Nourishing the brain on deep space missions: nutritional psychiatry in promoting resilience.

The grueling psychological demands of a journey into deep space coupled with ever-increasing distances away from home pose a unique problem: how can we best take advantage of the benefits of fresh foods in a place that has none? Here, we consider the biggest challenges associated with our current spaceflight food system, highlight the importance of supporting optimal brain health on missions into deep space, and discuss evidence about food components that impact brain health. We propose a future food system that leverages the gut microbiota that can be individually tailored to best support the brain and mental health of crews on deep space long-duration missions. Working toward this goal, we will also be making investments in sustainable means to nourish the crew that remains here on spaceship Earth.

Ethically cleared to launch?

Rules are needed for human research in commercial spaceflight.

Reimagining scientific conferences-a Keystone Symposia report.

Scientific conferences play an important role in advancing research, scholarship, and the careers of emerging scientists. The COVID-19 pandemic offered meeting organizers and researchers alike an opportunity to reimagine what scientific conferences could look like. Virtual conferences can increase inclusivity and accessibility while decreasing costs and carbon emissions. However, it is generally perceived that the digital world fails to adequately recapitulate many of the benefits of in-person face-to-face interactions; these include socializing, and collaborative environments that can forge new research directions and provide critical career development opportunities. On November 15 and 16, 2022, researchers, representatives from diverse scientific conference organizations, leaders in virtual platform technologies, and innovators in conference design gathered online for the Open Access Keystone eSymposium "Reimagining Scientific Conferences." The meeting focused on how conference organizers can leverage lessons from the pandemic and emerging virtual platforms to engage new audiences, rethink strategies for scientific exchange, and decrease the carbon footprint of in-person events.

Looking on the horizon; potential and unique approaches to developing radiation countermeasures for deep space travel.

Future lunar missions and beyond will require new and innovative approaches to radiation countermeasures. The Translational Research Institute for Space Health (TRISH) is focused on identifying and supporting unique approaches to reduce risks to human health and performance on future missions beyond low Earth orbit. This paper will describe three funded and complementary avenues for reducing the risk to humans from radiation exposure experienced in deep space. The first focus is on identifying new therapeutic targets to reduce the damaging effects of radiation by focusing on high throughput genetic screens in accessible, sometimes called lower, organism models. The second focus is to design innovative approaches for countermeasure development with special attention to nucleotide-based methodologies that may constitute a more agile way to design therapeutics. The final focus is to develop new and innovative ways to test radiation countermeasures in a human model system. While animal studies continue to be beneficial in the study of space radiation, they can have imperfect translation to humans. The use of three-dimensional (3D) complex in vitro models is a promising approach to aid the development of new countermeasures and personalized assessments of radiation risks. These three distinct and unique approaches complement traditional space radiation efforts and should provide future space explorers with more options to safeguard their short and long-term health.

Microbiome for Mars: surveying microbiome connections to healthcare with implications for long-duration human spaceflight, virtual workshop, July 13, 2020.

The inaugural "Microbiome for Mars" virtual workshop took place on July 13, 2020. This event assembled leaders in microbiome research and development to discuss their work and how it may relate to long-duration human space travel. The conference focused on surveying current microbiome research, future endeavors, and how this growing field could broadly impact human health and space exploration. This report summarizes each speaker's presentation in the order presented at the workshop.

Quantitative Pupillometry for Detection of Intracranial Pressure Changes During Head-Down Tilt.

BACKGROUND: There is a need to develop noninvasive methods to monitor intracranial pressure (ICP). Pupillary reactivity decreases in patients with elevated ICP with demonstrated cerebral edema. We sought to determine whether pupillary reactivity is affected when ICP is elevated in the absence of brain edema. METHODS: Healthy subjects and individuals with idiopathic intracranial hypertension (IIH) underwent pupillometry in different positions (upright, supine, and head-down tilt) and during different physiological maneuvers. A separate group of healthy subjects were tested in the upright resting position only. The pupillary dynamics were measured with a pupillometer. RESULTS: Healthy and IIH subjects were enrolled. In the healthy subjects the change from upright to head-down tilt led to a Neurological Pupil Index (NPI) decrease from 4.30 to 4.12, while maximum pupil size and minimum pupil size increased from 4.74 to 5.19 and 3.04 to 3.44, respectively. In the IIH group the maximum pupil size, minimum pupil size, and latency increased in magnitude with a decline in head tilt. The mean NPI of IIH subjects, 4.37, was greater than the healthy mean, 4.25. Also, the mean IIH Max and Min, 5.02 and 3.25, were greater than the healthy mean, 4.62 and 2.92. DISCUSSION: We observed changes in the pupillary reactivity in all subjects based on changes in position and task. There were also differences between the healthy and IIH subjects. This is consistent with our hypothesis that elevated intracranial pressure may result in decreased pupillary reactivity even in the absence of brain edema.Soeken TA, Alonso A, Grant A, Calvillo E, Gutierrez-Flores B, Clark J, Donoviel D, Bershad EM. Quantitative pupillometry for detection of intracranial pressure changes during head-down tilt. Aerosp Med Hum Perform. 2018; 89(8):717-723.

Internal Jugular Vein Volume During Head-Down Tilt and Carbon Dioxide Exposure in the SPACECOT Study.

BACKGROUND: Cerebral hemodynamics and venous outflow from the brain may be altered during exposure to microgravity or head-down tilt (HDT), an analog of microgravity, as well as by increased ambient CO2 exposure as experienced on the International Space Station. METHODS: Six healthy subjects underwent baseline tilt table testing at 0°, 6°, 12°, 18°, 24°, and 30° HDT. The right internal jugular (IJ) vein cross-sectional area (CSA) was measured at four intervals from the submandibular to the clavicular level and IJ volume was calculated. Further measurements of the IJ vein were made after ∼26 h of 12° HDT bed rest with either ambient air or 0.5% CO2 exposure, and plasma and blood volume were assessed after 4 h, 24 h, and 28.5 h HDT. RESULTS: IJ vein CSA and volume increased with progressively steeper HDT angles during baseline tilt table testing, with more prominent filling of the IJ vein at levels closer to the clavicle. Exposure to 26 h of 12° HDT bed rest with or without increased CO2, however, had little additional effect on the IJ vein. Further, bed rest resulted in a decrease in plasma volume and blood volume, although changes did not depend on atmospheric conditioning or correlate directly with changes in IJ vein CSA or volume. DISCUSSION: The hydrostatic effects of HDT can be clearly determined through measurement of the IJ vein CSA and volume; however, IJ vein dimensions may not be a reliable indicator of systemic fluid status during bed rest.Marshall-Goebel K, Stevens B, Rao CV, Suarez JI, Calvillo E, Arbeille P, Sangi-Haghpeykar H, Donoviel DB, Mulder E, Bershad EM, the SPACECOT Investigators Group. Internal jugular vein volume during head-down tilt and carbon dioxide exposure in the SPACECOT Study. Aerosp Med Hum Perform. 2018; 89(4):351-356.

Effects of -12° head-down tilt with and without elevated levels of CO2 on cognitive performance: the SPACECOT study.

Microgravity and elevated levels of CO2 are two common environmental stressors in spaceflight that may affect cognitive performance of astronauts. In this randomized, double-blind, crossover trial (SPACECOT), 6 healthy males (mean ± SD age: 41 ± 5 yr) were exposed to 0.04% (ambient air) and 0.5% CO2 concentrations during 26.5-h periods of -12° head-down tilt (HDT) bed rest with a 1-wk washout period between exposures. Subjects performed the 10 tests of the Cognition Test Battery before and on average 0.1, 5.2, and 21.0 h after the initiation of HDT bed rest. HDT in ambient air induced a change in response strategy, with increased response speed (+0.19 SD; P = 0.0254) at the expense of accuracy (-0.19 SD; P = 0.2867), resulting in comparable cognitive efficiency. The observed effects were small and statistically significant for cognitive speed only. However, even small declines in accuracy can potentially cause errors during mission-critical tasks in spaceflight. Unexpectedly, exposure to 0.5% CO2 reversed the response strategy changes observed under HDT in ambient air. This was possibly related to hypercapnia-induced cerebrovascular reactivity that favors cortical regions in general and the frontal cortex in particular, or to the CNS arousing properties of mildly to moderately increased CO2 levels. There were no statistically significant time-in-CO2 effects for any cognitive outcome. The small sample size and the small effect sizes are major limitations of this study and its findings. The results should not be generalized beyond the group of investigated subjects until they are confirmed by adequately powered follow-up studies. NEW & NOTEWORTHY Simulating microgravity with exposure to 21 h of -12° head-down tilt bed rest caused a change in response strategy on a range of cognitive tests, with a statistically significant increase in response speed at the expense of accuracy. Cognitive efficiency was not affected. The observed speed-accuracy tradeoff was small but may nevertheless be important for mission-critical tasks in spaceflight. Importantly, the change in response strategy was reversed by increasing CO2 concentrations to 0.5%.

Novel Indications for Commonly Used Medications as Radiation Protectants in Spaceflight.

BACKGROUND: In the space environment, the traditional radioprotective principles of time, distance, and shielding become difficult to implement. Additionally, the complex radiation environment inherent in space, the chronic exposure timeframe, and the presence of numerous confounding variables complicate the process of creating appropriate risk models for astronaut exposure. Pharmaceutical options hold tremendous promise to attenuate acute and late effects of radiation exposure in the astronaut population. Pharmaceuticals currently approved for other indications may also offer radiation protection, modulation, or mitigation properties along with a well-established safety profile. Currently there are only three agents which have been clinically approved to be employed for radiation exposure, and these only for very narrow indications. This review identifies a number of agents currently approved by the U.S. Food and Drug Administration (FDA) which could warrant further investigation for use in astronauts. Specifically, we examine preclinical and clinical evidence for statins, nonsteroidal anti-inflammatory drugs (NSAIDs), angiotensin converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), metformin, calcium channel blockers, ß adrenergic receptor blockers, fingolimod, N-acetylcysteine, and pentoxifylline as potential radiation countermeasures.McLaughlin MF, Donoviel DB, Jones JA. Novel indications for commonly used medications as radiation protectants in spaceflight. Aerosp Med Hum Perform. 2017; 88(7):665-676.

An international collaboration studying the physiological and anatomical cerebral effects of carbon dioxide during head-down tilt bed rest: the SPACECOT study.

Exposure to the microgravity environment results in various adaptive and maladaptive physiological changes in the human body, with notable ophthalmic abnormalities developing during 6-mo missions on the International Space Station (ISS). These findings have led to the hypothesis that the loss of gravity induces a cephalad fluid shift, decreased cerebral venous outflow, and increased intracranial pressure, which may be further exacerbated by increased ambient carbon dioxide (CO2) levels on the ISS. Here we describe the SPACECOT study (studying the physiological and anatomical cerebral effects of CO2 during head-down tilt), a randomized, double-blind crossover design study with two conditions: 29 h of 12° head-down tilt (HDT) with ambient air and 29 h of 12° HDT with 0.5% CO2 The internationally collaborative SPACECOT study utilized an innovative approach to study the effects of headward fluid shifting induced by 12° HDT and increased ambient CO2 as well as their interaction with a focus on cerebral and ocular anatomy and physiology. Here we provide an in-depth overview of this new approach including the subjects, study design, and implementation, as well as the standardization plan for nutritional intake, environmental parameters, and bed rest procedures.NEW & NOTEWORTHY A new approach for investigating the combined effects of cephalad fluid shifting and increased ambient carbon dioxide (CO2) is presented. This may be useful for studying the neuroophthalmic and cerebral effects of spaceflight where cephalad fluid shifts occur in an elevated CO2 environment.

Quantitative MRI volumetry, diffusivity, cerebrovascular flow, and cranial hydrodynamics during head-down tilt and hypercapnia: the SPACECOT study.

To improve the pathophysiological understanding of visual changes observed in astronauts, we aimed to use quantitative MRI to measure anatomic and physiological responses during a ground-based spaceflight analog (head-down tilt, HDT) combined with increased ambient carbon dioxide (CO2). Six healthy, male subjects participated in the double-blinded, randomized crossover design study with two conditions: 26.5 h of -12° HDT with ambient air and with 0.5% CO2, both followed by 2.5-h exposure to 3% CO2 Volume and mean diffusivity quantification of the lateral ventricle and phase-contrast flow sequences of the internal carotid arteries and cerebral aqueduct were acquired at 3 T. Compared with supine baseline, HDT (ambient air) resulted in an increase in lateral ventricular volume (P = 0.03). Cerebral blood flow, however, decreased with HDT in the presence of either ambient air or 0.5% CO2 (P = 0.002 and P = 0.01, respectively); this was partially reversed by acute 3% CO2 exposure. Following HDT (ambient air), exposure to 3% CO2 increased aqueductal cerebral spinal fluid velocity amplitude (P = 0.01) and lateral ventricle cerebrospinal fluid (CSF) mean diffusivity (P = 0.001). We concluded that HDT causes alterations in cranial anatomy and physiology that are associated with decreased craniospinal compliance. Brief exposure to 3% CO2 augments CSF pulsatility within the cerebral aqueduct and lateral ventricles.NEW & NOTEWORTHY Head-down tilt causes increased lateral ventricular volume and decreased cerebrovascular flow after 26.5 h. Additional short exposure to 3% ambient carbon dioxide levels causes increased cerebrovascular flow associated with increased cerebrospinal fluid pulsatility at the cerebral aqueduct. Head-down tilt with chronically elevated 0.5% ambient carbon dioxide and acutely elevated 3% ambient carbon dioxide causes increased mean diffusivity of cerebral spinal fluid within the lateral ventricles.

Clinical Validation of a Transcranial Doppler-Based Noninvasive Intracranial Pressure Meter: A Prospective Cross-Sectional Study.

BACKGROUND: Noninvasive intracranial pressure (ICP) measurement would represent a major advance for patients with neurological problems. The Vittamed ICP meter is an ultrasound-based device reported to have high agreement with lumbar puncture cerebrospinal fluid (CSF) pressure measurement. However, previous studies included mostly patients with normal levels of ICP. The purpose of our study was to perform an independent clinical validation study of a transcranial Doppler-based noninvasive ICP meter in patients anticipated to have a wide range of ICP. METHODS: In a prospective cross-sectional design, we simultaneously measured ICP with the Vittamed device and the invasive lumbar CSF pressure. The operator of each procedure was blinded to the result of the other method. Data were analyzed using Bland-Altman plots, Pearson correlation coefficients, and receiver operator characteristic curves. RESULTS: Twenty-four independent paired measurements of Vittamed and lumbar CSF pressure were obtained; with mean absolute difference between paired measures of 4.5 mmHg (standard deviation 3.1). The 95% limits of agreement were -10.5 to +11.0. The systematic bias (mean of paired differences) was negligible at 0.25 mmHg. The sensitivity, specificity, and area under the curve for ICP >20 mmHg were 0.73, 0.77, and 0.71, respectively. CONCLUSIONS: The Vittamed ICP meter had fair agreement with lumbar CSF pressure measurement. The wide limits of agreement would preclude using this version of the device as a stand-alone method for ICP determination, but may be useful if combined with other ICP screening methods. Ongoing improvements to the Vittamed hardware and software may lead to improvements in accuracy and clinical utility of this device.

Noninvasive Brain Physiology Monitoring for Extreme Environments: A Critical Review.

Our ability to monitor the brain physiology is advancing; however, most of the technology is bulky, expensive, and designed for traditional clinical settings. With long-duration space exploration, there is a need for developing medical technologies that are reliable, low energy, portable, and semiautonomous. Our aim was to review the state of the art for noninvasive technologies capable of monitoring brain physiology in diverse settings. A literature review of PubMed and the Texas Medical Center library sites was performed using prespecified search criteria to identify portable technologies for monitoring physiological aspects of the brain physiology. Most brain-monitoring technologies require a moderate to high degree of operator skill. Some are low energy, but many require a constant external power supply. Most of the technologies lack the accuracy seen in gold standard measures, due to the need for calibration, but may be useful for screening or monitoring relative changes in a parameter. Most of the technologies use ultrasound or electromagnetic radiation as energy sources. There is an important need for further development of portable technologies that can be operated in a variety of extreme environments to monitor brain health.

The impact of sex and gender on adaptation to space: executive summary.

This review article is a compendium of six individual manuscripts, a Commentary, and an Executive Summary. This body of work is entitled "The Impact of Sex and Gender on Adaptation to Space" and was developed in response to a recommendation from the 2011 National Academy of Sciences Decadal Survey, "Recapturing a Future for Space Exploration: Life and Physical Sciences for a New Era," which emphasized the need to fully understand sex and gender differences in space. To ensure the health and safety of male and female astronauts during long-duration space missions, it is imperative to examine and understand the influences that sex and gender have on physiological and psychological changes that occur during spaceflight. In this collection of manuscripts, six workgroups investigated and summarized the current body of published and unpublished human and animal research performed to date related to sex- and gender-based differences in the areas of cardiovascular, immunological, sensorimotor, musculoskeletal, reproductive, and behavioral adaptations to human spaceflight. Each workgroup consisted of scientists and clinicians from academia, the National Aeronautics and Space Administration (NASA), and other federal agencies and was co-chaired by one representative from NASA and one from the external scientific community. The workgroups met via telephone and e-mail over 6 months to review literature and data from space- and ground-based studies to identify sex and gender factors affecting crew health. In particular, the Life Sciences Data Archive and the Lifetime Surveillance of Astronaut Health were extensively mined. The groups identified certain sex-related differences that impact the risks and the optimal medical care required by space-faring women and men. It represents innovative research in sex and gender-based biology that impacts those individuals that are at the forefront of space exploration.

High-throughput screening of mouse knockout lines identifies true lean and obese phenotypes.

We developed a high-throughput approach to knockout (KO) and phenotype mouse orthologs of the 5,000 potential drug targets in the human genome. As part of the phenotypic screen, dual-energy X-ray absorptiometry (DXA) technology estimates body-fat stores in eight KO and four wild-type (WT) littermate chow-fed mice from each line. Normalized % body fat (nBF) (mean KO % body fat/mean WT littermate % body fat) values from the first 2322 lines with viable KO mice at 14 weeks of age showed a normal distribution. We chose to determine how well this screen identifies body-fat phenotypes by selecting 13 of these 2322 KO lines to serve as benchmarks based on their published lean or obese phenotype on a chow diet. The nBF values for the eight benchmark KO lines with a lean phenotype were > or =1 s.d. below the mean for seven (perilipin, SCD1, CB1, MCH1R, PTP1B, GPAT1, PIP5K2B) but close to the mean for NPY Y4R. The nBF values for the five benchmark KO lines with an obese phenotype were >2 s.d. above the mean for four (MC4R, MC3R, BRS3, translin) but close to the mean for 5HT2cR. This screen also identifies novel body-fat phenotypes as exemplified by the obese kinase suppressor of ras 2 (KSR2) KO mice. These body-fat phenotypes were confirmed upon studying additional cohorts of mice for KSR2 and all 13 benchmark KO lines. This simple and cost-effective screen appears capable of identifying genes with a role in regulating mammalian body fat.

A presenilin-independent aspartyl protease prefers the gamma-42 site cleavage.

beta-Amyloid peptides (Abeta40 and Abeta42) are the major constituents of amyloid plaques, which are one of the hallmarks of Alzheimer's disease (AD). The Abeta is derived from sequential cleavages of amyloid precursor protein (APP) by beta- and gamma-secretases. gamma-Secretase consists of at least four proteins where presenilins (PS1 and PS2 or PS) are the catalytic subunit involved in the gamma-site cleavage of APP. Secretion of both Abeta40 and Abeta42 is significantly reduced in PS1 knock-out cells and completely abolished in cells deficient for both PS1 and PS2. Consequently, both the PS proteins play essential roles in the production of the secretory of Abeta from cells. Recent studies in primary neurons, however, suggest that PSs are not required for intracellular Abeta42 accumulation; thus the intracellular Abeta42 appears to be generated in a PS-independent manner. Here we present the first biochemical evidence indicating that Abeta, especially Abeta42, can be generated in the absence of PS based on an in vitrogamma-secretase assay employing membranes prepared from PS-deficient Blastocyst-derived (BD) cells. This PS-independent gamma-secretase (PSIG) activity is sensitive to the changes in pH and displays an optimal activity at pH 6.0. Pepstatin A is a potent inhibitor for this proteolytic activity with IC50 of 1.2 nm and 0.4 nm for Abeta40 and Abeta42 generation, respectively. These results indicate that these PS-independent gamma-site cleavages are mediated by an aspartyl protease. More importantly, the PSIG activity displays a distinct preference in mediating the 42-site cleavage over the 40-site cleavage, thereby generating Abeta42 as the predominant product.

Presenilin 2 regulates the systolic function of heart by modulating Ca2+ signaling.

Genetic studies of families with familial Alzheimer's disease have implicated presenilin 2 (PS2) in the pathogenesis of this disease. PS2 is ubiquitously expressed in various tissues including hearts. In this study, we examined cardiac phenotypes of PS2 knockout (PS2KO) mice to elucidate a role of PS2 in hearts. PS2KO mice developed normally with no evidence of cardiac hypertrophy and fibrosis. Invasive hemodynamic analysis revealed that cardiac contractility in PS2KO mice increased compared with that in their littermate controls. A study of isolated papillary muscle showed that peak amplitudes of Ca2+ transients and peak tension were significantly higher in PS2KO mice than those in their littermate controls. PS2KO mouse hearts exhibited no change in expression of calcium regulatory proteins. Since it has been demonstrated that PS2 in brain interacts with sorcin, which serves as a modulator of cardiac ryanodine receptor (RyR2), we tested whether PS2 also interacts with RyR2. Immmunoprecipitation analysis showed that PS2, sorcin, and RyR2 interact with each other in HEK-293 cells overexpressing these proteins or in mouse hearts. Immunohistochemistry of heart muscle indicated that PS2 colocalizes with RyR2 and sorcin at the Z-lines. Elevated Ca2+ attenuated the association of RyR2 with PS2, whereas the association of sorcin with PS2 was enhanced. The enhanced Ca2+ transients and contractility in PS2KO mice were observed at low extracellular [Ca2+] but not at high levels of [Ca2+]. Taken together, our results suggest that PS2 plays an important role in cardiac excitation-contraction coupling by interacting with RyR2.