High frequency repetitive Transcranial Magnetic Stimulation promotes long lasting phrenic motoneuron excitability via GABAergic networks

• Published in: Respiratory physiology & neurobiology 2021-10, Vol.292, p.103704-103704, Article 103704
• Main Authors: Michel-Flutot, Pauline, Zholudeva, Lyandysha V., Randelman, Margo L., Deramaudt, Therese B., Mansart, Arnaud, Alvarez, Jean-Claude, Lee, Kun-Ze, Petitjean, Michel, Bonay, Marcel, Lane, Michael A., Vinit, Stéphane
• Format: Article
• Language: English
• Subjects: Animals; Diaphragm - drug effects; Diaphragm - physiology; Ecology, environment; Evoked Potentials, Motor - drug effects; Evoked Potentials, Motor - physiology; Female; GABA-A Receptor Agonists - pharmacology; GABA-B Receptor Agonists - pharmacology; GABAergic modulation; Health; Life Sciences; Motoneuron excitability; Motor Neurons - drug effects; Motor Neurons - physiology; Nerve Net - drug effects; Nerve Net - metabolism; Nerve Net - physiology; Phrenic Nerve - drug effects; Phrenic Nerve - metabolism; Phrenic Nerve - physiology; Preclinical model; Rats; Rats, Sprague-Dawley; rTMS; Transcranial Magnetic Stimulation
• ISSN: 1569-9048; 1878-1519
• DOI: 10.1016/j.resp.2021.103704

•Acute high frequency rTMS increases spinal motoneurons excitability.•Its effect is modulated by the GABAergic system.•The treated population is divided in “Responder” and “Non-responder” subpopulations. Repetitive transcranial magnetic stimulation (rTMS) is a promising, innovative, and non-invasive therapy used clinically. Efficacy of rTMS has been demonstrated to ameliorate psychiatric disorders and neuropathic pain through neuromodulation of affected neural circuits. However, little is known about the mechanisms and the specific neural circuits via which rTMS facilitates these functional effects. The aim of this study was to begin revealing the mechanisms by which rTMS may tap into existing neural circuits, by using a well characterized spinal motor circuit – the phrenic circuit. Here we hypothesized that rTMS can be used to enhance phrenic motoneuron excitability in anesthetized Sprague Dawley rats. Multiple acute rTMS protocols were used revealing 10 Hz rTMS protocol induced a robust, long-lasting increase in phrenic motoneuron excitability, functionally evaluated by diaphragm motor evoked potentials (59.1 ± 21.1 % of increase compared to baseline 60 min after 10 Hz protocol against 6.0 ± 5.8 % (p = 0.007) for Time Control, -5.8 ± 7.4 % (p < 0.001) for 3 Hz, and 5.2 ± 12.5 % (p = 0.008) for 30 Hz protocols). A deeper analyze allowed to discriminate “responder” and “non-responder” subgroups among 10 Hz rTMS treated animals. Intravenous injections of GABAA and GABAB receptor agonists prior to 10 Hz rTMS treatment, abolished the enhanced phrenic motoneuron excitability, suggesting GABAergic input plays a mechanistic role in rTMS-induced phrenic excitability. These data demonstrate that a single high frequency rTMS protocol at 10 Hz increases phrenic motoneuron excitability, mediated by a local GABAergic “disinhibition”. By understanding how rTMS can be used to affect neural circuits non-invasively we can begin to harness the therapeutic potential of this neuromodulatory strategy to promote recovery after disease or injury to the central nervous system.