NOTE: End date changed to 03/31/2025 per NSSC information (Ed., 4/4/24)

NOTE: End date changed to 03/31/2024 per NSSC information (Ed., 4/14/23)

• Relative intracranial pressure (ICP) measurements via distortion product otoacoustic emissions (distortion product otoacoustic emissions: DPOAE).

• Blood volume shifts along the body axis via near-infrared spectroscopy (NIRS).

• Intracranial blood inflow and outflow, via internal jugular vein (IJV) and carotid artery (CA) ultrasound cross-sectional imaging and Doppler.

• Cerebral pulsatility assessment, per our parabolic flight and SPACE-COT (Studying Physiological and Anatomical Cerebral Effects of CO2 and Tilt) :envihab NIRS study.

• Blood pressure at the level of the head via local, cuffless superficial temporal artery tonometry.

• Sagittal sinus blood volume imaging and monitoring using diffuse optical tomography (DOT).

• Cerebral edema assessment based on H2O concentration imaging, similar to that used in previous altitude sickness studies.

• Cerebral electrical activity, via electroencephalogram (EEG) measurements.

• Dynamic cerebral autoregulation (CAR) assessment during countermeasure (CM) challenges, which can be derived from the NIRS signals used in the above measurements.

Our tools will be made fully compatible with the planned SANS countermeasures, as well as with those of other teams proposing specific CMs. Along with the measures, we will provide the necessary expertise and analysis to quantify physiological changes associated with SANS countermeasures deployed during the 30-day HDT campaigns at :envihab. Our specific aims are as follows:

Aim 1: Develop an integrated collection of hardware to support multiple simultaneous, continuous brain monitoring/imaging capabilities, and ensure the hardware and measurements are fully compatible with all countermeasures deployed during the :envihab missions.

Aim 2: Characterize and quantify individual subjects’ physiological responses to each planned condition, including comparative assessment of SANS countermeasures.

Aim 3: Relate neurophysiological changes over the 30-day HDT—both with and without SANS-CMs—to cognitive and operational performance, sleep, mood, and ocular measures. This will include the Cognition battery, psychological/mood surveys, and a suite of ocular measures (OCT, fundoscopy). We will obtain as many measures as possible through data sharing and investigate the relationship of our neurophysiological measures to each of these outcome assessments.

Jointly, the planned measures and Aims will enable NASA to quantitatively evaluate and compare the (neuro)physiological changes and fluid shifts associated with HDT and SANS countermeasures.

Spaceflight associated neuro-ocular syndrome (SANS) is an unsolved risk for astronauts on long-duration missions. When diagnosed from Frisen grade papilledema on fundoscopy, some 10 of 68 astronauts have exhibited SANS, although related ocular findings are more common (e.g., acquired hyperopia, globe flattening, choroidal folds, retinal fiber nerve layer thickening), and current estimates are closer to a 75% prevalence of SANS in astronauts on 6-month missions. Unexpectedly, SANS signs do not always spontaneously resolve upon return to Earth gravity. While the cause of SANS is unknown, the hyperopia, globe flattening, and choroidal folds—coupled with typically normal or slightly elevated intraocular pressure (IOP)—suggests that intracranial pressure (ICP) may be elevated as compared to average Earth levels. Various pathophysiological mechanisms have been proposed for SANS, with particular suspicions regarding cephalad fluid shifts.

SANS Countermeasures

Most hypotheses regarding SANS involve headward fluid shifts as a factor, and various proposed SANS countermeasures (CMs)—including lower-body negative pressure (LBNP), veno-constrictive thigh cuffs (VTC), inspiratory resistance threshold devices (ITD), and artificial gravity (AG)—all involve “mechanical” redistribution of body fluids away from the head. Understanding the relative benefits of such CMs calls for assessments of perfusion and fluid flow into, within, and out of the cranium not only for potentially assessing and monitoring SANS but also to help quantify and compare the effect sizes of various CMs.

SANS-CM Study at DLR’s Envihab Facility

To address the lack of SANS CMs, NASA negotiated a plan with the German Aerospace Center’s :envihab facility to conduct 30-day head-down tilt (HDT) bedrest studies—the SANS-CM study. This effort currently includes 4 study arms:

1. 6o HDT bedrest alone (Reference) 2. 6o HDT bedrest plus two 3-hour periods per day seated upright (Seated CM) 3. 6o HDT bedrest plus two 3-hour periods per day of LBNP (LBNP CM) 4. 6o HDT bedrest plus one ~1-hour period of exercise followed by 6 hours of VTC (Exercise CM) Each arm targeted n=12 subjects, and different investigators were involved in different aspects of the overall SANS-CM study. Our contribution was the BRAIN-SANS (sub)project.

BRAIN-SANS Contribution

This BRAIN-SANS project (a component of SANS-CM) seeks to provide a wide range of brain-related measures for all subjects in all study arms. These include changes in (i) intracranial pressure (ICP), (ii) blood flow in/out of the brain, (iii) cerebral blood flow velocity, (iv) brain perfusion and oxygenation, (v) blood distribution along the body axis, (vi) intracranial pulsatility, (vii) sagittal sinus imaging of potential venous congestion, (viii) intracranial water concentration, (ix) functional brain activation, (x) electrical brain activity, as well as (xi) cognitive performance data (Cognition). We also plan to compare these measures with measures from other groups including ocular measures, mood and sleep, and 1-carbon single nucleotide polymorphisms.

ACHIEVEMENTS IN YEAR 5

Activities that were completed or will be completed by the end of the 5th year of the project are as follows:

Summary of All BRAIN-SANS Data: Overall, data collection went very well, with 6,615 of 6,780 expected data files—or 97.6% of all data files—accounted for. The minor amount of missing data arose from one subject dropout, plus occasional device faults or running behind schedule which prevented full data completion.

Ongoing Data Analysis: The majority of year 5 involved data quality assurance, preprocessing and analysis. Datasets being processed include distortion product otoacoustic emissions (DPOAE) (Dr. Voss; manuscript in preparation); IJV/ICA ultrasound imaging/flow data (Dr. Bershad; statistical analysis partially complete); NIRS fluid shift data (Dr. Strangman; presented at IWS2024 and manuscript in preparation); cerebrovascular pulsatility (Dr. McCaffrey; being presented at IWS2025 and manuscript in preparation); sagittal sinus congestion (Dr. Joshi; imaging analysis underway); cerebral oxygenation and cerebral water/CSF (Dr. Forselius; preprocessing underway); Cognition data (Dr. Basner; analysis nearing completion). In addition, data sharing with Drs. Huang, Zwart, and Clement were initiated, involving data transfer, dataset harmonization, and discussion of primary and secondary variables of interest. Analysis and manuscript preparation on all of the above datasets will continue in the coming year.

Preliminary Results: Cerebral blood volume showed a small shift into the head in the Control condition coupled with a large shift away from the legs. Transitioning to Seated led to no change in blood in the head or chest, substantial increases in the thigh, and large increases in the calf. The LBNP condition significantly reduced the blood volume in the chest and significantly increased blood volume in both the thigh and calf, to equal extents. Finally, the Exercise+VTC condition led to no significant changes in chest blood volume but greatly increased the blood in both the thigh and calf. This was sustained through the exercise period, the 30-minute “rest/gap” (when some loss of blood in the legs was anticipated), and increased further when the VTC was tightened. The effect size for Exercise+VTC was larger than seated, which was unexpected. Initial findings for DPOAE, IJV/CSA, as well as cerebrovascular pulsatility, also show distinct changes associated with the various CMs, although the relative effect sizes appear to be ranked differently across CMs depending on the measures. We will finalize individual analyses first before engaging in detailed inter-comparisons of the various neurophysiological measures collected via BRAIN-SANS. The remainder of year 5 and the coming year will involve further analysis and manuscript preparation and submission for all of the collected datasets.

SUMMARY

Year 5 provided major progress on multiple datasets within the BRAIN-SANS data collection suite. The very low rate of data loss and high-quality data (except from periods of uncontrolled subject motion during our multi-hour recordings) provide a strong base from which to address numerous hypotheses about the neurophysiology in the HDBR SANS analog as well as the effects of the investigated SANS countermeasures.

NOTE: End date changed to 03/31/2024 per NSSC information (Ed., 4/14/23)

• Relative intracranial pressure (ICP) measurements via distortion product otoacoustic emissions (distortion product otoacoustic emissions: DPOAE).

• Blood volume shifts along the body axis via near-infrared spectroscopy (NIRS).

• Intracranial blood inflow and outflow, via internal jugular vein (IJV) and carotid artery (CA) ultrasound cross-sectional imaging and Doppler.

• Cerebral pulsatility assessment, per our parabolic flight and SPACE-COT (Studying Physiological and Anatomical Cerebral Effects of CO2 and Tilt) :envihab NIRS study.

• Blood pressure at the level of the head via local, cuffless superficial temporal artery tonometry.

• Sagittal sinus blood volume imaging and monitoring using diffuse optical tomography (DOT).

• Cerebral edema assessment based on H2O concentration imaging, similar to that used in previous altitude sickness studies.

• Cerebral electrical activity, via electroencephalogram (EEG) measurements.

• Dynamic cerebral autoregulation (CAR) assessment during countermeasure (CM) challenges, which can be derived from the NIRS signals used in the above measurements.

Our tools will be made fully compatible with the planned SANS countermeasures, as well as with those of other teams proposing specific CMs. Along with the measures, we will provide the necessary expertise and analysis to quantify physiological changes associated with SANS countermeasures deployed during the 30-day HDT campaigns at :envihab. Our specific aims are as follows:

Aim 1: Develop an integrated collection of hardware to support multiple simultaneous, continuous brain monitoring/imaging capabilities, and ensure the hardware and measurements are fully compatible with all countermeasures deployed during the :envihab missions.

Aim 2: Characterize and quantify individual subjects’ physiological responses to each planned condition, including comparative assessment of SANS countermeasures.

Aim 3: Relate neurophysiological changes over the 30-day HDT—both with and without SANS-CMs—to cognitive and operational performance, sleep, mood, and ocular measures. This will include the Cognition battery, psychological/mood surveys, and a suite of ocular measures (OCT, fundoscopy). We will obtain as many measures as possible through data sharing and investigate the relationship of our neurophysiological measures to each of these outcome assessments.

Jointly, the planned measures and Aims will enable NASA to quantitatively evaluate and compare the (neuro)physiological changes and fluid shifts associated with HDT and SANS countermeasures.

Spaceflight associated neuro-ocular syndrome (SANS) is an unsolved risk for astronauts on long-duration missions. When diagnosed from Frisen grade papilledema on fundoscopy, some 10 of 68 astronauts have exhibited SANS, although related ocular findings are more common (e.g., acquired hyperopia, globe flattening, choroidal folds, retinal fiber nerve layer thickening), and current estimates are closer to a 75% prevalence of SANS in astronauts on 6-month missions. Unexpectedly, SANS signs do not always spontaneously resolve upon return to Earth gravity. While the cause of SANS is unknown, the hyperopia, globe flattening, and choroidal folds—coupled with typically normal or slightly elevated intraocular pressure (IOP)—suggests that intracranial pressure (ICP) may be elevated as compared to average Earth levels. Various pathophysiological mechanisms have been proposed for SANS, with particular suspicions regarding cephalad fluid shifts.

SANS Countermeasures

Most hypotheses regarding SANS involve headward fluid shifts as a factor, and various proposed SANS countermeasures (CMs)—including lower-body negative pressure (LBNP), veno-constrictive thigh cuffs (VTC), inspiratory resistance threshold devices (ITD), and artificial gravity (AG)—all involve “mechanical” redistribution of body fluids away from the head. Understanding the relative benefits of such CMs calls for assessments of perfusion and fluid flow into, within, and out of the cranium not only for potentially assessing and monitoring SANS but also to help quantify and compare the effect sizes of various CMs.

SANS-CM Study at DLR’s Envihab Facility

To address the lack of SANS CMs, NASA negotiated a plan with the German Aerospace Center’s :envihab facility to conduct 30-day head-down tilt (HDT) bedrest studies—the SANS-CM study. This effort currently includes 4 study arms: 1. 6o HDT bedrest alone (Reference) 2. 6o HDT bedrest plus two 3-hour periods per day seated upright (Seated CM) 3. 6o HDT bedrest plus two 3-hour periods per day of LBNP (LBNP CM) 4. 6o HDT bedrest plus one ~1-hour period of exercise followed by 6 hours of VTC (Exercise CM)

This last arm was changed from 1hr exercise+2hr VTC, completed twice per day. Each arm will consist of n=12 subjects and different investigators will be involved in different portions of the overall SANS-CM study.

BRAIN-SANS Contribution

This BRAIN-SANS project seeks to provide a wide range of brain-related measures for all subjects in all study arms. These include changes in (i) intracranial pressure (ICP), (ii) blood flow in/out of the brain, (iii) cerebral blood flow velocity, (iv) brain perfusion and oxygenation, (v) blood distribution along the body axis, (vi) intracranial pulsatility, (vii) sagittal sinus imaging of potential venous congestion, (viii) intracranial water concentration, (ix) functional brain activation, (x) electrical brain activity, as well as (xi) cognitive performance data (Cognition). We also plan to compare these measures with measures from other groups, including ocular measures, mood and sleep, 1-carbon single nucleotide polymorphisms, and MRI.

ACHIEVEMENTS IN YEAR 4

The 4th year of this project started shortly after Campaign 3 had completed and before Campaign 4 began (in May 2023). Activities that were completed or will be completed by the end of the 4th year of the project are as follows: Initiation and Completion of Campaign 4: BRAIN-SANS data collection for C4 was started on 5/5/2023 and completed on 7/1/2023. Per most prior campaigns, this involved data collection on 12 participants. As per prior reports, we performed data quality control assessments in semi-real time during data collection periods to help optimize the quality of the data that was being collected, as well as to make ongoing adjustments when changes affecting quality appeared. We collected 99.7% of all expected files in Campaign 4.

Summary of All BRAIN-SANS Data: Overall, data collection went very well, with 6,615 of 6,780 expected data files—or 97.6% of all data files—accounted for. The minor amount of missing data arose from one subject dropout, and device faults or running behind schedule which prevented full data completion.

Ongoing Data Processing: Data preprocessing was underway as of the last report and has been significantly ramped up in the past year. Distortion product otoacoustic emissions (DPOAE) preprocessing (by Dr. Voss) is 95% complete overall, with a poster presented at the 2024 Human Research Program Investigators' Workshop (HRP IWS). Ultrasound imaging/flow data (handled by Dr. Bershad) is approximately 60% complete. Cognition data analysis (Dr. Basner) is approximately 80% complete. NIRS (NINscan and Oxiplex) preprocessing is approximately 70% complete at this time. NIRS results detailing the effects of countermeasures on blood sequestration along the body axis were presented at the 2024 HRP IWS. Data processing remains a high-priority task, and we are currently seeking to engage interns and affiliates to help with the wealth of data (and data types) that require analysis.

Preliminary Results on Countermeasures: To summarize the NIRS results presented at HRP IWS 2024, there was a small shift of blood volume towards the head in the control condition, likely because at BDC (when subjects are ambulatory) the participants had only been head-down for <1 hr at the point of measurement. Transitioning to upright seated lead to no change in blood in the head or chest, substantial increases in the thigh, and large increases in the calf. The lower body negative pressure (LBNP) condition significantly reduced the blood volume in the chest and significantly increased blood volume in both the thigh and calf, to equal extents. This might be expected given the geometry of the LBMP vacuum chamber (compressing around the chest and applying uniform vacuum to both the upper and lower leg). Finally, the Exercise+VTC condition led to no significant changes in chest blood volume (trend towards decreases) but greatly increased the blood in both the thigh and calf. This was sustained through the exercise period, the 30-minute “gap” (when some loss of blood in the legs was anticipated), and increased further when the VTC was tightened. The effect size for Exercise+VTC was larger than seated, which was unexpected. These results are still being finalized.

The remainder of year 4 will involve completing quality control assessments for Campaigns 3 and 4, completion of the DPOAE analysis, completion of the Cognition data analysis, continued analysis of the ultrasound data, and finalizing unified code for preprocessing all NIRS and physiological data. The upcoming year will be devoted to final analyses and manuscript preparation and submission.

SUMMARY

Year 4 was a success, with the completion of all data collection with a very low rate of data loss. The large volume of data will take time to preprocess and analyze and, given the shift in the last DLR campaigns from the original schedule, we will be requesting a no-cost extension to continue the analysis and interpretation work in the upcoming year.

• Relative intracranial pressure (ICP) measurements via distortion product otoacoustic emissions (distortion product otoacoustic emissions: DPOAE).

• Blood volume shifts along the body axis via near-infrared spectroscopy (NIRS).

• Intracranial blood inflow and outflow, via internal jugular vein (IJV) and carotid artery (CA) ultrasound cross-sectional imaging and Doppler.

• Cerebral pulsatility assessment, per our parabolic flight and SPACE-COT (Studying Physiological and Anatomical Cerebral Effects of CO2 and Tilt) :envihab NIRS study.

• Blood pressure at the level of the head via local, cuffless superficial temporal artery tonometry.

• Sagittal sinus blood volume imaging and monitoring using diffuse optical tomography (DOT).

• Cerebral edema assessment based on H2O concentration imaging, similar to that used in previous altitude sickness studies.

• Cerebral electrical activity, via electroencephalogram (EEG) measurements.

• Dynamic cerebral autoregulation (CAR) assessment during countermeasure (CM) challenges, which can be derived from the NIRS signals used in the above measurements.

Our tools will be made fully compatible with the planned SANS countermeasures, as well as with those of other teams proposing specific CMs. Along with the measures, we will provide the necessary expertise and analysis to quantify physiological changes associated with SANS countermeasures deployed during the 30-day HDT campaigns at :envihab. Our specific aims are as follows:

Aim 1: Develop an integrated collection of hardware to support multiple simultaneous, continuous brain monitoring/imaging capabilities, and ensure the hardware and measurements are fully compatible with all countermeasures deployed during the :envihab missions.

Aim 2: Characterize and quantify individual subjects’ physiological responses to each planned condition, including comparative assessment of SANS countermeasures.

Aim 3: Relate neurophysiological changes over the 30-day HDT—both with and without SANS-CMs—to cognitive and operational performance, sleep, mood, and ocular measures. This will include the Cognition battery, psychological/mood surveys, and a suite of ocular measures (OCT, fundoscopy). We will obtain as many measures as possible through data sharing and investigate the relationship of our neurophysiological measures to each of these outcome assessments.

Jointly, the planned measures and Aims will enable NASA to quantitatively evaluate and compare the (neuro)physiological changes and fluid shifts associated with HDT and SANS countermeasures.

Spaceflight-associated neuro-ocular syndrome (SANS) is an unsolved risk for astronauts on long-duration missions. When diagnosed from Frisen grade papilledema on fundoscopy, some 10 of 68 astronauts have exhibited SANS, although related ocular findings are more common (e.g., acquired hyperopia, globe flattening, choroidal folds, retinal fiber nerve layer thickening), and current estimates are closer to a 75% prevalence of SANS in astronauts on 6-month missions. Unexpectedly, SANS signs do not always spontaneously resolve upon return to Earth gravity. While the cause of SANS is unknown, the hyperopia, globe flattening, and choroidal folds—coupled with typically normal or slightly elevated intraocular pressure (IOP)—suggests that intracranial pressure (ICP) may be elevated as compared to average Earth levels. Various pathophysiological mechanisms have been proposed for SANS, with particular suspicions regarding cephalad fluid shifts.

SANS Countermeasures

Most hypotheses regarding SANS involve headward fluid shifts as a factor, and various proposed SANS countermeasures (CMs)—including lower-body negative pressure (LBNP), veno-constrictive thigh cuffs (VTC), inspiratory resistance threshold devices (ITD), and artificial gravity (AG)—all involve “mechanical” redistribution of body fluids away from the head. Understanding the relative benefits of such CMs calls for assessments of perfusion and fluid flow into, within, and out of the cranium not only for potentially assessing and monitoring SANS but also to help quantify and compare the effect sizes of various CMs.

SANS-CM Study at DLR’s Envihab Facility

To address the lack of SANS CMs, NASA negotiated a plan with the German Aerospace Center’s :envihab facility to conduct 30-day head-down tilt (HDT) bedrest studies—the SANS-CM study. This effort currently includes 4 study arms: 1. 6o HDT bedrest alone (Reference) 2. 6o HDT bedrest plus two 3-hour periods per day seated upright (Seated CM) 3. 6o HDT bedrest plus two 3-hour periods per day of LBNP (LBNP CM) 4. 6o HDT bedrest plus one ~1-hour period of exercise followed by 6 hours of VTC (Exercise CM) This last arm was changed from 1hr exercise+2hr VTC, completed twice per day. Each arm will consist of n=12 subjects and different investigators will be involved in different portions of the overall SANS-CM study.

BRAIN-SANS Contribution

This BRAIN-SANS project seeks to provide a wide range of brain-related measures for all subjects in all study arms. These include changes in (i) intracranial pressure (ICP), (ii) blood flow in/out of the brain, (iii) cerebral blood flow velocity, (iv) brain perfusion and oxygenation, (v) blood distribution along the body axis, (vi) intracranial pulsatility, (vii) sagittal sinus imaging of potential venous congestion, (viii) intracranial water concentration, (ix) functional brain activation, (x) electrical brain activity, as well as (xi) cognitive performance data (Cognition). We also plan to compare these measures with measures from other groups, including ocular measures, mood and sleep, 1-carbon single nucleotide polymorphisms, and MRI.

ACHIEVEMENTS IN YEAR 3

We completed Campaigns 1 and 2 during year 2 of the project. During the 3rd year of project, we conducted the following major tasks: Campaign 2: Data acquisition (and troubleshooting as needed) was completed for the entirety of Campaign 2, from January-March 2022. A total of 1,542 data files (out of a nominally expected 1,656 data files) were collected for a 93.1% data collection rate. This was lower than in year 1, consequent to one subject that had to be removed from the study (n=11 completers in Campaign 2). Excluding this subject, the data collection rate was 98.5%. Quality control assessments for all C1 and C2 datasets were conducted during and immediately after the respective campaign.

Dry runs: Full-up dry runs were conducted with DLR personnel to adapt our integrated toolbox of devices for use during the exercise countermeasure activities.

Finalizing protocols: Consequent to the dry runs, we finalized all protocols for the control (HDT-only) and exercise+VTC arms of the study. This included tilt-testing for calibration, orthostatic tilt testing, rest measurements, and measurements during onset, maintenance and offset of countermeasures.

Preparation for and Initiation of Campaign 3: Experimental procedures for Campaign 3, including a 50/50 mix of control and exercise+VTC subjects, began January 23, 2023, and will continue until March 27, 2023. Preparations included adapting our toolbox to be robust to use during the exercise periods, delivering all needed hardware and materials to DLR for startup, and having an on-site presence for the initiation and BDC testing for Campaign 3. All data is evaluated for missing or erroneous data points, noise, and overall usability for analysis on a daily basis during the data collection period.

SUMMARY

Campaigns 1 and 2 (starting in year 2 and ending in year 3) proceeded well after substantial virtual and on-site dry-run procedures. Additional dry runs were conducted after the 9-month hiatus in the study at DLR to help ensure Campaigns 3 and 4 proceed smoothly as well. Data collection success rates have been high to date and are expected to be similarly successful in Campaigns 3 and 4. We are currently on track to complete Campaign 3 data collection by early March 2023 and complete Campaign 4 data collection by June 2023. At that point, final data processing and analysis will begin in earnest.

• Relative intracranial pressure (ICP) measurements via distortion product otoacoustic emissions (distortion product otoacoustic emissions: DPOAE).

• Blood volume shifts along the body axis via near-infrared spectroscopy (NIRS).

• Intracranial blood inflow and outflow, via internal jugular vein (IJV) and carotid artery (CA) ultrasound cross-sectional imaging and Doppler.

• Cerebral pulsatility assessment, per our parabolic flight and SPACE-COT (Studying Physiological and Anatomical Cerebral Effects of CO2 and Tilt) :envihab NIRS study.

• Blood pressure at the level of the head via local, cuffless superficial temporal artery tonometry.

• Sagittal sinus blood volume imaging and monitoring using diffuse optical tomography (DOT).

• Cerebral edema assessment based on H2O concentration imaging, similar to that used in our previous altitude sickness studies.

• Cerebral electrical activity, via electroencephalogram (EEG) measurements.

• Dynamic cerebral autoregulation (CAR) assessment during countermeasure (CM) challenges, which can be derived from the NIRS signals used in the above measurements.

Our tools will be made fully compatible with the planned SANS countermeasures, as well as with those of other teams proposing specific CMs. Along with the measures, we will provide the necessary expertise and analysis to quantify physiological changes associated with SANS countermeasures deployed during the 30-day HDT campaigns at :envihab. Our specific aims are as follows:

Aim 1: Develop an integrated collection of hardware to support multiple simultaneous, continuous brain monitoring/imaging capabilities, and ensure the hardware and measurements are fully compatible with all countermeasures deployed during the :envihab missions.

Aim 2: Characterize and quantify individual subjects’ physiological responses to each planned condition, including comparative assessment of SANS countermeasures.

Aim 3: Relate neurophysiological changes over the 30-day HDT—both with and without SANS-CMs—to cognitive and operational performance, sleep, mood, and ocular measures. This will include the Cognition battery, psychological/mood surveys, and a suite of ocular measures (OCT, fundoscopy). We will obtain as many measures as possible through data sharing and investigate the relationship of our neurophysiological measures to each of these outcome assessments.

Jointly, the planned measures and Aims will enable NASA to quantitatively evaluate and compare the (neuro)physiological changes and fluid shifts associated with HDT and SANS countermeasures.

Background:

Spaceflight associated neuro-ocular syndrome (SANS) is an unsolved risk for astronauts on long duration missions. When diagnosed from Frisen grade papilledema on fundoscopy, some 10 of 68 astronauts have exhibited SANS, although related ocular findings are more common (e.g., acquired hyperopia, globe flattening, choroidal folds, retinal fiber nerve layer thickening). Unexpectedly, SANS signs do not always spontaneously resolve upon return to Earth gravity. While the cause of SANS is unknown, the hyperopia, globe flattening, and choroidal folds—coupled with typically normal or slightly elevated intra-ocular pressure (IOP)—suggests that intracranial pressure (ICP) may be elevated as compared to average Earth levels. Various pathophysiological mechanisms have been proposed for SANS, with a particular suspicion regarding cephalad fluid shifts.

SANS Countermeasures:

Most hypotheses regarding SANS involve headward fluid shifts as a factor, and various proposed SANS countermeasures (CMs)—including lower-body negative pressure (LBNP), veno-constrictive thigh cuffs (VTC), inspiratory resistance threshold devices (ITD), and artificial gravity (AG) all involve “mechanical” redistribution of body fluids away from the head. Understanding the relative benefits of such CMs calls for assessments of perfusion and fluid flow into, within, and out of the cranium not only for potentially assessing and monitoring SANS, but also to help quantify and compare the effect sizes of various CMs.

SANS-CM Study at the German Space Agency (Deutsches Zentrum fur Luft-und Raumfahrt or "DLR") Envihab Facility:

To address the lack of SANS CMs, NASA negotiated a plan with the DLR German Aerospace Center’s Envihab (:envihab) facility to conduct 30-day head-down tilt (HDT) bedrest studies—the SANS-CM study. This effort currently includes 4 study arms:

1. 6o HDT bedrest alone (Reference) 2. 6o HDT bedrest plus two 3-hour periods per day seated upright (Seated CM) 3. 6o HDT bedrest plus two 3-hour periods per day of LBNP (LBNP CM) 4. 6o HDT bedrest plus two ~1-hour periods of exercise plus an additional 2 hours of VTC (Exercise CM)

Each arm will consist of n=12 subjects, and different investigators will be involved in different portions of the overall SANS-CM study.

BRAIN-SANS Contribution:

This BRAIN-SANS project seeks to provide a wide range of brain-related measures for all subjects in all study arms. These include changes in (i) intracranial pressure (ICP), (ii) blood flow in/out of the brain, (iii) cerebral blood flow velocity, (iv) brain perfusion and oxygenation, (v) blood distribution along the body axis, (vi) intracranial pulsatility, (vii) sagittal sinus imaging of potential venous congestion, (viii) intracranial water concentration, (ix) functional brain activation, (x) electrical brain activity, as well as (xi) cognitive performance data (Cognition). We also plan to compare these measures with measures from other groups including ocular measures, mood and sleep, 1-carbon single nucleotide polymorphisms, and magnetic resonance imaging (MRI).

ACHIEVEMENTS IN YEAR 2

By the end of the 2nd year of this project, we will have completed the following major tasks:

Hardware & Supplies Shipping: After COVID-related scheduling delays at DLR, all hardware for our BRAIN-SANS monitoring toolkit—developed in Aim 1—was shipped to the DLR for training and use.

Training: All :envihab personnel were trained to use the various toolkit instruments, including NINscan CW-NIRS (continuous wave/near-infrared spectroscopy) systems, the OptiplexTS RF-NIRS system, the Mimosa Acoustics HearID DPOAE (distortion-product otoacoustic emissions) system, and MAICO EasyTymp tympanometer.

Dry runs: Full-up dry runs were conducted with DLR personnel to demonstrate the integration of the above devices, as well as how to further integrate the DLR imaging ultrasound, transcranial Doppler (TCD), and finometer devices.

Finalizing protocols: The dry runs were used to finalize all protocols, customized to the specific DLR testing environment. This included tilt-testing for calibration, orthostatic tilt testing, rest measurements, and measurements during onset, maintenance, and offset of countermeasures.

Campaign 1: Data acquisition (and troubleshooting as needed) was completed for the entirety of Campaign 1, from Sept-Nov 2021. A total of 735 data files (out of a nominally expected 744 data files) were collected, for a 98.8% data collection rate. Quality control assessments for all Campaign 1 datasets were conducted during and immediately after Campaign 1.

Campaign 2: Preparations for Campaign 2—which is conceptually a repeat of Campaign 1 involving n=6 additional seated-upright CM subjects plus n=6 LBNP subjects—was initiated in Jan 2022 and is expected to complete in Mar 2022. Initial data collection sessions went smoothly.

SUMMARY

Despite challenges bought on by COVID-19 from the beginning of our funding, we initiated and completed running n=12 volunteers in Campaign 1 of the SANS-CM study (n=6 using the LBNP CM and n=6 as seated-upright controls). We have also started Campaign 2, with n=6 additional LBNP and n=6 seated-upright participants. We are on-track to complete Campaign 2 as planned. Campaigns 3-4 are currently scheduled to be conducted in the first half of 2023.

• Relative intracranial pressure (ICP) measurements via distortion product otoacoustic emissions (distortion product otoacoustic emissions: DPOAE).

• Blood volume shifts along the body axis via near-infrared spectroscopy (NIRS).

• Intracranial blood inflow and outflow, via internal jugular vein (IJV) and carotid artery (CA) ultrasound cross-sectional imaging and Doppler.

• Cerebral pulsatility assessment, per our parabolic flight and SPACE-COT (Studying Physiological and Anatomical Cerebral Effects of CO2 and Tilt) :envihab NIRS study.

• Blood pressure at the level of the head via local, cuffless superficial temporal artery tonometry.

• Sagittal sinus blood volume imaging and monitoring using diffuse optical tomography (DOT).

• Cerebral edema assessment based on H2O concentration imaging, similar to that used in our previous altitude sickness studies.

• Cerebral electrical activity, via electroencephalogram (EEG) measurements.

• Dynamic cerebral autoregulation (CAR) assessment during countermeasure (CM) challenges, which can be derived from the NIRS signals used in the above measurements.

Our tools will be made fully compatible with the planned SANS countermeasures, as well as with those of other teams proposing specific CMs. Along with the measures, we will provide the necessary expertise and analysis to quantify physiological changes associated with SANS countermeasures deployed during the 30-day HDT campaigns at :envihab. Our specific aims are as follows:

Aim 1: Develop an integrated collection of hardware to support multiple simultaneous, continuous brain monitoring/imaging capabilities, and ensure the hardware and measurements are fully compatible with all countermeasures deployed during the :envihab missions.

Aim 2: Characterize and quantify individual subjects’ physiological responses to each planned condition, including comparative assessment of SANS countermeasures.

Aim 3: Relate neurophysiological changes over the 30-day HDT—both with and without SANS-CMs—to cognitive and operational performance, sleep, mood, and ocular measures. This will include the Cognition battery, psychological/mood surveys, and a suite of ocular measures (OCT, fundoscopy). We will obtain as many measures as possible through data sharing and investigate the relationship of our neurophysiological measures to each of these outcome assessments.

Jointly, the planned measures and Aims will enable NASA to quantitatively evaluate and compare the (neuro)physiological changes and fluid shifts associated with HDT and SANS countermeasures.

Background

Spaceflight associated neuro-ocular syndrome (SANS) is an unsolved risk for astronauts on long duration missions. When diagnosed from Frisen grade papilledema on fundoscopy, some 10 of 68 astronauts have exhibited SANS, although related ocular findings are more common (e.g., acquired hyperopia, globe flattening, choroidal folds, retinal fiber nerve layer thickening). Unexpectedly, SANS signs do not always spontaneously resolve upon return to Earth gravity. While the cause of SANS is unknown, the hyperopia, globe flattening, and choroidal folds—coupled with typically normal or slightly elevated intra-ocular pressure (IOP)—suggests that intracranial pressure (ICP) may be elevated as compared to average Earth levels. Various pathophysiological mechanisms have been proposed for SANS, with a particular suspicion regarding cephalad fluid shifts.

SANS Countermeasures

Most hypotheses regarding SANS involve headward fluid shifts as a factor, and various proposed SANS countermeasures (CMs)—including lower-body negative pressure (LBNP), veno-constrictive thigh cuffs (VTC), inspiratory resistance threshold devices (ITD), and artificial gravity (AG) all involve “mechanical” redistribution of body fluids away from the head. Understanding the relative benefits of each CM calls for assessments of perfusion and fluid flow into, within, and out of the cranium not only for potentially assessing and monitoring SANS, but also to help quantify and compare the effect sizes of various CMs.

SANS-CM Study at German Aerospace Center's (DLR) Envihab Facility

To address the lack of SANS CMs, NASA has negotiated a plan with the German Aerospace Center’s :envihab facility to conduct 30-day head-down tilt (HDT) bedrest studies—the SANS-CM study. This effort has evolved to include 6 study arms:

1. 6o HDT bedrest alone (Reference); 2. 6o HDT bedrest plus two 3-hour periods seated upright (Seated CM); 3. 6o HDT bedrest plus 16 hours seated control (Control); 4. 6o HDT bedrest plus two 3-hour periods of LBNP (LBNP CM); 5. 6o HDT bedrest plus a B-complex vitamin supplement (Vit-B CM); 6. 6o HDT bedrest plus two ~1-hour periods of exercise plus VTC (Exercise CM).

Each arm will consist of n=12 subjects, and different investigators will be involved in different portions of the overall SANS-CM study.

BRAIN-SANS Contribution.This BRAIN-SANS project seeks to provide a wide range of brain-related measures for all subjects in all study arms. These include changes in (i) intracranial pressure (ICP), (ii) blood flow in/out of the brain, (iii) cerebral blood flow, (iv) brain perfusion and oxygenation, (v) blood distribution along the body axis, (vi) intracranial pulsatility, (vii) sagittal sinus imaging of potential, (viii) intracranial water concentration, (ix) functional brain activation, (x) electrical brain activity, as well as (xi) cognitive performance data (Cognition). We also plan to compare these measures with measures from other groups including ocular measures, mood and sleep, 1-carbon single nucleotide polymorphisms, and MRI.

ACHIEVEMENTS IN YEAR 1

By the end of the 1st year of this project, we will have completed the following major tasks:

Institutional Review Board (IRB) approval: Massachusetts General Hospital (MGH) granted Cede Review status to NASA on July 3, 2020. The NASA IRB granted full approval on Dec 8, 2020.

Integration of BRAIN-SANS with all study arms and other investigators: This involved increasing the scope from 3 study arms to 6 study arms, coordinating with other SANS-CM investigators for data sharing, and adjusting our measurement timeline based on feasibility, hardware, and personnel constraints.

Completion of Aim 1, development of the toolbox for multi-modal brain assessment: We assembled the required hardware and completed the needed customizations, configuration, and donning plans to achieve our measurement goals (see BRAIN-SANS Contribution, above). These measurements will be made during both rest and pre/during/post-countermeasure deployment.

Experimental preparations: We have all hardware ready for shipping to DLR, when that is warranted based on COVID-19 restrictions. We have assembled manuals for all devices to be used. We have also developed detailed protocols for DLR :envihab personnel to facilitate making the BRAIN-SANS measurements, as well as all training materials for virtual training of DLR personnel. During the training process, we expect that further optimizations will be made to the experimental protocol details—adding, removing, or modifying procedural steps to ensure more accurate, reliable, and thorough data collection from the study. This process will also continue into the early part of grant year 2 as the first SANS-CM Mission approaches. Ideally, further optimization can be completed in-person in the July-August 2021 timeframe.

SUMMARY

Despite challenges bought on by COVID-19 since the beginning of our funding, we have met all deadlines and achieved all required integration. We are thus on-track to conduct our component of the SANS-CM study as soon as it can feasibly be initiated.

• Intra-ocular pressure (IOP) tonometry, per our team’s prior SANS-relevant work.

• Relative intracranial pressure (ICP) measurements via distortion product otoacoustic emissions (distortion product otoacoustic emissions: DPOAE).

• Blood volume shifts along the body axis via near-infrared spectroscopy (NIRS).

• Intracranial blood inflow and outflow, via internal jugular vein (IJV) and carotid artery (CA) ultrasound cross-sectional imaging and Doppler.

• Cerebral pulsatility assessment, per our parabolic flight and SPACE-COT (Studying Physiological and Anatomical Cerebral Effects of CO2 and Tilt) :envihab NIRS study.

• Blood pressure at the level of the head via local, cuffless superficial temporal artery tonometry.

• Sagittal sinus blood volume imaging and monitoring using diffuse optical tomography (DOT).

• Cerebral edema assessment based on H2O concentration imaging, similar to that used in our previous altitude sickness studies.

• Cerebral electrical activity, via electroencephalogram (EEG) measurements.

• Dynamic cerebral autoregulation (CAR) assessment during countermeasure (CM) challenges, which can be derived from the NIRS signals used in the above measurements.

Our tools will be made fully compatible with the planned SANS countermeasures, as well as with those of other teams proposing specific CMs. Along with the measures, we will provide the necessary expertise and analysis to quantify physiological changes associated with SANS countermeasures deployed during the 30-day HDT campaigns at :envihab. Our specific aims are as follows:

Aim 1: Develop an integrated collection of hardware to support multiple simultaneous, continuous brain monitoring/imaging capabilities, and ensure the hardware and measurements are fully compatible with whatever countermeasures are deployed during the :envihab missions.

Aim 2: Characterize and quantify individual subjects’ physiological responses to each planned condition, including comparative assessment of SANS countermeasures.

Aim 3: Relate neurophysiological changes over the 30-day HDT—both with and without SANS-CMs—to cognitive and operational performance, sleep, mood, and ocular measures. Given NASA’s plan to deploy Standard Measures during the study, we expect data will be collected from Cognition, Robotic On-Board Trainer for Research (ROBoT-r), psychological/mood surveys, and the standard ocular measures (OCT, fundoscopy). We will obtain these measures through data sharing so we can investigate the relationship of our neurophysiological measures to each of these outcome assessments. We will focus particular attention on neurophysiological relationships with operational performance ROBoT-r, the development of which was led by Dr. Strangman and which we have deployed in Human Exploration Research Analog (HERA), Neumayer Station in Antarctica, and onboard the International Space Station (ISS).

Jointly, the planned measures and Aims will enable NASA to quantitatively evaluate and compare the (neuro)physiological changes and fluid shifts associated with HDT and SANS countermeasures.