Spinal Cord Associative Plasticity

SUMMARY
Experience leads to behavioral change through associative activity of neural circuits. Using this principle,
paired stimulation has been used to selectively strengthen circuits. We propose to target the spinal cord for
associative plasticity, exploiting strong interaction of descending motor connections and large diameter
afferents, which mediate the senses of joint position and muscle tension. In rats and humans, sub-threshold
cervical stimulation, which activates afferents, strongly augments motor cortex evoked muscle responses when
timed to converge in the spinal cord. When pairing is performed repeatedly in rats, spinal cord associative
plasticity (SCAP) is induced with a large and sustained increase in excitability. In rats with cervical spinal cord
injury (SCI), 10 days of SCAP significantly improved forelimb function. We hypothesize that SCAP will
strengthen spinal excitability, modulate reflexes, and increase pinch force in people with cervical SCI. Aim 1
tests the timing of pairing and the circuits mediating paired stimulation, key issues for proper targeting. Timing
cortical and spinal stimulation to converge in the spinal cord, as opposed to cortex, is predicted to be strongest.
We will use both non-invasive and invasive spinal cord stimulation. For non-invasive stimulation, we will
combine transcutaneous stimulation over the neck with transcranial magnetic stimulation over cortex. For
invasive stimulation, we will combine spinal epidural stimulation with transcranial electrical stimulation during
clinically indicated surgery. Aim 2 tests the effects of SCAP to produce a lasting increase in spinal excitability,
as measured by both cortical and spinal evoked potentials and pinch dynamometry. Controls will isolate the
changes induced specifically through pairing. Finally, Aim 3 tests whether paired motor cortex and cervical
spinal cord stimulation produces similar effects in people with the two most common causes of SCI, cervical
myelopathy and traumatic SCI, as uninjured participants. Spinal excitability is predicted to increase, pinch force
is expected to become stronger, and spinal reflexes are expected to diminish. The integrity of spinal pathways
will be measured with both physiology and analysis of cervical MRI. Together, these studies will fill critical gaps
about the nature of associative plasticity in the sensorimotor system and test a new strategy to strengthen
residual connections after SCI. This strategy will be tested with both invasive and non-invasive stimulation,
allowing direct comparison of these approaches for the first time. Thus, we intend to close gaps in our
understanding of how paired stimulation of sensorimotor circuits should be targeted to the spinal cord and
which residual circuits support the plasticity. This knowledge can optimize how we target electrical stimulation
to induce SCAP. Multiple methods of motor cortex and cervical spinal cord stimulation have been proven to be
safe, so these mechanistic studies can be translated quickly to efficacy trials.

Grant Number: 5R01NS124224-05
NIH Institute/Center: NIH
Principal Investigator: Jason Carmel