A Hebbian Approach to Retraining Spared Circuits after Spinal Cord Injury (P02.005)

Objective: 1) Characterize spared neural circuitry after spinal cord injury; 2) Determine efficacy of Hebbian exercises targeting neural circuits above the injury level. Background Spinal cord injury (SCI) only rarely causes complete cord transection. Even patients without volitional movement below a lesion often retain some intact circuitry. The fibers most likely to withstand SCI originate in the brainstem, which generally does not mediate conscious movement. To reestablish conscious control over spared circuits, treatments must strengthen connections between brainstem circuits and volitional corticospinal pathways ABOVE the injury. Using a Hebbian approach of 9Fire Together, Wire Together9, we plan to strengthen these connections with exercises that stimulate both cortical and brainstem pathways simultaneously. We have demonstrated the efficacy of this approach in a rodent SCI model (Harel et al., 2010). We now show further preclinical evidence for efficacy, and introduce a clinical study translating this strategy toward human SCI patients. Design/Methods: PRECLINICAL EXPERIMENTS: To extend our previous results, we compared efficacy of dual-mode (brainstem+corticospinal) to single-mode training in a unilateral pyramidotomy model. Multiple behavioral and histological outcomes were assessed. PLANNED CLINICAL STUDY: Chronic thoracic SCI patients are evaluated with a clinical-neurophysiological testing battery including computerized posturography, motor and sensory evoked potentials, and poly-electromyography. Motor-incomplete subjects are randomized into three groups: 1)treadmill training (spinal); 2)balance training (brainstem); or 3)dual-mode training (balance plus corticospinal hand exercises). Primary outcomes: Gait disability; MEP amplitudes at L4 and S1. Results: PRECLINICAL EXPERIMENTS: In mice with unilateral pyramidotomy, dual-mode but not single-mode exercise significantly improved skilled ladder climbing and several principal components of gait kinematics. Histological assessments of CST fiber sprouting will be presented. BASELINE CLINICAL MEASUREMENTS: Initial results of seated computerized posturography, evoked potentials, and poly-electromyography will be presented. Conclusions: Dual-mode exercise rehabilitation targeting cortical and brainstem pathways ABOVE spinal lesions improves outcomes in animal models of SCI. This rehabilitation approach is feasible for application toward human SCI patients. Supported by: NINDS K08NS056212. NINDS R01NS33020. Falk Medical Research Trust. Department of Veterans Affairs RR&D National Center of Excellence for the Medical Consequences of Spinal Cord Injury (#B4162-C). Disclosure: Dr. Harel has received personal compensation for activities with AlphaDetail and Beebe & O9Neil as a consultant. Dr. Song has nothing to disclose. Dr. Tang has nothing to disclose. Dr. Spungen has nothing to disclose. Dr. Strittmatter has received personal compensation for activities with Biogen Idec. Dr. Strittmatter has received royalty payments from Axerion Therapeutics. Dr. Strittmatter holds stock and/or stock options in Axerion Therapeutics. Dr. Strittmatter has received research support from Axerion Therapeutics.