Acute intermittent hypercapnic-hypoxia elicits central neural respiratory motor plasticity in humans.

Acute intermittent hypoxia (AIH) elicits long-term facilitation (LTF) of respiration. Although LTF is observed when CO2 is elevated during AIH in awake humans, the influence of CO2 on corticospinal respiratory motor plasticity is unknown. Thus, we tested the hypotheses that acute intermittent hypercapnic-hypoxia (AIHH): (1) enhances cortico-phrenic neurotransmission (reflecting volitional respiratory control); and (2) elicits ventilatory LTF (reflecting automatic respiratory control). Eighteen healthy adults completed four study visits. Day 1 consisted of anthropometry and pulmonary function testing. On Days 2, 3 and 4, in a balanced alternating sequence, participants received: AIHH, poikilocapnic AIH, and normocapnic-normoxia (Sham). Protocols consisted of 15, 60 s exposures with 90 s normoxic intervals. Transcranial (TMS) and cervical (CMS) magnetic stimulation were used to induce diaphragmatic motor-evoked potentials and compound muscle action potentials, respectively. Respiratory drive was assessed via mouth occlusion pressure (P0.1 ), and minute ventilation measured at rest. Dependent variables were assessed at baseline and 30-60 min after exposures. Increases in TMS-evoked diaphragm potential amplitudes were observed following AIHH vs. Sham (+28 ± 41%, P = 0.003), but not after AIH. No changes were observed in CMS-evoked diaphragm potential amplitudes. Mouth occlusion pressure also increased after AIHH (+21 ± 34%, P = 0.033), but not after AIH. Ventilatory LTF was not observed after any treatment. We demonstrate that AIHH elicits central neural mechanisms of respiratory motor plasticity and increases resting respiratory drive in awake humans. These findings may have important implications for neurorehabilitation after spinal cord injury and other neuromuscular disorders compromising breathing. KEY POINTS: The occurrence of respiratory long-term facilitation following acute exposure to intermittent hypoxia is believed to be dependent upon CO2 regulation - mechanisms governing the critical role of CO2 have seldom been explored. We tested the hypothesis that acute intermittent hypercapnic-hypoxia (AIHH) enhances cortico-phrenic neurotransmission in awake healthy humans. The amplitude of diaphragmatic motor-evoked potentials induced by transcranial magnetic stimulation was increased after AIHH, but not the amplitude of compound muscle action potentials evoked by cervical magnetic stimulation. Mouth occlusion pressure (P0.1 , an indicator of neural respiratory drive) was also increased after AIHH, but not tidal volume or minute ventilation. Thus, moderate AIHH elicits central neural mechanisms of respiratory motor plasticity, without measurable ventilatory long-term facilitation in awake humans.

Effect of acute intermittent hypoxia on cortico-diaphragmatic conduction in healthy humans.

Acute intermittent hypoxia (AIH) is a strategy to improve motor output in humans with neuromotor impairment. A single AIH session increases the amplitude of motor evoked potentials (MEP) in a finger muscle (first dorsal interosseous), demonstrating enhanced corticospinal neurotransmission. Since AIH elicits phrenic/diaphragm long-term facilitation (LTF) in rodent models, we tested the hypothesis that AIH augments diaphragm MEPs in humans. Eleven healthy adults (7 males, age = 29 ± 6 years) were tested. Transcranial and cervical magnetic stimulation were used to induce diaphragm MEPs and compound muscle action potentials (CMAP) recorded by surface EMG, respectively. Stimulus-response curves were generated prior to and 30-60 min after AIH. Diaphragm LTF was assessed by measurement of integrated EMG burst amplitude and frequency during eupnoeic breathing before and after AIH. Following baseline measurements, AIH was delivered from an oxygen generator connected to a facemask under poikilocapnic conditions (15 one minute episodes of 9% inspired oxygen with one minute room air intervals). There were no detectable changes in MEP (-1.5 ± 12.1%, p = 0.96) or CMAP (+0.1 ± 7.8%, p = 0.97) amplitudes across the stimulus-response curve. At stimulation intensities approximating 50% of the difference between minimum and maximum baseline amplitudes, MEP and CMAP amplitudes were also unchanged (p > 0.05). Further, no AIH effect was observed on diaphragm EMG activity during eupnoea post-AIH (p > 0.05). We conclude that unlike hand muscles, poikilocapnic AIH does not enhance diaphragm MEPs or produce diaphragm LTF in healthy humans.

Reliability of diaphragmatic motor-evoked potentials induced by transcranial magnetic stimulation.

The diaphragmatic motor-evoked potential (MEP) induced by transcranial magnetic stimulation (TMS) permits electrophysiological assessment of the cortico-diaphragmatic pathway. Despite the value of TMS for investigating diaphragm motor integrity in health and disease, reliability of the technique has not been established. The study aim was to determine within- and between-session reproducibility of surface electromyogram recordings of TMS-evoked diaphragm potentials. Fifteen healthy young adults participated (6 females, age = 29 ± 7 yr). Diaphragm activation was determined by gradually increasing the stimulus intensity from 60 to 100% of maximal stimulator output (MSO). A minimum of seven stimulations were performed at each intensity. A second block of stimuli was delivered 30 min later for within-day comparisons, and a third block was performed on a separate day for between-day comparisons. Reliability of diaphragm MEPs was assessed at 100% MSO using intraclass correlation coefficients (ICC) and 95% limits of agreement (LOA). MEP latency (ICC = 0.984, P < 0.001), duration (ICC = 0.958, P < 0.001), amplitude (ICC = 0.950, P < 0.001), and area (ICC = 0.956, P < 0.001) were highly reproducible within-day. Between-day reproducibility was good to excellent for all MEP characteristics (latency ICC = 0.953, P < 0.001; duration ICC = 0.879, P = 0.002; amplitude ICC = 0.789, P = 0.019; area ICC = 0.815, P = 0.012). Data revealed less precision between-day versus within-day, as evidenced by wider LOA for all MEP characteristics. Large within- and between-subject variability in MEP amplitude and area was observed. In conclusion, TMS is a reliable means of inducing diaphragm potentials in most healthy individuals.NEW & NOTEWORTHY Transcranial magnetic stimulation (TMS) is a noninvasive technique to assess neural impulse conduction along the cortico-diaphragmatic pathway. The reliability of diaphragm motor-evoked potentials (MEP) induced by TMS is unknown. Notwithstanding large variability in MEP amplitude, we found good-to-excellent reproducibility of all MEP characteristics (latency, duration, amplitude, and area) both within- and between-day in healthy adult men and women. Our findings support the use of TMS and surface EMG to assess diaphragm activation in humans.