Development and Validation of a Rodent FES Bicycle System

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Bone loss is a hallmark of severe spinal cord injury (SCI) that increases risk of fracture and contributes to the development of medical comorbidities that worsen mortality risk. The bone deficits occurring after SCI are precipitated by the central nervous system (CNS) insult and the subsequent musculoskeletal unloading, which has resulted in an emphasis on activity-based physical therapy (ABPT) modalities that reload the impaired limbs to restore bone integrity. Strategies that couple ABPT with electrical stimulation [e.g., functional electrical stimulation (FES) cycling] are intriguing because they improve muscle recovery in the impaired limbs by stimulating muscles to perform task-specific exercise and may promote sensorimotor recovery in the presence of some spared spinal tracts. However, the ability of FES cycling to restore bone mineral density (BMD) in the paralyzed limbs remains contentious after SCI, especially at the distal femur and proximal tibia sites that are most prone to fracture. These data indicate need to optimize FES parameters for bone restoration. The goal of this proposal is to develop and operationalize the first-ever ‘humanized’ FES bicycle system for rats. We will then use our system in future proposals to optimize FES parameters for bone recovery in a ‘high-throughput’ manner, using our rat severe SCI model that exhibits similar musculoskeletal pathophysiology to persons with severe traumatic SCI. To achieve our goal, we propose a novel high-risk / high-reward approach that will reverse-translate the design of a human FES bicycle to develop a FES system for rats consisting of 1) a rat bicycle that allows both FES directed and motorized pedaling on a crank shaft with modifiable resistance levels, 2) sensors that record pedal locations, torque, velocity and that provide real-time feedback on these pedaling parameters to a FES control system and a camera that records limb motions, and 3) a closed-loop switched control system that accurately regulates pedaling between FES, in positions where muscles contribute to pedaling, and an electrical motor coupled to the bicycle crank shaft that initiates in FES “dead zones” where muscle activity provides little pedaling contribution. Our approach is innovative because, if successful, it will provide a cost-effective and time-efficient means to optimize preclinical FES parameters for bone restoration, which can then be fast-tracked to clinical trials that will assist in developing personalized rehabilitation strategies for Veterans with SCI. To ensure our success, we have taken key steps, including: 1) constructing a motorized (passive) rat bicycle that serves as the platform for our hybrid FES directed / motorized cycle, 2) developing a closed-loop switched control system for human FES cycles that serves as a model for our control system, and 3) characterizing the locomotor, bone, and muscle deficits in our rat severe contusion SCI model, which we will use to test and validate the FES bicycle. Moreover, we have demonstrated that motorized (passive / isokinetic) cycling normalized reflex excitability and promoted locomotor and bone recovery (Preliminary Data) in SCI rats, providing rationale for cycling as the base ABPT modality in our proposal. While these components are in-place, our proposal remains high-risk / high-gain because success requires that we modify our existing rat bicycle, as described above; that we design, fabricate, model, and optimize a closed-loop switched control system that accurately regulates pedaling cadence in rats; and that we explore initial tolerability to repeated FES cycling bouts in our rat SCI model. Based on our findings, system refinement and re-testing may also be required. To address these steps, we have two Aims: Aim 1: Design and fabricate a rat bicycle and a closed-loop switched control system that alternates FES directed and motorized control of the crank shaft to produce continuous pedaling. Aim 2: Operationalize, validate, and test our FES bicycle system in rats with severe SCI.