Advanced Restoration Therapies in Spinal Cord Injury 0192 – FY07

Recent evidence suggests that functional electrical stimulation (FES) can improve certain functions in the CNS following injury or disease. Our preliminary clinical observations utilizing FES ergometry in the upper extremities in patients with spinal cord injuries (SCI) corroborate those findings. Using FES-based therapies in our clinic, we have seen neurological, physical, and functional improvements. However, we would like to study this program further to optimize the benefits of FES ergometry. Many studies now demonstrate that electrical stimulation can promote numerous aspects of regeneration following CNS injury, including axon myelination. We and others have shown that remyelination following SCI is one rational and effective approach to promoting recovery of function following experimental SCI. However, very few research groups are testing similar FES parameters in cell culture, animal models of SCI and in patients as part of one study. By systematically measuring the impact of FES on remyelination and functional recovery in these three settings, we hope to greatly advance our understanding of how FES promotes regeneration.

Objective/Hypothesis

To test the hypothesis that patterned neural activity induced by FES enhances recovery of function in the injured spinal cord in animal models and patients with paralysis. In addition, indices of remyelination will be measured in cell culture, animal models, and humans to test whether remyelination correlates with recovery of function.

Study Design

SA1: A randomized, controlled, single-blinded trial will be performed in patients with SCI receiving passive ergometry only compared with patients receiving ergometry in combination with FES. Neurological and functional outcome measures will be used at 4 and 6 months to test the efficacy of each intervention.

SA 2: Advanced MRI techniques will be used to correlate conventional ASIA scoring with myelin profiles in 10 patients with SCI over the course of 12 months.

SA3: FES will be performed in rats with SCI, using different frequencies and durations of stimulation. Outcome measures will assess oligodendrocyte birth, proliferation, differentiation, and myelinating ability.

SA4: FES will be modeled in neural stem cell cultures, using electrical field stimulation. Again, we will vary the frequency and durations of stimulation, and measure the rates of oligodendrocyte birth, proliferation, and differentiation and of axonal myelination. In addition, we will investigate how clinically relevant GABA agonists and the activity-dependent growth factor BDNF alter the cultures’ responses to stimulation.

SA5: We will develop training programs designed to educate peer health-care professionals at Kennedy Krieger and other centers in the application of FES in patients with SCI.

Relevance

The studies proposed here will rigorously test the efficacy of FES-based restorative therapies in promoting neurological and functional recovery in patients with SCI. The integrative approach will facilitate the discovery of recovery mechanisms in cell culture and animal models, while using MRI will better correlate anatomical indices of regeneration with standard clinical assessments. These findings will be applied in a clinical setting to optimize the FES-based therapies. Finally, we will use a new training program to disseminate the findings to centers across the country so that the therapeutic approaches can be better understood and applied to patients. This work will therefore facilitate the recovery of patients with SCI at centers throughout the United States.