Does the supplementary motor area keep patients with Ondine's curse syndrome breathing while awake?

Abstract

Background: Congenital central hypoventilation syndrome (CCHS) is a rare neuro-respiratory disorder associated with mutations of the PHOX2B gene. Patients with this disease experience severe hypoventilation during sleep and are consequently ventilator-dependent. However, they breathe almost normally while awake, indicating the existence of cortical mechanisms compensating for the deficient brainstem generation of automatic breathing. Current evidence indicates that the supplementary motor area plays an important role in modulating ventilation in awake normal humans. We hypothesized that the wake-related maintenance of spontaneous breathing in patients with CCHS could involve supplementary motor area.

Methods: We studied 7 CCHS patients (5 women; age: 20-30; BMI: 22.1 ± 4 kg.m(-2)) during resting breathing and during exposure to carbon dioxide and inspiratory mechanical constraints. They were compared with 8 healthy individuals. Segments of electroencephalographic tracings were selected according to ventilatory flow signal, from 2.5 seconds to 1.5 seconds after the onset of inspiration. After artefact rejection, 80 or more such segments were ensemble averaged. A slow upward shift of the EEG signal starting between 2 and 0.5 s before inspiration (pre-inspiratory potential) was considered suggestive of supplementary motor area activation.

Results: In the control group, pre-inspiratory potentials were generally absent during resting breathing and carbon dioxide stimulation, and consistently identified in the presence of inspiratory constraints (expected). In CCHS patients, pre-inspiratory potentials were systematically identified in all study conditions, including resting breathing. They were therefore significantly more frequent than in controls.

Conclusions: This study provides a neurophysiological substrate to the wakefulness drive to breathe that is characteristic of CCHS and suggests that the supplementary motor area contributes to this phenomenon. Whether or not this "cortical breathing" can be taken advantage of therapeutically, or has clinical consequences (like competition with attentional resources) remains to be determined.

Figure 1. Schematic representation of the method used to identify pre-inspiratory potentials from the raw EEG signal and the ventilatory flow signal.

(Adapted from Raux et al., Anesthesiology——with permission from the authors and the publisher.) Artwork Robin Jacqueline. The EEG signal is segmented in epochs defined according to the ventilatory flow signal (1). These epochs are ensemble averaged (2). The resulting signal is inspected visually for a putative pre-inspiratory potential (3) of which the presence is ascertained through the calculation of a linear regression over the region of interest and comparison of the slope of this regression with 0. See “Methods” for details. Pre-inspiratory potentials and the related motor potentials are normally absent during quiet breathing.

Figure 2. Average pre-inspiratory EEG tracings in one of the control subjects.

In each of the panels, the top trace depicts the Cz-EEG signal, and the bottom trace depicts ventilatory flow. The vertical line indicates the onset of inspiration. In the three “control condition” panels (control 1: resting ventilation with minimal constraint, namely a respiratory inductance plethysmography vest only; control 2: resting ventilation while breathing through a pneumoatchograph; control 3: as control 2, but during the washout period following inspiratory loading), inspiration is not preceded by any change in the EEG signal (absence of pre-inspiratory potentials). In the “CO₂ stimulated breathing” panel, inspiration is also not preceded by any change in the EEG signal (absence of pre-inspiratory potentials). In contrast, in the “inspiratory threshold loading” panel, inspiration is preceded by a shift upward of the EEG trace (horizontal double arrowed red line) that is characteristic of a pre-inspiratory potential. This pattern exactly corresponds to what is expected in normal individuals .

Figure 3. Average pre-inspiratory EEG tracings in one of the congenital central hypoventilation syndrome patient.

In each of the panels, the top trace depicts the Cz-EEG signal, and the bottom trace depicts ventilatory flow. The vertical line indicates the onset of inspiration. In the “inspiratory threshold loading” panel, inspiration is preceded by a shift upward of the EEG trace (horizontal double arrowed red line) that is characteristic of a pre-inspiratory potential. This observation is similar to that made in normal individuals . In contrast to normal individuals however, a pre-inspiratory potential can also be seen, abnormally, in the three “control condition” panels (control 1: resting ventilation with minimal constraint, namely a respiratory inductance plethysmography vest only; control 2: resting ventilation while breathing through a pneumoatchograph; control 3: as control 2, but during the washout period following inspiratory loading) and in the “CO₂ stimulated breathing” panel.