Modeling the impact of thoracic pressure on intracranial pressure.

A potential contribution to the progression of Spaceflight Associated Neuro-ocular Syndrome is the thoracic-to-spinal dural sac transmural pressure relationship. In this study, we utilize a lumped-parameter computational model of human cerebrospinal fluid (CSF) systems to investigate mechanisms of CSF redistribution. We present two analyses to illustrate potential mechanisms for CSF pressure alterations similar to those observed in microgravity conditions. Our numerical evidence suggests that the compliant relationship between thoracic and CSF compartments is insufficient to solely explain the observed decrease in CSF pressure with respect to the supine position. Our analyses suggest that the interaction between thoracic pressure and the cardiovascular system, particularly the central veins, has greater influence on CSF pressure. These results indicate that future studies should focus on the holistic system, with the impact of cardiovascular changes to the CSF pressure emphasized over the sequestration of fluid in the spine.

Modeling and simulation credibility assessments of whole-body finite element computational models for use in NASA extravehicular activity applications.

Computational finite element (FE) models are used in suited astronaut injury risk assessments; however, these models' verification, validation, and credibility (VV&C) procedures for simulating injuries in altered gravity environments are limited. Our study conducts VV&C assessments of THUMS and Elemance whole-body FE models for predicting suited astronaut injury biomechanics using eight credibility factors, as per NASA-STD-7009A. Credibility factor ordinal scores are assigned by reviewing existing documentation describing VV&C practices, and credibility sufficiency thresholds are assigned based on input from subject matter experts. Our results show the FE models are credible for suited astronaut injury investigation in specific ranges of kinematic and kinetic conditions correlating to highway and contact sports events. Nevertheless, these models are deficient when applied outside these ranges. Several credibility elevation strategies are prescribed to improve models' credibility for the NASA-centric application domain.

Estimating medical risk in human spaceflight.

NASA and commercial spaceflight companies will soon be retuning humans to the Moon and then eventually sending them on to Mars. These distant planetary destinations will pose new risks-in particular for the health of the astronaut crews. The bulk of the evidence characterizing human health and performance in spaceflight has come from missions in Low Earth Orbit. As missions last longer and travel farther from Earth, medical risk is expected to contribute an increasing proportion of total mission risk. To date, there have been no reliable estimates of how much. The Integrated Medical Model (IMM) is a Probabilistic Risk Assessment (PRA) Monte-Carlo simulation tool developed by NASA for medical risk assessment. This paper uses the IMM to provide an evidence-based, quantified medical risk estimate comparison across different spaceflight mission durations. We discuss model limitations and unimplemented capabilities providing insight into the complexity of medical risk estimation for human spaceflight. The results enable prioritization of medical needs in the context of other mission risks. These findings provide a reasonable bounding estimate for medical risk in missions to the Moon and Mars and hold value for risk managers and mission planners in performing cost-benefit trades for mission capability and research investments.

Numerical characterization of astronaut CaOx renal stone incidence rates to quantify in-flight and post-flight relative risk.

Changes in urine chemistry potentially alter the risk of renal stone formation in astronauts. Quantifying spaceflight renal stone incidence risk compared to pre-flight levels remains a significant challenge for assessing the appropriate vehicle, mission, and countermeasure design. A computational biochemistry model representing CaOx crystal precipitation, growth, and agglomeration is combined with a probabilistic analysis to predict the in- and post-flight CaOx renal stone incidence risk ratio (IRR) relative to pre-flight values using 1517 astronaut 24-h urine chemistries. Our simulations predict that in-flight fluid intake alone would need to increase from current prescriptions of 2.0-2.5 L/day to ~3.2 L/day to approach the CaOx IRR of the pre-flight population. Bone protective interventions would reduce CaOx risk to pre-flight levels if Ca excretion alone is reduced to <150 mg/day or if current levels are diminished to 190 mg/day in combination with increasing fluid intake to 2.5-2.7 L/day. This analysis provides a quantitative risk assessment that can influence the critical balance between engineering and astronaut health requirements.

Predicting Space Radiation Single Ion Exposure in Rodents: A Machine Learning Approach.

This study presents a data-driven machine learning approach to predict individual Galactic Cosmic Radiation (GCR) ion exposure for 4He, 16O, 28Si, 48Ti, or 56Fe up to 150 mGy, based on Attentional Set-shifting (ATSET) experimental tests. The ATSET assay consists of a series of cognitive performance tasks on irradiated male Wistar rats. The GCR ion doses represent the expected cumulative radiation astronauts may receive during a Mars mission on an individual ion basis. The primary objective is to synthesize and assess predictive models on a per-subject level through Machine Learning (ML) classifiers. The raw cognitive performance data from individual rodent subjects are used as features to train the models and to explore the capabilities of three different ML techniques for elucidating a range of correlations between received radiation on rodents and their performance outcomes. The analysis employs scores of selected input features and different normalization approaches which yield varying degrees of model performance. The current study shows that support vector machine, Gaussian naive Bayes, and random forest models are capable of predicting individual ion exposure using ATSET scores where corresponding Matthews correlation coefficients and F1 scores reflect model performance exceeding random chance. The study suggests a decremental effect on cognitive performance in rodents due to ≤150 mGy of single ion exposure, inasmuch as the models can discriminate between 0 mGy and any exposure level in the performance score feature space. A number of observations about the utility and limitations in specific normalization routines and evaluation scores are examined as well as best practices for ML with imbalanced datasets observed.

Machine Learning Models to Predict Cognitive Impairment of Rodents Subjected to Space Radiation.

This research uses machine-learned computational analyses to predict the cognitive performance impairment of rats induced by irradiation. The experimental data in the analyses is from a rodent model exposed to ≤15 cGy of individual galactic cosmic radiation (GCR) ions: 4He, 16O, 28Si, 48Ti, or 56Fe, expected for a Lunar or Mars mission. This work investigates rats at a subject-based level and uses performance scores taken before irradiation to predict impairment in attentional set-shifting (ATSET) data post-irradiation. Here, the worst performing rats of the control group define the impairment thresholds based on population analyses via cumulative distribution functions, leading to the labeling of impairment for each subject. A significant finding is the exhibition of a dose-dependent increasing probability of impairment for 1 to 10 cGy of 28Si or 56Fe in the simple discrimination (SD) stage of the ATSET, and for 1 to 10 cGy of 56Fe in the compound discrimination (CD) stage. On a subject-based level, implementing machine learning (ML) classifiers such as the Gaussian naïve Bayes, support vector machine, and artificial neural networks identifies rats that have a higher tendency for impairment after GCR exposure. The algorithms employ the experimental prescreen performance scores as multidimensional input features to predict each rodent's susceptibility to cognitive impairment due to space radiation exposure. The receiver operating characteristic and the precision-recall curves of the ML models show a better prediction of impairment when 56Fe is the ion in question in both SD and CD stages. They, however, do not depict impairment due to 4He in SD and 28Si in CD, suggesting no dose-dependent impairment response in these cases. One key finding of our study is that prescreen performance scores can be used to predict the ATSET performance impairments. This result is significant to crewed space missions as it supports the potential of predicting an astronaut's impairment in a specific task before spaceflight through the implementation of appropriately trained ML tools. Future research can focus on constructing ML ensemble methods to integrate the findings from the methodologies implemented in this study for more robust predictions of cognitive decrements due to space radiation exposure.

Credible practice of modeling and simulation in healthcare: ten rules from a multidisciplinary perspective.

The complexities of modern biomedicine are rapidly increasing. Thus, modeling and simulation have become increasingly important as a strategy to understand and predict the trajectory of pathophysiology, disease genesis, and disease spread in support of clinical and policy decisions. In such cases, inappropriate or ill-placed trust in the model and simulation outcomes may result in negative outcomes, and hence illustrate the need to formalize the execution and communication of modeling and simulation practices. Although verification and validation have been generally accepted as significant components of a model's credibility, they cannot be assumed to equate to a holistic credible practice, which includes activities that can impact comprehension and in-depth examination inherent in the development and reuse of the models. For the past several years, the Committee on Credible Practice of Modeling and Simulation in Healthcare, an interdisciplinary group seeded from a U.S. interagency initiative, has worked to codify best practices. Here, we provide Ten Rules for credible practice of modeling and simulation in healthcare developed from a comparative analysis by the Committee's multidisciplinary membership, followed by a large stakeholder community survey. These rules establish a unified conceptual framework for modeling and simulation design, implementation, evaluation, dissemination and usage across the modeling and simulation life-cycle. While biomedical science and clinical care domains have somewhat different requirements and expectations for credible practice, our study converged on rules that would be useful across a broad swath of model types. In brief, the rules are: (1) Define context clearly. (2) Use contextually appropriate data. (3) Evaluate within context. (4) List limitations explicitly. (5) Use version control. (6) Document appropriately. (7) Disseminate broadly. (8) Get independent reviews. (9) Test competing implementations. (10) Conform to standards. Although some of these are common sense guidelines, we have found that many are often missed or misconstrued, even by seasoned practitioners. Computational models are already widely used in basic science to generate new biomedical knowledge. As they penetrate clinical care and healthcare policy, contributing to personalized and precision medicine, clinical safety will require established guidelines for the credible practice of modeling and simulation in healthcare.

Acute effects of posture on intraocular pressure.

Many experiments have documented the response of intraocular pressure (IOP) to postural change. External forces caused by gravitational orientation change produce a dynamic response that is encountered every day during normal activities. Tilting the body at a small downward angle is also relevant to studying the effects of hypogravity (spaceflight), including ocular changes. We examined data from 36 independent datasets from 30 articles on IOP response to postural change, representing a total population of 821 subjects (≥1173 eyes) with widely varying initial and final postures. We confirmed that IOP was well predicted by a simple quantity, namely the hydrostatic pressure at the level of the eye, although the dependence was complex (nonlinear). Our results show that posturally induced IOP change can be explained by hydrostatic forcing plus an autoregulatory contribution that is dependent on hydrostatic effects. This study represents data from thousands of IOP measurements and provides insight for future studies that consider postural change in relation to ocular physiology, intraocular pressure, ocular blood flow and aqueous humor dynamics.

Forecasting Postflight Hip Fracture Probability Using Probabilistic Modeling.

A probabilistic model predicts hip fracture probability for postflight male astronauts during lateral fall scenarios from various heights. A biomechanical representation of the hip provides impact load. Correlations relate spaceflight bone mineral density (BMD) loss and postflight BMD recovery to bone strength (BS). Translations convert fracture risk index (FRI), the ratio of applied load (AL) to BS, to fracture probability. Parameter distributions capture uncertainty and Monte Carlo simulations provide probability outcomes. The fracture probability for a 1 m fall 0 days postflight is 15% greater than preflight and remains 6% greater than pre-flight at 365 days postflight. Probability quantification provides insight into how spaceflight induced BMD loss affects fracture probability. A bone loss rate reflecting improved exercise countermeasures and dietary intake further reduces the postflight fracture probability to 6% greater than preflight at 0 days postflight and 2% greater at 365 days postflight. Quantification informs assessments of countermeasure effectiveness. When preflight BMD is one standard deviation below mean astronaut preflight BMD, fracture probability at 0 days postflight is 34% greater than the preflight fracture probability calculated with mean BMD and 28% greater at 365 days postflight. Quantification aids review of astronaut BMD fitness for duty standards. Increases in postflight fracture probability are associated with an estimated 18% reduction in postflight BS. Therefore, a 0.82 deconditioning coefficient modifies force application limits for crew vehicles.

Credibility, Replicability, and Reproducibility in Simulation for Biomedicine and Clinical Applications in Neuroscience.

Modeling and simulation in computational neuroscience is currently a research enterprise to better understand neural systems. It is not yet directly applicable to the problems of patients with brain disease. To be used for clinical applications, there must not only be considerable progress in the field but also a concerted effort to use best practices in order to demonstrate model credibility to regulatory bodies, to clinics and hospitals, to doctors, and to patients. In doing this for neuroscience, we can learn lessons from long-standing practices in other areas of simulation (aircraft, computer chips), from software engineering, and from other biomedical disciplines. In this manuscript, we introduce some basic concepts that will be important in the development of credible clinical neuroscience models: reproducibility and replicability; verification and validation; model configuration; and procedures and processes for credible mechanistic multiscale modeling. We also discuss how garnering strong community involvement can promote model credibility. Finally, in addition to direct usage with patients, we note the potential for simulation usage in the area of Simulation-Based Medical Education, an area which to date has been primarily reliant on physical models (mannequins) and scenario-based simulations rather than on numerical simulations.

The impact of ocular hemodynamics and intracranial pressure on intraocular pressure during acute gravitational changes.

Exposure to microgravity causes a bulk fluid shift toward the head, with concomitant changes in blood volume/pressure, and intraocular pressure (IOP). These and other factors, such as intracranial pressure (ICP) changes, are suspected to be involved in the degradation of visual function and ocular anatomical changes exhibited by some astronauts. This is a significant health concern. Here, we describe a lumped-parameter numerical model to simulate volume/pressure alterations in the eye during gravitational changes. The model includes the effects of blood and aqueous humor dynamics, ICP, and IOP-dependent ocular compliance. It is formulated as a series of coupled differential equations and was validated against four existing data sets on parabolic flight, body inversion, and head-down tilt (HDT). The model accurately predicted acute IOP changes in parabolic flight and HDT, and was satisfactory for the more extreme case of inversion. The short-term response to the changing gravitational field was dominated by ocular blood pressures and compliance, while longer-term responses were more dependent on aqueous humor dynamics. ICP had a negligible effect on acute IOP changes. This relatively simple numerical model shows promising predictive capability. To extend the model to more chronic conditions, additional data on longer-term autoregulation of blood and aqueous humor dynamics are needed.NEW & NOTEWORTHY A significant percentage of astronauts present anatomical changes in the posterior eye tissues after spaceflight. Hypothesized increases in ocular blood volume and intracranial pressure (ICP) in space have been considered to be likely factors. In this work, we provide a novel numerical model of the eye that incorporates ocular hemodynamics, gravitational forces, and ICP changes. We find that changes in ocular hemodynamics govern the response of intraocular pressure during acute gravitational change.

Characterization of the mechanical behavior of the optic nerve sheath and its role in spaceflight-induced ophthalmic changes.

Visual impairment and intracranial pressure (VIIP) syndrome is characterized by a number of permanent ophthalmic changes, including loss of visual function. It occurs in some astronauts during long-duration spaceflight missions. Thus, understanding the pathophysiology of VIIP is currently a major priority in space medicine research. It is hypothesized that maladaptive remodeling of the optic nerve sheath (ONS), in response to microgravity-induced elevations in intracranial pressure (ICP), contributes to VIIP. However, little is known about ONS biomechanics. In this study, we developed a custom mechanical testing system that allowed for unconfined lengthening, twisting, and circumferential distension of the porcine ONS during inflation and axial loading. Data were fit to a four-fiber family constitutive equation to extract material and structural parameters. Inflation testing showed a characteristic "cross-over point" in the pressure-diameter curves under different axial loads in all samples that were tested; the cross-over pressure was [Formula: see text] mmHg ([Formula: see text]). Large sample-to-sample variations were observed in the circumferential strain, while only modest variations were observed in the circumferential stress. Multiphoton microscopy revealed that the collagen fibers of the ONS were primarily oriented axially when the tissue was loaded. The existence of this cross-over behavior is expected to be neuroprotective, as it would avoid optic nerve compression during routine changes in gaze angle, so long as ICP was within the normal range. Including these observations into computational models of VIIP will help provide insight into the pathophysiology of VIIP and could help identify risk factors and potential interventions.

Development, Validation, and Implementation of a Medical Judgment Metric.

Background: Medical decision making is a critical, yet understudied, aspect of medical education. Aims: To develop the Medical Judgment Metric (MJM), a numerical rubric to quantify good decisions in practice in simulated environments; and to obtain initial preliminary evidence of reliability and validity of the tool. Methods: The individual MJM items, domains, and sections of the MJM were built based on existing standardized frameworks. Content validity was determined by a convenient sample of eight experts. The MJM instrument was pilot tested in four medical simulations with a team of three medical raters assessing 40 participants with four levels of medical experience and skill. Results: Raters were highly consistent in their MJM scores in each scenario (intraclass correlation coefficient 0.965 to 0.987) as well as their evaluation of the expected patient outcome (Fleiss's Kappa 0.791 to 0.906). For each simulation scenario, average rater cut-scores significantly predicted expected loss of life or stabilization (Cohen's Kappa 0.851 to 0.880). Discussion: The MJM demonstrated preliminary evidence of reliability and validity.

Finite Element Modeling of Factors Influencing Optic Nerve Head Deformation Due to Intracranial Pressure.

PURPOSE: Visual impairment and intracranial pressure (VIIP) syndrome is a health concern for long-duration spaceflight, and a proposed risk factor is elevation of intracranial pressure (ICP). Our goal was to use finite element modeling to simulate how elevated ICP and interindividual differences affect tissue deformation within the optic nerve head (ONH). METHODS: We considered three ICP conditions: the upright and supine position on earth and an elevated ICP assumed to occur in chronic microgravity. Within each condition we used Latin hypercube sampling to consider a range of pressures and ONH tissue mechanical properties, determining the influence of each input on the following outcome measures: peak strains in the prelaminar tissue, lamina cribrosa, and retrolaminar optic nerve. Elevated strains can alter cell phenotype and induce tissue remodeling. RESULTS: Elevating ICP increased the strains in the retrolaminar optic nerve. Variations in IOP, ICP, and in optic nerve and lamina cribrosa stiffness had the strongest influence on strains within the ONH. We predicted that 5% to 47% of individuals in microgravity would experience peak strains in the retrolaminar optic nerve larger than expected on earth. Having a soft optic nerve or pia mater and elevated ICP were identified as risk factors for these "extreme" strains. CONCLUSIONS: Intracranial pressure and mechanical properties of the ONH influence the risk for experiencing extreme strains in the retrolaminar optic nerve. These extreme strains may activate mechanosensitive cells that induce tissue remodeling and are a risk factor for the development of VIIP. Future studies must also consider variations in ONH anatomy.

Microgravity-induced fluid shift and ophthalmic changes.

Although changes to visual acuity in spaceflight have been observed in some astronauts since the early days of the space program, the impact to the crew was considered minor. Since that time, missions to the International Space Station have extended the typical duration of time spent in microgravity from a few days or weeks to many months. This has been accompanied by the emergence of a variety of ophthalmic pathologies in a significant proportion of long-duration crewmembers, including globe flattening, choroidal folding, optic disc edema, and optic nerve kinking, among others. The clinical findings of affected astronauts are reminiscent of terrestrial pathologies such as idiopathic intracranial hypertension that are characterized by high intracranial pressure. As a result, NASA has placed an emphasis on determining the relevant factors and their interactions that are responsible for detrimental ophthalmic response to space. This article will describe the Visual Impairment and Intracranial Pressure syndrome, link it to key factors in physiological adaptation to the microgravity environment, particularly a cephalad shifting of bodily fluids, and discuss the implications for ocular biomechanics and physiological function in long-duration spaceflight.

Predicting head injury risk during International Space Station increments.

INTRODUCTION: NASA's Human Research Program is using a probabilistic risk assessment approach to identify acute and chronic medical risks to manned spaceflight. The objective of this project was to estimate the likelihood of a neurological head injury to a crewmember severe enough to require medical assessment, treatment, or evacuation during a typical International Space Station (ISS) increment. METHODS: A 2 degree-of-freedom analytical model of the human head was created to allow for analysis of the impact response. The output of the model is acceleration of the head, which was used to determine the probability that the simulated impact resulted in a head injury with an Abbreviated Injury Scale (AIS) score of 3 or greater. These data were then integrated into a probabilistic risk assessment, which outputs a likelihood of injury with a representative measure of the uncertainty. RESULTS: A Monte Carlo simulation was performed to vary input parameters over their defined distributions. The mean probability of a moderate neurological injury (AIS 3 or greater) occurring due to a head impact by a crewmember translating through the ISS is 1.16 x 10(-4) per 6-mo mission increment (2.32 x 10(-4) per year). DISCUSSION: Our head injury prediction model has shown that there is a low, yet not insignificant, probability of neurological head injury of AIS score 3 or greater. The results from this simulation will be input into the parent Integrated Medical Model, which incorporates the risks of over 80 different medical events in order to inform mission planning scenarios.

An extravehicular suit impact load attenuation study to improve astronaut bone fracture prediction.

INTRODUCTION: Understanding the contributions to the risk of bone fracture during spaceflight is essential for mission success. METHODS: A pressurized extravehicular activity (EVA) suit analogue test bed was developed, impact load attenuation data were obtained, and the load at the hip of an astronaut who falls to the side during an EVA was characterized. Offset (representing the gap between the EVA suit and the astronaut's body), impact load magnitude, and EVA suit operating pressure were factors varied in the study. The attenuation data were incorporated into a probabilistic model of bone fracture risk during spaceflight, replacing the previous load attenuation value that was based on commercial hip protector data. RESULTS: Load attenuation was more dependent on offset than on pressurization or load magnitude, especially at small offset values. Load attenuation factors for offsets between 0.1-1.5 cm were 0.69 +/- 0.15, 0.49 +/- 0.22, and 0.35 +/- 0.18 for mean impact forces of 4827, 6400, and 8467 N, respectively. Load attenuation factors for offsets of 2.8-5.3 cm were 0.93 +/- 0.2, 0.94 +/- 0.1, and 0.84 +/- 0.5 for the same mean impact forces. The mean and 95th percentile bone fracture risk index predictions were each reduced by 65-83%. The mean and 95th percentile bone fracture probability predictions were both reduced approximately 20-50%. DISCUSSION: The reduction in uncertainty and improved confidence in bone fracture predictions increased the fidelity and credibility of the fracture risk model and its benefit to mission design and in-flight operational decisions.

Theoretical analysis of the mechanisms of a gender differentiation in the propensity for orthostatic intolerance after spaceflight.

BACKGROUND: A tendency to develop reentry orthostasis after a prolonged exposure to microgravity is a common problem among astronauts. The problem is 5 times more prevalent in female astronauts as compared to their male counterparts. The mechanisms responsible for this gender differentiation are poorly understood despite many detailed and complex investigations directed toward an analysis of the physiologic control systems involved. METHODS: In this study, a series of computer simulation studies using a mathematical model of cardiovascular functioning were performed to examine the proposed hypothesis that this phenomenon could be explained by basic physical forces acting through the simple common anatomic differences between men and women. In the computer simulations, the circulatory components and hydrostatic gradients of the model were allowed to adapt to the physical constraints of microgravity. After a simulated period of one month, the model was returned to the conditions of earth's gravity and the standard postflight tilt test protocol was performed while the model output depicting the typical vital signs was monitored. CONCLUSIONS: The analysis demonstrated that a 15% lowering of the longitudinal center of gravity in the anatomic structure of the model was all that was necessary to prevent the physiologic compensatory mechanisms from overcoming the propensity for reentry orthostasis leading to syncope.

Development and validation of a predictive bone fracture risk model for astronauts.

There are still many unknowns in the physiological response of human beings to space, but compelling evidence indicates that accelerated bone loss will be a consequence of long-duration spaceflight. Lacking phenomenological data on fracture risk in space, we have developed a predictive tool based on biomechanical and bone loading models at any gravitational level of interest. The tool is a statistical model that forecasts fracture risk, bounds the associated uncertainties, and performs sensitivity analysis. In this paper, we focused on events that represent severe consequences for an exploration mission, specifically that of spinal fracture resulting from a routine task (lifting a heavy object up to 60 kg), or a spinal, femoral or wrist fracture due to an accidental fall or an intentional jump from 1 to 2 m. We validated the biomechanical and bone fracture models against terrestrial studies of ground reaction forces, skeletal loading, fracture risk, and fracture incidence. Finally, we predicted fracture risk associated with reference missions to the moon and Mars that represented crew activities on the surface. Fracture was much more likely on Mars due to compromised bone integrity. No statistically significant gender-dependent differences emerged. Wrist fracture was the most likely type of fracture, followed by spinal and hip fracture.

Intimal thickness is not associated with wall shear stress patterns in the human right coronary artery.

OBJECTIVE: Low wall shear stress has been implicated in atherogenesis throughout the arterial tree, including the right coronary artery (RCA). The objective of this study was to determine the level of covariation of intimal thickness and wall shear stress in the human RCA. METHODS AND RESULTS: Postmortem histological measurements of intimal thickness were compared with wall shear stresses calculated from computational flow modeling in 4 human right coronary arteries. A statistically significant correlation between intimal thickness and wall shear stress was found in only 1 of the 4 arteries studied. CONCLUSIONS: Wall shear stress does not appear to be related to intimal thickness in the 4 RCAs studied.