The specific objectives of the countermeasure battery are: to preserve muscle strength and cardiovascular fitness; to minimize decrements in postural stability, dynamic balance, and the ability to make corrective actions prior to a fall; to preserve functional performance on mission relevant tasks; and to minimize bone loss in the proximal femur. To accomplish these objectives, we have constructed a unique multi-functional countermeasure device which integrates cardiovascular, balance control, and resistance training functions. The stepper system provides cardiovascular exercise. When the stepper is locked down, the device may be utilized for lower body strengthening exercises such as squats, leg extensions, and abductor/adductor exercises. For balance training, the stepper/resistive system is mounted on a Stuart Platform allowing 3D translations with a range of +/- 10 cm and pitch/yaw/roll of +/- 10 degrees.

In the second and third years of the study, based on a request from the Human Research Program, we rescoped the project to carry out a training study in which we have evaluated the ability of combined countermeasure device (CCD) exercise to generate improvements in cardiovascular function and lower body resistive strength. 15 subjects underwent a 12 week training study which involved three weekly one hour sessions of cardiovascular and lower body resistive training. The cardiovascular training initially involved stepper exercise (5 subjects, 5% mean 12 week improvement in VO2max, non-significant change), but based on poor results we changed the aerobic protocol to bike exercise (10 subjects, 27% mean 12 week improvement in VO2max, p=0.004), following a design simulation illustrating that a compact exercise bike could be folded into the footprint of the CCD. The 10 subjects exercised on the bike showed improvements ranging from 17%-38%. Leg press strength increased in all 15 subjects over 12 weeks (mean change 68%, range 47-85%, p=0.0001). Isokinetic strength measures showed variable response, with hip abduction, adduction, and ankle plantarflexion strength increasing by 22%, 31%, and 13%, respectively (all p<0.05), but leg extension, leg flexion, and hip flexion strength showed non-significant increases. Weight lifted by all subjects in each exercise increased significantly (all exercises p=0.0001). Thus, we were able to conclude that CCD exercise was well tolerated, and could produce significant improvements in physical fitness, thus achieving the goal of the training study.

Because a project goal is to develop an exercise protocol in which squatting and hip ab/adduction exercise protect against hip bone loss, Dr. Cavanagh's group adapted the Lifemodeler computational tool to simulate the effect of the muscle contractions produced by CCD squatting and ab/adduction exercise. LifeModeler incorporates contractions of 47 muscles in the leg, and fully models all of the CCD exercise. To validate, Drs. Cavanagh and Hanson used the Orthoload Database, which contains results from studies of volunteers who received hip prostheses instrumented with strain sensors, allowing for calculation of hip loading forces associated with different exercises, including abduction and squatting. Simulating the exercise protocols used in the Orthoload Study, the Lifemodeler calculations produced hip loads that were in quantitative agreement with the measured Orthoload results. These calculations showed that 1g CCD abduction exercise produced peak forces of 4 body weights on the hip, compared to 2.5 body weights for squatting. On June 4, we presented our training study and Lifemodeler work to the Human Health Countermeasures (HHC) Control Board. Based on the heavy load on the Bedrest Facility, the CCD was not placed into the bedrest study, but followup on our ab/adduction results were considered highly exciting. Based on this, we carried out a study to evaluate the effects of ab/adduction exercise on hip bone strength and density measured by quantitative computed tomography and finite element modeling. We compared standard Advanced Resistive Exercise Device (aRED) lower body exercise, combined aRED, and ab/adduction and ab/adduction only, maintaining the same number of repetitions per group, in a 16 week study, with three exercise sessions per week. Eight subjects were assigned to each group. aRED exercise resulted in increased spine and femoral neck bone density, as well as increased hip strength by FEM in the stance loading condition. Ab/Add exercise showed increased cortical bone volume at the trochanter and a borderline insignificant increase of hip strength by FEM in the fall loading condition. The combined group showed no changes. Thus, while AbAdd exercise appears to have a modest osteogenic effect, any application of this approach for prevention of hip bone loss would require additional exercise. Given the modest osteogenic effect we observed, the value of Ab/Adductor exercise may rest more in preservation of functional mobility and fall protection rather than bone loss prevention.

The specific objectives of the countermeasure battery are: to preserve muscle strength and cardiovascular fitness; to minimize decrements in postural stability, dynamic balance, and the ability to make corrective actions prior to a fall; to preserve functional performance on mission relevant tasks; and to minimize bone loss in the proximal femur. To accomplish these objectives, we have constructed a unique multi-functional countermeasure device which integrates cardiovascular, balance control, and resistance training functions. The stepper system provides cardiovascular exercise. When the stepper is locked down, the device may be utilized for lower body strengthening exercises such as squats, leg extensions and abductor/adductor exercises. To facilitate balance training, the stepper/resistive system is mounted on a Stuart Platform allowing 3D translations with a range of +- 10 cm and pitch/yaw/roll of +-10 degrees. In the second and third years of the study, based on a request from the Human Research Program, we have rescoped the project to carry out a training study in which we have evaluated the ability of CCD exercise to generate improvements in cardiovascular function and lower body resistive strength. 15 subjects underwent a 12 week training study which involved three weekly one hour sessions of cardiovascular and lower body resistive training. The cardiovascular training initially involved stepper exercise (5 subjects, 5% mean 12 week improvement in VO2max, non-significant change), but based on poor results we changed the aerobic protocol to bike exercise (10 subjects, 27% mean 12 week improvement in VO2max, p0.004), following a design simulation illustrating that a compact exercise bike could be folded into the footprint of the CCD. The 10 subjects exercised on the bike showed improvements ranging from 17%-38%. Leg press strength increased in all 15 subjects over 12 weeks (mean change 68%, range 47-85%, p=0.0001). Isokinetic strength measures showed variable response, with hip abduction, adduction and ankle plantarflexion strength increasing by 22%, 31% and 13% respectively (all p<0.05), but leg extension, leg flexion and hip flexion strength showed non-significant increases. Weight lifted by all subjects in each exercise increased significantly (all exercises p=0.0001) over the course of the study. Thus, from our training study data, we were able to conclude that CCD exercise was well tolerated, and could produce significant improvements in physical fitness, thus achieving the goal of the training study. Because one of the key goals of the project is to develop a novel exercise protocol in which squatting and hip ab/adduction exercise are employed to protect against hip bone loss, Dr. Cavanagh's group has adapted the Lifemodeler computational tool to simulate the effect of the muscle contractions produced by CCD squatting and ab/adduction exercise on the hip. This calculation incorporates the contractions of 47 muscles in the leg, and fully models all of the CCD exercise. To validate this model, Drs. Cavanagh and Hanson utilized the Orthoload Database, which contains results from studies of volunteers who received hip prostheses instrumented with strain sensors, allowing for calculation of hip loading forces associated with different exercises, including abduction and squatting. Simulating the exercise protocols used in the Orthoload Study, the Lifemodeler calculations produced hip loads that were in quantitative agreement with the measured Orthoload results, validating the use of Lifemodeler to estimate load forces on the hip associated with CCD exercises. These calculations showed that in 1g, CCD abduction exercise produced peak forces of four body weights on the hip, compared to 2.5 body weights for squatting exercise. On June 4, we presented the results of our training study and Lifemodeler work to the HHC Control Board. Based on the heavy load on the Bedrest Facility placed by the ongoing aRED studies, it was decided not to place the CCD into the bedrest study, but followup on our ab/adduction results were considered highly exciting and worthy of pursuit. Based on this evaluation, we plan for the final year of our grant, a detailed evaluation of the effects of ab/adduction exercise on hip bone strength and density as measured by quantitative computed tomography and finite element modeling. This study will compare standard aRED lower body exercise, combined aRED and ab/adduction and ab/adduction only, maintaining the same number of repetitions per group.

We believe that the compact characteristics of the CCD which are optimal for the spaceflight environment will also fulfill the needs for an in-house exercise device or for a nursing home. It is well known that impaired balance is associated with aging and with an increased risk of falling. Balance training exercise in the elderly has been shown to reduce risk of falls. In particular, resistive exercise has been shown to increase muscle strength in the elderly, and increases in muscle strength and balance are associated with improvements in performance and mobility, which are important determinants of quality of life in the elderly. Finally, by focusing on resistive exercise in the abductor and adductor muscle groups, this device is expected both to improve lateral balance and reduce the rate of age-related bone loss by stressing those muscle groups that attach at the hip and thus provide significant mechanical loads on the proximal femur.

15 subjects completed our 12 week training study, which involved pre- and post training evaluation of VO2max, leg press strength, and isokinetic measures of knee extension and flexion strength, hip ab/adduction strength, hip flexion strength and ankle plantarflexion strength. 5 subjects underwent a 12 week training study which involved three weekly one hour sessions of cardiovascular and lower body resistive training. The cardiovascular training initially involved stepper exercise (5 subjects, 5% mean 12 week improvement in VO2max, non-significant change), but based on poor results we changed the aerobic protocol to bike exercise (10 subjects, 26% mean 12 week improvement in VO2max, p<0.05), following a 3D design simulation illustrating that a compact exercise bike could be folded into the footprint of the CCD. The 910 subjects exercised on the bike showed improvements ranging from 17%-38% (95 CI). Leg press strength increased in all 15 subjects over 12 weeks (mean change 68%, range 47-85% 95CI, p=0.0001). Isokinetic strength measures showed variable response, with hip abduction, adduction and ankle plantarflexion strength increasing by 22%, 31% and 13% respectively (all p<0.05), but leg extension, leg flexion and hip flexion strength showing non-significant increases. Weight lifted by all subjects in each exercise increased significantly over the course of the study. Thus, from our training study data, we were able to conclude that CCD exercise was well tolerated, and could produce dramatic improvements in physical fitness, thus achieving the goal of the training study.

LifeModeler Calculations: Dr. Cavanagh's group has adapted the Lifemodeler computational tool to estimate the peak hip loads exerted by the muscle contractions produced by CCD squatting and ab/adduction exercise. This calculation incorporates the contractions of 47 muscles in the leg, and fully models all of the CCD exercises. To validate this model, Drs. Cavanagh and Hanson utilized the Orthoload Database, which contains results from studies of volunteers who received hip prostheses instrumented with strain sensors, allowing for calculation of hip loading forces associated with different exercises, including abduction and squatting. Simulating the exercise protocols used in the Orthoload Study, the Lifemodeler calculations produced hip loads that were in quantitative agreement with the measured Orthoload results, validating the use of Lifemodeler to estimate load forces on the hip associated with CCD exercises. These calculations showed that in 1g, CCD abduction exercise produced forces of four body weights on the hip, compared to 2.5 body weights for squatting exercise.

We believe that the compact characteristics of the CCD which are optimal for the spaceflight environment will also fulfill the needs for an in-house exercise device or for a nursing home. It is well known that impaired balance is associated with aging and with an increased risk of falling. Balance training exercise in the elderly has been shown to reduce risk of falls. In particular, resistive exercise has been shown to increase muscle strength in the elderly, and increases in muscle strength and balance are associated with improvements in performance and mobility, which are important determinants of quality of life in the elderly. Finally, by focusing on resistive exercise in the abductor and adductor muscle groups, this device is expected both to improve lateral balance and reduce the rate of age-related bone loss by stressing those muscle groups that attach at the hip and thus provide significant mechanical loads on the proximal femur.

The current year of the study, ending 8/31/09, was devoted to starting a training study to demonstrate that cardiovascular and resistive exercise could improve measures of muscle strength and endurance. The study components included training on the CCD at our facility and pre- intermediate and post training testing at the Exercise Laboratory at the Clinical Research Center (CRC) of the UCSF Clinical and Translational Science Institute. We have made considerable progress:

1) The CCD was installed in 12/2008. We also brought new personnel onto the project so that the training study could be carried out at UCSF. Mr. Tim Streeper, an Exercise Physiologist, was brought in to lead the training study. Dr. Lynda Frassetto, Medical Director of the CRC, joined as our Study Physician. Dr. Kathleen Mulligan, director of the CRC Exercise Lab, became a co-investigator. Drs. Frassetto and Mulligan have been instrumental in use of the CRC for the pre and post training strength and VO2max testing.

2) We carried out pilot studies to reveal issues with the study logistics and operation of the CCD. These pilot studies revealed multiple technical issues with the operation of the device in strength training and stepping mode. These problems were identified and fixed in the first part of 2009, which delayed the projected start of the training study from March to May 2009.

3) We started the training study in May 2009. As of time of this report, three subjects have finished the full twelve week study, with four more subjects in initial and intermediate phases of the study. By the end of the project period, four subjects will have completed training.

4) Initial results are positive. On average, with three subjects complete, VO2max increases by an average of 7%, and leg press strength by 60%. Hip abductor and adductor strength increase by 20 and 68% respectively. Given that the technical problems associated with the early part of the study have been addressed, we expect to make considerable progress towards completing the study in the coming year.

We believe that the compact characteristics of the CCD which are optimal for the spaceflight environment will also fulfill the needs for an in-house exercise device or for a nursing home. It is well known that impaired balance is associated with aging and with an increased risk of falling. Balance training exercise in the elderly has been shown to reduce risk of falls. In particular, resistive exercise has been shown to increase muscle strength in the elderly, and increases in muscle strength and balance are associated with improvements in performance and mobility, which are important determinants of quality of life in the elderly. Finally, by focusing on resistive exercise in the abductor and adductor muscle groups, this device is expected both to improve lateral balance and reduce the rate of age-related bone loss by stressing those muscle groups that attach at the hip and thus provide significant mechanical loads on the proximal femur.

For cardiovascular exercise, the stepper is bolted to the platform. The stepper allows for 8" maximum displacement between petals at high stepping rates. Balance training is carried out during the stepping motion, as the subject moves the passive Stewart platform in concert with the displayed visual cues.

For resistive lower body exercise, the subject is loaded onto the platform with four pneumatic subject load devices attached to the subject through a shoulder harness.

Together, the SLDs provide a maximum resistive load up to 435 lbs in 5 lb increments. The device is designed to support the following resistive exercises:

• Squats: 20" maximum vertical displacement with a maximum load up to 435 lbs. This exercise is carried out on an empty platform with the stepper removed.

• Abductor/Adductor exercises: the stepper is removed and replaced with a horizontal rail system allowing 15" horizontal leg motion in each direction against a maximum load up to 435 lbs.

• Heel raises are performed with the device configured for squats, against a maximum load of 435 lbs.

• Leg extensions are carried out with the device configured for squats. A bungee configuration is employed to produce high levels of resistance.

The device in its current form will be transferred to UCSF where it will be employed in a training study with the goal of qualifying the CCD for eventual inclusion in the Flight Analog Project bedrest study. For eventual flight status, the device will be redesigned to obviate the need to replace the stepper and horizontal rail adjustment in transition between exercise modalities.

We aim to devise a time-efficient integrated battery of countermeasures that can be conducted in the confines of the lunar habitat to minimize the risk of musculoskeletal injury. These countermeasures will be validated using a 10-degree head-up bed-rest simulation of a lunar mission. The specific objectives of the countermeasure battery will be to preserve muscle strength and cardiovascular fitness; to minimize decrements in postural stability, dynamic balance and the ability to make corrective actions prior to a fall; to preserve functional performance on mission-relevant tasks; and to minimize bone loss in the proximal femur.

This will be accomplished through a combination of novel resistance exercises on a device designed by our commercial partner that will load specific muscle groups at the hip and in the lower extremity. It will also allow balance and coordination training. We hypothesize that the combined effect of this multifaceted intervention will be to significantly reduce the risk of a work-related falls and subsequent injuries. We will test our hypothesis by randomizing half of our subjects to a group which will undergo the integrated countermeasure and the other half to a control group. Pre- and post-bed rest, we will compare indices of balance, muscle strength, and skeletal density and function using a combination of functional and strength tests, serum and urine bone markers, and CT and DXA imaging of the hip, spine and tibia.