NOTE: End date is 6/30/2013 per NSSC and PI (Ed., 9/25/13)

NOTE: End date is 9/30/2013 per D. Risin/JSC (Ed., 7/11/13)

NOTE: To be extended per J. Maher/JSC (Ed., 4/2013)

Our project directly addresses the Critical Path Roadmap Risks and Questions for NASA regarding disc injury (IRP Gap-B4): Is damage to joint structure, intervertebral discs, or ligaments incurred during or following hypogravity exposure? The goal of this research is to characterize space-flight induced changes comprehensively in disc morphology, biochemistry, metabolism, and kinematics. These data will be correlated with measures of back pain intensity and disability. Crewmembers will be imaged pre-flight to establish baseline data and to characterize measurement repeatability. After long-term microgravity exposure (about 180 days on ISS), crewmembers will be studied while maintaining supine posture as soon as possible after return to 1-G in order to quantify the acute effects of prolonged space flight. Also, pre- and post-flight, they will be imaged supine and in standing upright posture at one body weight and again at 1.1 body weight so that MR images are obtained before and after axial body-weight loads. Pre-flight tests will be done within L-120 to L-60 days before the scheduled space flight. Post-flight tests will be undertaken1-7 days and 30-60 days after landing to investigate re-adaptation to 1-G and to distinguish immediate and longer-term recoveries. Our proposed measures represent a comprehensive set of tests that evaluate exposure severity, potential injury mechanisms, and pain generator localization.

Our research will aid understanding of spinal pain and deconditioning during prolonged microgravity and of the higher incidence of disc prolapse or herniation following re-exposure to 1-G with a long-term view to prevent such spinal deconditioning with exercise or other physiologic countermeasures.

To improve our tests and protocol, we amended our JSC-CPHS Protocol 10-072 to include the cervical spine and to reduce the total scanning time for our upright MRI tests of ISS crews before and after flight. This modification reduces the risk (reducing overall scanning time from 80 min to 60 min and having the crew member sit in a fourth scan) and raises the benefit of our protocol by including the cervical spine which has the highest incidence of post-flight disc herniation. The risk of herniated vertebral discs was reported recently for 321 astronauts (Johnston et al., 2010). The incidence of disc herniation was the highest (41%) in the cervical spine, compared to 9% in matched controls. During pilot studies on the PI last year, we were able to streamline the upright MRI studies of the lumbar spine to less than the proposed 80 minutes. We were also able to add scans of my cervical spine for a total scanning time of 60 minutes.

In January 2013, we renewed our IRB protocol successfully and submitted a minor amendment to our JSC-IRB Protocol 0303 “Risk of Intervertebral Disc Damage after Prolonged Space Flight” that was approved. In brief we moved our Biering-Sorensen test from JSC Building 261, Exercise Physiology Lab under the direction of Dr. Lori Ploutz-Snyder to UTMB Radiology Imaging Center - Victory Lakes 2240 Gulf Freeway South, League City, Texas 77573 (phone 409-772-7150), under the direction of Drs. Eric Walser and Roy Riascos-Castaneda. We believe this amendment will reduce crew time related to our pre- and post-flight testing of crew members.

For each ISS increment over the past year, we have carefully reviewed the Experiment Summaries received prior to each increment. By reviewing the experiment summaries for all international space agency’s science teams, we developed a top-level understanding of the operations of other experiments requesting subjects in each increment. Thus, we were able to identify 1) conflicts that cannot be resolved by scheduling, 2) experiments that are mutually exclusive, and 3) conflicts that require further discussion during implementation.

Over the past year with the help of our NASA Technical Monitors Steve Hing and Susan Torney, we have reviewed and re-reviewed the detailed Flight Experiment Requirements Document, Experiment Document for Risk of Intervertebral Disc Damage after Prolonged Space Flight. This was important to do after our first Pre- and Post-Flight testing sessions for our first crew member for IVD.

Assessment of data retrieved from the first subject has been completed. Comparing the pre- and post- flight data, there was an observed: 1) Increase in lumbar IVD heights as demonstrated by morphological measures of the supine MRI scans, 2) Increased lumbar IVD compressibility with upright MRI scans, 3) Increased stiffness using Spinal Kinematics tests, and 4) Increased low back pain post-flight using the visual-analog scale. In terms of scientific progress, we now have a sample size of one after completing our first, full Pre- and Post-Flight testing sessions for our first crew member for IVD. Thus, it is not possible to make valid conclusions based on this preliminary sample size. However, the images we acquired are very high in quality and give us confidence that future tests will be very successful.

Our research will aid understanding of spinal pain and deconditioning during prolonged microgravity and of the higher incidence of disc prolapse or herniation following re-exposure to 1-G with a long-term view to prevent such spinal deconditioning with exercise or other physiologic countermeasures.

In terms of tests, we improved the set-up and safety of the Biering-Sorensen Test and received approval for our Test Readiness Review on 17 Feb 2012. On June 2011 we submitted an Investigation Summary Form for our project which was officially approved as “IVD.”

After responding to the NASA-JSC CPHS, we received official approval of our amended NASA protocol and consent form on 21 June 2011. The significant revisions are summarized below and reflect changes made to improve the science and reduce the time commitment and radiation risk to crew members. We added UTMB Victory Lakes MRI Facility as the supine MRI site to reduce travel time from JSC. Pre- and post-flight, crew will be imaged at Upright MRI in Clear Lake during supine posture and then upright posture with normal weight bearing and after donning a back pack with 10% body weight load. This weight-bearing procedure is more natural than supine loading at 50% body weight. Specific Aim 4 and all methods related to PET scan were deleted to reduce the time commitment and radiation risk to crew members. A pre-flight familiarization of the Biering-Sorensen trunk strength test was added. Prior to any test day, we requested a log of medications taken by the crew member over the previous 48 hours. Also, prior to any test day, we requested a log of exercises (type, intensity and duration) performed by the crew member over the previous 7 days. Moreover, we requested a log of all in-flight exercises performed by the crew member. We will also share muscle strength data with the JSC Exercise Physiology and Countermeasures Lab. One of our four testing sessions (formerly Session C) was deleted, reducing post-flight testing time from 345 min to 320 min not including travel time. We reduced total radiation dose from 30.9 mSv to 3.4 mSv. The Consent was revised to reflect the changes outlined above.

We were selected for flight on 25 July 2011 and we received approval from the JAXA IRB on 27 May 2011. In Sept 2011, we briefed two ISS crews and received Consent from two crew members. In Nov-Dec 2011, we drafted an Intervertebral Disc Damage (IVD) Science Verification Test (SVT) Plan. This SVT plan outlined the IVD tests with specific steps regarding scheduling, test preparation, test completion, and data transfer to verify the experiment system was adequate to support the scientific objectives.

On 6 Jan 2012 we submitted a renewal and amendment to our JSC-CPHS Protocol 10-072. The changes to our JSC-CPHS Protocol 10-072 (since it was initially approved on 7 Feb 2011) included the removal of two Co-Is (Alavi and Sayad-Shah) who are no longer involved in the study and addition of a new Co-I, Scott Parazynski, MD. We clarified that all pre-flight tests will be conducted within L-120 to L-60 days before the scheduled space flight. All post-flight tests will occur during the period R+1-7. However, it should be noted that the MRI and MRS tests will be repeated during the R+30-60 day period. The later MRI and MRS tests will monitor recovery of the discs. It was emphasized that no new tests are added. We also uploaded our Legacy protocol to the new NASA JSC CPHS web site and also, uploaded new Letters of Support and Conflict of Interest statements.

In Nov 2011, UCSF graduate student Cory Laws presented a poster at the American Society for Gravitational and Space Biology (ASGSB) Annual Meeting entitled ‘Increased risk of disc herniation following spaceflight: a biomechanical model’. These data represent work to develop analytical and experimental (human cadaveric) models that can be used to clarify mechanisms of microgravity-induced disc injury. These models will be used to help interpret data collected from crew members as well as develop potential countermeasures. Cory Laws was featured in the Student Spotlight in the most recent ASGSB newsletter ( https://www.asgsr.org/images/stories/pdf/ASGSB_Spring_2012_FINAL_C.pdf ).

In Dec 2011, Sayson, Lotz, Parazynski, and Hargens submitted a review paper “Back Pain in Space and Post-Flight Spine Injury: Mechanisms and Countermeasure Development,” based on a presentation at the 2011 IAA Humans in Space meeting in Houston, TX. This paper was conditionally accepted for possible publication in Acta Astronautica.

On 5 Feb 2012, Dr Jeff Lotz presented a talk at the Orthopaedic Research Society entitled “Spines in Space: Microgravity Effects on Spinal Discs.”

On 14 February 2012, Dr Alan Hargens presented a talk at the Human Research Program Investigators' Workshop entitled “Mechanism of Post-Flight Herniation of Intervertebral Discs.” Following the Human Research Program Investigators' Workshop, we performed additional pilot studies of our upright MRI at the Upright MRI facility nearby NASA JSC. Based on our studies on 17 Feb 2012, we further amended our JSC-CPHS Protocol 10-072 to include the cervical spine and reduced the total scanning time for our upright MRI tests of ISS crews before and after flight. This modification reduced the risk (reducing overall scanning time from 80 min to 60 min and having the crew member sit in a fourth scan) and raised the benefit of our protocol by including the cervical spine which has the highest incidence of post-flight disc herniation. The risk of herniated vertebral discs was reported recently for 321 astronauts (Johnston et al., 2010). The incidence of disc herniation was the highest (41%) in the cervical spine, compared to 9% in matched controls. Our amendment was approved by the JSC-CPHS on 28 March 2012. During pilot studies on the PI last month, we were able to streamline the upright MRI studies of the lumbar spine to less than the proposed 80 minutes. We were also able to add scans of my cervical spine for a total scanning time of 60 minutes.

On 13 March 2012, Dr. Jeff Lotz gave an invited presentation to the Department of Orthopaedic Surgery at the University of Hong Kong entitled "The Effects of Microgravity on the Human Lumbar Spine."

On 24 April 2012 we briefed two additional crew members as well as conducted a full pilot study of the MRI and dynamic fluoroscopy studies to be performed at Victory Lakes. Two sets of studies were performed on two volunteers to both verify protocols and data integrity; and also to assess the ability to discriminate diurnal fluctuations in disc anatomy, biomechanics, hydration, and metabolic profile. For the first time, all of these data sets will be correlated within and across individuals. We had allotted 2 hours to both tests and were able to reduce the time by 15 minutes. With these extra 15 minutes, we plan to submit a modification to the CPHS, to include the cervical spine given the prevalence of disc herniations in this region. This will allow us to compare both upright and supine MRI.

Our research will aid understanding of spinal pain and deconditioning during prolonged microgravity and of the higher incidence of disc prolapse or herniation following re-exposure to 1-G with a long-term view to prevent such spinal deconditioning with exercise or other physiologic countermeasures.

Next, we submitted our approved UCSD protocol to the NASA-JSC CPHS on 29 July 2010. The NASA-JSC CPHS tabled their full review of our UCSD-approved protocol until their NASA Radiation Isotopes Subcommittee reviewed and approved it. After we were contacted in late August 2010 to provide more information on radiation dosages and to reduce dosages to levels as low as reasonably achievable, the NASA Radiation Isotopes Subcommittee met on 15 September 2010 to reconsider our protocol. After consideration of the reduced dosages and the impact upon astronaut career limits, the NASA Radiation Isotopes Subcommittee approved the proposal with the specification that the Consent Form be revised and individualized to provide astronauts with both career limit impact and health risks of combined space flight and scientific investigation induced-radiation exposures. Prior to an ISS Investigator Working Group meeting on 22 November 2010, the PI received feedback from Drs. Jan Meck and Scott Parazynski that the Astronaut Office thought that the radiation levels were too high and crew consent would be difficult to obtain. Thus, during a meeting of two Co-Is (Drs. Lotz and Chiang) and myself, we decided to delete the post-pre-flight PET test using Na-F and make all PET tests optional for crew members as follows:

1) Post-flight FDG of the whole spine only (10 mSv/0.42 mSv/day=24 extra days on ISS)

2) Pre- and Post-flight FDG scans of the whole spine (48 extra days on ISS)

3) Post-flight Na-F if abnormal post-flight MRI (7.5mSv/0.42mSv/day= 18 extra days on ISS)

4) No PET scans- minimal radiation from fluoroscopy only (3.4 mSv or 8 extra days on ISS)

These four options would allow crew members to decide what radiation dosage best suits their career limits and helps them manage their individual risks.

Also, following the ISS Investigator Working Group meeting on 22 November 2010, we moved our MRI and MRS testing site to UTMB Victory Lakes to reduce ISS crew transport times and evaluated the standard, back strength tests that are performed using the NASA JSC Biodex equipment. We decided that Biodex data will be of value to us, but we also need a form of endurance test in spine posture as the isometric endurance is more functional outcome for spinal fatigue. Below is a list of our action items from the ISS Investigator Working Group meeting on 22 November 2010, followed by our responses: 1. For IVD, SPRINT, ICV: a. Gather all MRI requirements. See attached NASA IRB application to be submitted tomorrow. b. Determine if Victory Lakes can accommodate all MRI requirements. Yes, we think so depending on NASA’s negotiations with UTMB for use of their facilities. c. Determine to what degree, if any, MRI sessions can be combined. Not possible as far as we know as we request R+1 imaging. d. Determine washout time for tracers (how long between IVD and ICV MRI’s). No washout time.

2. For FTT, SPRINT and IVD: a. Can any muscle function/strength measurements from SPRINT/FTT be shared with IVD? No, but we are checking is CSE tests are sufficient for our purposes.

After responding to the NASA-JSC CPHS, we received official approval of our revised NASA protocol and consent form on 7 February 2011.

Before and after this approval by the NASA-JSC CPHS, we have been coordinating and optimizing our protocol and pre- and post-flight crew-testing schedule with several personnel from the Biomedical Research and Countermeasures Projects Branch and the Bioastronautics Team of the International Space Station Medical Project at NASA JSC.

On 12 April 2011, Sayson and Hargens presented a review paper “Back Pain Mechanisms in Space” at the IAA Humans in Space meeting in Houston, TX: J.V. Sayson, A.R. Hargens. Back Pain Mechanisms in Space. IAA 18th Humans in Space Symposium: “Integration and Cooperation in the Next Golden Age of Human Space Flight.” April 11-15, 2011.

On 14 April 2011, also at the IAA 18th Humans in Space Symposium, our team presented an abstract “STS-131: Effects of Microgravity on the Creep Behavior of Murine Intervertebral Discs.” J.F. Bailey, K.K. Cheng, A.R. Hargens, K. Masuda, and J.C. Lotz. STS-131: Effects of Microgravity on the Creep Behavior of Murine Intervertebral Discs. IAA 18th Humans in Space Symposium: “Integration and Cooperation in the Next Golden Age of Human Space Flight.” April 11-15, 2011.

Following this meeting, we performed pilot studies of our upright MRI, spinal kinematics, MRI and MRS tests at facilities nearby NASA JSC. The times for each test were within the limits which we cited in our IRB applications; and the tests were valuable in order to optimize tests on actual crew members planned for next year. We plan to conduct another pilot test in San Diego 19 May 2011 in order to optimize further the back pack design and stability conditions for our upright MRI tests. Related to the tests of spinal kinematics, we noted an upright L5/S1 motion curve with three peaks in one of our investigators who served as a control subject. Our expert, Adam Deitz, compared the results multiple times with the raw images and confirmed that the graph was true to the motion in the video. We found that our control subject is highly mobile, especially in the upper lumbar region. Based on the recumbent flexion/extension data, it appears that his L5/S1 is the least stiff of all of his spinal segments, and that L3/L4 and L4/L5 are the most-stiff segments. These pilot studies demonstrate that dynamic fluoroscopy is a very sensitive tool for quantifying lumbar motion and should provide valuable information as to how long-duration space flight alters spinal movement patterns.

Also, at the IAA Humans in Space meeting in Houston, our team was informed that our proposed PET/CT tests of spinal inflammation and injury were deleted because they were deemed to be insufficiently valuable from a benefit/risk ratio. We hope to receive a formal letter from NASA explaining this decision.

We are finalizing a review paper “Back Pain in Space and Post-Flight Spine Injury: Mechanisms and Countermeasure Development” by J Sayson, J Lotz, S Parazynski and A Hargens for submission to Acta Astronautica within the next month.

The next few months will include revising our UCSD and NASA IRB applications to incorporate changes related to the PET/CT scans and other minor adjustments which were derived from our pilot studies in April 2011.

Our project directly addresses the Critical Path Roadmap Risks and Questions for NASA regarding disc injury (IRP Gap-B4): Is damage to joint structure, intervertebral discs, or ligaments incurred during or following hypogravity exposure? The goal of this research is to comprehensively characterize space-flight induced changes in disc morphology, biochemistry, metabolism, and kinematics. These data will be correlated with measures of back pain intensity and disability. Crewmembers will be imaged twice pre-flight (over a one-month time frame) to establish baseline data and to characterize measurement repeatability. After long-term microgravity exposure (180 days on ISS), crewmembers will be studied while maintaining supine posture as soon as possible after return to 1-G in order to quantify the acute effects of prolonged space flight. Also, pre- and post-flight, they will don a compression device so that MR images are obtained before and after 50% axial body weight load. This compression device loads the spine and simulates 50% BW load (not including loads from muscles) on the lumbar spine in upright posture. Subsequently, crewmembers will be tested after 3- and 6-months of re-adaptation to 1-G in order to distinguish immediate and longer-term recoveries. Our proposed measures represent a comprehensive set of tests that evaluate exposure severity, potential injury mechanisms, and pain generator localization.

Our research will aid understanding of spinal pain and deconditioning during prolonged microgravity and of the higher incidence of disc prolapse or herniation following re-exposure to 1-G with a long-term view to prevent such spinal deconditioning with exercise or other physiologic countermeasures.