We have demonstrated that the physiological state of the lumbosacral spinal circuitry of spinal rats and cats can be modulated with spinal cord epidural stimulation (EDS) and/or administration of pharmacological agents to generate weight-bearing standing and stepping over a range of speeds, loads, and directions. We have translated some of these results to humans by implanting 3 motor complete spinal cord injured (SCI) subjects about three years post-injury with an epidural electrode array over the lumbosacral spinal cord. In less than one month post-electrode implant, the subjects could stand independently, and after up to 7 months of daily EDS and motor training, voluntary control of both legs was evident in the presence of EDS, whereas complete paralysis remained in absence of EDS. We propose to employ a similar stimulation strategy for the recovery of upper limb function. We will include extensive testing of spinal rats to guide our strategy to test for upper extremity improvement in human SCI subjects. We will use off-the-shelf FDA approved pharmacological and stimulation modalities to: 1) Determine the optimal stimulation parameters, i.e., electrode placement and stimulation intensity, frequency and duration, for facilitating forelimb fine motor function in rats with a cervical SCI. Using existing FDA-approved epidural electrodes, we will demonstrate in patients with a cervical SCI that cervical EDS can facilitate arm-hand function. 2) Identify an effective mode of administration, define the dose- response pharmacokinetics, and determine the effectiveness of a monoaminergic agonist to facilitate upper limb function after a cervical SCI. We will assess the effectiveness of existing FDA-approved pharmacological agents (i.e., buspirone and as an alternative, bromocriptine), and determine their effectiveness in improving forelimb control in subjects with a cervical SCI. 3) Define the dose-response properties of monoaminergic agonists when combined with EDS in facilitating forelimb function in rats after a cervical SCI. We will demonstrate the efficacy of ES in combination with a pharmacological intervention in facilitating arm and hand function in humans after a cervical SCI. 4) Determine whether motor training of spinal rats will further enhance the recovery of motor function when combined with pharmacological and/or EDS interventions. 5) Develop a protocol for machine learning to enable rapid selection of the optimal pharmacological and EDS parameters for motor recovery in rats and in human subjects. If successful, this could represent the beginning of a paradigm shift in the use of minimally invasive strategies combined with rehabilitative approaches to realize significant improvement in upper limb function after paralysis.

Public Health Relevance

It now seems possible to apply three interventions (epidural stimulation, administration of pharmacological agents, and motor training) to control the excitability of localized neural circuits in humans with a cervical spinal cord injury (SCI), thus enabling these individuals to regain use of their arms and hands. This enabling effect is similar to that observed with improved postural and locomotor function after a mid-thoracic SCI. We will reach critical milestones that will provide the basis for a series of clinical trials for furter defining the efficacy of these interventions.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-ETTN-B (52))
Program Officer
Peng, Grace
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Schools of Medicine
Los Angeles
United States
Zip Code
Freyvert, Yevgeniy; Yong, Nicholas Au; Morikawa, Erika et al. (2018) Engaging cervical spinal circuitry with non-invasive spinal stimulation and buspirone to restore hand function in chronic motor complete patients. Sci Rep 8:15546
Gerasimenko, Yury; Sayenko, Dimitry; Gad, Parag et al. (2017) Feed-Forwardness of Spinal Networks in Posture and Locomotion. Neuroscientist 23:441-453
Alam, Monzurul; Garcia-Alias, Guillermo; Jin, Benita et al. (2017) Electrical neuromodulation of the cervical spinal cord facilitates forelimb skilled function recovery in spinal cord injured rats. Exp Neurol 291:141-150
Hoffman, Haydn; Sierro, Tiffany; Niu, Tianyi et al. (2017) Rehabilitation of hand function after spinal cord injury using a novel handgrip device: a pilot study. J Neuroeng Rehabil 14:22
Lu, Daniel C; Edgerton, V Reggie; Modaber, Morteza et al. (2016) Engaging Cervical Spinal Cord Networks to Reenable Volitional Control of Hand Function in Tetraplegic Patients. Neurorehabil Neural Repair 30:951-962
Lee, Sunghoon Ivan; Park, Eunjeong; Huang, Alex et al. (2016) Objectively quantifying walking ability in degenerative spinal disorder patients using sensor equipped smart shoes. Med Eng Phys 38:442-9
Desautels, Thomas A; Choe, Jaehoon; Gad, Parag et al. (2015) An Active Learning Algorithm for Control of Epidural Electrostimulation. IEEE Trans Biomed Eng 62:2443-2455
Gad, Parag; Roy, Roland R; Choe, Jaehoon et al. (2015) Electrophysiological mapping of rat sensorimotor lumbosacral spinal networks after complete paralysis. Prog Brain Res 218:199-212
Hoffman, Haydn; Lee, Sunghoon I; Garst, Jordan H et al. (2015) Use of multivariate linear regression and support vector regression to predict functional outcome after surgery for cervical spondylotic myelopathy. J Clin Neurosci 22:1444-9
Gad, Parag; Roy, Roland R; Choe, Jaehoon et al. (2015) Electrophysiological biomarkers of neuromodulatory strategies to recover motor function after spinal cord injury. J Neurophysiol 113:3386-96

Showing the most recent 10 out of 16 publications