Transspinal-Transcortical Paired Stimulation for Neuroplasticity and Recovery After SCI

People with spinal cord injury (SCI) have motor dysfunction that results in substantial social, personal, and economic costs. Uncontrolled muscle spasticity and motor dysfunction result in disabilities that significantly reduce quality of life. Several rehabilitation interventions are utilized to treat muscle spasticity and motor dysfunction after SCI in humans. However, because most interventions rely on sensory afferent feedback that is interpreted by malfunctioned neuronal networks, rehabilitation efforts are greatly compromised. On the other hand, changes in the function of nerve cells connecting the brain and spinal cord have been reported following repetitive electromagnetic stimulation delivered over the head and legs or arms at specific time intervals. In addition, evidence suggests that electrical signals delivered to the spinal cord can regenerate spinal motor neurons in injured animals. A fundamental knowledge gap still exists on neuroplasticity and recovery of leg motor function in people with SCI after repetitive transspinal cord and transcortical stimulation. In this project, it is proposed that repetitive pairing of transspinal cord stimulation with transcortical stimulation strengthens the connections between the brain and spinal cord, decreases ankle spasticity, and improves leg movement. People with motor incomplete SCI will receive transspinal - transcortical paired associative stimulation at rest and during assisted stepping. The effects of this novel neuromodulation paradigm will be established via clinical tests and noninvasive neurophysiological methods that assess the pathways connecting the brain with the spinal cord.

Motor dysfunction after SCI results in substantial personal, social, and economic costs. Secondary complications related to muscle spasticity and motor dysfunction significantly reduce quality of life. Rehabilitation efforts are compromised because most therapeutic interventions rely heavily on sensory afferent feedback that is interpreted by malfunctioned neuronal networks. On the other hand, electrical signals delivered over the spine regenerate neurons of the spinal cord in injured animals, and paired associative stimulation produces enduring neuronal plasticity in healthy and injured humans and animals. A fundamental knowledge gap still exists on induction of functional neuroplasticity and recovery of leg motor function following repetitive pairing of transspinal cord stimulation with transcortical stimulation in people with motor incomplete SCI. Our central working hypothesis is that transspinal cord stimulation paired with transcortical stimulation strengthens corticospinal neuronal connections, decreases ankle spasticity, and improves leg motor function. This notion is based on the concept tested in the applicant's laboratory that this novel stimulation paradigm potentiates synaptic actions and activity of spared but compromised axons providing the necessary environment for functional neuroplasticity. The rationale of this research study is that neuromodulation methods that can modify effectively the input-output relations of cortical and spinal neuronal pathways in people with motor incomplete SCI are needed. Based on strong preliminary data, two specific aims will be addressed: Specific Aim 1: Establish induction of transspinal-transcortical paired associative stimulation (PAS) neuroplasticity and improvements in leg sensorimotor function in people with motor incomplete SCI when PAS is administered during robotic-assisted gait training. Cortical and corticospinal neuronal circuits via state-of-the-art neurophysiological methods in seated (Aim 1A), soleus H-reflex excitability during assisted stepping (Aim 1B), and sensorimotor function evaluated via standardized clinical tests (Aim 1C) will be assessed before and after 15 sessions of transspinal-transcortical PAS delivered with subjects supine. Specific Aim 2: Establish induction of transcortical-transspinal PAS neuroplasticity and improvements in leg sensorimotor function in people with motor incomplete SCI when PAS is administered during assisted stepping. Cortical and corticospinal neuroplasticity via state-of-the-art neurophysiological methods in seated (Aim 2A), soleus H-reflex excitability during assisted stepping (Aim 2B), and leg sensorimotor function evaluated via standardized clinical tests (Aim 2C) will be assessed before and after 15 sessions of transspinal-transcortical PAS delivered during assisted stepping. It is hypothesized that transspinal-transcortical PAS delivered at rest or during assisted stepping strengthens corticospinal connections, increases spinal inhibition, decreases ankle spasticity, and improves leg motor function. Further, transspinal-transcortical PAS delivered during assisted stepping normalizes the abnormal phase-dependent soleus H-reflex modulation commonly observed during stepping in people with motor incomplete SCI. To test the project hypotheses, 12 people with motor incomplete SCI will receive 20 sessions of transspinal-transcortical or transcortical-transspinal PAS during assisted stepping. In people with SCI, and assess improvements in leg motor function with standardized clinical tests. In all subjects, assessments of neuroplasticity in cortical, corticospinal, and spinal neuronal networks will be administered. These results will advance considerably the field of spinal cord research and change the standard of care because there is great potential for development of novel and effective rehabilitation strategies to manage spasticity and improve motor function after SCI in humans.

Individuals with Spinal Cord Injury will be assigned to receive robotic gait training with the Lokomat combined with paired non-invasive thoracolumbar transspinal stimulation and non-invasive brain stimulation.

Robotic gait training will be administered along with paired non-invasive transspinal stimulation over the thoracolumbar region and non-invasive brain stimulation during assisted stepping.

Robotic gait training will be administered along with paired non-invasive brain stimulation and non-invasive transspinal stimulation over the thoracolumbar region during assisted stepping.

Individuals with spinal cord injury will receive 20 daily sessions of robotic gait training. During assisted stepping, they will receive also paired non-invasive transspinal stimulation and non-invasive brain stimulation during the stance phase of gait. Before and after training standardized clinical and neurophysiological tests will be used to assess recovery of sensorimotor function.

Individuals with spinal cord injury will receive 20 daily sessions of robotic gait training. During assisted stepping, they will receive also paired non-invasive brain stimulation and non-invasive transspinal stimulation during the stance phase of gait. Before and after training standardized clinical and neurophysiological tests will be used to assess recovery of sensorimotor function.

Neurophysiological tests probing cortical and corticospinal excitability will be measured before and after the intervention. Single-pulse transcranial magnetic stimulation (TMS) will be used to assemble the recruitment curve of motor evoked potentials, and paired-pulse TMS will be used to probe changes in cortical inhibitory and facilitatory neuronal circuits.

Neurophysiological tests probing spinal reflex excitability will be measured before and after each intervention by posterior tibial and sural nerves stimulation during Lokomat-assisted stepping depicting the amplitude modulation of the soleus H-reflex, tibialis anterior flexor reflex, and interlimb reflexes.

Inclusion Criteria: Clinical diagnosis of motor incomplete spinal cord injury (SCI). SCI is above thoracic 12 vertebra. Absent permanent ankle joint contractures. SCI occurred 6 months before enrollment to the study. Exclusion Criteria: Supraspinal lesions Neuropathies of the peripheral nervous system Degenerative neurological disorders Presence of pressure sores Urinary tract infection Neoplastic or vascular disorders of the spine or spinal cord Pregnant women or women who suspect they may be or may become pregnant People with cochlear implants, pacemaker, and implanted simulators People with history of seizures People with implanted Baclofen pump

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