The supplementary motor area exerts a tonic excitatory influence on corticospinal projections to phrenic motoneurons in awake humans

Abstract

Introduction: In humans, cortical mechanisms can interfere with autonomic breathing. Respiratory-related activation of the supplementary motor area (SMA) has been documented during voluntary breathing and in response to inspiratory constraints. The SMA could therefore participate in the increased resting state of the respiratory motor system during wake (i.e. "wakefulness drive to breathe").

Methods: The SMA was conditioned by continuous theta burst magnetic stimulation (cTBS, inhibitory) and 5 Hz conventional rTMS (5 Hz, excitatory). The ensuing effects were described in terms of the diaphragm motor evoked response (DiMEPs) to single-pulse transcranial magnetic stimulation over the motor cortex. DiMEPs were recorded at baseline, and at 3 time-points ("post1", "post2", "post3") up to 15 minutes following conditioning of the SMA.

Results: cTBS reduced the amplitude of DiMEPs from 327.5 ± 159.8 µV at baseline to 243.3 ± 118.7 µV, 217.8 ± 102.9 µV and 240.6 ± 123.9 µV at post 1, post 2 and post 3, respectively (F = 6.341, p = 0.002). 5 Hz conditioning increased the amplitude of DiMEPs from 184.7 ± 96.5 µV at baseline to 270.7 ± 135.4 µV at post 3 (F = 4.844, p = 0.009).

Conclusions: The corticospinal pathway to the diaphragm can be modulated in both directions by conditioning the SMA. This suggests that the baseline respiratory activity of the SMA represents an equipoise from which it is possible to move in either direction. The resting corticofugal outflow from the SMA to phrenic motoneurones that this study evidences could putatively contribute to the wakefulness drive to breathe.

Figure 1. Experimental design.

Twenty motor-evoked potentials were recorded for both the diaphragm (DiMEPs) and the first dorsal interosseous (FDIMEPs) at baseline and at three time points (Post 1, Post 2 and Post 3) after the rTMS protocols (cTBS or 5 Hz) over the supplementary motor area (SMA). The time indicates time after the end of rTMS.

Figure 2. Average waveform of diaphragm motor-evoked potentials (DiMEPs) for a single subject evoked by single-pulse TMS over the motor cortex at baseline and at 3 time-points following the inhibitory protocol (cTBS) over the SMA.

Arrows indicate the time of stimulation.

Figure 3. Average amplitude of diaphragm motor-evoked potentials (DiMEPs) for all subjects evoked at baseline and at 3 time-points following inhibitory (cTBS, white circles) and excitatory (5 Hz, black circles) conditioning of the SMA.

Values are expressed as% of baseline and as mean±SD. * = p<0.05 vs. baseline following post hoc tests.

Figure 4. Schematic representations of descending projections to the phrenic motoneurones and corticocortical projections between the SMA and diaphragm primary motor representation (M1Dia).

We showed that inhibitory conditioning of the SMA by repetitive transcranial magnetic stimulation (rTMS, “1”) results in a depressed response of the diaphragm to stimulation of M1dia (“2”). We hypothesise that this is due to inhibition of the corticocortical connections between the SMA and MIdia (“3”) and this suggests that there is a resting facilitatory tonic projection between these areas (shown in red). There are other descending pathways to the phrenic motoneurones that are not shown for clarity (i.e. from the limbic cortex).