Peripheral hyperstimulation alters site of disease onset and course in SOD1 rats

Angelo C. Lepore, Christopher Tolmie, John O'Donnell, Megan C. Wright, Christine Dejea, Britta Rauck, Ahmet Hoke, Anthony R. Ignagni, Raymond P. Onders, Nicholas J. Maragakis

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


In amyotrophic lateral sclerosis (ALS), the exogenous temporal triggers that result in initial motor neuron death are not understood. Overactivation and consequent accelerated loss of vulnerable motor neurons is one theory of disease initiation. The vulnerability of motor neurons in response to chronic peripheral nerve hyperstimulation was tested in the SOD1G93A rat model of ALS. A novel in vivo technique for peripheral phrenic nerve stimulation was developed via intra-diaphragm muscle electrode implantation at the phrenic motor endpoint. Chronic bilateral phrenic nerve hyperstimulation in SOD1G93A rats accelerated disease progression, including shortened lifespan, hastened motor neuron loss and increased denervation at diaphragm neuromuscular junctions. Hyperstimulation also resulted in focal decline in adjacent forelimb function. These results show that peripheral phrenic nerve hyperstimulation accelerates cell death of vulnerable spinal motor neurons, modifies both temporal and anatomical onset of disease, and leads to involvement of disease in adjacent anatomical regions in this ALS model.

Original languageEnglish
Pages (from-to)252-264
Number of pages13
JournalNeurobiology of Disease
Issue number3
StatePublished - Sep 2010


  • ALS
  • Amyotrophic lateral sclerosis
  • Diaphragm
  • Diaphragm pacing
  • Diaphragm stimulation
  • Disease onset
  • Environment
  • Motor neuron
  • Neurodegeneration
  • Phrenic nerve
  • Respiratory
  • SOD1


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