Grants

Current External Funding

1)  NYS Dept of Health (Spinal Cord Injury Research Board): DOH01-2015-TRANS1-00013 (Martin, PI; Carmel, Burke Rehab/Cornell, co-PI; Harel, Mt Sinai School of Medicine/Bronx VA Hospital, co-PI); 6-1-16 to 5-31-21; Combined Motor Cortex and Spinal Cord Stimulation to Promote Arm and Hand Function After Chronic Cervical Spinal Cord Injury.

Translating a Promising Therapy for Spinal Cord Injury from Animals to Humans

Scientific Abstract:

For people with cervical SCI, regaining hand function is their highest priority. Currently there are no effective treatments for people living with paralysis or profound weakness after spinal cord injury SCI. The goal of this project is to strengthen residual corticospinal tract (CST) connections after partial injury using combined motor cortex and spinal cord stimulation to improve arm and hand function. The CST is critical for skilled hand movement in health, and for the loss of movement with injury.

To restore arm and hand function, the parts of the brain that control movements must be reconnected with the spinal cord motor circuits that control the muscles of the body. Whereas the problem of reconnecting the brain and spinal cord after SCI is an active area of neuroscience research, most approaches, such as axon regeneration or cell replacement, offer promise only over the long term. In humans, most SCIs are motor incomplete, and even when complete there is often significant amounts of spared spinal cord white matter. Animal research suggests that the partial spontaneous recovery that may occur after SCI is partly mediated by sprouting of spared motor pathway axons. However, sprouting after injury and spontaneous partial recovery is very limited; sprouting must be augmented to become effective. Our research in rats demonstrated that brain and spinal cord stimulation restores motor skills in rats after CST injury. Most significant for the population of people living with SCI, this approach is effective in the chronic phase of injury.

Our research in rats has shown that CST axon sprouting after injury can be substantially augmented by electrical stimulation of the origin of the pathway, the motor cortex. After severing the entire CST from one hemisphere by a brain lesion, motor cortex stimulation can abrogate movement impairments and restore motor skills in rats. This is mediated by the stimulated motor cortex. Most significant for the population of people living with SCI, this approach works in the chronic phase of the lesion; it does not depend on a short duration critical period after injury.

Recently, we have translated this electrical stimulation protocol in an exciting way. We developed a protocol that reduces the amount of brain stimulation from a 6 hours a day to less than 30 minutes each day by using an electrical intermittent theta burst stimulation (iTBS) pattern to activate motor cortex in combination with trans-spinal direct current stimulation (tsDCS) to activate the cervical spinal cord. Using finite element method (FEM) modeling, a mathematical approach that combines high-resolution MRI and CT imaging with tissue conductivities, we showed selective targeting of the cervical enlargement with tsDCS. Thus, by combining brain and spinal cord electrical stimulation in rodents with this corticospinal system injury we achieve durable CST axonal sprouting, strengthening of CST connections, and movement recovery.

In this proposal we intend to bring this promising therapeutic approach to humans with cervical SCI. Three laboratories—the Martin lab (CUNY School of Medicine at CCNY), Carmel lab (Burke Rehabilitation), and Harel lab (Bronx VA/Mt Sinai School of Medicine)—will devote intensive resources to tackle the highly focused problem of harnessing neural activity-dependent plasticity to promote arm and hand functions in cervical injured people.

Our translational strategy has 3 goals: 1) to replicate the rehabilitative effects of iTBS+tsDCS in rats, developed in the Martin lab, in an independent laboratory (Carmel/Burke); 2) to translate stimulation therapy to a large-animal model, and 3) to test the safety and feasibility of this approach in people with chronic, motor incomplete, SCI.

Thus, with a five year time line, we intend to translate a validated and promising therapy to a large animal model and then to humans with chronic cervical SCI. Our approach can be fully non-invasive and, if shown to be effective, can be rapidly implemented to help treat the people with chronic SCI.

Lay Abstract:

For people with cervical SCI, regaining hand function is their highest priority. Currently there are no effective treatments for people living with paralysis or profound weakness after SCI. The goal of this project is to translate a promising therapy for improving arm and hand function after partial spinal cord injury to humans. The approach promotes repair of residual corticospinal tract (CST) connections using combined motor cortex and spinal cord stimulation. The CST is critical for skilled hand movement in health, and for the loss of movement after injury.

To restore arm and hand function, the parts of the brain controlling movements must be reconnected with the spinal cord motor circuits controlling body muscles. In humans, most SCIs are motor incomplete. Animal research suggests that the partial spontaneous recovery that may occur after SCI is partly mediated by sprouting of spared motor pathway axons. However, sprouting after injury and spontaneous partial recovery are very limited; sprouting must be augmented to become effective. Our research in rats demonstrated that brain and spinal cord stimulation fully restores motor skills in rats after CST injury. Most significant for the population of people living with SCI, this approach is effective in the chronic phase of injury.

This proposal has 3 goals. In Goal 1, we plan to replicate the rehabilitative effects of stimulation in rat in an independent laboratory. In Goal 2, we apply the replicated protocol to a large animal cervical SCI model. Replication and large animal models are necessary steps in establishing robust therapies. In Goal 3, we will study people with chronic, motor incomplete, SCI to test the safety and feasibility of this approach. Our approach can be fully non-invasive and, if effective, can be rapidly implemented to help treat the people with chronic SCI.

2) NIH/NINDS: R01NS079569 (Martin, PI); 5/1/13 – 4/30/18; Repairing maladaptive corticospinal tract development

3) NIH/NINDS: 1R01NS064004-06 (Martin, PI); 9/30/13 – 9/29/18; Lesion and activity dependent corticospinal tract plasticity.

4) NYS Dept of Health: DOH01-CARTID-2015-00070 (Martin, PI); Repairing the Damaged Corticospinal Tract after Cervical Spinal Cord Injury 11-1-15 to 10-31-18.