Journal in Which the Study was Published: Cell Reports
Author: Jared Cregg, Neurosciences graduate student at Case Western Reserve University School of Medicine in Cleveland, Ohio is first author on the study. His advisor, Jerry Silver, PhD, Professor of Neurosciences at Case Western Reserve University School of Medicine in Cleveland, Ohio is senior author.
Background: Spinal cord injury, most commonly caused by vehicle accidents or falls, leaves approximately 17,000 Americans paralyzed each year. The damage can be severe, with less than 1% of those injured experiencing complete neurologic recovery. Many of those injured must rely on mechanical ventilators to breathe. Explained Cregg, “Respiratory signals originate in the brain and are relayed to motor neurons in the spinal cord, which then allow the diaphragm to contract. These signals are cut off after cervical spinal cord injury.”
Constant mechanical ventilation significantly increases a person’s risk of fatal infection. Bacteria can colonize breathing tubes in direct contact with the lungs, leading to pneumonia or septicemia—leading causes of death for spinal cord injury patients. Patients using ventilators can also experience diaphragm muscle atrophy from lack of use, eliminating their chances of ever breathing independently. Together with colleagues, Jerry Silver, PhD, has been developing ways to restore diaphragm function after spinal cord injury, in part to reduce patient reliance on ventilators.
How the Study Was Conducted: A team of ten researchers, led by Silver, studied spinal cord injuries in rodents, and their associated neural networks. Silver’s team previously developed a grafting technique that allows nerves coming from the brain to “bridge” spinal cord injuries and activate neurons below spinal cord lesions. In the new study, the researchers examined how electrical signals could be transmitted using portions of this alternative network to stimulate the diaphragm.
The research team included members of the Spinal Cord and Brain Injury Research Center in the Department of Neuroscience at the University of Kentucky College of Medicine.
Results: “We have discovered a way that may allow animals to breathe in a model of quadriplegia without the need for a respirator,” Cregg said. The new study showed quadriplegic rodents—those who underwent complete cervical spinal cord injury—had no spontaneous electrical impulses below the injury site. But by treating the rodents with pharmacologic agents, the researchers were able to induce “bursts” of electricity and show they originated in the spinal cord—not the brain. The researchers then used a laboratory technique called optogenetics to harness the impulses and induce electrical signals in the diaphragm. Optogenetics uses light to flip switches inside neurons, allowing researchers to turn on and off specific portions of the nervous system.
In neonatal mouse experiments, C1 spinal cord injuries eliminated brain-derived respiration. But, the researchers discovered electrical signals could still be transmitted from the spinal cord to the diaphragm in these mice. Even with severe spinal cord injury, the mice could maintain intermittent electrical bursts in their diaphragms consistent with breathing patterns. The findings show that the diaphragm can operate via nerve circuitry entirely separate from the brain.
Said Cregg, “Our results unexpectedly showed that diaphragm motor neurons can be controlled by two independent networks—the classical breathing network in the brain, and a spinal cord network we identify for the first time. Importantly, while previous studies hypothesized that these were parts of the same network, we show that they act completely independently.”
The newly discovered network could help spinal cord injury patients bypass missing brain signals and restore motor function below injury sites. This could include diaphragm function, to ultimately reduce their reliance on ventilators.
The researchers plan to study the new network in “more anatomical detail.” In their experiments, diaphragm electrical activity could not be induced after C8 spinal cord injury. This information will help the team further map the new circuitry.
Author Comment: “We have discovered a way to control the diaphragm in the absence of input from the brain. This exciting discovery may pave the way for future strategies aimed at augmenting motor output after cervical spinal cord injury.” Cregg said.
“Results from our previous studies indicated that there was unexpected complexity in the spinal circuits controlling diaphragm motor neurons. In order to understand how to promote function after injury, we needed to first understand how these circuits operate,” Cregg said.
“Our technology is still far out in terms of developing a corollary approach in humans, as our experiments indicating that we can control diaphragm motor output after cervical spinal cord injury were performed in rodent models. The technology will still need to undergo a lot of future development before it could ever be implemented as an approach to solving the human condition,” Cregg cautioned.
Said the authors, “Those attempting to enhance regeneration of [nerve cells] and restoration of a ‘simple’ motor behavior may need to consider the dynamic interplay between intact networks and networks that undergo dramatic reorganization caudal to a spinal lesion.”
Limitations: Although rodents in the study displayed nerve impulses in their diaphragms, they were not able to breathe independently in the spinal cord injury experiments. Additional research will be required to fully restore breathing function in animal models after spinal cord injury, and to ultimately translate such therapeutic approaches to humans.
Funding & Disclosures: This work was supported by National Science Foundation grant DGE-0951783 (to J.M.C.); National Institutes of Health grants NS101105 (to W.J.A.), NS085037 (to P.P.), NS074199 (to L.T.L.), and NS025713 (to J.S.); the University of Kentucky College of Medicine (W.J.A.); Case Western Reserve University (P.P.); and the Mt. Sinai Foundation (P.P.).
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