NOTE: Title change to "Role of the Cranial Venous Circulation in Microgravity-Associated Visual Changes" (original proposal title was "Ocular Venous Contributions to Spaceflight Visual Impairment")--Ed., 2/6/14

Aim #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. We developed a numerical model that predicts alterations in the hemodynamics of the cranial venous system produced by changes in hydrostatic gradients and fluid shifts. While models describing the cranial venous system exist in the literature, incorporation of hydrostatic gradient and fluid shift effects is novel. Our computer model consists of two parts—a system model and a structural model. The system model describes flow and pressure in the circulatory system, the cerebral spinal fluid regulatory system, and the eye's aqueous humor regulatory system. The structural model uses a separate decoupled finite element model to describe the eye globe and structures contained within. The structural model was developed on a separate parallel effort funded by the NASA EPSCoR (Established Program to Stimulate Competitive Research) program. Both the system level model and the structural model account for changes in tissue properties that may be induced in microgravity, as well as effects of microgravity exposure duration. We validated the computer model with magnetic resonance imaging (MRI) measurements of venous flow, venous volume, venous pressure, intracranial compliance, CSF volume, and flow pulsatility during cephalad fluid shifts both supine and prone. We also used measurements of intraocular pressure (IOP) and other ocular parameters obtained outside of the MRI magnet. This model and supporting data will provide a means to develop hypotheses about how microgravity produces visual changes over time and may allow predictions about which subjects may be at risk for visual deficits associated with microgravity.

Aim #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. During this reporting period, we published the results on the effects of posture on eye parameters in the prone and supine postures over 60 minutes. These data are essential for understanding the effects of changes in the gravitational vector on the eye. We completed studies on 14 individuals both inside and outside of the MR device in both the supine and prone postures. MR Imaging was also done with and without lower body negative pressure (LBNP) and lower body positive pressure (LBPP). These data have been incorporated into the model and are being prepared for publication.

Aim #3: Identify individuals with common intracranial venous variants, and study them using the protocol outlined in Aim #2. Our cohort of subjects included subjects with a range of venous anatomy, which was adequate for our purposes.

1. Built a comprehensive model of the cerebrovascular circulation that includes a circulatory sub-model, an aqueous humor submodel, and a cerebrospinal fluid submodel.

2. Model includes effects of hydrostatic gradients and tissue weight, making it well suited for predicting microgravity effects.

3. Model validated using physiologic data from the lab studies that examined the effects of posture (prone vs. supine) and fluid shifts (LBNP) on the cerebrovascular circulation using detailed measurements of the eye and cerebrovascular circulation using various ocular measures (optical coherence tomography, optical biometry) and MRI measures of arterial, venous, and CSF flow.

4. Overall model description and outputs for sample microgravity conditions being prepared for publication.

Aim #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.

1. Completed a study on the short-term effects of posture and microgravity (using parabolic flight) on the eye and published the results.

2. Completed a study on the longer-term (60 minutes) effects of posture (changes in direction of hydrostatic gradients going from supine to prone) and fluid shifts on the eye and published the results.

3. Completed a study on the effects of posture/changes in the direction of hydrostatic gradients and fluid shifts on the cerebrovascular circulation and CSF using MR imaging. Results are being prepared for publication.

Aim #3: Identify individuals with common intracranial venous variants, and study them using the protocol outlined in Aim #2.

1. Subjects studied for this project had a range of venous anatomy that is suitable for further analysis.

NOTE: Title change to "Role of the Cranial Venous Circulation in Microgravity-Associated Visual Changes" (original proposal title was "Ocular Venous Contributions to Spaceflight Visual Impairment")--Ed., 2/6/14

Aim #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. During this reporting period, we advanced and expanded the numerical model. Specifically, we introduced collapsible vessels, which allows behavior such as body-orientation-dependent flow shunting in the jugular veins (i.e., jugular vein collapse in the upright position) to be modeled. We also used transmural pressure across the boundaries of model components (e.g., vessels and fluid cavities) to capture the effects of tissue weights and the resulting gravity dependent impact on the circulatory and cerebrospinal fluid (CSF) systems. Finally, we targeted integration of the circulatory and CSF sub-models, providing mass and pressure communications between the two sub-models.

Aim #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. During this reporting period, we developed the protocol to collect the data for this experiment. We conducted an experiment with 10 subjects and determined that ocular measures plateau after an average of 12 minutes upon entering the posture. This will be used to ensure consistent data for all subjects. We designed and built a MRI-compatible chamber to provide lower body positive and negative pressures, aimed at creating cephalad fluid shift similar to that experienced in space flight. The apparatus will be used in the MRI studies. We plan to finalize the apparatus and employ it in the test campaign during the next reporting period. The imaging protocol needed to collect our parameters for the model was established through an iterative process to establish the optimum trade-off between scan accuracy, data needed for the model, and subject acceptability. The analysis techniques for the MRI data were also established. We developed tools to aid hypothesis development of the etiology behind visual changes in long duration space flight. We developed graphical descriptions of the potential mechanisms for the microgravity-induced ocular and visual changes. We have acquired several devices to measure key parameters needed in the studies, such as an anterior segment module, episcleral venous pressure device, and a BIOPAC continuous, noninvasive blood pressure system. The data collected from these devices will be use to provide additional information for the model.

Aim #3: Identify individuals with common intracranial venous variants, and study them using the protocol outlined in Aim #2. Aim 3 is an objective for our third year. The data collection methods have been established in this reporting period through our Aim 2 objectives. In our initial cohort of pilot subjects, we have identified subjects with anatomical variants--a primary interest of this experiment. Over the next reporting year, we will collect data from our experiments for Aims #2 and #3. These data will feed directly into the model. We provide tools to develop hypotheses about the etiology of microgravity induced visual changes. Our models will help predict which subjects may be at risk for the visual deficits associated with microgravity, and could help develop potential countermeasures in the future.

Aim #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. The main efforts this reporting period were to design and test the MRI-compatible LBNP/LBPP (lower body negative pressure/lower body positive pressure) chamber, test the MRI imaging protocols, and develop the MRI data analysis tools needed for the studies. We also conducted a posture experiment with 10 subjects and determined that ocular measures plateau after an average of 12 minutes upon entering a new posture (e.g., seating, supine, prone). This will be used to ensure consistent data for all subjects in the MRI studies. The MRI-compatible LBNP/LBPP chamber will be employed it in the test campaign during the next reporting period. The optimal parameters for collecting and analyzing MRI data were established, which involved examine the trade off between scan accuracy, data needed for the model, and subject acceptability. We developed tools to aid hypothesis development of the etiology behind visual changes in long duration space flight. We developed graphical descriptions of the potential mechanisms for the microgravity-induced ocular and visual changes. We have acquired several devices to measure key parameters, such as an anterior segment module, episcleral venous pressure device, and a BIOPAC continuous, noninvasive blood pressure system. The data collected from these devices will be use to provide additional information for the model.

Aim #3: Identify individuals with common intracranial venous variants, and study them using the protocol outlined in Aim #2. Aim 3 is an objective for our third year. The data collection methods have been established in this reporting period through our Aim 2 objectives. In our initial cohort of pilot subjects, we have identified subjects with anatomical variants, the primary interest of this aim.

--Key findings/developments: Work in the past year has focused on constructing the model (Aim #1), and developing the protocols, hardware and experimental designs needed for Aim #2. For Aim #1, the key developments since October have been to (a) evaluate and select the best software for the modeling needed in the project, and (b) use the software to design a numerical model for the circulatory system that includes gravitational forces and the effects of gravity on tissue weight/tissue compliance. We are using the Simscape modeling environment. The primary strengths of this environment are the ability to leverage (a) MATLAB's robust set of solvers for systems of differential equations, (b) Simscape's automatic construction of the overall set of differential equations based on the variable relationships defined in each component block, and (c) the existing fluid component models available in the Simscape and SimHydraulics libraries. A lumped parameter circulatory system has been developed. The system includes a gravity dependent pressure drop element to capture the effects of changing orientation within a gravitational field on flow systems with multiple flow loops and branch points (such as the circulatory system). The model also includes flexible tubes that change size according to external pressure differences (i.e. modeling the effects of collapsing veins such as the internal jugular veins). Work on the overall modeling design for the circulatory system is also applicable to the CSF circulation model. Data from the studies in Aim #2 and existing data from NASA will be used to test the model.

For Aim #2, several elements are under development to permit the MRI imaging studies planned for year 2. An MRI compatible LBNP device has been constructed, and is beginning initial trials within the MRI magnet. This device will be important for producing fluid shifts for the MRI imaging studies. MRI imaging protocols are being tested to optimize the tradeoff between measurement accuracy and test time. The current protocol will assess vascular anatomy, as well as venous, arterial, and CSF flows in and out of the head. Sequences are also included to provide information on eye flow, and sequences to measure regional brain tissue compliance will be assessed. The MRI studies will be complemented by ocular measurements made in different body positions, with and without fluid shifts, outside of the magnet. These posture studies have been advanced significantly by the acquisition of a Heidelberg Spectralis Optical Coherence Tomography device in the past year. This new device will greatly enhance the data collection for the postural studies beyond what had been proposed initially. A similar device is being used on the ISS to evaluate astronauts. An additional advance has been progress in obtaining existing data from NASA that can be used to help build the model. To date, we have received data from a bed rest study, and just recently received approval to receive deidentified OCT, MRI, and other astronaut data.

---Impact of key findings on hypotheses, technology requirements, objectives, and specific aims of the original proposal. The model development is a core objective of the project. The development of a model including gravitational and tissue compressive forces is novel, and will be essential for predicting microgravity effects. Work over the past 10 months has developed the major scaffolding for the circulatory system model. The primary subsystems are represented and the model includes both body orientation and gravitational effects. Further refinement of model parameters is needed to fine-tune the system to represent the circulatory flow system more accurately. From there, detail and complexity will be added to the model as needed to capture the effects of blood flow and pressures on the eye fluid system. To complete this work we developed custom units within Simscape to incorporate gravity dependence and custom compliance inputs. These custom units allow us to construct flow loops with branch points sensitive to body orientation. We plan to extend this work during the next reporting period by completing development of the shared pressure boundary unit and fluid exchange units to create model coupling between the CSF and circulatory system, the CSF and eye, and the circulatory system and aqueous humor regulatory system. The LBNP device and MRI protocols will be essential for completing the objectives planned for year 2 of the project.

--Proposed research plan for the coming year. In the remainder of the existing year and in the coming year, we will increase the complexity of the model and extend it to the CSF circulation. In the next year we will begin the MRI studies that include both changes in gravitational orientation (supine/prone) and fluid shifts (LBNP/LBPP).