Short-term cognitive loading deteriorates breathing pattern and gas exchange in adult patients with congenital central hypoventilation syndrome

Abstract

Question: Human PHOX2B mutations result in life-threatening sleep-related hypoventilation (congenital central hypoventilation syndrome, CCHS). Most patients retain ventilatory activity when awake through a respiratory-related cortical network. We hypothesised that this need to mobilise cortical resources to breathe would lead to breathing-cognition interferences during cognitive loading.

Patients and methods: Seven adult CCHS patients (five women; median age 21) performed standard neuropsychological tests (paced auditory serial addition test - calculation capacity, working memory, sustained and divided attention; trail making test - visuospatial exploration capacity, cognitive processing speed, attentional flexibility; Corsi block-tapping test - visuospatial memory, short-term memory, working memory) during unassisted breathing and under ventilatory support. Ventilatory variables and transcutaneous haemoglobin oxygen saturation were recorded. Cortical connectivity changes between unassisted breathing and ventilatory support were assessed using electroencephalographic recordings (EEG).

Results: Baseline performances were lower than expected in individuals of this age. During unassisted breathing, cognitive loading coincided with increased breathing variability, and decreases in oxygen saturation inversely correlated with an increasing number of apnoeic cycles per minute (rho -0.46, 95% CI -0.76 to -0.06, p=0.01). During ventilatory support, cognitive tasks did not disrupt breathing pattern and were not associated with decreased oxygen saturation. Ventilatory support was associated with changes in EEG cortical connectivity but not with improved test performances.

Conclusions: Acute cognitive loads induce oxygen desaturation in adult CCHS patients during unassisted breathing, but not under ventilatory support. This justifies considering the use of ventilatory support during mental tasks in CCHS patients to avoid repeated episodes of hypoxia.

FIGURE 1

Experimental plan of the study. Tests performed during unassisted breathing (UB) are shown in the gray italic typeface, and tests performed during ventilatory support (VS) are shown in bold black typeface. EEG: electroencephalogram; PASAT: paced auditory serial addition test; TMT: trail making test; Corsi: Corsi block-tapping test.

FIGURE 2

Oxygen saturation (S_pO2) at the beginning and end of neuropsychological tests during unassisted breathing. PASAT: paced auditory serial addition test (six patients performed the test; A and B pooled, n=12); TMT: trail making test (n=7); Corsi: Corsi block-tapping test (all patients performed the test, but S_pO2 measurement failed in one case; n=6). *: p<0.05.

FIGURE 3

Breath-by-breath variability (coefficients of variation) of ventilatory variables during unassisted breathing in baseline condition (10-min recording) and during neuropsychological tests (totality of the recording). The boxes represent the 25–75th percentile of the data with indication of the median, and the whiskers depict the full range of the data. f_B : breathing frequency; V_T: tidal volume; t_I: inspiratory time; t_E: expiratory time. “10 min”: baseline value; PASAT: paced auditory serial addition test, versions A and B; TMT: trail making test, versions A and B; Corsi: Corsi block-tapping test. *: p<0.05 versus baseline; **p<0.01 versus baseline.

FIGURE 4

a) Example of ventilatory flow recordings in two selected patients (Patient #1 and Patient #2) during unassisted resting breathing at baseline (top trace), during the performance of a PASAT test (middle trace) and during the performance of a TMT test (bottom trace), illustrating breathing irregularities and the occurrence of apnoeic cycles. b) Frequency of apnoeas during unassisted breathing in baseline condition (10-min recording) and during neuropsychological tests (totality of the recording) (apnoeas were defined as breathing cycles with an expiratory time (t_E) above the mean t_E measured during unassisted breathing augmented by 3 standard deviations). The boxes represent the 25–75th percentile of the data with indication of the median, and the whiskers depict the full range of the data. “10 min”: baseline value; PASAT: paced auditory serial addition test, versions A and B; TMT: trail making test, versions A and B; Corsi: Corsi block-tapping test. *: p<0.05 versus baseline.

FIGURE 5

Correlation between decreases in oxygen saturation measured by pulse oximetry (S_pO2) from baseline to the end of neuropsychological tests and number of apnoeas per minute during tests completion (pooled data: PASAT A n=6, PASAT B n=6, TMT-A and TMT-B in sequence n=7, Corsi n=6–7 patients performed the test, but S_pO2 failed in one case). PASAT: paced auditory serial addition test; TMT: trail making test; Corsi: Corsi block-tapping test.

FIGURE 6

Schematic representation of the cortical facilitation theory of the neural drive to breathe, depicting the interactions between bulbospinal and corticospinal inputs on spinal respiratory motoneurons during: a) sleep in normal humans; b) wakefulness in normal humans; c) wakefulness in patients with central congenital hypoventilation syndrome (CCHS); d) sleep in patients with CCHS; e) acute cognitive load in patients with CCHS. From top to bottom, the horizontal bands correspond to 1: activation of respiratory-related cortical networks and intensity of corticospinal respiratory output (purple arrows); 2: status of the respiratory central pattern generators in the brainstem (normal: solid circle; defective: blurred circle) and intensity of the bulbospinal respiratory output (red arrow); 3: membrane potential (FT: firing threshold; EEMP: end-expiratory membrane potential) and firing rate (AP: action potentials) of respiratory spinal motoneurons; 4: net neural drive to breathe (bulbospinal contribution in red, corticospinal contribution in purple); 5: breathing pattern. In band 3, the vertical red double arrows represent the difference between end-expiratory membrane polarity and firing threshold that must be cancelled by the bulbospinal respiratory output for inspiration to occur (red dotted line). The vertical purple double arrows depict the effects of cortical facilitation. The presence of a corticospinal input to spinal respiratory motoneurons raises their membrane potential closer to the firing threshold, making a given bulbospinal output more efficient at producing ventilation (facilitation; column b versus a). In patients with CCHS during wakefulness (column c), the decreased bulbospinal output resulting from the PHOX2B mutation deleterious impact on central respiratory pattern generators is “compensated” by increased activation of a respiratory-related cortical network [1]. The absence of this corticospinal input during sleep (column d) can explain (and in any case contributes to) sleep-related hypoventilation. According to this cortical facilitation theory of the neural drive to breathe, the observations of the present study (breathing pattern disorganisation during cognitive loading, with correlation to desaturations) could relate to cognitive loading reducing the cortical resources available for breathing through a dual-tasking effect (column e).