Regenerating motor bridge axons refine connections and synapse on lumbar motoneurons to bypass chronic spinal cord injury

Abstract

To restore motor control after spinal cord injury requires reconnecting the brain with spinal motor circuits below the lesion. A bridge around the injury is an important alternative to promoting axon regeneration through the injury. Previously, we reported a novel motor bridge in rats. The thirteenth thoracic nerve was detached from the muscle it innervates and the cut end implanted caudally into the lumbar gray matter where motor bridge axons regenerate. In this study, we first determined that regenerating bridge axons project to spinal motor circuits. Stable projections were present in ventral motor laminae of the cord, including putative synapses directly on motoneurons, 2 months after insertion in the intact cord. At this time, earlier-forming dorsal horn projections were mostly eliminated. Regenerating axons were effective in evoking leg motor activity as early as 2 weeks. We next determined that bridge axons could regenerate caudal to a chronic injury. We hemisected the spinal cord at L2 and inserted the bridge nerve 1 month later at L5 and found ventral laminae projections similar to those in intact animals, including onto motoneurons directly. Finally, we determined that the bridge circuit could be activated by neural pathways rostral to its origin. For spinally hemisected animals, we electrically stimulated the rostral spinal cord and recorded evoked potentials from the bridge and, in turn, motor responses in the sciatic nerve. Our findings suggests that bridge motoneurons could be used by descending motor pathways as premotor interneurons to transmit neural signals to bypass a chronic spinal injury.

Spinal cord bypass surgery using peripheral nerve transfers: review of translational studies and a case report on its use following complete spinal cord injury in a human

“…Sectioning the peripheral nerve bridge in animal models abolishes limb movement. 2,3 We suspect that a similar result would occur if our patient underwent an appropriate intercostal nerve block. Unfortunately, in the absence of any reasonable expectation of a clinical benefit, this procedure would be unethical, and we have not advocated it.…”

“…Peripheral nerve fibers grew into the ventral horn of the spinal cord and made functional synapses on alpha motor neurons. 2,3 Stimulation of the transferred nerve generated visible contractions in the paralyzed lower extremity. Furthermore, this strategy partially ameliorated the spasticity that results following cord hemisection.…”

“…Stimulation of the transferred peripheral nerve results in limb movement when sufficient recovery time has elapsed in a rodent model. 2,3 Intermittent stimulation produces intermittent leg movement through these novel spinal cord synapses, not through another pathway, such as via the spinal nerve roots. There is no evidence to suggest that the growth of a peripheral nerve directly into the spinal roots even occurs.…”

Improved technique for stereotactic placement of nerve grafts between two locations inside the rat brain

“…However, other studies have also noticed the easy in-growth but difficult outgrowth effect of peripheral nerves or other grafts in which Schwann cells are involved (Carter et al, 1998). Several strategies, such as the coadministration of trophic factors (Zhou et al, 1996) or the implantation of olfactory enseathing cells might be used to improve the ability of axons to cross the glial barrier and make distal synapses (Campos et al, 2008). In any case, the main objective of this paper is to describe the grafting technique.…”

Peripheral Nerve Grafts Support Regeneration after Spinal Cord Injury

“…Here, we will discuss some basic technical aspects of using a PNG to promote regeneration, the application of PNGs to a variety of injury conditions (including a delayed grafting [chronic injury] approach), the use of PNGs in a combinatorial treatment strategy, and the translation of peripheral nerve (PN) grafting to large animal models of spinal cord injury (SCI). This review focuses on results obtained from grafting peripheral nerve segments into the injured spinal cord, but it would be remiss not to mention that alternative approaches using components of peripheral nerves (e.g., purified Schwann cells in implantable guidance channels [11][12][13][14][15][16][17][18][19][20][21], or the re-routing of a peripheral nerve from its target muscle to enter the spinal cord distal to an injury [22][23][24]) have demonstrated considerable success in establishing connectivity across a lesion site. Notably, the number of Electronic supplementary material The online version of this article (doi:10.1007/s13311-011-0024-6) contains supplementary material, which is available to authorized users.…”