravity, isolation, altered immune, altered sleep) on crew health and/or CNS/ cognitive functioning to develop threshold limits and validate countermeasures for any identified adverse crew health and/or operationally-relevant performance outcomes.
(3) SM-104:Evaluate how weightlessness-induced changes in sensorimotor/vestibular function relate to and/or interact with changes in other brain functions (sleep, cognition, attention).
Flight Assignment/Project Notes: NOTE: End date changed to 6/30/2023 per NSSC information (Ed., 2/20/23)

NOTE: End date changed to 1/1/2023 per L. Barnes-Moten/JSC (Ed., 1/12/22)

NOTE: Changed end date to 1/01/2022 per NSSC information (Ed., 3/12/21)

NOTE: Changed end date to 1/01/2021 per L. Juliette/HRP (Ed., 2/19/2020)

NOTE: Changed end date to 12/28/2019 per NSSC information (Ed., 10/9/19)

Task Description: This original project is currently in no-cost extension, and a directed study is being performed, “Dose-Response Relationship of CO2 and Glymphatic Function.” This Annual Report covers the directed study only, as a final report has been previously submitted for the original project. Recent characterizations of glymphatic and meningeal lymphatic systems in rodents and in humans has resulted in a re-evaluation of the anatomical routes for cerebrospinal fluid (CSF) and interstitial fluid flow, as well as the physiological roles for these pathways in central nervous system (CNS) health. Information on the brain glial lymphatic, or ‘glymphatic’ pathway in humans was published in just the past two years, and described in mice in 2012 (Iliff et al. 2012, Iliff et al. 2013, de Leon et al. 2017, Ringstad et al. 2017). A bona fide lymphatic vasculature lining dural sinuses and meninges was first described in mice in 2015, and 2017 in humans (Aspelund et al. 2015, Louveau et al. 2015, Absinta et al. 2017). Fundamentally, research is needed to confirm whether specific factors driving this flow in rodents also apply to humans. These questions have direct relevance to NASA mission operations because, in addition to changing in response to irregular sleep patterns, it has been hypothesized that changes in cerebral blood flow (CBF) and molecular signaling in response to exercise, hypo/hyperoxia, and hypo/hypercarbia can have a significant impact on glymphatic function (Xie et al. 2013). No data currently exist specific to glymphatic responses from hypercapnia in humans or in mice. It is compelling, however, that nearly half of the subjects participating in a recent head down tilt bed rest campaign (“VaPER”), which combined 30 days of bed rest with 0.5% CO2 levels, developed early signs of SANS (Laurie et al. 2019). These subjects also exhibited other “hits” in Zwart and Smith’s multiple hit model of SANS, including B vitamin status and genotype for 1-carbon metabolism genes (Zwart et al. 2019). Thus, it is important to examine whether elevated CO2 impacts clearance through the brain’s glymphatic system, providing a potential mechanism through which elevated CO2 might be associated with SANS. Therefore, in the current directed project, we are conducting a dose-response investigation of whether and how CO2 levels impact contrast clearance through the brain’s glympatic system. Preliminary results show clearance of injected contrast through to various brain and optic regions over a period of six hours in ambient air.

References

Iliff, J. J., M. Wang, Y. Liao, B. A. Plogg and W. Peng (2012). "A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid ß." Sci Transl Med 4: 147ra111.

Iliff, J. J., H. Lee and M. Yu (2013). "Brain-wide pathway for waste clearance captured by contrast- enhanced MRI." J Clin Invest 123: 1299-1309.

de Leon, M. J., Y. Li and N. Okamura (2017). "Cerebrospinal fluid clearance in Alzheimer disease measured with dynamic PET." J Nucl Med 58: 1471-1476.

Ringstad, G., S. A. S. Vatnehol and P. K. Eide (2017). "Glymphatic MRI in idiopathic normal pressure hydrocephalus." Brain 140: 2691-2705.

Aspelund, A., S. Antila, S. T. Proulx, T. V. Karlsen, S. Karaman, M. Detmar, H. Wiig and K. Alitalo (2015). "A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules." J Exp Med 212: 991-999.

Louveau, A., I. Smirnov, T. J. Keyes, J. D. Eccles, S. J. Rouhani, J. D. Peske, N. C. Derecki, D. Castle, J. W. Mandell, K. S. Lee, T. H. Harris and J. Kipnis (2015). "Structural and functional features of central nervous system lymphatic vessels." Nature 523: 337-341.

Absinta, M., S. K. Ha and G. Nair (2017). "Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI." Elife 6: e29738.

Xie, L., H. Kang, Q. Xu, M. J. Chen, Y. Liao, M. Thiyagarajan, J. O’Donnell, D. J. Christensen, C. Nicholson, J. J. Iliff, T. Takano, R. Deane and M. Nedergaard (2013). "Sleep drives metabolite clearance from the adult brain." Science 342: 373-377.

Laurie, S., Macias, BR, Dunn, JT, Young, M, Stern, C, Lee, SM, & Stenger, MB (2019). "Optic disc edema after 30 days of strict head-down tilt bed rest." Ophthalmology 126(3): 467-468.

Zwart, S., Laurie, SS, Chen, JJ, Macias, BR, Lee, SMC, Stenger, M, Grantham, B, Carey, K, Young, M, & Smith, SM (2019). "Association of genetics and B vitamin status with the magnitude of optic disc edema during 30-day strict head-down tilt bed rest." JAMA Ophthalmol 137(10):1195–1200.

Research Impact/Earth Benefits: This research will examine brain function under various levels of CO2, providing data on the impact of hypercapnic environments on the timeline for clearance of waste through the brain.

Task Progress & Bibliography Information FY2023 
Task Progress: Wostyn et al. have proposed that impaired waste clearance from the brain and eye ocular contributes to Spaceflight Associated Neuro-ocular Syndrome (SANS) (cf. (Wostyn 2018)). Moreover, the enclosed environment of the International Space Station (ISS) results in elevated CO2 levels in comparison to ambient air on Earth, which is linked to a greater incidence of headaches in the crew (Law 2014). Research with rodent models has shown that elevated CO2 impairs brain waste clearance (Goodman 2020). Moreover, a human neuroimaging study reports that brain structures involved in waste clearance are enlarged when people breathe elevated CO2 (Zong 2020). Thus, it is essential to examine whether elevated CO2 impacts clearance through the brain’s waste system, providing a potential mechanism through which elevated CO2 might be associated with SANS. Therefore, in the current directed project, we will conduct a dose-response investigation of whether and how CO2 levels impact brain waste clearance.

Specific Aims: Aim 1: Characterize the dose-response effect of elevated CO2 on clearance of gadolinium contrast into the human brain's glymphatic system over a period of approximately 24 hours. We hypothesize that increasing CO2 across three dose levels (1.0%, 1.5%, and 2.0%) will slow contrast clearance in a linear dose-response fashion.

Aim 2: Assess changes in brain-derived stress biomarkers in the blood that correlate with neurological changes in response to elevated CO2. We hypothesize that increasing CO2 will lead to an increase in biomarkers in peripheral blood in a dose-response fashion. Moreover, we predict that individual differences in these biomarkers will be associated with individual differences in glymphatic clearance rates.

Aim 3: Evaluate neurobehavioral responses in response to elevated CO2. We hypothesize that elevated CO2 will lead to deficits in neurobehavioral function in a dose-response fashion. Moreover, we predict that individual differences in these responses will be associated with individual differences in glymphatic clearance rates.

We completed this study with MRI at 90 and 360 minutes after intravenous gadolinium injection. Delayed brain and ocular signal enhancement is thought to reflect waste clearance. We found some structures that showed higher signal enhancement and others that showed less signal enhancement when participants breathed elevated CO2 relative to ambient air.

Bibliography: Description: (Last Updated: 01/24/2024) 

Show Cumulative Bibliography
 
Articles in Peer-reviewed Journals Richmond SB, Rane S, Hanson MR, Albayram M, Iliff JJ, Kernagis D, Rosenberg JT, Seidler RD. "Quantification approaches for magnetic resonance imaging following intravenous gadolinium injection: A window into brain-wide glymphatic function." Eur J Neurosci. 2023 May;57(10):1689-1704. https://doi.org/10.1111/ejn.15974 ; PubMed PMID: 36965006 , May-2023
Back to Search Results    
Project Title:  Bed Rest Combined with 0.5% CO2 as a Spaceflight Analog to Study Neurocognitive Changes: Extent, Longevity, and Neural Bases Reduce
Fiscal Year: FY 2022 
Division: Human Research 
Research Discipline/Element:
HRP HFBP:Human Factors & Behavioral Performance (IRP Rev H)
 Start Date: 06/29/2017  
End Date: 06/30/2023  
Task Last Updated: 04/27/2022 		 Download report in PDF pdf
Principal Investigator/Affiliation:   Seidler, Rachael D. Ph.D. / University of Florida 
Address:  Applied Physiology & Kinesiology 
FLG 142, P.O. Box 118205 
Gainesville , FL 32611-8205 		 Email: rachaelseidler@ufl.edu 
Phone: 352-294-1722  
Congressional District: 3 
Web:  
 Organization Type: UNIVERSITY 
Organization Name: University of Florida 
Joint Agency:  
Comments: NOTE: PI moved to University of Florida in July 2017; previous affiliation was University of Michigan.  
Co-Investigator(s)
Affiliation: 
Bloomberg, Jacob  Ph.D. NASA Johnson Space Center 
Mulavara, Ajitkumar  Ph.D. Universities Space Research Association 
Kuehn, Simone  Ph.D. Max Planck Institute for Human Development 
Stahn, Alexander  Ph.D. University of Pennsylvania 
Roberts, Donna  M.D. Medical University of South Carolina 
Kernagis, Dawn  Ph.D. University of North Carolina 
Key Personnel Changes / Previous PI: April 2021 report: For the augmentation study. Dr. Dawn Kernagis of University of North Carolina is a co investigator.
Project Information: Grant/Contract No. 80NSSC17K0021 
Responsible Center: NASA JSC 
Grant Monitor: Whitmire, Alexandra  
Center Contact:  
alexandra.m.whitmire@nasa.gov 
Unique ID: 11455  		Solicitation / Funding Source: 2014-15 HERO NNJ14ZSA001N-MIXEDTOPICS. Appendix E: Behavioral Health & Human Health Countermeasures Topics 
Grant/Contract No.: 80NSSC17K0021 
Project Type: GROUND 
Flight Program:  
TechPort: No  		No. of Post Docs: 3 
No. of PhD Candidates: 4 
No. of Master's Candidates:  
No. of Bachelor's Candidates:   		No. of PhD Degrees:  
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) HFBP:Human Factors & Behavioral Performance (IRP Rev H)
Human Research Program Risks: (1) BMed:Risk of Adverse Cognitive or Behavioral Conditions and Psychiatric Disorders
(2) Sensorimotor:Risk of Altered Sensorimotor/Vestibular Function Impacting Critical Mission Tasks
Human Research Program Gaps: (1) BMed-101:We need to identify, quantify, and validate the key selection factors for astronaut cognitive and behavioral strengths (e.g., resiliency) and operationally-relevant performance threats for increasingly Earth independent, long-duration, autonomous, and/or long-distance exploration missions.
(2) BMed-108:Given each crewmember will experience multiple spaceflight hazards simultaneously, we need to identify and characterize the potential additive, antagonistic, or synergistic impacts of multiple stressors (e.g., space radiation, altered gravity, isolation, altered immune, altered sleep) on crew health and/or CNS/ cognitive functioning to develop threshold limits and validate countermeasures for any identified adverse crew health and/or operationally-relevant performance outcomes.
(3) SM-104:Evaluate how weightlessness-induced changes in sensorimotor/vestibular function relate to and/or interact with changes in other brain functions (sleep, cognition, attention).
Flight Assignment/Project Notes: NOTE: End date changed to 6/30/2023 per NSSC information (Ed., 2/20/23)

NOTE: End date changed to 1/1/2023 per L. Barnes-Moten/JSC (Ed., 1/12/22)

NOTE: Changed end date to 1/01/2022 per NSSC information (Ed., 3/12/21)

NOTE: Changed end date to 1/01/2021 per L. Juliette/HRP (Ed., 2/19/2020)

NOTE: Changed end date to 12/28/2019 per NSSC information (Ed., 10/9/19)

Task Description: This original project is currently in no-cost extension, and a directed study is being performed, “Dose-Response Relationship of CO2 and Glymphatic Function.” This Annual Report covers the directed study only, as a final report has been previously submitted for the original project. Recent characterizations of glymphatic and meningeal lymphatic systems in rodents and in humans has resulted in a re-evaluation of the anatomical routes for cerebrospinal fluid (CSF) and interstitial fluid flow, as well as the physiological roles for these pathways in central nervous system (CNS) health. Information on the brain glial lymphatic, or ‘glymphatic’ pathway in humans was published in just the past two years, and described in mice in 2012 (Iliff et al. 2012, Iliff et al. 2013, de Leon et al. 2017, Ringstad et al. 2017). A bona fide lymphatic vasculature lining dural sinuses and meninges was first described in mice in 2015, and 2017 in humans (Aspelund et al. 2015, Louveau et al. 2015, Absinta et al. 2017). Fundamentally, research is needed to confirm whether specific factors driving this flow in rodents also apply to humans. These questions have direct relevance to NASA mission operations because, in addition to changing in response to irregular sleep patterns, it has been hypothesized that changes in cerebral blood flow (CBF) and molecular signaling in response to exercise, hypo/hyperoxia, and hypo/hypercarbia can have a significant impact on glymphatic function (Xie et al. 2013). No data currently exist specific to glymphatic responses from hypercapnia in humans or in mice. It is compelling, however, that nearly half of the subjects participating in a recent head down tilt bed rest campaign (“VaPER”), which combined 30 days of bed rest with 0.5% CO2 levels, developed early signs of SANS (Laurie et al. 2019). These subjects also exhibited other “hits” in Zwart and Smith’s multiple hit model of SANS, including B vitamin status and genotype for 1-carbon metabolism genes (Zwart et al. 2019). Thus, it is important to examine whether elevated CO2 impacts clearance through the brain’s glymphatic system, providing a potential mechanism through which elevated CO2 might be associated with SANS. Therefore, in the current directed project, we are conducting a dose-response investigation of whether and how CO2 levels impact contrast clearance through the brain’s glympatic system. Preliminary results show clearance of injected contrast through to various brain and optic regions over a period of six hours in ambient air.

References

Iliff, J. J., M. Wang, Y. Liao, B. A. Plogg and W. Peng (2012). "A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid ß." Sci Transl Med 4: 147ra111.

Iliff, J. J., H. Lee and M. Yu (2013). "Brain-wide pathway for waste clearance captured by contrast- enhanced MRI." J Clin Invest 123: 1299-1309.

de Leon, M. J., Y. Li and N. Okamura (2017). "Cerebrospinal fluid clearance in Alzheimer disease measured with dynamic PET." J Nucl Med 58: 1471-1476.

Ringstad, G., S. A. S. Vatnehol and P. K. Eide (2017). "Glymphatic MRI in idiopathic normal pressure hydrocephalus." Brain 140: 2691-2705.

Aspelund, A., S. Antila, S. T. Proulx, T. V. Karlsen, S. Karaman, M. Detmar, H. Wiig and K. Alitalo (2015). "A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules." J Exp Med 212: 991-999.

Louveau, A., I. Smirnov, T. J. Keyes, J. D. Eccles, S. J. Rouhani, J. D. Peske, N. C. Derecki, D. Castle, J. W. Mandell, K. S. Lee, T. H. Harris and J. Kipnis (2015). "Structural and functional features of central nervous system lymphatic vessels." Nature 523: 337-341.

Absinta, M., S. K. Ha and G. Nair (2017). "Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI." Elife 6: e29738.

Xie, L., H. Kang, Q. Xu, M. J. Chen, Y. Liao, M. Thiyagarajan, J. O’Donnell, D. J. Christensen, C. Nicholson, J. J. Iliff, T. Takano, R. Deane and M. Nedergaard (2013). "Sleep drives metabolite clearance from the adult brain." Science 342: 373-377.

Laurie, S., Macias, BR, Dunn, JT, Young, M, Stern, C, Lee, SM, & Stenger, MB (2019). "Optic disc edema after 30 days of strict head-down tilt bed rest." Ophthalmology 126(3): 467-468.

Zwart, S., Laurie, SS, Chen, JJ, Macias, BR, Lee, SMC, Stenger, M, Grantham, B, Carey, K, Young, M, & Smith, SM (2019). "Association of genetics and B vitamin status with the magnitude of optic disc edema during 30-day strict head-down tilt bed rest." JAMA Ophthalmol 137(10):1195–1200.

Research Impact/Earth Benefits: This research will examine brain function under various levels of CO2, providing data on the impact of hypercapnic environments on the timeline for clearance of waste through the brain.

Task Progress & Bibliography Information FY2022 
Task Progress: We are completing the aims listed below. A manuscript reporting our preliminary findings is currently under review.

We propose a coordinated, multi-institution program to characterize glymphatic and neurobehavioral function in response to risks associated with working and living in space. Human subjects’ data collection will be completed at the University of Florida site.

Specific Aims: Aim 1: Characterize the dose-response effect of elevated CO2 on clearance of gadolinium contrast into the human brain glymphatic system over a period of approximately 24 hours. We hypothesize that increasing CO2 from 2 mmHg (2,500 ppm) to 3 mmHg (~4,000 ppm) and 4 mmHg (~6,600 ppm) will slow contrast clearance in a linear dose-response fashion.

Our glymphatic MR imaging approach parallels techniques used successfully in other studies (Absinta, Ha et al. 2017, Deike-Hofmann 2019). We will acquire MR images (T1-SPACE, 3D MPRAGE and T2-Flair with high in-plane resolution) immediately before and one hour after intravenous injection of a standard gadolinium contrast agent (gadobutrol). We will scan subjects at an additional two time points, approximately three and eight hours after contrast administration. The exact timing of these additional scans will be determined via pilot testing, funded by our Office of Naval Research grant, to identify the timeline for peak distribution of gadolinium into the brain’s lymphatic vessels and the ventricles, perineural space of the optic nerve, and aqueous chamber of the eye (Deike-Hofmann 2019). Participants will complete four MRI scans breathing ambient air or one of three elevated CO2 levels.

Aim 2: Assess changes in brain-derived stress biomarkers in the blood that correlate with neurological changes in response to elevated CO2. We hypothesize that increasing CO2 will lead to an increase in biomarkers in peripheral blood in a dose-response fashion. Moreover, we predict that individual differences in these biomarkers will associate with individual differences in glymphatic clearance rates.

Aim 3: Evaluate neurobehavioral responses in response to elevated CO2. We hypothesize that elevated CO2 will lead to deficits in neurobehavioral function in a dose-response fashion. Moreover, we predict that individual differences in these responses will associate with individual differences in glymphatic clearance rates.

References:

Absinta, M., S. K. Ha and G. Nair (2017). "Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI." Elife 6: e29738.

Deike-Hofmann, K., Reuter, J, Haase, R, Paech, D, Gnirs, R, Bickelhaupt, S, Forsting, M, Heubel, CP,Schlemmer, H-P, Radbruch, A (2019). "Glymphatic pathway of gadolinium-based contrast agents through the brain: overlooked and misinterpreted." Invest Radiol 54: 229-237.

Bibliography: Description: (Last Updated: 01/24/2024) 

Show Cumulative Bibliography
 
Abstracts for Journals and Proceedings Richmond S, Hupfeld KE, McGregor H, Schwartz D, Luther M, Beltran N, Kofman I, De Dios Y, Riascos R, Wood S, Bloomberg J, Silbert L, Iliff J, Seidler R, Piantino J. "Effects of spaceflight and analog environments on perivascular morphology." 2022 NASA Human Research Program Investigators’ Workshop, Virtual, February 7-10, 2022.

Abstracts. 2022 NASA Human Research Program Investigators’ Workshop, Virtual, February 7-10, 2022. , Feb-2022

Abstracts for Journals and Proceedings Richmond S, Levendovszky S, Ramclam R, Kernagis D, Albayram M, Rosenberg J, Iliff J, Seidler R. "Glymphatic function in extreme environments. Poster presentation at the 2022 NASA Human Research Program Investigators' Workshop." 2022 NASA Human Research Program Investigators’ Workshop, Virtual, February 7-10, 2022.

Abstracts. 2022 NASA Human Research Program Investigators’ Workshop, Virtual, February 7-10, 2022. , Feb-2022

Back to Search Results    
Project Title:  Bed Rest Combined with 0.5% CO2 as a Spaceflight Analog to Study Neurocognitive Changes: Extent, Longevity, and Neural Bases Reduce
Fiscal Year: FY 2021 
Division: Human Research 
Research Discipline/Element:
HRP HFBP:Human Factors & Behavioral Performance (IRP Rev H)
 Start Date: 06/29/2017  
End Date: 01/01/2023  
Task Last Updated: 04/25/2021 		 Download report in PDF pdf
Principal Investigator/Affiliation:   Seidler, Rachael D. Ph.D. / University of Florida 
Address:  Applied Physiology & Kinesiology 
FLG 142, P.O. Box 118205 
Gainesville , FL 32611-8205 		 Email: rachaelseidler@ufl.edu 
Phone: 352-294-1722  
Congressional District: 3 
Web:  
 Organization Type: UNIVERSITY 
Organization Name: University of Florida 
Joint Agency:  
Comments: NOTE: PI moved to University of Florida in July 2017; previous affiliation was University of Michigan.  
Co-Investigator(s)
Affiliation: 
Bloomberg, Jacob  Ph.D. NASA Johnson Space Center 
Mulavara, Ajitkumar  Ph.D. Universities Space Research Association 
Kuehn, Simone  Ph.D. Max Planck Institute for Human Development 
Stahn, Alexander  Ph.D. University of Pennsylvania 
Roberts, Donna  M.D. Medical University of South Carolina 
Kernagis, Dawn  Ph.D. University of North Carolina 
Key Personnel Changes / Previous PI: April 2021 report: For the augmentation study. Dr. Dawn Kernagis of University of North Carolina is a co investigator.
Project Information: Grant/Contract No. 80NSSC17K0021 
Responsible Center: NASA JSC 
Grant Monitor: Whitmire, Alexandra  
Center Contact:  
alexandra.m.whitmire@nasa.gov 
Unique ID: 11455  		Solicitation / Funding Source: 2014-15 HERO NNJ14ZSA001N-MIXEDTOPICS. Appendix E: Behavioral Health & Human Health Countermeasures Topics 
Grant/Contract No.: 80NSSC17K0021 
Project Type: GROUND 
Flight Program:  
TechPort: No  		No. of Post Docs: 3 
No. of PhD Candidates: 4 
No. of Master's Candidates:  
No. of Bachelor's Candidates:   		No. of PhD Degrees:  
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) HFBP:Human Factors & Behavioral Performance (IRP Rev H)
Human Research Program Risks: (1) BMed:Risk of Adverse Cognitive or Behavioral Conditions and Psychiatric Disorders
(2) Sensorimotor:Risk of Altered Sensorimotor/Vestibular Function Impacting Critical Mission Tasks
Human Research Program Gaps: (1) BMed-101:We need to identify, quantify, and validate the key selection factors for astronaut cognitive and behavioral strengths (e.g., resiliency) and operationally-relevant performance threats for increasingly Earth independent, long-duration, autonomous, and/or long-distance exploration missions.
(2) BMed-108:Given each crewmember will experience multiple spaceflight hazards simultaneously, we need to identify and characterize the potential additive, antagonistic, or synergistic impacts of multiple stressors (e.g., space radiation, altered gravity, isolation, altered immune, altered sleep) on crew health and/or CNS/ cognitive functioning to develop threshold limits and validate countermeasures for any identified adverse crew health and/or operationally-relevant performance outcomes.
(3) SM-104:Evaluate how weightlessness-induced changes in sensorimotor/vestibular function relate to and/or interact with changes in other brain functions (sleep, cognition, attention).
Flight Assignment/Project Notes: NOTE: End date is now 1/1/2023 per L. Barnes-Moten/JSC (Ed., 1/12/22)

NOTE: Changed end date to 1/01/2022 per NSSC information (Ed., 3/12/21)

NOTE: Changed end date to 1/01/2021 per L. Juliette/HRP (Ed., 2/19/2020)

NOTE: Changed end date to 12/28/2019 per NSSC information (Ed., 10/9/19)

Task Description: This original project is currently in no-cost extension, and a directed study is being performed, “Dose-Response Relationship of CO2 and Glymphatic Function.” This Annual Report covers the directed study only, as a final report has been previously submitted for the original project. Recent characterizations of glymphatic and meningeal lymphatic systems in rodents and in humans has resulted in a re-evaluation of the anatomical routes for cerebrospinal fluid (CSF) and interstitial fluid flow, as well as the physiological roles for these pathways in central nervous system (CNS) health. Information on the brain glial lymphatic, or ‘glymphatic’ pathway in humans was published in just the past two years, and described in mice in 2012 (Iliff et al. 2012, Iliff et al. 2013, de Leon et al. 2017, Ringstad et al. 2017). A bona fide lymphatic vasculature lining dural sinuses and meninges was first described in mice in 2015, and 2017 in humans (Aspelund et al. 2015, Louveau et al. 2015, Absinta et al. 2017). Fundamentally, research is needed to confirm whether specific factors driving this flow in rodents also apply to humans. These questions have direct relevance to NASA mission operations because, in addition to changing in response to irregular sleep patterns, it has been hypothesized that changes in cerebral blood flow (CBF) and molecular signaling in response to exercise, hypo/hyperoxia, and hypo/hypercarbia can have a significant impact on glymphatic function (Xie et al. 2013). No data currently exist specific to glymphatic responses from hypercapnia in humans or in mice. It is compelling, however, that nearly half of the subjects participating in a recent head down tilt bed rest campaign (“VaPER”), which combined 30 days of bed rest with 0.5% CO2 levels, developed early signs of SANS (Laurie et al. 2019). These subjects also exhibited other “hits” in Zwart and Smith’s multiple hit model of SANS, including B vitamin status and genotype for 1-carbon metabolism genes (Zwart et al. 2019). Thus, it is important to examine whether elevated CO2 impacts clearance through the brain’s glymphatic system, providing a potential mechanism through which elevated CO2 might be associated with SANS. Therefore, in the current directed project, we are conducting a dose-response investigation of whether and how CO2 levels impact contrast clearance through the brain’s glympatic system. Preliminary results show clearance of injected contrast through to various brain and optic regions over a period of six hours in ambient air.

References

Iliff, J. J., M. Wang, Y. Liao, B. A. Plogg and W. Peng (2012). "A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid ß." Sci Transl Med 4: 147ra111.

Iliff, J. J., H. Lee and M. Yu (2013). "Brain-wide pathway for waste clearance captured by contrast- enhanced MRI." J Clin Invest 123: 1299-1309.

de Leon, M. J., Y. Li and N. Okamura (2017). "Cerebrospinal fluid clearance in Alzheimer disease measured with dynamic PET." J Nucl Med 58: 1471-1476.

Ringstad, G., S. A. S. Vatnehol and P. K. Eide (2017). "Glymphatic MRI in idiopathic normal pressure hydrocephalus." Brain 140: 2691-2705.

Aspelund, A., S. Antila, S. T. Proulx, T. V. Karlsen, S. Karaman, M. Detmar, H. Wiig and K. Alitalo (2015). "A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules." J Exp Med 212: 991-999.

Louveau, A., I. Smirnov, T. J. Keyes, J. D. Eccles, S. J. Rouhani, J. D. Peske, N. C. Derecki, D. Castle, J. W. Mandell, K. S. Lee, T. H. Harris and J. Kipnis (2015). "Structural and functional features of central nervous system lymphatic vessels." Nature 523: 337-341.

Absinta, M., S. K. Ha and G. Nair (2017). "Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI." Elife 6: e29738.

Xie, L., H. Kang, Q. Xu, M. J. Chen, Y. Liao, M. Thiyagarajan, J. O’Donnell, D. J. Christensen, C. Nicholson, J. J. Iliff, T. Takano, R. Deane and M. Nedergaard (2013). "Sleep drives metabolite clearance from the adult brain." Science 342: 373-377.

Laurie, S., Macias, BR, Dunn, JT, Young, M, Stern, C, Lee, SM, & Stenger, MB (2019). "Optic disc edema after 30 days of strict head-down tilt bed rest." Ophthalmology 126(3): 467-468.

Zwart, S., Laurie, SS, Chen, JJ, Macias, BR, Lee, SMC, Stenger, M, Grantham, B, Carey, K, Young, M, & Smith, SM (2019). "Association of genetics and B vitamin status with the magnitude of optic disc edema during 30-day strict head-down tilt bed rest." JAMA Ophthalmol 137(10):1195–1200.

Research Impact/Earth Benefits: This research will examine brain function under various levels of CO2, providing data on the impact of hypercapnic environments on the timeline for clearance of waste through the brain.

Task Progress & Bibliography Information FY2021 
Task Progress: To date, we have had eight participants in the study, all tested under ambient or normal air conditions. This was to help us better define the required scanning timeline for the CO2 portion of the study. Participants came to the MRI center and were administered gadobutrol via intravenous injection. They remained supine throughout the day, with the exception of getting in and out of the MR scanner and using the restroom. We scanned participants prior to injection and at several timepoints throughout the day. We administered multiple structural MRI sequences. Throughout the MRI visit, we are monitoring participant vital signs, including heart rate, blood pressure, respiration, and blood oxygen saturation to ensure subject safety after contrast injection.

Our results illustrate increases in signal intensity as contrast disburses throughout the brain over the day, including into the dura and other regions.

Bibliography: Description: (Last Updated: 01/24/2024) 

Show Cumulative Bibliography
 
Abstracts for Journals and Proceedings Hanson MR, Richmond SB, Kernagis DN, Rosenberg JT, Albayram MS, Rane SD, Iliff JJ, Seidler RD. "Taking Out the Trash: The Time Course of IV Gadolinium-Based Contrast Agent Through the Glymphatic System in Humans." Lightning Talk Presentation, Society for Neuroscience (North-Central Florida) Regional Meeting, Virtual Format (2021).

Lightning Talk Presentation, Society for Neuroscience (North-Central Florida) Regional Meeting, Virtual Format (2021). , Mar-2021

Abstracts for Journals and Proceedings Richmond SB, Hanson MR, Kernagis DN, Rosenberg JT, Iliff JJ, Seidler RD. "Effects of Hypercapnic Environments on Glymphatic Function." Poster / Lightning Talk Presentation, 2021 NASA Human Research Program Investigators’ Workshop, Virtual, February 1-4, 2021.

HRP IWS abstract booklet. 2021 NASA Human Research Program Investigators’ Workshop, Virtual, February 1-4, 2021. , Feb-2021

Articles in Peer-reviewed Journals Hupfeld KE, McGregor HR, Reuter-Lorenz PA, Seidler RD. "Microgravity effects on the human brain and behavior: dysfunction and adaptive plasticity." Neurosci Biobehav Rev. 2021 Mar;122:176-89. Review. https://doi.org/10.1016/j.neubiorev.2020.11.017 ; PMID: 33454290 , Mar-2021
Articles in Peer-reviewed Journals Salazar AP, Hupfeld KE, Lee JK, Beltran NE, Kofman IS, De Dios YE, Mulder E, Bloomberg JJ, Mulavara AP, Seidler RD. "Neural working memory changes during a spaceflight analog with elevated carbon dioxide: A pilot study." Front Syst Neurosci. 2020 Jul 28;14:48. https://doi.org/10.3389/fnsys.2020.00048 ; PMID: 32848641; PMCID: PMC7399639 , Jul-2020
Articles in Peer-reviewed Journals McGregor HR, Lee JK, Mulder ER, De Dios YE, Beltran NE, Kofman IS, Bloomberg JJ, Mulavara AP, Seidler RD. "Brain connectivity and behavioral changes in a spaceflight analog environment with elevated CO2." Neuroimage. 2021 Jan 15;225:117450. https://doi.org/10.1016/j.neuroimage.2020.117450 ; PMID: 33075558 , Jan-2021
Articles in Peer-reviewed Journals Banker LA, Salazar AP, Lee JK, Beltran NE, Kofman IS, De Dios YE, Mulder E, Bloomberg JJ, Mulavara AP, Seidler RD. "The effects of a spaceflight analog with elevated CO2 on sensorimotor adaptation." J Neurophysiol. 2021 Feb 1;125(2):426-36. https://doi.org/10.1152/jn.00306.2020 ; PMID: 33296611 , Feb-2021
Articles in Peer-reviewed Journals McGregor HR, Lee JK, Mulder ER, De Dios YE, Beltran NE, Kofman IS, Bloomberg JJ, Mulavara AP, Smith SM, Zwart SR, Seidler RD. "Ophthalmic changes in a spaceflight analog are associated with brain functional reorganization." Hum Brain Mapp. 2021 Sep;42(13):4281-97. https://doi.org/10.1002/hbm.25546 ; PMID: 34105833; PMCID: PMC8357001 , Sep-2021
Articles in Peer-reviewed Journals Salazar AP, Hupfeld KE, Lee JK, Banker LA, Tays GD, Beltran NE, Kofman IS, De Dios YE, Mulder E, Bloomberg JJ, Mulavara AP, Seidler RD. "Visuomotor adaptation brain changes during a spaceflight analog with elevated carbon dioxide (CO2): A pilot study." Front Neural Circuits. 2021 Jun 7;15:659557. https://doi.org/10.3389/fncir.2021.659557 ; PMID: 34163332; PMCID: PMC8215599 , Jun-2021
Articles in Peer-reviewed Journals Lee JK, Koppelmans V, Pasternak O, Beltran NE, Kofman IS, De Dios YE, Mulder ER, Mulavara AP, Bloomberg JJ, Seidler RD. "Effects of spaceflight stressors on brain volume, microstructure, and intracranial fluid distribution." Cereb Cortex Commun. 2021 Mar 30;2(2):tgab022. https://doi.org/10.1093/texcom/tgab022 ; PMID: 34296167; PMCID: PMC8152913 , Mar-2021
Back to Search Results    
Project Title:  Bed Rest Combined with 0.5% CO2 as a Spaceflight Analog to Study Neurocognitive Changes: Extent, Longevity, and Neural Bases Reduce
Fiscal Year: FY 2020 
Division: Human Research 
Research Discipline/Element:
HRP HFBP:Human Factors & Behavioral Performance (IRP Rev H)
 Start Date: 06/29/2017  
End Date: 01/01/2023  
Task Last Updated: 04/22/2020 		 Download report in PDF pdf
Principal Investigator/Affiliation:   Seidler, Rachael D. Ph.D. / University of Florida 
Address:  Applied Physiology & Kinesiology 
FLG 142, P.O. Box 118205 
Gainesville , FL 32611-8205 		 Email: rachaelseidler@ufl.edu 
Phone: 352-294-1722  
Congressional District: 3 
Web:  
 Organization Type: UNIVERSITY 
Organization Name: University of Florida 
Joint Agency:  
Comments: NOTE: PI moved to University of Florida in July 2017; previous affiliation was University of Michigan.  
Co-Investigator(s)
Affiliation: 
Bloomberg, Jacob  Ph.D. NASA Johnson Space Center 
Mulavara, Ajitkumar  Ph.D. Universities Space Research Association 
Kuehn, Simone  Ph.D. Max Planck Institute for Human Development 
Stahn, Alexander  Ph.D. University of Pennsylvania 
Roberts, Donna  M.D. Medical University of South Carolina 
Key Personnel Changes / Previous PI: April 2020 report: Dr. Donna Roberts, Medical University of South Carolina, had a project added on to our VaPER study in which she collected MRI perfusion scans on the same subjects at the same time points and is CoInvestigator during this time.
Project Information: Grant/Contract No. 80NSSC17K0021 
Responsible Center: NASA JSC 
Grant Monitor: Williams, Thomas  
Center Contact: 281-483-8773 
thomas.j.will1@nasa.gov 
Unique ID: 11455  		Solicitation / Funding Source: 2014-15 HERO NNJ14ZSA001N-MIXEDTOPICS. Appendix E: Behavioral Health & Human Health Countermeasures Topics 
Grant/Contract No.: 80NSSC17K0021 
Project Type: GROUND 
Flight Program:  
TechPort: No  		No. of Post Docs: 2 
No. of PhD Candidates: 3 
No. of Master's Candidates:  
No. of Bachelor's Candidates:   		No. of PhD Degrees:  
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) HFBP:Human Factors & Behavioral Performance (IRP Rev H)
Human Research Program Risks: (1) BMed:Risk of Adverse Cognitive or Behavioral Conditions and Psychiatric Disorders
(2) Sensorimotor:Risk of Altered Sensorimotor/Vestibular Function Impacting Critical Mission Tasks
Human Research Program Gaps: (1) BMed-101:We need to identify, quantify, and validate the key selection factors for astronaut cognitive and behavioral strengths (e.g., resiliency) and operationally-relevant performance threats for increasingly Earth independent, long-duration, autonomous, and/or long-distance exploration missions.
(2) BMed-108:Given each crewmember will experience multiple spaceflight hazards simultaneously, we need to identify and characterize the potential additive, antagonistic, or synergistic impacts of multiple stressors (e.g., space radiation, altered gravity, isolation, altered immune, altered sleep) on crew health and/or CNS/ cognitive functioning to develop threshold limits and validate countermeasures for any identified adverse crew health and/or operationally-relevant performance outcomes.
(3) SM-104:Evaluate how weightlessness-induced changes in sensorimotor/vestibular function relate to and/or interact with changes in other brain functions (sleep, cognition, attention).
Flight Assignment/Project Notes: NOTE: Changed end date to 1/01/2023 per JSC-SA Grant Technical Officer (Ed., 2/23/22)

NOTE: Changed end date to 1/01/2022 per NSSC information (Ed., 3/12/21)

NOTE: Changed end date to 1/01/2021 per L. Juliette/HRP (Ed., 2/19/2020)

NOTE: Changed end date to 12/28/2019 per NSSC information (Ed., 10/9/19)

Task Description: NRA NNJ14ZSA001N-MIXEDTOPICS requests proposals in the area of “Risk Characterization and Monitoring of Behavioral Health and Performance Relevant Outcomes” to determine the effects of 30 days head down tilt bed rest in a 0.5% CO2 environment on neurobehavioral signs and symptoms, neurostructural and neurofunctional alterations, and changes in cognitive function and operational task performance. Our Neuromapping studies measure precisely these metrics in a flight study and a 70 days head down tilt bed rest study under normative conditions. Here, our overarching goal is to quantify neurocognitive changes and associated neural structural and functional alterations occurring as a result of a 30 days head down tilt bed rest plus 0.5% CO2 environment, serving as a spaceflight analog exposure. We will identify the relationship between these neural changes and behavioral function. Our approach utilizes cutting edge neuroimaging techniques and a broad ranging battery of sensory, motor, and cognitive assessments to investigate neuroplastic and maladaptive brain changes occurring in a spaceflight analog environment. Success in this endeavor would 1) result in identification of the underlying neural mechanisms and operational risks of changes in behavior with a spaceflight analog, and 2) identify whether a return to normative behavioral function following bed rest is associated with a restitution of brain structure and function or instead is supported by substitution with compensatory brain processes. Moreover, addition of a CO2 group will enable us to parse out the multiple mechanisms contributing to any spaceflight induced neural structural and behavioral changes that we observe in our ongoing flight projects ((NASA flight project, Seidler Principal Investigator (PI); ILSRA--International Life Sciences Research Announcement flight study, Stahn PI)), and comparison with our recently completed bed rest projects (Seidler and Stahn, PIs) will allow us to delineate brain and behavioral changes occurring with long term exposure to slightly elevated CO2 levels.

Research Impact/Earth Benefits: This project uses long duration head down tilt bed rest as a spaceflight environment analog. The intervention mimics several aspects of human spaceflight, including a shift of fluids towards the head and unloading of the body. Thus the results are relevant for clinical populations on Earth, including individuals who are bed ridden for extended periods of time. Moreover, the shifts that occur in how the brain weights sensory information show some similarities with age changes in sensory processing. Thus understanding how the brain and behavior change in response to this environment can also shed insight into the aging process on Earth.

Task Progress & Bibliography Information FY2020 
Task Progress: We are currently investigating spaceflight effects on brain structure and function in our ongoing NASA funded project NNX11AR02G “Spaceflight Effects on Neurocognitive Performance: Extent, Longevity, and Neural Bases.” Under the current project "Bed Rest Combined with 0.5% CO2 as a Spaceflight Analog to Study Neurocognitive Changes: Extent, Longevity, and Neural Bases" (NASA 80NSSC17K0021) we collected data with our battery of structural and functional MR brain imaging, cognitive, and operational task metrics at: envihab in a head down tilt bed rest study with elevated ambient CO2 levels. With the current project, we have been able to determine the neural and neurocognitive effects of unloading, reduced sensory inputs, increased cephalic fluid distribution, and 0.5% CO2. The latter was not achieved in our previous bed rest study, but has critical importance as International Space Station crewmembers have exhibited symptoms of CO2 exposure at smaller CO2 levels than what is typically seen in Earth-based studies (Law et al., 2014). Thus, we are able to 1) identify the underlying neural mechanisms and operational risks of spaceflight-induced changes in behavior using a well-established spaceflight analog, and 2) identify whether a return to normative behavioral function following recovery from prolonged bed rest plus 0.5% CO2 exposure is associated with a restitution of brain structure and function or instead is supported by substitution with compensatory brain processes. Longer duration exposure to elevated CO2 levels results in increased cerebral blood flow and mild performance impairments. It is thus very important to examine interactions of CO2 and head down tilt on brain structure, function, and operational behaviors. Space Station crewmembers have exhibited symptoms of CO2 exposure at lower levels than typically occur on Earth (Law et al., 2014). Moreover, addition of a CO2 group will enable us to parse out the multiple mechanisms contributing to any spaceflight induced neural structural and behavioral changes that we observe in our ongoing flight project. We have addressed this with the following project aims:

Aim 1: Identify changes in brain structure, function, and network integrity as a function of 30 days head down tilt bed rest plus 0.5% CO2 and characterize their time course.

Aim 2: Specify relationships between structural and functional brain changes and performance and characterize their time course.

Aim 3: Identify predictors of individual differences in bed rest plus 0.5% CO2 responses.

Data collection for this project was successfully completed at the :enivhab facility in Cologne, Germany, in December 2017 and all data have been transferred. We are finalizing analysis of these data and have already published some manuscripts reporting the results. Interestingly, nearly half of the subjects in this campaign developed signs of Spaceflight Associated Neuro-ocular Syndrome (SANS), which affects approximately half of long duration astronauts. This allowed us the unique opportunity to compare the two subgroups. These analyses comparing SANS and noSANS subjects should be interpreted with caution, however. The overall project enrollment was 11 subjects, which was already below the number for which our experiments were powered. Comparing subgroups with five and six subjects makes generalization of the findings very difficult.

Reference: Law J, Van Baalen M, Foy M, Mason SS, Mendez C, Wear ML, Meyers VE, Alexander D. Relationship between carbon dioxide levels and reported headaches on the International Space Station. J Occup Environ Med. 2014 May;56(5):477-83.

Bibliography: Description: (Last Updated: 01/24/2024) 

Show Cumulative Bibliography
 
Articles in Peer-reviewed Journals Hupfeld KE, Lee JK, Gadd NE, Kofman IS, De Dios YE, Bloomberg JJ, Mulavara AP, Seidler RD. "Neural correlates of vestibular processing during a spaceflight analog with elevated carbon dioxide (CO2): A pilot study." Front Syst Neurosci. 2020 Jan 10;13:80. https://doi.org/10.3389/fnsys.2019.00080 ; PubMed PMID: 31998084; PubMed Central PMCID: PMC6965349 , Jan-2020
Articles in Peer-reviewed Journals Lee JK, De Dios Y, Kofman I, Mulavara AP, Bloomberg JJ, Seidler RD. "Head down tilt bed rest plus elevated CO2 as a spaceflight analog: Effects on cognitive and sensorimotor performance." Front Hum Neurosci. 2019 Oct 17;13:355. eCollection 2019. https://doi.org/10.3389/fnhum.2019.00355 ; PubMed PMID: 31680909; PubMed Central PMCID: PMC6811492 , Oct-2019
Back to Search Results    
Project Title:  Bed Rest Combined with 0.5% CO2 as a Spaceflight Analog to Study Neurocognitive Changes: Extent, Longevity, and Neural Bases Reduce
Fiscal Year: FY 2019 
Division: Human Research 
Research Discipline/Element:
HRP HFBP:Human Factors & Behavioral Performance (IRP Rev H)
 Start Date: 06/29/2017  
End Date: 01/01/2021  
Task Last Updated: 04/30/2019 		 Download report in PDF pdf
Principal Investigator/Affiliation:   Seidler, Rachael D. Ph.D. / University of Florida 
Address:  Applied Physiology & Kinesiology 
FLG 142, P.O. Box 118205 
Gainesville , FL 32611-8205 		 Email: rachaelseidler@ufl.edu 
Phone: 352-294-1722  
Congressional District: 3 
Web:  
 Organization Type: UNIVERSITY 
Organization Name: University of Florida 
Joint Agency:  
Comments: NOTE: PI moved to University of Florida in July 2017; previous affiliation was University of Michigan.  
Co-Investigator(s)
Affiliation: 
Bloomberg, Jacob  Ph.D. NASA Johnson Space Center 
Mulavara, Ajitkumar  Ph.D. Universities Space Research Association 
Kuehn, Simone  Ph.D. Max Planck Institute for Human Development 
Stahn, Alexander  Ph.D. University of Pennsylvania 
Project Information: Grant/Contract No. 80NSSC17K0021 
Responsible Center: NASA JSC 
Grant Monitor: Williams, Thomas  
Center Contact: 281-483-8773 
thomas.j.will1@nasa.gov 
Unique ID: 11455  		Solicitation / Funding Source: 2014-15 HERO NNJ14ZSA001N-MIXEDTOPICS. Appendix E: Behavioral Health & Human Health Countermeasures Topics 
Grant/Contract No.: 80NSSC17K0021 
Project Type: GROUND 
Flight Program:  
TechPort: No  		No. of Post Docs: 2 
No. of PhD Candidates: 2 
No. of Master's Candidates:  
No. of Bachelor's Candidates:   		No. of PhD Degrees:  
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) HFBP:Human Factors & Behavioral Performance (IRP Rev H)
Human Research Program Risks: (1) BMed:Risk of Adverse Cognitive or Behavioral Conditions and Psychiatric Disorders
(2) Sensorimotor:Risk of Altered Sensorimotor/Vestibular Function Impacting Critical Mission Tasks
Human Research Program Gaps: (1) BMed-101:We need to identify, quantify, and validate the key selection factors for astronaut cognitive and behavioral strengths (e.g., resiliency) and operationally-relevant performance threats for increasingly Earth independent, long-duration, autonomous, and/or long-distance exploration missions.
(2) BMed-108:Given each crewmember will experience multiple spaceflight hazards simultaneously, we need to identify and characterize the potential additive, antagonistic, or synergistic impacts of multiple stressors (e.g., space radiation, altered gravity, isolation, altered immune, altered sleep) on crew health and/or CNS/ cognitive functioning to develop threshold limits and validate countermeasures for any identified adverse crew health and/or operationally-relevant performance outcomes.
(3) SM-104:Evaluate how weightlessness-induced changes in sensorimotor/vestibular function relate to and/or interact with changes in other brain functions (sleep, cognition, attention).
Flight Assignment/Project Notes: NOTE: Changed end date to 1/01/2021 per L. Juliette/HRP (Ed., 2/19/2020)

NOTE: Changed end date to 12/28/2019 per NSSC information (Ed., 10/9/19)

Task Description: NRA NNJ14ZSA001N-MIXEDTOPICS requests proposals in the area of “Risk Characterization and Monitoring of Behavioral Health and Performance Relevant Outcomes” to determine the effects of 30 days head down tilt bed rest in a 0.5% CO2 environment on neurobehavioral signs and symptoms, neurostructural and neurofunctional alterations, and changes in cognitive function and operational task performance. Our Neuromapping studies measure precisely these metrics in a flight study and a 70 days head down tilt bed rest study under normative conditions. Here, our overarching goal is to quantify neurocognitive changes and associated neural structural and functional alterations occurring as a result of a 30 days head down tilt bed rest plus 0.5% CO2 environment, serving as a spaceflight analog exposure. We will identify the relationship between these neural changes and behavioral function. Our approach utilizes cutting edge neuroimaging techniques and a broad ranging battery of sensory, motor, and cognitive assessments to investigate neuroplastic and maladaptive brain changes occurring in a spaceflight analog environment. Success in this endeavor would 1) result in identification of the underlying neural mechanisms and operational risks of changes in behavior with a spaceflight analog, and 2) identify whether a return to normative behavioral function following bed rest is associated with a restitution of brain structure and function or instead is supported by substitution with compensatory brain processes. Moreover, addition of a CO2 group will enable us to parse out the multiple mechanisms contributing to any spaceflight induced neural structural and behavioral changes that we observe in our ongoing flight projects ((NASA flight project, Seidler Principal Investigator (PI); ILSRA flight study, Stahn PI)), and comparison with our recently completed bed rest projects (Seidler and Stahn, PIs) will allow us to delineate brain and behavioral changes occurring with long term exposure to slightly elevated CO2 levels.

Research Impact/Earth Benefits: This project uses long duration head down tilt bed rest as a spaceflight environment analog. The intervention mimics several aspects of human spaceflight, including a shift of fluids towards the head and unloading of the body. Thus the results are relevant for clinical populations on Earth, including individuals who are bed ridden for extended periods of time. Moreover, the shifts that occur in how the brain weights sensory information show some similarities with age changes in sensory processing. Thus understanding how the brain and behavior change in response to this environment can also shed insight into the aging process on Earth.

Task Progress & Bibliography Information FY2019 
Task Progress: Data collection for this project was successfully completed at the :enivhab facility in Cologne, Germany, in December 2017 and all data have been transferred. We are in the process of completing data analyses and preparing manuscripts for submission. To date, we have found a facilitation of processing speed and a decrement in functional mobility for subjects undergoing head down bed rest (HDBR) HDBR+CO2 relative to our previous study of HDBR in ambient air. This suggests there may be combinatorial effects of elevated CO2 and the other physiological effects of HDBR including headward fluid shifts and body unloading.

Interestingly, approximately half of the participants in this campaign developed signs of Spaceflight Associated Neuro-Ocular Syndrome (SANS). We found that participants who exhibited signs of SANS became more visually dependent and shifted their speed-accuracy tradeoff, such that they were slower but more accurate than those that did not incur ocular changes. These small subgroup findings suggest that SANS may have an impact on mission relevant performance inflight via sensory reweighting.

In addition, we have found brain changes that occur throughout the HDBR+CO2 intervention, with correlate with pre to post bed rest changes in behavior. For example, we have found that connectivity between sensorimotor and higher-order visual brain areas increases with bed rest; moreover, greater increases were associated with more slowing on a functional mobility test post bed rest.

We also found that subjects who did and did not develop signs of SANS were different at the outset of the study. Subjects who did not develop SANS had strong connectivity within a visual processing network at baseline, whereas those that did, did not have significant connectivity within this network.

We are completing data analyses and preparing several manuscripts for submission.

Bibliography: Description: (Last Updated: 01/24/2024) 

Show Cumulative Bibliography
 
 None in FY 2019
Back to Search Results    
Project Title:  Bed Rest Combined with 0.5% CO2 as a Spaceflight Analog to Study Neurocognitive Changes: Extent, Longevity, and Neural Bases Reduce
Fiscal Year: FY 2018 
Division: Human Research 
Research Discipline/Element:
HRP HFBP:Human Factors & Behavioral Performance (IRP Rev H)
 Start Date: 06/29/2017  
End Date: 06/28/2019  
Task Last Updated: 05/11/2018 		 Download report in PDF pdf
Principal Investigator/Affiliation:   Seidler, Rachael D. Ph.D. / University of Florida 
Address:  Applied Physiology & Kinesiology 
FLG 142, P.O. Box 118205 
Gainesville , FL 32611-8205 		 Email: rachaelseidler@ufl.edu 
Phone: 352-294-1722  
Congressional District: 3 
Web:  
 Organization Type: UNIVERSITY 
Organization Name: University of Florida 
Joint Agency:  
Comments: NOTE: PI moved to University of Florida in July 2017; previous affiliation was University of Michigan.  
Co-Investigator(s)
Affiliation: 
Bloomberg, Jacob  Ph.D. NASA Johnson Space Center 
Mulavara, Ajitkumar  Ph.D. Universities Space Research Association 
Kuehn, Simone  Ph.D. Max Planck Institute for Human Development 
Stahn, Alexander  Ph.D. University of Pennsylvania 
Project Information: Grant/Contract No. 80NSSC17K0021 
Responsible Center: NASA JSC 
Grant Monitor: Williams, Thomas  
Center Contact: 281-483-8773 
thomas.j.will1@nasa.gov 
Unique ID: 11455  		Solicitation / Funding Source: 2014-15 HERO NNJ14ZSA001N-MIXEDTOPICS. Appendix E: Behavioral Health & Human Health Countermeasures Topics 
Grant/Contract No.: 80NSSC17K0021 
Project Type: GROUND 
Flight Program:  
TechPort: No  		No. of Post Docs: 2 
No. of PhD Candidates: 2 
No. of Master's Candidates:  
No. of Bachelor's Candidates:   		No. of PhD Degrees:  
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) HFBP:Human Factors & Behavioral Performance (IRP Rev H)
Human Research Program Risks: (1) BMed:Risk of Adverse Cognitive or Behavioral Conditions and Psychiatric Disorders
(2) Sensorimotor:Risk of Altered Sensorimotor/Vestibular Function Impacting Critical Mission Tasks
Human Research Program Gaps: (1) BMed-101:We need to identify, quantify, and validate the key selection factors for astronaut cognitive and behavioral strengths (e.g., resiliency) and operationally-relevant performance threats for increasingly Earth independent, long-duration, autonomous, and/or long-distance exploration missions.
(2) BMed-108:Given each crewmember will experience multiple spaceflight hazards simultaneously, we need to identify and characterize the potential additive, antagonistic, or synergistic impacts of multiple stressors (e.g., space radiation, altered gravity, isolation, altered immune, altered sleep) on crew health and/or CNS/ cognitive functioning to develop threshold limits and validate countermeasures for any identified adverse crew health and/or operationally-relevant performance outcomes.
(3) SM-104:Evaluate how weightlessness-induced changes in sensorimotor/vestibular function relate to and/or interact with changes in other brain functions (sleep, cognition, attention).
Task Description: NRA NNJ14ZSA001N-MIXEDTOPICS requests proposals in the area of “Risk Characterization and Monitoring of Behavioral Health and Performance Relevant Outcomes” to determine the effects of 30 days head down tilt bed rest in a 0.5% CO2 environment on neurobehavioral signs and symptoms, neurostructural and neurofunctional alterations, and changes in cognitive function and operational task performance. Our Neuromapping studies measure precisely these metrics in a flight study and a 70 days head down tilt bed rest study under normative conditions. Here, our overarching goal is to quantify neurocognitive changes and associated neural structural and functional alterations occurring as a result of a 30 days head down tilt bed rest plus 0.5% CO2 environment, serving as a spaceflight analog exposure. We will identify the relationship between these neural changes and behavioral function. Our approach utilizes cutting edge neuroimaging techniques and a broad ranging battery of sensory, motor, and cognitive assessments to investigate neuroplastic and maladaptive brain changes occurring in a spaceflight analog environment. Success in this endeavor would 1) result in identification of the underlying neural mechanisms and operational risks of changes in behavior with a spaceflight analog, and 2) identify whether a return to normative behavioral function following bed rest is associated with a restitution of brain structure and function or instead is supported by substitution with compensatory brain processes. Moreover, addition of a CO2 group will enable us to parse out the multiple mechanisms contributing to any spaceflight induced neural structural and behavioral changes that we observe in our ongoing flight projects ((NASA flight project, Seidler Principal Investigator (PI); ILSRA flight study, Stahn PI)), and comparison with our recently completed bed rest projects (Seidler and Stahn, PIs) will allow us to delineate brain and behavioral changes occurring with long term exposure to slightly elevated CO2 levels.

Research Impact/Earth Benefits: This project uses long duration head down tilt bed rest as a spaceflight environment analog. The intervention mimics several aspects of human spaceflight, including a shift of fluids towards the head and unloading of the body. Thus the results are relevant for clinical populations on Earth, including individuals who are bed ridden for extended periods of time. Moreover, the shifts that occur in how the brain weights sensory information show some similarities with age changes in sensory processing. Thus understanding how the brain and behavior change in response to this environment can also shed insight into the aging process on Earth.

Task Progress & Bibliography Information FY2018 
Task Progress: Data collection for this project was successfully completed at the :enivhab facility in Cologne, Germany, in December 2017 and all data have been transferred. We are currently analyzing these data. To date, we have some preliminary findings for our behavioral measures and for brain changes when processing vestibular stimuli. Interestingly, a couple of the behavioral measures show improvements in performance for subjects in the bed rest plus CO2 environment, particularly in comparison to subjects who were in our previous bed rest study with ambient air measured over similar timepoints. For example, there was a decrease in cognitive processing speed for participants in our previous bed rest study but an improvement here when bed rest was coupled with 0.5% CO2. This finding parallels reports from the SPACECOT experiment, which was a shorter duration pilot study of bed rest plus elevated CO2. These findings may be linked to the increased respiration rate that is seen in elevated CO2 conditions.

One of the tests that we use to evaluate brain function in our ongoing studies is a functional MRI session coupled with vestibular stimulation. The latter is achieved using a clinical device which we have modified and validated for use in the MRI environment. Typical stimulation with this device results in activation of the vestibular cortex and deactivation of brainstem, cerebellum, somatosensory, and visual cortices. Our preliminary findings with this dataset reveal that frontal, sensorimotor, temporal, and visual cortices show increasing responses to vestibular stimulation during bed rest plus elevated CO2, which dissipate after subjects leave bed rest and return to ambient air conditions. Regions in the brainstem exhibited the opposite pattern, with decreasing responses during bed rest coupled with CO2 followed by recovery. We also statistically compared the slope of brain changes over time in this group with subjects who previously participated in our bed rest study with ambient air. We found that participants who had elevated CO2 in combination with bed rest exhibited greater changes in frontal, somatosensory, and visual cortices than those that experienced bed rest alone. These findings suggest that bed rest plus elevated CO2 may result in reduced neural efficiency and / or greater sensory reweighting than that seen with bed rest alone. We will continue to analyze these data and evaluate brain-behavior change associations.

Bibliography: Description: (Last Updated: 01/24/2024) 

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Project Title:  Bed Rest Combined with 0.5% CO2 as a Spaceflight Analog to Study Neurocognitive Changes: Extent, Longevity, and Neural Bases Reduce
Fiscal Year: FY 2017 
Division: Human Research 
Research Discipline/Element:
HRP HFBP:Human Factors & Behavioral Performance (IRP Rev H)
 Start Date: 06/29/2017  
End Date: 06/28/2019  
Task Last Updated: 01/11/2018 		 Download report in PDF pdf
Principal Investigator/Affiliation:   Seidler, Rachael D. Ph.D. / University of Florida 
Address:  Applied Physiology & Kinesiology 
FLG 142, P.O. Box 118205 
Gainesville , FL 32611-8205 		 Email: rachaelseidler@ufl.edu 
Phone: 352-294-1722  
Congressional District: 3 
Web:  
 Organization Type: UNIVERSITY 
Organization Name: University of Florida 
Joint Agency:  
Comments: NOTE: PI moved to University of Florida in July 2017; previous affiliation was University of Michigan.  
Co-Investigator(s)
Affiliation: 
Bloomberg, Jacob  Ph.D. NASA Johnson Space Center 
Mulavara, Ajitkumar  Ph.D. Universities Space Research Association 
Kuehn, Simone  Ph.D. Max Planck Institute for Human Development 
Stahn, Alexander  Ph.D. University of Pennsylvania 
Project Information: Grant/Contract No. 80NSSC17K0021 
Responsible Center: NASA JSC 
Grant Monitor: Williams, Thomas  
Center Contact: 281-483-8773 
thomas.j.will1@nasa.gov 
Unique ID: 11455  		Solicitation / Funding Source: 2014-15 HERO NNJ14ZSA001N-MIXEDTOPICS. Appendix E: Behavioral Health & Human Health Countermeasures Topics 
Grant/Contract No.: 80NSSC17K0021 
Project Type: GROUND 
Flight Program:  
TechPort: No  		No. of Post Docs:  
No. of PhD Candidates:  
No. of Master's Candidates:  
No. of Bachelor's Candidates:   		No. of PhD Degrees:  
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) HFBP:Human Factors & Behavioral Performance (IRP Rev H)
Human Research Program Risks: (1) BMed:Risk of Adverse Cognitive or Behavioral Conditions and Psychiatric Disorders
(2) Sensorimotor:Risk of Altered Sensorimotor/Vestibular Function Impacting Critical Mission Tasks
Human Research Program Gaps: (1) BMed-101:We need to identify, quantify, and validate the key selection factors for astronaut cognitive and behavioral strengths (e.g., resiliency) and operationally-relevant performance threats for increasingly Earth independent, long-duration, autonomous, and/or long-distance exploration missions.
(2) BMed-108:Given each crewmember will experience multiple spaceflight hazards simultaneously, we need to identify and characterize the potential additive, antagonistic, or synergistic impacts of multiple stressors (e.g., space radiation, altered gravity, isolation, altered immune, altered sleep) on crew health and/or CNS/ cognitive functioning to develop threshold limits and validate countermeasures for any identified adverse crew health and/or operationally-relevant performance outcomes.
(3) SM-104:Evaluate how weightlessness-induced changes in sensorimotor/vestibular function relate to and/or interact with changes in other brain functions (sleep, cognition, attention).
Task Description: NRA NNJ14ZSA001N-MIXEDTOPICS requests proposals in the area of “Risk Characterization and Monitoring of Behavioral Health and Performance Relevant Outcomes” to determine the effects of 30 days head down tilt bed rest in a 0.5% CO2 environment on neurobehavioral signs and symptoms, neurostructural and neurofunctional alterations, and changes in cognitive function and operational task performance. Our Neuromapping studies measure precisely these metrics in a flight study and a 70 days head down tilt bed rest study under normative conditions. Here, our overarching goal is to quantify neurocognitive changes and associated neural structural and functional alterations occurring as a result of a 30 days head down tilt bed rest plus 0.5% CO2 environment, serving as a spaceflight analog exposure. We will identify the relationship between these neural changes and behavioral function. Our approach utilizes cutting edge neuroimaging techniques and a broad ranging battery of sensory, motor, and cognitive assessments to investigate neuroplastic and maladaptive brain changes occurring in a spaceflight analog environment. Success in this endeavor would 1) result in identification of the underlying neural mechanisms and operational risks of changes in behavior with a spaceflight analog, and 2) identify whether a return to normative behavioral function following bed rest is associated with a restitution of brain structure and function or instead is supported by substitution with compensatory brain processes. Moreover, addition of a CO2 group will enable us to parse out the multiple mechanisms contributing to any spaceflight induced neural structural and behavioral changes that we observe in our ongoing flight projects ((NASA flight project, Seidler Principal Investigator (PI); ILSRA flight study, Stahn PI)), and comparison with our recently completed bed rest projects (Seidler and Stahn, PIs) will allow us to delineate brain and behavioral changes occurring with long term exposure to slightly elevated CO2 levels.

Research Impact/Earth Benefits:

Task Progress & Bibliography Information FY2017 
Task Progress: New project for FY2017.

Bibliography: Description: (Last Updated: 01/24/2024) 

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