When a patient is in the early stages of amyotrophic lateral sclerosis (ALS), neurons innervating the diaphragm begin to die. Although breathing is fairly normal at early disease stages, it sharply declines in late stages of the disease. Why?

Researchers at Cincinnati Children’s suspected that accessory respiratory muscles (ARMs) play a compensatory role at early stages of ALS. ARMs are known to enhance ventilation when demands are high, such as during exercise. But they typically are not used to assist breathing at rest. Using a well-characterized mouse model of ALS (SOD1^G93A), Cincinnati Children’s neuroscientist Steven Crone, PhD, led a study to observe ARM activity and study the circuits controlling them throughout disease progression.

Crone and his team utilized electromyography and unrestrained whole body plethysmography to measure both breathing and muscle activity in the mouse models at rest. As the disease progressed and symptoms such as limb weakness began to appear, ARM activity increased and ventilation was maintained. In the late stages of disease, however, ventilation declined; ARMs were no longer being recruited for ventilation, even though they were being used for other behaviors, such as grooming. The team also noted that starting early in disease progression, the V2a class of neurons in the brainstem and spinal cord degenerated. The degeneration of these neurons, which are part of the circuitry controlling ARMs, may contribute to ARM failure at late stages of disease. The study was published in Experimental Neurology (August 2016).

“These results have wide-ranging implications for any patient with a disease that leads to neuromuscular weakness, such as ALS, spinal cord injury and spinal muscular atrophy,” says Crone. “If we can figure out how to prolong the function of circuits that control the ARMs, maybe we can slow down or prevent neuromuscular degeneration and delay the need for a respirator. Our ongoing research will explore ways to modulate these circuits and improve breathing, whether through drug therapy, gene therapy or surgical transplantation.”

Crone is part of the Cincinnati Children’s division of neurosurgery and the developmental neurobiology research group led by Kenneth Campbell, PhD, who holds the Robert and Sarah McLaurin Chair of Pediatric Neurosurgery Research. This group is part of a larger collective of Cincinnati Children’s neuroscientists whose 20 laboratories are dedicated to identifying more effective therapies and better clinical delivery for a wide range of neurological conditions.