NOTE: End date changed to 06/30/2025 per V. Lehman/JSC (Ed., 3/18/25)

NOTE: End date changed to 12/31/2024 per NSSC information (Ed., 7/23/24)

NOTE: End date changed to 08/31/2024 per M. Stenger/NASA HHC Element Scientist and C. Ribeiro/NASA HHC (Ed., 1/12/24)

The glymphatic system functions to distribute solutes and clear waste from the brain via cerebrospinal fluid (CSF) circulation and interstitial fluid flow along its perivascular spaces. Glymphatic clearance has been implicated as a key determinant of brain health, acting to remove or redistribute metabolic products, inflammatory and immune-mediated molecules, as well as additional solutes for disposal. Glymphatic dysfunction may cause the failure of interstitial solute clearance or derangement of cranial fluid dynamics resulting from the mismatch between CSF influx and interstitial fluid efflux, with negative impacts on brain homeostasis. It is not known at this point how the environmental stressors of microgravity exposure impact glymphatic function.

Microgravity exposure produces a fluid shift towards the head, resulting in compression of the top of the brain against the skull, prompting morphological and physiological brain alterations. We have shown that spaceflight results in brain free water redistribution. The resulting changes generate increased intracranial pressures, alter cerebral blood flow, and have been linked to visual impairments. The functional impact of these brain fluid shifts remains to be determined. Head-down tilt (HDT) bedrest has been used as a spaceflight analog; we have reported similar brain positional and fluid shifts in this environment, supporting the notion that these mechanical effects are due to microgravity or rotation of the body in HDT relative to the gravitational vector.

In addition to altered gravitational effects, astronauts are exposed to increased carbon dioxide (CO2) levels (hypercapnia) in the enclosed environment of the International Space Station. CO2 is a potent vasomodulator; hypercapnia increases both cerebral blood flow and arterial blood pressure. It has been reported that hypercapnia reduces glymphatic exchange in mice. Currently, the effect of elevated CO2 exposure on human glymphatic function remains unknown. Because astronauts are exposed concurrently to microgravity and elevated CO2, here, we propose to study the combinatorial effects of HDT and elevated CO2 on this system.

In the proposed study, we will investigate the individual and combined effects of simulated microgravity and hypercapnia on human glymphatic function. Using acute HDT bedrest and exposure to elevated CO2, this study will be a critical first step towards understanding the potential interactions of microgravity and elevated CO2 on perivascular glymphatic function and brain health.

NOTE: End date changed to 06/30/2025 per V. Lehman/JSC (Ed., 3/18/25)

NOTE: End date changed to 12/31/2024 per NSSC information (Ed., 7/23/24)

NOTE: End date changed to 08/31/2024 per M. Stenger/NASA HHC Element Scientist and C. Ribeiro/NASA HHC (Ed., 1/12/24)

SPECIFIC AIM 1: To measure the effects of HDT positioning on human glymphatic function. SPECIFIC AIM 2: To assess the combined effect of breathing elevated CO2 and HDT on human glymphatic function.

We have completed data collection with five participants and another three are in progress. The preliminary findings were presented at the NASA Human Research Program (HRP) Investigators' Workshop (IWS) in Galveston, TX. Our previous project in which we were testing the effects of elevated CO2 in supine participants revealed that the presence of elevated CO2 slowed glymphatic clearance from the vitreous chamber of the eye. That is, there was greater contrast-induced signal intensity on the gas day relative to the ambient air day at the 90-minute post-contrast injection time point. With the preliminary findings that we presented at the NASA HRP IWS, the results suggest that the addition of the head-down tilt positioning slows glymphatic clearance from this region at this 90-minute time point even more than elevated CO2 alone. It remains to be seen if this finding holds with the collection and analysis of additional participants’ data and statistical assessment.

NOTE: End date changed to 08/31/2024 per M. Stenger/NASA HHC Element Scientist and C. Ribeiro/NASA HHC (Ed., 1/12/24)

The glymphatic system functions to distribute solutes and clear waste from the brain via cerebrospinal fluid (CSF) circulation and interstitial fluid flow along its perivascular spaces.

Glymphatic clearance has been implicated as a key determinant of brain health, acting to remove or redistribute metabolic products, inflammatory and immune-mediated molecules, as well as additional solutes for disposal [4]. Glymphatic dysfunction may cause the failure of interstitial solute clearance or derangement of cranial fluid dynamics resulting from the mismatch between CSF influx and interstitial fluid efflux, with negative impacts on brain homeostasis. It is not known at this point how the environmental stressors of microgravity exposure impact glymphatic function.

In the proposed study, we will investigate the individual and combined effects of simulated microgravity and hypercapnia on human glymphatic function. Using acute head-down tilt (HDT) bedrest and exposure to elevated CO2, this study will be a critical first step toward understanding the potential interactions of microgravity and elevated CO2 on perivascular glymphatic function and brain health.

Progress to Date We identified a vendor for an MRI-safe foam wedge to place participants in the head-down tilt position. We acquired it and have conducted pilot testing to ensure that it does not create signal distortion in the MRI environment. We also confirmed that it is tolerable for participants to remain head-down tilt on the wedge for the duration of the testing day (approximately eight hours). We are currently in process of recruiting participants and collecting data in the head-down tilt position with and without elevated CO2.