Effects of repetitive transcranial magnetic stimulation of upper airway muscles during sleep in obstructive sleep apnea patients

Abstract

We tested the hypothesis that stimulating the genioglossus by repetitive transcranial magnetic stimulation (rTMS) during the ascendant portion of the inspiratory flow of airflow-limited breaths would sustain the recruitment of upper airway dilator muscles over time and improve airway dynamics without arousing obstructive sleep apnea (OSA) patients. In a cross-sectional design, nine OSA patients underwent a rTMS trial during stable non-rapid eye movement (NREM) sleep. Submental muscle motor threshold (SUB) and motor-evoked potential were evaluated during wakefulness and sleep. During NREM sleep, maximal inspiratory flow, inspiratory volume, inspiratory time, shifts of electroencephalogram frequency, and pulse rate variability were assessed under three different stimulation paradigms completed at 1.2 sleep SUB stimulation output: 1) 5Hz-08 (stimulation frequency: 5 Hz; duration of train stimulation: 0.8 s); 2) 25Hz-02 (stimulation frequency: 25 Hz; duration of train stimulation: 0.2 s); and 3) 25Hz-04 (stimulation frequency: 25 Hz; duration of train stimulation: 0.4 s). SUB increased during NREM sleep (wakefulness: 23.8 ± 6.1%; NREM: 26.8 ± 5.2%; = 0.001). Two distinct airflow patterns were observed in response to rTMS: with and without initial airflow drops, without other airflow variables change regardless the stimulation paradigm applied. Finally, rTMS-induced cortical and/or autonomic arousal were observed in 36, 26, and 35% of all delivered rTMS trains during 5Hz-08, 25Hz-02, and 25Hz-04 stimulation paradigms, respectively. In conclusion, rTMS does not provide any airflow improvement of flow-limited breaths as seen with nonrepetitive TMS of upper airway dilator muscles. However, rTMS trains were free of arousals in the majority of cases. upper airway dilator muscles; obstructive sleep apnea; repetitive transcranial magnetic stimulation; motor-evoked potentials; sleep leading to intermittent hypoxemia, arousal, and poor sleep quality (10) in association with cardiovascular (35), metabolic (27), and neurological disorders (29). The increased UA collapsibility observed during sleep in OSA patients is attributed to the ineffectiveness of UA dilator muscles to stabilize the pharynx when an intrathoracic negative pressure gradient is generated by the contraction of inspiratory muscles (10). The contraction of UA dilator muscles represents the only counteracting force against all others that tend to collapse the UA, emphasizing the importance of the mechanical effectiveness of these muscles (36). The UA dilator muscles can be effectively stimulated via electrical stimulation of hypoglossal nerve, resulting in an airflow improvement and a decrease in OSA severity (11, 33). Transcranial magnetic stimulation (TMS) is another noninvasive and painless way to achieve a contraction of UA dilator muscles (34), which can be used both in healthy and apneic subjects, during wakefulness (4) and sleep (21). TMS-induced twitches applied during sleep over the corticomotor somatotopic representation of the tongue on isolated breaths briefly recruit UA dilator muscles and improve airflow dynamics of flow-limited respiratory cycles without arousing OSA patients (21). Moreover, twitches applied during consecutive breathing cycles in such subjects further improve airflow dynamics of flow-limited respiratory cycles (22). Repetitive TMS (rTMS) is a variant of TMS where trains of TMS are applied. We recently reported the occurrence of a paradoxical deleterious mechanical effect of rTMS applied during wakefulness, using simultaneously a phrenic nerve magnetic stimulation to elicit a contraction of the diaphragm dissociated from activation of the UA dilator muscles, resulting in flow-limited twitches (28). However, the specific effects of rTMS during sleep on the UA mechanical properties remain unknown. Thus the main objective of this study was to assess the immediate mechanical effects of rTMS applied during sleep on the patterns of flow-limited breaths and UA muscles electromyographic (EMG) activity. Our hypothesis was that rTMS should improve the pattern of UA obstruction during sleep.