Short Title: Ocular Health (Ocular Health Study)

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Space Medicine Medical Operations/NASA JSC

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Directed

Aims:
The International Space Station (ISS) Ocular Health Study aims to systematically gather physiological data to characterize the Risk of Spaceflight-Induced Intracranial Hypertension/Vision Alterations on crewmembers assigned to long-duration (6-12 month) ISS increments. The data collected will mirror Medical Requirements Integration Documents (MRID) requirements and testing performed during annual medical exams. The frequency of in-flight and postflight testing will be increased to more accurately assess changes that occur in the visual, vascular, and central nervous systems upon exposure to microgravity and induction of fluid shifting. Monitoring in-flight changes, in addition to postflight recovery, is the main focus of this protocol. A data sharing plan with Medical Operations will reduce redundancy of data acquisition. Preflight, in-flight and postflight measures include: tonometry, ocular ultrasound, fundoscopy, visual acuity, and optical coherence tomography (OCT); while magnetic resonance imaging (MRI), and bio-microscopy will be captured preflight and postflight exclusively. Three additional, non-MRID measures, will be collected preflight, in-flight and postflight, including blood pressure and cardiac output to assess vascular compliance, and transcranial Doppler (TCD) for Pulsatility Index (PI) to assess a surrogate measure of ICP. Data collection will begin one year prior to flight, continue in-flight approximately every 30 days, and continue through to one year postflight. In circumstances where abnormalities may persist beyond one year, postflight data will continue to be collected, but as per the MRID requirements (MedB 1.10) and Visual Impairment/Intracranial Pressure (VIIP) clinical practice guidelines.

Short Title: Fluid Shifts - Stenger

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:

The primary hypothesis of this proposal is that long duration space flight will induce a cephalad fluid shift and redistribution of fluid from intra- to extravascular space, resulting in increased facial interstitial thickness. This fluid redistribution will be more significant in a subset of astronauts that will also experience eye morphology changes and vision disturbances.

Specific Aim I: Determine distribution and compartmentalization of fluid volume (intracellular, extracellular, interstitial) during space flight and plasma volume after space flight.

Hypothesis 1: Plasma volume will be decreased post-flight compared to pre-flight.
Extracellular fluid volume will be decreased, intracellular fluid volume will be increased, and total body water will not change during long duration space flight.

Hypothesis 2: Ultrasound measures of fluid shift (interstitial thickness, venous diameter) and near infrared spectroscopy measures of tissue hydration will be elevated in the upper body and decreased in the lower body, during and after long duration space flight.

Specific Aim II: Determine effect of fluid distribution on visual acuity and its surrogates.

Hypothesis 3: Intraocular pressure, measured by tonometry, and optic nerve sheath diameter, a surrogate measure of intraocular pressure, will be increased with long duration space flight. The magnitude of this increase will be related to the magnitude of the measures of cephalad fluid shift.

Hypothesis 4: The magnitude of the changes in visual acuity will be related to the magnitude of the increase in optic nerve sheath diameter and tonometry measures of intraocular pressure.

Hypothesis 5: Recovery of visual acuity will be dependent on the recovery of optic nerve sheath diameter measures to preflight levels.

Specific Aim III: Correlate central venous pressure (CVP) to intraocular pressure as measured by tonometry and its surrogates.

Hypothesis 6: Central venous pressure will be elevated in those subjects who have elevated intraocular pressure after spaceflight, but not in subjects who do not have an elevation in intraocular pressure.

Specific Aim IV: Compare fluid shift measures and eye anatomy between acute 25 head down tilt and measures obtained during long duration space flight.

Hypothesis 7: The degree of pressure and anatomical changes to the eye during acute tilt will predict which subjects experience structural and functional changes during space flight.

Hypothesis 8: Post-bed flight acute tilts will reveal sub-clinical alterations that have occurred due to long duration space flight.

Specific Aim V: Compare the results obtained from space flight with those obtained from acute tilt and chronic head-down bed rest studies to assess whether bed rest is an adequate model of these space flight-induced adaptations. These comparisons will result from data sharing activities with bed rest measurements.

Hypothesis 9: The magnitude of the long duration space flight cephalad fluid shift on measures of fluid re-distribution can be predicted by the magnitude of similar responses during an acute pre-flight head-down tilt test.

Hypothesis 10: Observed magnitude in acute fluid shifts will be similar between spaceflight and bed rest, however the chronic distribution of that fluid between body compartments will be different between space flight and its analog. Changes in eye anatomy and function will be temporary in bed rest, while those observed during and following long-duration spaceflight will persist for months-years in some astronauts.

Short Title: Fluid Shifts - Dulchavsky

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:
The primary hypothesis of this proposal is that long duration space flight will induce a cephalad fluid shift and redistribution of fluid from intra- to extravascular space, resulting in increased facial interstitial thickness. This fluid redistribution will be more significant in a subset of astronauts that will also experience eye morphology changes and vision disturbances.

Specific Aim I: Determine distribution and compartmentalization of fluid volume (intracellular, extracellular, interstitial) during space flight and plasma volume after space flight.

Hypothesis 1: Plasma volume will be decreased post-flight compared to pre-flight.
Extracellular fluid volume will be decreased, intracellular fluid volume will be increased, and total body water will not change during long duration space flight.

Hypothesis 2: Ultrasound measures of fluid shift (interstitial thickness, venous diameter) and near infrared spectroscopy measures of tissue hydration will be elevated in the upper body and decreased in the lower body, during and after long duration space flight.

Specific Aim II: Determine effect of fluid distribution on visual acuity and its surrogates.

Hypothesis 3: Intraocular pressure, measured by tonometry, and optic nerve sheath diameter, a surrogate measure of intraocular pressure, will be increased with long duration space flight. The magnitude of this increase will be related to the magnitude of the measures of cephalad fluid shift.

Hypothesis 4: The magnitude of the changes in visual acuity will be related to the magnitude of the increase in optic nerve sheath diameter and tonometry measures of intraocular pressure.

Hypothesis 5: Recovery of visual acuity will be dependent on the recovery of optic nerve sheath diameter measures to preflight levels.

Specific Aim III: Correlate central venous pressure (CVP) to intraocular pressure as measured by tonometry and its surrogates.

Hypothesis 6: Central venous pressure will be elevated in those subjects who have elevated intraocular pressure after spaceflight, but not in subjects who do not have an elevation in intraocular pressure.

Specific Aim IV: Compare fluid shift measures and eye anatomy between acute 25 head down tilt and measures obtained during long duration space flight.

Hypothesis 7: The degree of pressure and anatomical changes to the eye during acute tilt will predict which subjects experience structural and functional changes during space flight.

Hypothesis 8: Post-bed flight acute tilts will reveal sub-clinical alterations that have occurred due to long duration space flight.

Specific Aim V: Compare the results obtained from space flight with those obtained from acute tilt and chronic head-down bed rest studies to assess whether bed rest is an adequate model of these space flight-induced adaptations. These comparisons will result from data sharing activities with bed rest measurements.

Hypothesis 9: The magnitude of the long duration space flight cephalad fluid shift on measures of fluid re-distribution can be predicted by the magnitude of similar responses during an acute pre-flight head-down tilt test.

Hypothesis 10: Observed magnitude in acute fluid shifts will be similar between spaceflight and bed rest, however the chronic distribution of that fluid between body compartments will be different between space flight and its analog. Changes in eye anatomy and function will be temporary in bed rest, while those observed during and following long-duration spaceflight will persist for months-years in some astronauts.

Short Title: Fluid Shifts - Hargens

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:
The primary hypothesis of this proposal is that long duration space flight will induce a cephalad fluid shift and redistribution of fluid from intra- to extravascular space, resulting in increased facial interstitial thickness. This fluid redistribution will be more significant in a subset of astronauts that will also experience eye morphology changes and vision disturbances.

Specific Aim I: Determine distribution and compartmentalization of fluid volume (intracellular, extracellular, interstitial) during space flight and plasma volume after space flight.

Hypothesis 1: Plasma volume will be decreased post-flight compared to pre-flight.
Extracellular fluid volume will be decreased, intracellular fluid volume will be increased, and total body water will not change during long duration space flight.

Hypothesis 2: Ultrasound measures of fluid shift (interstitial thickness, venous diameter) and near infrared spectroscopy measures of tissue hydration will be elevated in the upper body and decreased in the lower body, during and after long duration space flight.

Specific Aim II: Determine effect of fluid distribution on visual acuity and its surrogates.

Hypothesis 3: Intraocular pressure, measured by tonometry, and optic nerve sheath diameter, a surrogate measure of intraocular pressure, will be increased with long duration space flight. The magnitude of this increase will be related to the magnitude of the measures of cephalad fluid shift.

Hypothesis 4: The magnitude of the changes in visual acuity will be related to the magnitude of the increase in optic nerve sheath diameter and tonometry measures of intraocular pressure.

Hypothesis 5: Recovery of visual acuity will be dependent on the recovery of optic nerve sheath diameter measures to preflight levels.

Specific Aim III: Correlate central venous pressure (CVP) to intraocular pressure as measured by tonometry and its surrogates.

Hypothesis 6: Central venous pressure will be elevated in those subjects who have elevated intraocular pressure after spaceflight, but not in subjects who do not have an elevation in intraocular pressure.

Specific Aim IV: Compare fluid shift measures and eye anatomy between acute 25 head down tilt and measures obtained during long duration space flight.

Hypothesis 7: The degree of pressure and anatomical changes to the eye during acute tilt will predict which subjects experience structural and functional changes during space flight.

Hypothesis 8: Post-bed flight acute tilts will reveal sub-clinical alterations that have occurred due to long duration space flight.

Specific Aim V: Compare the results obtained from space flight with those obtained from acute tilt and chronic head-down bed rest studies to assess whether bed rest is an adequate model of these space flight-induced adaptations. These comparisons will result from data sharing activities with bed rest measurements.

Hypothesis 9: The magnitude of the long duration space flight cephalad fluid shift on measures of fluid re-distribution can be predicted by the magnitude of similar responses during an acute pre-flight head-down tilt test.

Hypothesis 10: Observed magnitude in acute fluid shifts will be similar between spaceflight and bed rest, however the chronic distribution of that fluid between body compartments will be different between space flight and its analog. Changes in eye anatomy and function will be temporary in bed rest, while those observed during and following long-duration spaceflight will persist for months-years in some astronauts.

Short Title: Cephalad Fluid Redistribution

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:
In order to fully characterize intracranial adaptation to long-term microgravity, we will use magnetic resonance imaging (MRI) which is the terrestrial gold standard. MRI allows direct visualization and functional characterization of the intracranial contents. Indeed, MR imaging is the clinical standard of care in evaluating patients with idiopathic intracranial hypertension. We will use a suite of advanced MRI sequences in conjunction with gadolinium contrast and a CO₂ challenge to: 1) characterize weightlessness-induced intracranial compartmental fluid volume changes at the macroscopic (brain, CSF), microscopic (brain tissue water) and vascular (venous) levels following adaptation to long-term spaceflight and 2) assess for potential resultant hemodynamic changes (cerebral perfusion) in the brain. This proposal represents the most relevant and advanced suit of MRI techniques for the characterization of intracranial compartmental fluid and hemodynamic changes induced by long-term microgravity. The specific sequences will be carried out by the recognized experts in each area and in most cases, the developer of the specific technique.

Short Title: DTI

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Space Medicine Medical Operations/NASA JSC

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:

The study uses diffusion tensor MRI of the brain to investigate alterations in nerve structure in correlation with intracranial pressure and compliance measures in astronauts pre- and post- microgravity exposure. The examination of brain microstructure has not been investigated in this context before and may reveal alterations to the brains of crewmembers.

 

The hypothesis that will be tested is that the degree of alteration in diffusion tensor (DT) metrics, including fractional anisotropy (FA) and mean diffusivity (MD), in cerebral optic and corticospinal (CST) tracts in astronauts correlates with the presence, severity, and duration of symptoms. This hypothesis will be tested using the following specific aims:

 

1. Quantify pre- and postflight diffusion tensor (DT) metrics, in the optic and corticospinal tracts of approximately 10 short duration (space shuttle missions) crewmembers, whose images are available for analysis.

 

2. Quantify pre- and postflight diffusion tensor (DT) metrics, in the optic and corticospinal tracts of approximately 10 long-duration (ISS missions) crewmembers whose images are available for analysis, starting with those scanned in 2010 and ending with those completing their mission by June 2013.

 

3. Determine and compare the presence of a significant alteration in DT metrics in those with and without in-flight and postflight signs/symptoms known to be secondary to microgravity exposure, and evaluate degree of correlation between DT metrics alteration and symptom/sign presence, severity and duration.

4. Obtain noninvasive MR measurement of intracranial compliance and pressure (MRICP) and evaluate the degree of correlation between DT metrics alteration and MRICP results.

 

5. Utilize all results to introduce an optimized conventional and diffusion MR imaging protocol.

Short Title: MR-ICP CSF Dynamics Retrospective

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Space Medicine Medical Operations/NASA JSC

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Directed

Aims:
This retrospective study will evaluate pre and postflight MRI data from long-duration (15) and short-duration (10) crew members to determine cerebrospinal fluid (CSF) dynamics, to identify potential changes due to space flight and the relationship with the VIIP syndrome.

Short Title: Vascular Compliance

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

NSBRI

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:

 

1. Determine whether noninvasive measures of venous and arterial compliance are altered by long-duration spaceflight exposure in ISS astronauts and whether these changes are related to the development of the VIIP Syndrome.

2. Using 14-days of 6° head-down tilt bed rest as a model of spaceflight, evaluate the effect of aging on vascular compliance using a subject population similar to younger (25-35 yrs) and older (45-55 yrs) astronaut cohorts.

3. Determine whether previous spaceflight experience or training in high performance jet aircraft predispose astronauts to lower venous compliance and/or the development of the VIIP syndrome.

Short Title: Microgravity ICP

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

NSBRI

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:

The primary objective of this study is to directly measure intracranial pressure, cerebral hemodynamics, and structure of the visual apparatus during changes in hydrostatic gradients (parabolic flight) that mimic microgravity exposure. To accomplish this objective the following hypotheses will be tested.

Hypothesis 1: The transition from the upright to the supine posture increases intracranial and right atrial pressures without a clinically significant change in ocular structure. The location of the intracranial hydrostatic indifference point (where rotation around that Gy axis in the Gz plane causes no change in hydrostatic pressure) determines the magnitude of the increase in ICP during changes in posture and in microgravity; if so, this characteristic could be a testable a risk factor for visual impairment in space.

 

Hypothesis 2: Microgravity-induced changes (via parabolic flight) in cerebral pressures and flow will be greater than those observed during bed rest.

To test these hypotheses, we will accomplish the following specific aims:

Specific Aim 1: We will recruit adult patients whom, because of prior medical treatment, have a brain access port from which ICP can be measured with little risk to the patient. Importantly, the selected patients will have no intracranial or cardiovascular pathology, and thus ICP can be measured accurately. Simultaneous measurement of right atrial pressure and arterial pressure will be combined with echo/Doppler measures of the middle cerebral artery, carotid and jugular vessels, and ocular ultrasound for central retinal and ciliary artery blood flow, globe size, shape and optic sheath diameter during 24 hours of head down tilt bedrest. These measures will allow a comprehensive assessment of cerebrovascular hemodynamics during routine gravitational transients. The hydrostatic indifference point will be determined in each volunteer.

Additional measurements will be made with modest increases in carbon dioxide concentrations, and during strength exercise to determine the independent and additive effects of these confounding stimuli. Finally, after the 24 hour measurements are completed, ICP will be monitored as the subject does a series of head maneuvers including lifting the head up on a pillow, and inflation of braslets to see if these simple interventions alter intracranial pressure.

Specific Aim 2: Subjects from Aim 1 will be exposed to parabolic flight (on a separate day) to achieve brief periods of microgravity. This protocol will allow comparison between real microgravity, and usual terrestrial changes in hydrostatic gradients during daily life (e.g., from supine to upright). Similar to aim 1, measurements will be obtained at rest, during exercise, and during small increases in carbon dioxide concentrations (10 parabolas each). The study of intracranial and cardiocerebral hemodynamics in microgravity has been largely unexplored. Only a careful dissection of the pathophysiology will allow the development of effective countermeasures that could ultimately lead to reducing the risk of visual impairments during space flight. Thus, this project will serve as the essential science base required to address a potential critical impediment to safe, long-duration space flight.

Short Title: CSF Exosome Ground

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:
This study will investigate changes in brain gene expression via exosome analysis in patients suffering from ICP elevation of varied severity (idiopathic intracranial hypertension –IIH). Our target population will be preferentially individuals with moderate ICP increase since their condition resembles more closely that of the astronauts exposed to microgravity in long duration spaceflight.

Short Title: Rodent CSF

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Human Health Countermeasures

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:

This study will investigate the hypothesis that hindlimb suspension induces structural and functional changes in choroid plexus (where CSF is produced) and arachnoid granulations (where CSF is absorbed), including evidence of inflammation or fibrosis, changes in aquaporin level and changes in cell-cell adhesion protein expression. Such changes are hypothesized to occur concomitant with fluid shift caused by the positional change, which may affect the production and paracellular/ transcellular CSF outflow and thus, CSF homeostasis. Supraphysiologic pressures in the in vitro model also simulates this fluid shift and allows for direct measurement of changes in paracellular/transcellular CSF outflow through the arachnoid cell layer. This task will evaluate and investigate these measures in a cohort of hindlimb suspended rats. Task completion will contribute to closing the knowledge gap surrounding the etiology of the VIIP syndrome by characterizing and quantifying the observed physiological changes.

 

In consideration of the experimental design of the parent animal experiment and its organization in cohorts, this study proposes the following specific aims:

1. To perform genome-wide expression analysis in the CP and AV of rats subjected to HS and their normal posture controls, including analysis of the expression of aquaporins (water-selective channels) at various time points within each of the two cohorts available for tissue sharing.

2. To study and compare the ultrastructure of the CP and AG and the localization and distribution of aquaporins and of cellular junction proteins (tight junctions, desmosomes, adherens junctions) of the endothelial cell layer of the venous sinuses, in normal posture and in HR rats within each cohort.

*Note: Due to the fact that it is unlikely that frozen brain will be made available from cohort 1 (young male rats), we will not be able to investigate gender or age differences in the response to

HS. Only longitudinal comparisons will be possible within each cohort. Depending on the sequence of cohorts implemented in the parental animal study, we will be provided with tissue from old male rats or young female rats (cohort 3) and any one of young males, young females, or aged males, exposed to enriched CO2 (cohort 4).

 

Short Title: Exercise Modality

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:

Characterize the impact of 3 exercise modalities used by astronauts on cerebral blood flow, ICP, and IOP. Use head down tilt (HDT), a ground based analog that is well established to elicit similar cephalad fluid shifts as spaceflight. Evaluate 3 HDT sessions: 1) HDT + resistance exercise, 2) HDT + moderate intensity aerobic exercise, and 3) HDT + high intensity aerobic exercise. During and following each HDT session cerebral blood flow, IOP, and ICP will be measured.

Short Title: Cerebrospinal Fluid Dynamics

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Funding Status: Planned-Funded - Task expected to be within budget

Procurement Mechanism(s):

Directed

Aims:
A prospective study to evaluate pre and postflight MRI data from long duration crew members to determine cerebrospinal fluid (CSF) dynamics, including CSF production and velocity to identify potential changes due to space flight and the relationship with the VIIP syndrome.

Short Title: Thirty-day CO2 Bedrest - Laurie

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Behavioral Health & Performance

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:

Specific Aim I

Determine if changes consistent with VIIP develop during 30 days of BR combined with 0.5% CO₂ and determine if physiologic changes such as an increase in P_ETCO₂, PCO₂ sensitivity, or noninvasive estimates of intracranial pressure (nICP) occur and correlate with VIIP symptoms.

 

Specific Aim II

Determine if 30 days of BR combined with 0.5% CO₂ causes changes in cognitive function, mood, or anxiety and if these changes correlate with the development of VIIP symptoms. We will use two cognitive function assessment tools: the Cognition battery, which is currently undergoing testing in other NASA analog environments and on ISS, and the Defense Automated Neurobehavioral Assessment (DANA), an additional tool to assess cognitive changes, mood, and anxiety that includes a normative database based on testing with active military personnel and athletes.

 

Specific Aim III

Determine if 30 days of BR combined with 0.5% CO₂ causes sleep disruption, alters circadian and ultradian rhythms, and if these changes correlate with the development of VIIP symptoms.

Short Title: Direct Intracranial Pressure Measurement

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Space Medicine Medical Operations/NASA JSC

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:

Specific Aim 1: Determine whether ICP in space is elevated in comparison to baseline ICP on Earth, and whether ICP after return to Earth differs from baseline values by measuring ICP in astronauts before, during, and after an ISS mission by invasive methods.

Specific Aim 2: Validate noninvasive ICP measurement methods and their correlation with invasive ICP before, during, and after spaceflight, and to quantify their error of measurement.

Specific Aim 3: Determine the correlation of ICP changes to other indicators of VIIP by collecting biomarkers of VIIP for correlation to ICP.

In addition to opening pressures, blood, urine, and cerebrospinal fluid (CSF) will be collected for biochemical and cytological analyses, including biomarkers unique to elevated ICP and choroid plexus and white matter damage. This study will be performed in conjunction with Zanello's "Multimodal Modeling towards Noninvasive Assessment of Intracranial Pressure in Weightlessness and Biomarker Identification of Predisposition to VIIP Syndrome."

Short Title: Ocular Structure - Flight

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Space Medicine Medical Operations/NASA JSC

Funding Status: Planned-Funded - Task expected to be within budget

Procurement Mechanism(s):

Solicited

Aims:

Data from Ocular Health (Otto), Fluid Shifts (Stenger/Hargens/Dulchavsky), Cranial Venous Circulation (Buckey), and Opthalmic Changes Modeling (Ethier) will inform the direction of this prospective flight study, which is anticipated to examine pre- and postflight measures of ocular structure and biomechanics (e.g. crowded disk, scleral thickness, optic canal opening, posterior eye radius, degree of myopia, intraocular pressure (IOP), corneal thickness, retinal pigmented epithelial angle (RPE), lens, and translaminar pressure gradient).  The task will contribute to gap closure by characterizing any pre/postflight changes in ocular structure and correlating these measures to the incidence and magnitude of symptoms of the VIIP syndrome.

 

Short Title: Long Term VIIP Impacts

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Funding Status: Planned-Funded - Task expected to be within budget

Procurement Mechanism(s):

Solicited

Aims:
VIIP has been previously titled NASA's number one health-related space flight risk. For 6-month missions the in-flight risk appears to be low, but the long-term VIIP-related consequences of a 6-month exposure to the space flight environment are yet unknown.

This task proposes to evaluate data from all past 6-month fliers (including those who flew long-duration missions on MIR and early in the ISS program), to evaluate whether there is any evidence for VIIP-related vision decline that is outside of the norm for the general age-matched population.

A secondary aim is to evaluate cognitive function in older, retired astronauts, compared with another high-functioning age-matched population (for example: retired military or commercial pilots) to evaluate whether there is any evidence that would support that elevated intracranial pressure, speculated to occur in space flight, detrimentally affects long term cognitive parameters.

This task will likely involve recruitment of past crewmembers (many of whom are now retired) to return to JSC for specialized testing.

Short Title: CSF Production and Outflow (Animal)

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Funding Status: Planned-Funded - Task expected to be within budget

Procurement Mechanism(s):

Solicited

Aims:

1. Investigate the role of cranial lymphatic drainage in a hind-limb suspended animal model
2. Determine whether hindlimb suspension induces structural and functional changes in choroid plexus (where CSF is produced) and arachnoid granulations (where CSF is absorbed)

 

This study will investigate the hypothesis that hindlimb suspension induces structural and functional changes in choroid plexus (where CSF is produced) and arachnoid granulations (where CSF is absorbed), including evidence of inflammation or fibrosis, changes in aquaporin level and changes in cell-cell adhesion protein expression. Such changes are hypothesized to occur concomitant with fluid shift caused by the positional change, which may affect the production and paracellular/ transcellular CSF outflow and thus, CSF homeostasis. Supraphysiologic pressures in the in vitro model also simulates this fluid shift and allows for direct measurement of changes in paracellular/transcellular CSF outflow through the arachnoid cell layer. This task will evaluate and investigate these measures in a cohort of hindlimb suspended animals. Task completion will contribute to closing the knowledge gap surrounding the etiology of the VIIP syndrome by characterizing and quantifying the observed physiological changes.

Short Title: Compartment Syndrome

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Funding Status: Planned-Funded - Task expected to be within budget

Procurement Mechanism(s):

Solicited

Aims:
1. Investigate whether compartmentalization is a component of VIIP. Use an animal model to assess venous engorgement of the eye and pressurized optic nerve sheath without elevated intracranial pressure.
2. Evaluate ischemia, inflammation, and locally toxic substances.

Short Title: Biomarker Noninvasive ICP

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:

Specific Aim 1 (Hypothesis #1 and #2)

- To develop and validate a noninvasive ICP estimation (nICP) approach for a specific

population of crewmembers based on a noninvasive ICP framework (NICF). The anticipated

input parameters may include: arterial blood pressure (ABP), electrocardiogram signals, cerebral

blood flow velocity (CBFV), heart and ventilation rate, tympanic membrane displacement by

Cochlear and Cerebrospinal Fluid Pressure (CCFP), ophthalmic artery blood pressure by

Vittamed. The NICF has been only tested using ABP and CBFV data from brain injury patients.

The additional noninvasive data elements provide different aspects of cerebral physiology under

influence of ICP. Therefore, integrating them under the NICF is very likely to improve nICP

accuracy.

4

Specific Aim 2 (Hypothesis #2)

- To longitudinally estimate ICP in crew members before, during and after spaceflight using the

model developed in Aim 1.

Specific Aim 3 (Hypothesis #3)

- To use novel methods of mRNA and microRNA profiling to identify candidate urinary and

plasma biomarkers that align with VIIP-related physiologic variables.

Specific Aim 4 (Hypothesis #4)

-To measure and correlate novel biomarkers in urine and blood of crew members with measures

of estimated ICP, pre-, in- and post-flight.

-To use all noninvasive measures plus biomarkers as input to build a predictive model that will

inform the likelihood of a given crew member developing VIIP post flight.



This study will be performed in conjunction with Williams' "Zero G and ICP." It also informs gaps VIIP3, VIIP13, and CV7.

Short Title: 1C, PCOS, and VIIP

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Directed

Aims:

1. Test for SNPs of each of 44 major genes (351 SNPs) involved in one-carbon metabolism in astronauts, and relate these to existing biochemical, vision and related medical data.
2. Gather ethnicity data from the crewmembers, and determine whether ethnicity is predictive of vision issues after long-duration space flight.
3. Compare biochemical, genetic, and ophthalmological data from PCOS patients and an age-matched control group.

 

Short Title: Thirty-day CO2 Bedrest - Alperin

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Behavioral Health & Performance

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:
1. Use novel technology that quantifies the degree of the globe distortions by MRI to assess the efficacy of head-down bed rest as a ground-based analog for VIIP. Detect and measure the magnitude of changes in globe flattening, optic nerve protrusion, visual acuity, and other related imaging measures that might be induced by subjects undergoing 30 days of head-down bed rest. The magnitude of the changes observed in bed rest will be compared to those measured in astronauts with and without signs of the VIIP syndrome.

2.  Assess the efficacy of bed rest as a behavioral, health, and performance stressor. Neurocognitive tests, some of which are similar to those performed aboard ISS, will be administered to the subjects and compared to available data from ISS to determine the efficacy of the bed-rest model as a ground-based analog for cognitive and behavioral modifiers.

Short Title: AG dose

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:

Characterize the relationship between gravitational dose and acute physiologic responses of the cardiovascular, cerebrovascular, ocular, muscular, and sensorimotor systems.

Short Title: Pull-Push Gz Fluid Shifts

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Aims:

Specific Aim 1: To determine the impact of sequential +1 Gz followed by -0.3 Gz stress

on cerebrovascular and ocular structure and function without the orthostatic intolerance

countermeasures normally applied in astronauts returning from space flight.

Hypothesis: Following +1.0 Gz exposure, –Gz exposure will increase jugular vein

distention and pressure, increase intraocular and intracranial pressure, and distend

optic nerve sheath diameter but not change cerebral blood flow velocity.

Specific Aim 2: To determine the effect of anti-orthostatic countermeasures (fluid

loading, gradient compression garments, legs up posture with foot pressure) on the +1

Gz to -0.3 Gz induced fluids shift and subsequent impact on cerebral and ocular

structure and function.

Hypothesis: The addition of the anti-orthostatic countermeasures will exacerbate ocular

and vascular effects induced by the HDT fluid shift and will overcome the ability of

cerebral autoregulation to minimize these changes resulting in clinically significant

elevations in ICP.

Short Title: VIIP SCHOLAR

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:

 The aim is to develop modeling tools that: (i) compute fluid shifts in microgravity; (ii) compute how these shifts lead to biomechanical insult to the optic nerve in astronauts; and (iii) estimate the effect that these insults have on optic nerve function. These tools will directly build upon, and interface with, models of ocular biomechanics and fluid shifts that are currently being developed in

the NASA-funded MONSTR Sim project. Four specific aims were proposed:

SA1: Measure key physiologic parameters needed for modeling, including effects of intracranial pressure on optic nerve sheath

diameter, optic nerve tortuosity, craniospinal volume and cerebral blood flow.

SA2: Incorporate “quasi-1D” effects into existing compartment models, allowing us to evaluate the effects of microgravity and

countermeasures on CSF and blood flows/pressures.

SA3: Extend finite element models of ocular biomechanics, specifically modeling: (i) optic nerve kinking, and (ii) compression of optic

nerve fiber bundles in the lamina cribrosa; and relate kinking/compression to an index of axoplasmic insult/stasis.

SA4: Carry out parametric studies integrating the above models to identify individual-specific factors that: (i) predispose for the

development of VIIP syndrome, and (ii) influence the efficacy of proposed countermeasures, both useful for risk profiling

Short Title: Ultrasound ICP

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Exploration Medical Capability NSBRI

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:
1. Develop a volumetric ultrasound ophthalmic imaging system with improved image quality providing user independent, 3D imaging of the full ocular anatomy for pre-flight scans, postflight scans, and in-flight scans with minimal crew time and ground guidance during image capture.

2. Enable multimodality volume registration of in-flight ultrasound and pre-flight magnetic resonance (MR) ophthalmic scans enabling the ability to longitudinally track structural alterations in response to microgravity and correlate these ocular structural changes with elevated ICP and visual acuity changes.

3. Non-invasively monitor the ICP based on reliable measurements of the optic nerve sheath diameter and posterior globe flattening determined from volumetric ultrasound scan scans performed by non-expert operators with minimal image capture time required.

4. Non-invasively observe intracranial dynamics through measurement of the pulsation in the retinal blood flow and the optic nerve sheath from ultrasound image sequences and demonstrate the interaction between ICP and cerebral hemodynamics as they relate to cerebrospinal compensatory reserve.

Short Title: Retinal Vascular Remodeling

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:

Alterations in vascular patterning of the human retina responding to fluid shifts incurred by spaceflight will be mapped and quantified by analyzing existing pre- and postflight Optical Coherence Tomography (OCT) images. A complementary analysis of retrospective bedrest images will also be performed.

Short Title: Non-invasive Intracranial Pressure (ICP) Validation

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

NSBRI

Funding Status: Planned-Funded - Task expected to be within budget

Procurement Mechanism(s):

Aims:
This study will perform the flight validation of the non-invasive ICP device identified during ground testing by comparing to a direct intracranial pressure measurement (lumbar puncture or a direct implantable probe).

Short Title: Retinal Vascular Remodeling - Flight

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Space Medicine Medical Operations/NASA JSC

Funding Status: Planned-Unfunded - Task not within current budget

Procurement Mechanism(s):

Aims:

This study aims to use Optical Coherence Tomography (OCT) imaging pre-, in-, and postflight to evaluate for retinal microvascular remodeling that might occur pre-symptomatically as a result of adaptation to microgravity. The task will contribute to knowledge base closure by documenting microvascular structural changes in the eye that might precede clinical manifestations of the VIIP syndrome, thus allowing early diagnosis.

Short Title: Vittamed 2

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

NSBRI

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Directed

Aims:
1. Assess the accuracy of the newest generation of the non-invasive intracranial pressure (ICP) meter (Vittamed) compared to simultaneous ICP measurement in subjects with an Ommaya reservoir or undergoing lumbar CSF pressure measurements.

2. Assess the accuracy (sensitivity and specificity) of the non-invasive ICP meter to detect acute changes in ICP induced by body tilt in Ommaya reservoir undergoing invasive ICP measurements, or in patients undergoing lumbar CSF drainage.

Short Title: Ocular Blood Flow SBIR

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:
There is currently no device that performs both structural and hemodynamic analysis of the retina and choroid. The PI proposes an integrated device that can do both, and moreover include both spatial and temporal resolution.

Short Title: metabolomic alterations

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:

Identify metabolomic profiles associated with simulated space flight induced

physiological outcomes.

Identify changes in metabolomic pathways associated with simulated space flight

induced physiological changes by applying metabolomic approaches described in Aim 1 on

longitudinally collected urine and serum samples.

Test whether plasma metabolites have the potential to regulate cellular

metabolism and if specific changes in metabolism may be a means of detecting the risk for or

monitoring the progression of physiological outcomes induced by a simulated space flight

Short Title: Rodent model for VIIP

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Human Health Countermeasures

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:
To determine if the cephalic fluid shift seen during microgravity exposure is the causative factor leading to the ocular changes seen in astronauts after long-term space flight (Watkins and Barr 2010) (Mader, Gibson et al. 2011). The Hind Limb Suspended (HLS) rat model of microgravity will be used to answer the following specific aims. The HLS rat model will allow us to approach these questions and more rapidly achieve the program objectives. A 90-day suspension experiment utilizing the rat model, which we have performed numerous times, is roughly equivalent to a 2.5-year exploration class mission, or bedrest study, in a human subject based on lifespans.

Specific Aim 1. To determine if the microgravity model of rat hindlimb suspension (HLS)
results in increased intracranial (IOP) and intraocular (IOP) pressures, as well as alterations in ophthalmic anatomy and/or function.

In order to answer this specific aim, we will test the following hypotheses:

Hypothesis 1a. HLS male rats will have a higher ICP and IOP than control male rats. Further, the HLS male rats will have altered ophthalmic morphology and function including, but not limited to, flattening of the globe, increased diameter of the optic nerve and alterations in retinal function.
Hypothesis 1b. Post-suspension, ICP and IOP will return to pre-suspension levels and ophthalmic morphology and function will also recover over time.

Specific Aim 2. To determine if there is a gender differences in the ophthalmic responses to increased ICP and IOP.

In order to answer this specific aim, we will test the following hypotheses:

2a. HLS will results in increased ICP, IOP and altered ophthalmic features in female animals compared to female controls, but the responses will not be different from HLS males studied in
Specific Aim 1.
2b. Post-suspension recovery of ICP, IOP and ophthalmic features in female rats will not have a longer time course compared to the HLS males of Specific Aim 1.

Specific Aim 3. To determine if aging increases the ophthalmic responses to increased ICP and IOP.

In order to answer this specific aim, we will test the following hypotheses:

3a. The effects of HLS on ICP, IOP and ophthalmic features will be greater in older animals compared to both age-matched controls and the younger HLS males of Specific Aim 1.
3b. Post-suspension recovery of ICP, IOP and ophthalmic features will have a longer time course in older rats compared to the younger HLS males of Specific Aim 1.

Specific Aim 4. To determine if elevated atmospheric carbon dioxide (CO2) levels affect the ophthalmic responses to increased ICP and IOP in male rats.

In order to answer this specific aim, we will test the following hypotheses:

4a. The effects of HLS in young male rats on ICP, IOP and ophthalmic features will be increased in a mildly hypercapnic environment compared both to hypercapnic controls and the HLS males of Specific Aim 1 in room air.

4b. Post-suspension recovery of ICP, IOP and ophthalmic features in young male rats will have a longer time course in male rats simultaneously exposed to HLS and increased CO2 levels, compared to controls and the recovery of HLS males in Specific Aim 1 in room air.

This study combines two studies from the 2011 NRA: C. Fuller and S. Zanello.

Short Title: Hindlimb Suspension Model ICP

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:
The awarded study was combined with a complementary analog study from 2011 NRA PI: Charles Fuller.

To determine if the cephalic fluid shift seen during microgravity exposure is the causative factor leading to the ocular changes seen in astronauts after long-term space flight (Watkins and Barr 2010) (Mader, Gibson et al. 2011). The Hind Limb Suspended (HLS) rat model of microgravity will be used to answer the following specific aims. The HLS rat model will allow us to approach these questions and more rapidly achieve the program objectives. A 90-day suspension experiment utilizing the rat model, which we have performed numerous times, is roughly equivalent to a 2.5-year exploration class mission, or bedrest study, in a human subject based on lifespans.

Specific Aim 1. To determine if the microgravity model of rat hindlimb suspension (HLS)
results in increased intracranial (IOP) and intraocular (IOP) pressures, as well as alterations in ophthalmic anatomy and/or function.

In order to answer this specific aim, we will test the following hypotheses:

Hypothesis 1a. HLS male rats will have a higher ICP and IOP than control male rats. Further, the HLS male rats will have altered ophthalmic morphology and function including, but not limited to, flattening of the globe, increased diameter of the optic nerve and alterations in retinal function.
Hypothesis 1b. Post-suspension, ICP and IOP will return to pre-suspension levels and ophthalmic morphology and function will also recover over time.

Specific Aim 2. To determine if there is a gender differences in the ophthalmic responses to increased ICP and IOP.

In order to answer this specific aim, we will test the following hypotheses:

2a. HLS will results in increased ICP, IOP and altered ophthalmic features in female animals compared to female controls, but the responses will not be different from HLS males studied in
Specific Aim 1.
2b. Post-suspension recovery of ICP, IOP and ophthalmic features in female rats will not have a longer time course compared to the HLS males of Specific Aim 1.

Specific Aim 3. To determine if aging increases the ophthalmic responses to increased ICP and IOP.

In order to answer this specific aim, we will test the following hypotheses:

3a. The effects of HLS on ICP, IOP and ophthalmic features will be greater in older animals compared to both age-matched controls and the younger HLS males of Specific Aim 1.
3b. Post-suspension recovery of ICP, IOP and ophthalmic features will have a longer time course in older rats compared to the younger HLS males of Specific Aim 1.

Specific Aim 4. To determine if elevated atmospheric carbon dioxide (CO2) levels affect the ophthalmic responses to increased ICP and IOP in male rats.

In order to answer this specific aim, we will test the following hypotheses:

4a. The effects of HLS in young male rats on ICP, IOP and ophthalmic features will be increased in a mildly hypercapnic environment compared both to hypercapnic controls and the HLS males of Specific Aim 1 in room air.

4b. Post-suspension recovery of ICP, IOP and ophthalmic features in young male rats will have a longer time course in male rats simultaneously exposed to HLS and increased CO2 levels, compared to controls and the recovery of HLS males in Specific Aim 1 in room air.

Short Title: Cranial Venous Circulation

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

NSBRI

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:

1. Develop a numerical model to estimate changes in intracranial venous

flow, volume, compliance and pressure in response to a fluid shift and changes in

hydrostatic gradients. Include tissue compressive forces in the model.

2. Determine the cranial venous changes produced by fluid shifts and

altered hydrostatic gradients. Use interventions that can produce fluid shifts

(lower body negative pressure and lower body positive pressure) and alter

hydrostatic gradients (supine and prone postures). These experiments are

designed to provide data for validating and verifying the model developed as a

part of Aim #1.

3. Identify individuals with common intracranial venous variants, and study

them using the protocol outlined in Aim #2.

By building and validating a numerical model, we will be able to use the model to: (a)

develop hypotheses about spaceflight visual changes, (b) provide estimates of likely

changes in intracranial pressure and venous pressure in space, and (c) offer predictions

about future visual changes in an individual. This could provide unique insights into the

etiology of microgravity-induced vision changes, as well as serve as a diagnostic tool.

Short Title: Ophthalmic Changes Modeling

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Human Health Countermeasures

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:

1. Develop validated tools for computing IOP and ICP in microgravity. These tools will be based on modeling of fluid shifts between the eye and various compartments in the cardiovascular, cerebrospinal and lymphatic systems.

2. Develop validated finite element-based tools for computing the biomechanical environment and subsequent connective tissue remodeling in the optic nerve head, optic nerve sheath and posterior globe. These tools will be complemented by a model of the eye's optical performance.

3. Integrate the models from Aims 1 and 2 to produce a unified, open and extensible software package that can predict ocular biomechanics and ocular connective tissue remodeling under microgravity conditions.

4. Use the integrated model of Aim 3 to study clinically observable attributes and determine the role they may play in the development of VIIP.

Short Title: Thirty-day CO2 Bedrest - Laurie

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Behavioral Health & Performance

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:

Specific Aim I

Determine if changes consistent with VIIP develop during 30 days of BR combined with 0.5% CO₂ and determine if physiologic changes such as an increase in P_ETCO₂, PCO₂ sensitivity, or noninvasive estimates of intracranial pressure (nICP) occur and correlate with VIIP symptoms.

 

Specific Aim II

Determine if 30 days of BR combined with 0.5% CO₂ causes changes in cognitive function, mood, or anxiety and if these changes correlate with the development of VIIP symptoms. We will use two cognitive function assessment tools: the Cognition battery, which is currently undergoing testing in other NASA analog environments and on ISS, and the Defense Automated Neurobehavioral Assessment (DANA), an additional tool to assess cognitive changes, mood, and anxiety that includes a normative database based on testing with active military personnel and athletes.

 

Specific Aim III

Determine if 30 days of BR combined with 0.5% CO₂ causes sleep disruption, alters circadian and ultradian rhythms, and if these changes correlate with the development of VIIP symptoms.

Short Title: DA VIIP

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

NASA GRC

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Directed

Aims:
VIIP modeling activities. This is a collaborative effort between Glenn Research Center, Johnson Space Center, and external scientists.

Short Title: SPACECOT

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

NSBRI

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Directed

Aims:

Specific Aim 1 – Determine the qualitative and quantitative changes in CBF, ICV, ICP, cognitive function and ocular structure from 1% CO2 /-12 degree HDT condition compared to ambient air/-12 degree HDT and ambient air/upright conditions using non-invasive brain/ocular monitoring devices and MRI.

Specific Aim 2 – Determine the acute (2 hours) effects of 3% CO2 /-12 HDT on CBF, ICV and cognitive function and ocular structure compared to 1% CO2 /-12 HDT, ambient/-12 HDT or ambient air/upright conditions using non-invasive brain/ocular monitoring devices and MRI.

Specific Aim 3 – Evaluate the suitability of Envihab-DLR to successful implement multiple measures in 3 simultaneous subjects in bed-rest position, and perform NASA standard measures for ground-based analogs of spaceflight.

Short Title: Thirty-day CO2 Bedrest - Alperin

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Behavioral Health & Performance

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:
1. Use novel technology that quantifies the degree of the globe distortions by MRI to assess the efficacy of head-down bed rest as a ground-based analog for VIIP. Detect and measure the magnitude of changes in globe flattening, optic nerve protrusion, visual acuity, and other related imaging measures that might be induced by subjects undergoing 30 days of head-down bed rest. The magnitude of the changes observed in bed rest will be compared to those measured in astronauts with and without signs of the VIIP syndrome.

2.  Assess the efficacy of bed rest as a behavioral, health, and performance stressor. Neurocognitive tests, some of which are similar to those performed aboard ISS, will be administered to the subjects and compared to available data from ISS to determine the efficacy of the bed-rest model as a ground-based analog for cognitive and behavioral modifiers.

Short Title: Ocular Blood Flow SBIR

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:
There is currently no device that performs both structural and hemodynamic analysis of the retina and choroid. The PI proposes an integrated device that can do both, and moreover include both spatial and temporal resolution.

Short Title: Fluid Shifts - Stenger

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:

The primary hypothesis of this proposal is that long duration space flight will induce a cephalad fluid shift and redistribution of fluid from intra- to extravascular space, resulting in increased facial interstitial thickness. This fluid redistribution will be more significant in a subset of astronauts that will also experience eye morphology changes and vision disturbances.

Specific Aim I: Determine distribution and compartmentalization of fluid volume (intracellular, extracellular, interstitial) during space flight and plasma volume after space flight.

Hypothesis 1: Plasma volume will be decreased post-flight compared to pre-flight.
Extracellular fluid volume will be decreased, intracellular fluid volume will be increased, and total body water will not change during long duration space flight.

Hypothesis 2: Ultrasound measures of fluid shift (interstitial thickness, venous diameter) and near infrared spectroscopy measures of tissue hydration will be elevated in the upper body and decreased in the lower body, during and after long duration space flight.

Specific Aim II: Determine effect of fluid distribution on visual acuity and its surrogates.

Hypothesis 3: Intraocular pressure, measured by tonometry, and optic nerve sheath diameter, a surrogate measure of intraocular pressure, will be increased with long duration space flight. The magnitude of this increase will be related to the magnitude of the measures of cephalad fluid shift.

Hypothesis 4: The magnitude of the changes in visual acuity will be related to the magnitude of the increase in optic nerve sheath diameter and tonometry measures of intraocular pressure.

Hypothesis 5: Recovery of visual acuity will be dependent on the recovery of optic nerve sheath diameter measures to preflight levels.

Specific Aim III: Correlate central venous pressure (CVP) to intraocular pressure as measured by tonometry and its surrogates.

Hypothesis 6: Central venous pressure will be elevated in those subjects who have elevated intraocular pressure after spaceflight, but not in subjects who do not have an elevation in intraocular pressure.

Specific Aim IV: Compare fluid shift measures and eye anatomy between acute 25 head down tilt and measures obtained during long duration space flight.

Hypothesis 7: The degree of pressure and anatomical changes to the eye during acute tilt will predict which subjects experience structural and functional changes during space flight.

Hypothesis 8: Post-bed flight acute tilts will reveal sub-clinical alterations that have occurred due to long duration space flight.

Specific Aim V: Compare the results obtained from space flight with those obtained from acute tilt and chronic head-down bed rest studies to assess whether bed rest is an adequate model of these space flight-induced adaptations. These comparisons will result from data sharing activities with bed rest measurements.

Hypothesis 9: The magnitude of the long duration space flight cephalad fluid shift on measures of fluid re-distribution can be predicted by the magnitude of similar responses during an acute pre-flight head-down tilt test.

Hypothesis 10: Observed magnitude in acute fluid shifts will be similar between spaceflight and bed rest, however the chronic distribution of that fluid between body compartments will be different between space flight and its analog. Changes in eye anatomy and function will be temporary in bed rest, while those observed during and following long-duration spaceflight will persist for months-years in some astronauts.

Short Title: Fluid Shifts - Hargens

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:
The primary hypothesis of this proposal is that long duration space flight will induce a cephalad fluid shift and redistribution of fluid from intra- to extravascular space, resulting in increased facial interstitial thickness. This fluid redistribution will be more significant in a subset of astronauts that will also experience eye morphology changes and vision disturbances.

Specific Aim I: Determine distribution and compartmentalization of fluid volume (intracellular, extracellular, interstitial) during space flight and plasma volume after space flight.

Hypothesis 1: Plasma volume will be decreased post-flight compared to pre-flight.
Extracellular fluid volume will be decreased, intracellular fluid volume will be increased, and total body water will not change during long duration space flight.

Hypothesis 2: Ultrasound measures of fluid shift (interstitial thickness, venous diameter) and near infrared spectroscopy measures of tissue hydration will be elevated in the upper body and decreased in the lower body, during and after long duration space flight.

Specific Aim II: Determine effect of fluid distribution on visual acuity and its surrogates.

Hypothesis 3: Intraocular pressure, measured by tonometry, and optic nerve sheath diameter, a surrogate measure of intraocular pressure, will be increased with long duration space flight. The magnitude of this increase will be related to the magnitude of the measures of cephalad fluid shift.

Hypothesis 4: The magnitude of the changes in visual acuity will be related to the magnitude of the increase in optic nerve sheath diameter and tonometry measures of intraocular pressure.

Hypothesis 5: Recovery of visual acuity will be dependent on the recovery of optic nerve sheath diameter measures to preflight levels.

Specific Aim III: Correlate central venous pressure (CVP) to intraocular pressure as measured by tonometry and its surrogates.

Hypothesis 6: Central venous pressure will be elevated in those subjects who have elevated intraocular pressure after spaceflight, but not in subjects who do not have an elevation in intraocular pressure.

Specific Aim IV: Compare fluid shift measures and eye anatomy between acute 25 head down tilt and measures obtained during long duration space flight.

Hypothesis 7: The degree of pressure and anatomical changes to the eye during acute tilt will predict which subjects experience structural and functional changes during space flight.

Hypothesis 8: Post-bed flight acute tilts will reveal sub-clinical alterations that have occurred due to long duration space flight.

Specific Aim V: Compare the results obtained from space flight with those obtained from acute tilt and chronic head-down bed rest studies to assess whether bed rest is an adequate model of these space flight-induced adaptations. These comparisons will result from data sharing activities with bed rest measurements.

Hypothesis 9: The magnitude of the long duration space flight cephalad fluid shift on measures of fluid re-distribution can be predicted by the magnitude of similar responses during an acute pre-flight head-down tilt test.

Hypothesis 10: Observed magnitude in acute fluid shifts will be similar between spaceflight and bed rest, however the chronic distribution of that fluid between body compartments will be different between space flight and its analog. Changes in eye anatomy and function will be temporary in bed rest, while those observed during and following long-duration spaceflight will persist for months-years in some astronauts.

Short Title: Fluid Shifts - Dulchavsky

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:
The primary hypothesis of this proposal is that long duration space flight will induce a cephalad fluid shift and redistribution of fluid from intra- to extravascular space, resulting in increased facial interstitial thickness. This fluid redistribution will be more significant in a subset of astronauts that will also experience eye morphology changes and vision disturbances.

Specific Aim I: Determine distribution and compartmentalization of fluid volume (intracellular, extracellular, interstitial) during space flight and plasma volume after space flight.

Hypothesis 1: Plasma volume will be decreased post-flight compared to pre-flight.
Extracellular fluid volume will be decreased, intracellular fluid volume will be increased, and total body water will not change during long duration space flight.

Hypothesis 2: Ultrasound measures of fluid shift (interstitial thickness, venous diameter) and near infrared spectroscopy measures of tissue hydration will be elevated in the upper body and decreased in the lower body, during and after long duration space flight.

Specific Aim II: Determine effect of fluid distribution on visual acuity and its surrogates.

Hypothesis 3: Intraocular pressure, measured by tonometry, and optic nerve sheath diameter, a surrogate measure of intraocular pressure, will be increased with long duration space flight. The magnitude of this increase will be related to the magnitude of the measures of cephalad fluid shift.

Hypothesis 4: The magnitude of the changes in visual acuity will be related to the magnitude of the increase in optic nerve sheath diameter and tonometry measures of intraocular pressure.

Hypothesis 5: Recovery of visual acuity will be dependent on the recovery of optic nerve sheath diameter measures to preflight levels.

Specific Aim III: Correlate central venous pressure (CVP) to intraocular pressure as measured by tonometry and its surrogates.

Hypothesis 6: Central venous pressure will be elevated in those subjects who have elevated intraocular pressure after spaceflight, but not in subjects who do not have an elevation in intraocular pressure.

Specific Aim IV: Compare fluid shift measures and eye anatomy between acute 25 head down tilt and measures obtained during long duration space flight.

Hypothesis 7: The degree of pressure and anatomical changes to the eye during acute tilt will predict which subjects experience structural and functional changes during space flight.

Hypothesis 8: Post-bed flight acute tilts will reveal sub-clinical alterations that have occurred due to long duration space flight.

Specific Aim V: Compare the results obtained from space flight with those obtained from acute tilt and chronic head-down bed rest studies to assess whether bed rest is an adequate model of these space flight-induced adaptations. These comparisons will result from data sharing activities with bed rest measurements.

Hypothesis 9: The magnitude of the long duration space flight cephalad fluid shift on measures of fluid re-distribution can be predicted by the magnitude of similar responses during an acute pre-flight head-down tilt test.

Hypothesis 10: Observed magnitude in acute fluid shifts will be similar between spaceflight and bed rest, however the chronic distribution of that fluid between body compartments will be different between space flight and its analog. Changes in eye anatomy and function will be temporary in bed rest, while those observed during and following long-duration spaceflight will persist for months-years in some astronauts.

Short Title: Exercise Modality

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:

Characterize the impact of 3 exercise modalities used by astronauts on cerebral blood flow, ICP, and IOP. Use head down tilt (HDT), a ground based analog that is well established to elicit similar cephalad fluid shifts as spaceflight. Evaluate 3 HDT sessions: 1) HDT + resistance exercise, 2) HDT + moderate intensity aerobic exercise, and 3) HDT + high intensity aerobic exercise. During and following each HDT session cerebral blood flow, IOP, and ICP will be measured.

Short Title: Mechanical Countermeasures - Marketed Devices

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Human Health Countermeasures NSBRI

Funding Status: Active - Currently funded and in progress

Procurement Mechanism(s):

Solicited

Aims:

The objective is to test two qualitatively distinct countermeasures (CMs) for VIIP, based on the

assumption that VIIP is caused—or influenced—by cephalad fluid shifts. Studies will be

conducted at MGH as well as at Baylor College of Medicine/NSBRI Center for Space Medicine.

Aim 1: Identify and characterize cerebrovascular and/or ophthalmological parameters altered

by cephalad fluid shifts that are mitigated by mechanical countermeasures.

Aim 2: Identify and characterize any rebound effects or other adverse occurrences when use of

the mechanical countermeasure device is discontinued.

Aim 3: Quantify the effect of two mechanical countermeasures on their ability to reduce

invasively-measured continuous ICP.

Aim 4: Determine if gradual CM discontinuation is safer than abrupt discontinuation.

Aim 5: Quantify the relationship between CM exposure time vs. ICP reduction (and rebound).

Short Title: Vision Countermeasure Optimization

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Funding Status: Planned-Funded - Task expected to be within budget

Procurement Mechanism(s):

Aims:
This is a flight study that will optimize a combination countermeasure of pharmaceuticals with aerobic exercise and/or mechanical intervention to mitigate the VIIP syndrome. This follow-on study to VIIP Countermeasure Development was scrubbed from the HHC flight queue and should not be reflected in the ISSMP Fly-off plan. It remains as a placeholder task in the IRP.

Short Title: Drug Vision (VIIP) Countermeasure Flight

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Funding Status: Planned-Funded - Task expected to be within budget

Procurement Mechanism(s):

Solicited

Aims:
Flight testing of the ground validated pharmaceutical countermeasure to determine the efficacy when used during flight to mitigate the VIIP syndrome. Might include acetazolamide, manipulation of AQP1 and AQP4, atrial natriuretic peptide to decrease ICP, and drug to decrease CSF production.

Short Title: VIIP Countermeasures Development

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Funding Status: Planned-Funded - Task expected to be within budget

Procurement Mechanism(s):

Solicited

Aims:

This is a follow-on study to “Fluid Shifts.” The aims will be determined by the outcome of Fluid Shifts and will be specified in a future update to the Research Plan.  At this time, an evaluation of one or more of the following measures is anticipated to be investigated as a potential target for further countermeasure development: cephalad fluid shift, CO_2, exercise, sodium consumption and/or changes in vascular function, neurohumoral control of vascular function, baroreflex sensitivity, sympathetic nervous system tone, endothelial nitric oxide production, endothelin, and inflammatory cytokines.

Short Title: Vision Countermeasures Bedrest

Responsible HRP Element: Human Health Countermeasures

Collaborating Org(s):

Funding Status: Planned-Funded - Task expected to be within budget

Procurement Mechanism(s):

Solicited

Aims:

This ground analog study will evaluate various countermeasures to mitigate the VIIP syndrome. The countermeasures, which are yet TBD, may include mechanical or other interventions and may be evaluated alone or in combination.