Repetitive Transcranial Magnetic Stimulation (rTMS) Elicits Long Lasting Phrenic Motoneuron Excitability Increase in the Rat: Possible Treatment for Respiratory Insufficiency?

Repetitive transcranial magnetic stimulation (rTMS) is a cortical neuromodulatory technique shown to be effective in a clinical setting. However, the underlying mechanisms are poorly understood, thus emphasizing the need to reverse translate the technique to prelinical animal models. We have recently demonstrated the feasibility of using TMS to evaluate diaphragmatic corticomotor pathways by recording specific motor evoked potentials from the diaphragm (MEPdia) in naïve rats as well as in a preclinical rat model of neurological respiratory deficit (C2 hemisection, Vinit et al., PLoS One 2014, 2016). Based on these encouraging preliminary results, we evaluated the evolution of the phrenic motoneuron excitability (by assessing MEPdia) following acute high frequency rTMS protocol applied to the cortical and subcortical areas in a respiratory neurobiology animal model. In an anesthetized adult rat preparation, we applied a repetitive high frequency rTMS protocol (9 trains of 100 biphasic pulses at 10Hz, with 30s intervals, under the motor threshold stimulation of the animal) and evaluated the phrenic motoneuron excitability by recording MEPdia before and up to 60 min post‐rTMS session. This acute high frequency rTMS protocol led to a robust and long lasting increase in phrenic motoneuron excitability (89.9 ± 21 % increase from baseline compared to time control animals 12.6 ± 14.6 %; p<0.002) at 60 min post rTMS protocol. Interestingly, pretreatment with Clonazepam (GABA A agonist) or Baclofen (GABA B agonist) before rTMS blocked this increase in respiratory excitability (9.1 ± 9.2 % and −2.3 ± 10.6 % respectively; p<0.001). Trans‐synaptic retrograde labeling with pseudorabies virus from the diaphragm revealed pre‐phrenic interneurons with GABA A and GABA B receptors, supporting the notion that GABAergic modulation of respiratory excitability could be induced by rTMS. To conclude, one single rTMS protocol induces a long‐lasting increase in respiratory excitability in naïve animals, by disinhibiting GABAergic receptors. Ongoing experiments investigating whether chronic daily rTMS might extend this acute effect. These data serve as foundations for future applications of rTMS to further enhance functional recovery of respiration after high cervical injury. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .