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

Neurobiol Dis. 2010 Sep;39(3):252-64. doi: 10.1016/j.nbd.2010.03.021. Epub 2010 Apr 8.


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 SOD1(G93A) 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 SOD1(G93A) 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.

MeSH terms

  • Action Potentials / physiology*
  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / pathology
  • Amyotrophic Lateral Sclerosis / physiopathology*
  • Analysis of Variance
  • Animals
  • Electric Stimulation
  • Electrodes, Implanted
  • Electromyography
  • Female
  • Hand Strength / physiology*
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Male
  • Motor Neurons / metabolism
  • Motor Neurons / pathology
  • Muscle, Skeletal / physiopathology*
  • Nerve Degeneration / metabolism
  • Nerve Degeneration / pathology
  • Nerve Degeneration / physiopathology
  • Phrenic Nerve / metabolism
  • Phrenic Nerve / physiopathology*
  • Rats
  • Rats, Transgenic
  • Superoxide Dismutase / metabolism*
  • Superoxide Dismutase-1


  • Sod1 protein, rat
  • Superoxide Dismutase
  • Superoxide Dismutase-1