Based on the combined efforts of a multidisciplinary and multi-university team, this research program will develop a novel, flexible, high density electrode array technology for epidural spinal cord stimulation. This technology has the potential to significantly improve the recovery of posture and locomotion in individuals with a severe spinal cord injury. High density epidural electrode arrays will enable us to take advantage of two key features of spinal cord circuitry that are essential for rehabilitating posture and locomotion. First, the spinal circuitry interprets and transduces sensory information into state-dependent motor activity. Second, the locomotor network is highly plastic and adapts when provided with persistent sensory cues during training, thus enabling recovery to occur. Epidural stimulation facilitates both of these important processes and we hypothesize that it will be particularly beneficial after an SCI, when descending motor control is lost. Since sensory and motor processing occurs throughout the dorsal spinal cord, the distributed stimulation capability of the proposed high density electrode arrays will provide comprehensive access to the diffusely located components of the locomotor network. We hypothesize that, when combined with motor training, multi-site epidural stimulation will enable finer and more robust control of locomotion of SCI subjects than previously possible. This research program is composed of two parallel tracks. The first, and major, track focuses on developing, testing, and characterizing the arrays in a complete SCI rat model. Our preliminary animal experiments have demonstrated success in promoting recovery of stepping of complete spinal cord injured rats when the hindlimbs are trained regularly with robotic devices and when the spinal cord is stimulated epidurally at a single or at two sites. In this research program, we will design, fabricate, and test a series of electrode arrays that vary in size, electrode count, and density. We will test these high density arrays on SCI rats using various design combinations, culminating in an experiment that will test a combined therapy using a high density stimulating array coupled with assist-as-needed robotic training. A second parallel track will explore the use of conventional electrode technology, which historically has been used mainly for suppressing spasticity and back pain, to facilitate standing and stepping in human subjects with a severe spinal cord injury. We hypothesize that the combination of epidural stimulation with task specific motor training will enable individuals with an injury that presently precludes independent stepping and standing, to regain these functions. The combined results of our animal studies and human studies would prepare our team for subsequent work that focused on translating the high density array technologies to human clinical studies. This proposal will be conducted as a collaboration between the University of California (Los Angeles), Caltech, and the University of Louisville, with assistance from an expert team of clinicians, engineers, and scientists located in Vienna, Austria.

Public Health Relevance

In this proposal we will develop new multielectrode arrays, which will be surgically placed on the connective tissue sheath surrounding the spinal cord, that can be used to stimulate specific regions of the spinal cord to help SCI subjects recover the ability to stand or step. These electrode arrays will help us take advantage of two built-in features of the spinal cord neural circuits that are associated with the ability to stand and step: 1) interpretation of complicated, dynamic sensory information and 2) use-dependent plasticity of these spinal circuits. We hypothesize that the combination of stimulation of the spinal cord and either stand or step training will allow individuals with a spinal cord injury to regain these functions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
3R01EB007615-05S1
Application #
8609358
Study Section
Special Emphasis Panel (ZRG1-NT-K (01))
Program Officer
Peng, Grace
Project Start
2008-09-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$591,507
Indirect Cost
$130,308
Name
University of California Los Angeles
Department
Physiology
Type
Schools of Arts and Sciences
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Gad, Parag N; Roy, Roland R; Zhong, Hui et al. (2014) Initiation of bladder voiding with epidural stimulation in paralyzed, step trained rats. PLoS One 9:e108184
Angeli, Claudia A; Edgerton, V Reggie; Gerasimenko, Yury P et al. (2014) Altering spinal cord excitability enables voluntary movements after chronic complete paralysis in humans. Brain 137:1394-409
Sayenko, Dimitry G; Angeli, Claudia; Harkema, Susan J et al. (2014) Neuromodulation of evoked muscle potentials induced by epidural spinal-cord stimulation in paralyzed individuals. J Neurophysiol 111:1088-99
Gad, Parag; Lavrov, Igor; Shah, Prithvi et al. (2013) Neuromodulation of motor-evoked potentials during stepping in spinal rats. J Neurophysiol 110:1311-22
Gad, Parag; Choe, Jaehoon; Nandra, Mandheerej Singh et al. (2013) Development of a multi-electrode array for spinal cord epidural stimulation to facilitate stepping and standing after a complete spinal cord injury in adult rats. J Neuroeng Rehabil 10:2
Shah, Prithvi K; Garcia-Alias, Guillermo; Choe, Jaehoon et al. (2013) Use of quadrupedal step training to re-engage spinal interneuronal networks and improve locomotor function after spinal cord injury. Brain 136:3362-77
Musienko, Pavel; Courtine, Gregoire; Tibbs, Jameson E et al. (2012) Somatosensory control of balance during locomotion in decerebrated cat. J Neurophysiol 107:2072-82
Johnson, Will L; Jindrich, Devin L; Roy, Roland R et al. (2012) Quantitative metrics of spinal cord injury recovery in the rat using motion capture, electromyography and ground reaction force measurement. J Neurosci Methods 206:65-72
Edgerton, V R; Roy, R R (2012) A new age for rehabilitation. Eur J Phys Rehabil Med 48:99-109
Shah, Prithvi K; Song, James; Kim, Samuel et al. (2011) Rodent estrous cycle response to incomplete spinal cord injury, surgical interventions, and locomotor training. Behav Neurosci 125:996-1002

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