Demonstration of a second rapidly conducting cortico-diaphragmatic pathway in humans

Abstract

Functional imaging studies in normal humans have shown that the supplementary motor area (SMA) and the primary motor cortex (PMC) are coactivated during various breathing tasks. It is not known whether a direct pathway from the SMA to the diaphragm exists, and if so what properties it has. Using transcranial magnetic stimulation (TMS) a site at the vertex, representing the diaphragm primary motor cortex, has been identified. TMS mapping revealed a second area 3 cm anterior to the vertex overlying the SMA, which had a rapidly conducting pathway to the diaphragm (mean latency 16.7 +/- 2.4 ms). In comparison to the vertex, the anterior position was characterized by a higher diaphragm motor threshold, a greater proportional increase in motor-evoked potential (MEP) amplitude with voluntary facilitation and a shorter silent period. Stimulus-response curves did not differ significantly between the vertex and anterior positions. Using paired TMS, we also compared intracortical inhibition/facilitation (ICI/ICF) curves. In comparison to the vertex, the MEP elicited from the anterior position was not inhibited at short interstimulus intervals (1-5 ms) and was more facilitated at long interstimulus intervals (9-20 ms). The patterns of response were identical for the costal and crural diaphragms. We conclude that the two coil positions represent discrete areas that are likely to be the PMC and SMA, with the latter wielding a more excitatory effect on the diaphragm.

Figures

Figure 1. Typical diaphragm motor-evoked potential

Diaphragm motor-evoked potential (MEP) elicited by 100% stimulation at the vertex during a submaximal inspiratory effort. Principal features are latency (arrow 1), amplitude (arrow 2) and finish of silent period (arrow 3).

Figure 2. Relationship between the amplitude of the costal diaphragm MEP and coil position relative to the vertex

Individual and mean responses are represented by dashed and continuous lines, respectively. All stimulations were performed at 100% of stimulator output. Values are expressed as a percentage of the response elicited at the vertex. Each square corresponds to the mean of an individual subject. Each triangle corresponds to the mean (+ s.e.m.) of eight subjects. MEP amplitude varied significantly with change in coil position (P < 0.0001). The response to stimulation was characterized by two peaks representing the primary motor cortex (vertex) and supplementary motor area (vertex + 3 cm).

Figure 3. Individual relationship between the silent period (SP) of the costal diaphragm MEP and scalp position of the coil relative to the vertex

Individual and global relationships are represented by dashed and continuous lines, respectively. All stimulations were performed at 100% of stimulator output during 60% of maximal inspiratory effort. MEP silent period in each position is expressed as a percentage of that elicited by 100% stimulation at the vertex. Each square corresponds to the mean of each subject. Each triangle corresponds to the mean (+ s.e.m.) of six subjects. MEP amplitude varied significantly with change in scalp position (P < 0.0001). The response to stimulation was characterized by two peaks representing the primary motor cortex (vertex) and supplementary motor area (vertex + 3 cm).

Figure 4. Costal diaphragm MEP100

MEP elicited by 100% stimulation over the anterior position (upper trace) and vertex (lower trace) during a maximal inspiratory effort. The silent period, measured from the onset of MEP to resumption of EMG activity, was shorter for the anterior position (P = 0.03).

Figure 5. Magnetic resonance imaging

Anatomical location of the primary motor cortex and supplementary motor area relative to the vertex and the 3 cm anterior position in one subject. A, markers used to identify the two positions. B shows that these markers were situated at −20 and +10 mm on an anterior–posterior axis and overlay the primary motor cortex (PMC) and supplementary motor area (SMA), respectively, which were identified according to Tallairach's handbook.

Figure 5. Magnetic resonance imaging

Anatomical location of the primary motor cortex and supplementary motor area relative to the vertex and the 3 cm anterior position in one subject. A, markers used to identify the two positions. B shows that these markers were situated at −20 and +10 mm on an anterior–posterior axis and overlay the primary motor cortex (PMC) and supplementary motor area (SMA), respectively, which were identified according to Tallairach's handbook.

Figure 6. Relationship between stimulation intensity and amplitude of the diaphragm MEP

The amplitude of the diaphragm MEP was elicited by stimulation of the vertex (▴) and anterior position (▪). MEP amplitude is expressed as a percentage of the MEP amplitude elicited by 100% stimulation over the vertex. Each point corresponds to the mean (+ s.e.m.) in six subjects for the costal (A) and five subjects for the crural (B) diaphragm, respectively.

Figure 6. Relationship between stimulation intensity and amplitude of the diaphragm MEP

The amplitude of the diaphragm MEP was elicited by stimulation of the vertex (▴) and anterior position (▪). MEP amplitude is expressed as a percentage of the MEP amplitude elicited by 100% stimulation over the vertex. Each point corresponds to the mean (+ s.e.m.) in six subjects for the costal (A) and five subjects for the crural (B) diaphragm, respectively.

Figure 7. Effect of maximal inspiratory effort on the amplitude of the diaphragm MEP elicited by 100% stimulation

Black columns represent the vertex, grey columns the anterior position. Relaxed and facilitated MEP100-vertex and MEP100-anterior amplitude is expressed in microvolts. Facilitated MEP100-vertex and MEP100-anterior are also expressed as percentage increase of relaxed MEP100-vertex and MEP100-anterior amplitude. Each point corresponds to the mean (+ s.e.m.) in six and five subjects for the costal (A) and crural (B) diaphragm, respectively. For the costal and crural diaphragms, there was a significant increase in amplitude of MEP100-vertex (P = 0.03 and P = 0.04) and MEP100-anterior (P = 0.03 and P = 0.04) with maximal inspiratory effort. Maximal inspiratory effort induced a significantly greater increase in MEP100-anterior amplitude than MEP100-vertex amplitude, for both parts of the diaphragm (P = 0.03 and P = 0.04).

Figure 7. Effect of maximal inspiratory effort on the amplitude of the diaphragm MEP elicited by 100% stimulation

Black columns represent the vertex, grey columns the anterior position. Relaxed and facilitated MEP100-vertex and MEP100-anterior amplitude is expressed in microvolts. Facilitated MEP100-vertex and MEP100-anterior are also expressed as percentage increase of relaxed MEP100-vertex and MEP100-anterior amplitude. Each point corresponds to the mean (+ s.e.m.) in six and five subjects for the costal (A) and crural (B) diaphragm, respectively. For the costal and crural diaphragms, there was a significant increase in amplitude of MEP100-vertex (P = 0.03 and P = 0.04) and MEP100-anterior (P = 0.03 and P = 0.04) with maximal inspiratory effort. Maximal inspiratory effort induced a significantly greater increase in MEP100-anterior amplitude than MEP100-vertex amplitude, for both parts of the diaphragm (P = 0.03 and P = 0.04).

Figure 8. ICI/ICF curves of the diaphragm MEP

Diaphragm MEP elicited by paired transcranial magnetic stimulation (TMS) of the vertex (▴) and anterior position (▪). MEP amplitude is expressed as a percentage of the response to the test stimulus alone (MEPTS). Each point corresponds to the mean (+ s.e.m.) in six and five subjects for the costal (A) and crural (B) diaphragms, respectively. At both scalp positions, there was a significant change in MEP amplitude with increase in interstimulus interval for the costal and crural diaphragms (both P < 0.0001). There was a significant difference between the vertex and anterior position ICI/ICF curves for the costal (P = 0.03) and crural (P = 0.01) diaphragm, with less inhibition and more facilitation of the costal and crural diaphragms from the anterior position.

Figure 8. ICI/ICF curves of the diaphragm MEP

Diaphragm MEP elicited by paired transcranial magnetic stimulation (TMS) of the vertex (▴) and anterior position (▪). MEP amplitude is expressed as a percentage of the response to the test stimulus alone (MEPTS). Each point corresponds to the mean (+ s.e.m.) in six and five subjects for the costal (A) and crural (B) diaphragms, respectively. At both scalp positions, there was a significant change in MEP amplitude with increase in interstimulus interval for the costal and crural diaphragms (both P < 0.0001). There was a significant difference between the vertex and anterior position ICI/ICF curves for the costal (P = 0.03) and crural (P = 0.01) diaphragm, with less inhibition and more facilitation of the costal and crural diaphragms from the anterior position.