Periodic breathing and genetics

The episodic waxing and waning of ventilation is a fundamental event in sleep apnea syndromes. Post-hypoxic frequency decline (PHFD) and periodic breathing (PB) are evoked by brief hypoxic exposures in unanaesthetized and unrestrained inbred C57BL/6J mice, but not in A/J mice; and expression of PHFD differs not only among these mice strains but in among rat strains as well. These observations along with the current literature on genetic factors that operate on ventilatory behavior at rest and with chemosensory drive lead to the hypothesis that genetic factors infer some proportion of risk for the ventilatory instability observed in human sleep apnea syndromes.     

Regularity of daily life in relation to personality, age, gender, sleep quality and circadian rhythms

A diary-like instrument to measure lifestyle regularity (the 'Social Rhythm Metric'-SRM) was given to 96 subjects (48 women, 48 men), 39 of whom repeated the study after at least one year, with additional objective measures of rest/activity. Lifestyle regularity as measured by the SRM related to age, morningness, subjective sleep quality and time-of-day variations in alertness, but not to gender, extroversion or neuroticism. Statistically significant test-retest correlations of about 0.4 emerged for SRM scores over the 12-30 month delay. Diary-based estimates of bedtime and waketime appeared fairly reliable. In a further study of healthy young men, 4 high SRM scorers ('regular') had a deeper nocturnal body temperature trough than 5 low SRM scorers ('irregular'), suggesting a better functioning circadian system in the 'regular' group.     

Chemoreflex control of ventilation is altered during wakefulness in humans with OSA

We hypothesized that patients with obstructive sleep apnea (OSA) have a different awake ventilatory response to carbon dioxide above and below eupnea compared with normal. Eight male subjects with OSA and control subjects matched for gender, race, age, height and weight voluntarily hyperventilated during wakefulness to reduce the partial pressure of carbon dioxide (PET(CO2)) below 25 mmHg. Subjects were then switched into a rebreathing bag containing a normocapnic (42 mmHg) hypoxic [partial pressure of end tidal oxygen (PET(O2))=50 mmHg (H50)] or hyperoxic [PET(O2)=140 mmHg (H140)] gas mixture. During the trial PET(CO2) increased while PET(O2) was maintained at a constant level. The point at which ventilation and PET(CO2) increased linearly was considered to be the carbon dioxide ventilatory recruitment threshold (VRT(CO2)). Measurements of ventilation and its components (i.e. tidal volume and breathing frequency) were made below this threshold and the slope of the minute ventilation; tidal volume or breathing frequency response above the threshold was determined. Four trials for a given oxygen level were completed. The PET(CO2) that demarcated the VRT(CO2) was increased (H(50)=43.43+/-0.92 vs. 41.05+/-0.67; H(140)=47.65+/-0.80 vs. 45.28+/-0.75), as were measures of ventilation below the threshold (H(50)=18.50+/-2.11 vs. 13.44+/-1.43; H(140)=19.66+/-2.71 vs. 10.83+/-1.24) in the OSA subjects compared with control. In contrast the OSA and control subjects did not respond differently to changes in PET(CO2) above the threshold. We conclude that the PET(CO2) that delineates the VRT(CO2) and ventilation below this threshold is elevated in subjects with OSA.     

Effects of exogenous melatonin on sleep and circadian rhythms in women with premenstrual dysphoric disorder

We previously found normal polysomnographic (PSG) sleep efficiency, increased slow-wave sleep (SWS), and a blunted melatonin secretion in women with premenstrual dysphoric disorder (PMDD) compared to controls. Here, we investigated the effects of exogenous melatonin in five patients previously studied. They took 2 mg of slow-release melatonin 1 h before bedtime during their luteal phase (LP) for three menstrual cycles. At baseline, patients spent every third night throughout one menstrual cycle sleeping in the laboratory. Measures included morning urinary 6-sulfatoxymelatonin (aMt6), PSG sleep, nocturnal core body temperature (CBT), visual analog scale for mood (VAS-Mood), Prospective Record of the Impact and Severity of Menstrual Symptoms (PRISM), and ovarian plasma hormones. Participants also underwent two 24-hour intensive physiological monitoring (during the follicular phase and LP) in time-isolation/constant conditions to determine 24-hour plasma melatonin and CBT rhythms. The same measures were repeated during their third menstrual cycle of melatonin administration. In the intervention condition compared to baseline, we found increased urinary aMt6 (p < 0.001), reduced objective sleep onset latency (p = 0.01), reduced SWS (p < 0.001), and increased Stage 2 sleep (p < 0.001). Increased urinary aMt6 was correlated with reduced SWS (r = −0.51, p < 0.001). Circadian parameters derived from 24-hour plasma melatonin and CBT did not differ between conditions, except for an increased melatonin mesor in the intervention condition (p = 0.01). Ovarian hormones were comparable between the conditions (p ≥ 0.28). Symptoms improved in the intervention condition, as measured by the VAS-Mood (p = 0.02) and the PRISM (p < 0.001). These findings support a role for disturbed melatonergic system in PMDD that can be partially corrected by exogenous melatonin.     

Fractal characteristics of breath to breath timing in sleeping infants

We examined interbreath interval (IBI) time series of 19 term infants during active and quiet sleep for fractal properties using Fano factor analysis. For each time series we calculated the fractal exponent (alpha), comparing alpha for the original time series with two forms of surrogate data, a temporally independent surrogate set and an autoregressive surrogate set. alpha values were normally distributed between 0.79 and -0.22, and did not differ with sleep state. The fractal characteristics of the original time series were not retained in the temporally independent surrogate time series indicating that the distribution of intervals alone was not fractal, but were retained using autoregressive surrogates with an order of 10, suggesting that the fractal properties of the IBI time series were related to correlations between successive breaths. These observations suggest that some of the respiratory variability that occurs during sleep in infants, which in the past has been regarded as stochastic noise, may be the product of deterministic processes.     

Neurochemical perspectives on the control of breathing during sleep

A specific depression of minute ventilation occurs during sleep in normal subjects. This sleep-related ventilatory depression is partially related to mechanical events and upper airway atonia but some data also indicate that it is likely to be centrally mediated. This paper reviews the anatomical and neurochemical connections between sleep/wake- and respiratory-related areas in an attempt to identify the potential implication of sleep-related neurochemicals (serotonin, catecholamines, GABA, acetylcholine) in the sleep-related hypoventilation. The review of available data suggests that the sleep-related ventilatory depression depends upon the enhanced GABAergic activity together with a loss of suprapontine influence depending on the cessation of activity of the reticular formation. During REM sleep, an additional inhibitory activity emerges from the pontine cholinergic neurons, which contributes to the breathing irregularities and the associated depression of minute ventilation and ventilatory response to chemical stimuli. This model may contribute to a better understanding of the neurochemical environment of respiratory neurons during sleep, which remains a question of importance regarding the numerous pathological states that are linked to specific perturbations of breathing control during sleep.     

Adaptation to daily meal-timing and its effect on circadian temperature rhythms in two inbred strains of mice

Inbred strains of mice differ in their adjustment to a mealtime out of phase with the light-dark cycle. When food access was restricted to the first 4 h of the light span, C3H/2Ibg mice steadily lost weight and died, while C57BL/6J mice recovered baseline levels of food intake within a few days. C57BL meal-timed mice also showed delayed circadian body temperature rhythms so that peak temperatures coincided with the time of food availability. Both strains were able to adapt when the period of food availability was gradually shifted to the first 12 h of the 16-h light period. C57BL mice again phase-delayed their body temperature rhythms, while C3H mice exhibited highly variable individual responses, and over half continued to increase temperature in anticipation of lights-off. These results suggest that the timing of body temperature rhythms of C57BL mice may be more easily altered relative to the light-dark cycle than that of C3H mice.This work was supported in part by NIH Grant GM 21993 to C.B.L.     

Effects of afferent input on the breathing pattern continuum in the tambaqui (Colossoma macropomum)

This study used a decerebrate and artificially-ventilated preparation to examine the roles of various afferent inputs in breathing pattern formation in the tambaqui (Colossoma macropomum). Three general breathing patterns were observed: (1) regular breathing; (2) frequency cycling and (3) episodic breathing. Under normoxic, normocapnic conditions, 50% of control fish exhibited regular continuous breathing and 50% exhibited frequency cycling. Denervation of the gills and oro-branchial cavity promoted frequency cycling. Central denervation of the glossopharyngeal and vagus nerves produced episodic breathing. Regardless of the denervation state, hyperoxia produced either frequency cycling or episodic breathing while hypoxia and hypercarbia shifted the pattern to frequency cycling and continuous breathing. We suggest that these breathing patterns represent a continuum from continuous to episodic breathing with waxing and waning occupying an intermediate stage. The data further suggest that breathing pattern is influenced by both specific afferent input from chemoreceptors and generalised afferent input while chemoreceptors specific for producing changes in breathing pattern may exist in fish.     

Interaction effect of obstructive sleep apnea and periodic limb movements during sleep on heart rate variability

We aimed at assessing cardiac autonomic function by heart rate variability during sleep in patients with obstructive sleep apnea and periodic limb movements during sleep, and to compare it with that of patients with obstructive sleep apnea only, periodic limb movements during sleep only, and controls. We also aimed at investigating the interaction effect between apnea–hypopnea index and periodic limb movement index on heart rate variability. Four groups of patients (n = 42 each, total = 168) were identified based on the presence/absence of obstructive sleep apnea and periodic limb movements during sleep: + obstructive sleep apnea/? periodic limb movements during sleep (5 ≤ apnea–hypopnea index < 30 events per hr), ? obstructive sleep apnea/+ periodic limb movements during sleep (periodic limb movement index > 15 events per hr), + obstructive sleep apnea/+ periodic limb movements during sleep, ? obstructive sleep apnea/? periodic limb movements during sleep (controls). All groups were matched for age, sex and body mass index. Time‐ and frequency‐domain heart rate variability measures were calculated over 5‐min periods of stable stage 2 non‐rapid eye movement sleep. In patients with both obstructive sleep apnea and periodic limb movements during sleep, LFnu and LF/HF ratio were higher than in those with obstructive sleep apnea only, periodic limb movements during sleep only, and controls, while HFnu was the lowest among the four groups. LFnu, HFnu and LF/HF ratio were significantly and independently associated with minimal oxygen saturation in the + obstructive sleep apnea/+ periodic limb movements during sleep group. There was a significant interaction effect between apnea–hypopnea index and periodic limb movement index on LF/HF ratio (p = 0.038) in patients with obstructive sleep apnea. Patients with elevated apnea–hypopnea index and elevated periodic limb movement index exhibited higher sympathovagal balance compared with those with high apnea–hypopnea index and low periodic limb movement index, and compared with those with low apnea–hypopnea index (regardless of periodic limb movement index). Increased sympathetic activation and decreased parasympathetic control appear to be related to the severity of oxygen desaturation. Apnea–hypopnea index and periodic limb movement index had interactive effects on increased sympathovagal balance in patients with obstructive sleep apnea.     

Individual differences in the phase and amplitude of the human circadian temperature rhythm: with an emphasis on morningness-eveningness

We studied the relationship between the phase and the amplitude of the circadian temperature rhythm using questionnaires that measure individual differences in personality variables, variables that relate to circadian rhythms, age and sex. The ambulatory core body temperature of 101 young men and 71 young women was recorded continuously over 6 days. The temperature minimum (Tmin) and amplitude (Tamp) were derived by fitting a complex cosine curve to each day's data for each subject. Participants completed the Horne-Ostberg Morningness-Eveningness Questionnaire (MEQ), the Circadian Type Inventory (CTI) and the MMPI-2, scored for the Psychopathology-5 (PSY-5) personality variables. We found that the average Tmin occurred at 03.50 h for morning-types (M-types), 05.02 h for the neither-types and 06.01 h for evening-types (E-types). Figures were presented that could provide an estimate of Tmin given an individual's morningness-eveningness score or weekend wake time. The Tmin occurred at approximately the middle of the 8-h sleep period, but it occurred closer to wake in subjects with later Tmin values and increasing eveningness. In other words, E-types slept on an earlier part of their temperature cycle than M-types. This difference in the phase-relationship between temperature and sleep may explain why E-types are more alert at bedtime and sleepier after waking than M-types. The Tmin occurred about a half-hour later for men than women. Another interesting finding included an association between circadian rhythm temperature phase and amplitude, in that subjects with more delayed phases had larger amplitudes. The greater amplitude was due to lower nocturnal temperature.     

Modeling of the expiratory flow pattern of spontaneously breathing cats

A mathematical model was developed describing the entire expiratory flow pattern during spontaneous, tidal breathing in the absence of expiratory muscle activity. It provides estimates for the time constants of the respiratory system (tau RS(model)) and of the decay of continuing inspiratory muscle activity in early expiration (tau mus(model)). In ten anesthetized, tracheostomized cats flow, tracheal pressure and diaphragmatic EMG were measured during normal expirations and expirations with four different added resistances. No significant differences were found between tau RS(model) (0.21-0.49 sec) obtained by fitting the model to the flow data and tau RS obtained from the straight part of the expiratory flow-volume curve. tau mus(model) (0.050-0.052 sec) was comparable to similar time constants obtained from the integrated diaphragmatic EMG or from end-inspiratory, tracheal occlusion pressure. Fitted peak flow and time to peak tidal expiratory flow were not significantly different from those measured. In conclusion, for spontaneously breathing, anesthetized cats our model provides a close fit of the expiratory flow and parameter estimates were comparable with independently measured values.     

Normalizing effect of antidepressant imipramine on changes in circadian movement pattern of pinealectomized rats after a change in timing of the period of daylight

Department of Pharmacology, Stavropol' Medical Institute. (Presented by Academician of the Academy of Medical Sciences of the USSR D. A. Kharkevich.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 112, No. 12, pp. 595–597, December, 1991.     

Tachykinins in the control of breathing by hypoxia: pre- and post-genomic era

This article highlights major findings from physiological and pharmacological studies conducted in the pre- and post-genomic era examining the roles of substance P (SP) and other tachykinins in the response of the carotid body to hypoxia, in the ventilatory response to hypoxia and in respiratory rhythm generation. In the post-genomic period, the hypoxic ventilatory responses of mice carrying targeted deletion of genes that affect synthesis or degradation or receptor interaction of SP have been examined by us and also by other investigators. A brief summary of the findings from these investigations will also be presented. The combined observations from the pre- and post-genomic era strongly support the involvement of SP and also other tachykinins in the control of respiration during hypoxia.     

The effect of the timing, quality and quantity of sleep upon the depression (masking) of body temperature on an irregular sleep/wake schedule

SUMMARY  Eight subjects were studied on an irregular sleep/wake schedule which was designed so that prior wake time and the time of day when 4-h sleep periods were taken were both balanced. Rectal temperature and the sleep EEG were measured throughout the 8-d protocol. A purification method was used to estimate the depression of rectal temperature (masking) caused by the first and second halves of each 4-h sleep period. On average this was 0.187 ± 0.015°C during the first 2h and 0.262 ± 0.017°C during the second 2h. Masking increases beyond the first 2 h of sleep, but any effects due to the phase of the rectal temperature when sleep is taken are very weak. However, masking did increase (that is, the temperature was depressed more) when the amount of prior wake time was greater than 4 h. When the effects of sleep content variables were considered also, masking was still greater in the second half of sleep and tended to increase with the amount of slow-wave sleep, but it decreased with increasing amounts of time awake during a sleep period (sleep latency or sleep discontinuity). Some implications of these results for the mechanism of sleep-induced masking are considered.     

The length-force relationship of the human genioglossus in patients with obstructive sleep apnea

During sleep, patients with obstructive sleep apnea (OSA) have repetitive episodes of upper airway collapse, which are terminated by increased activity of upper airway dilator muscles. The repetitive activation of the genioglossus (GG) may result in muscle remodeling. We hypothesized that OSA patients have an altered length-force relationship, increased force generation and/or decreased force maintenance as compared with control subjects. The GG length-force relationship was determined in 12 patients with OSA and 12 normal control subjects. The optimum length of the GG (LO) was at a longer muscle length in OSA patients than in control subjects. At longer muscle lengths, OSA patients produced greater percentages of their maximum protrusion force than control subjects. Force maintenance was not significantly different between the two groups. We conclude that in OSA patients relative to normal controls, the length-force relationship of the GG is altered, specifically at longer muscle lengths. We speculate that the GG is remodeled in OSA patients and that this facilitates airway re-opening to terminate obstructive events.     

Ventilatory pattern and chemosensitivity in M1 and M3 muscarinic receptor knockout mice

Acetylcholine (ACh) acting through muscarinic receptors is thought to be involved in the control of breathing, notably in central and peripheral chemosensory afferents and in regulations related to sleep-wake states. By using whole-body plethysmography, we compared baseline breathing at rest and ventilatory responses to acute exposure (5 min) to moderate hypoxia (10% O(2)) and hypercapnia (3 and 5% CO(2)) in mice lacking either the M(1) or the M(3) muscarinic receptor, and in wild-type matched controls. M(1) knockout mice showed normal minute ventilation (V(E)) but elevated tidal volume (V(T)) at rest, and normal chemosensory ventilatory responses to hypoxia and hypercapnia. M(3) knockout mice had elevated V(E) and V(T) at rest, a reduced V(T) response slope to hypercapnia, and blunted V(E) and frequency responses to hypoxia. The results suggest that M(1) and M(3) muscarinic receptors play significant roles in the regulation of tidal volume at rest and that the afferent pathway originating from peripheral chemoreceptors involves M(3) receptors.     

Sleep‐disordered breathing and nocturnal hypoventilation in children with the MECP2 duplication syndrome: A case series and review of the literature

There is limited knowledge on the occurrence of respiratory manifestations and sleep‐disordered breathing in particular in children with the MECP2 duplication syndrome. Although sleep‐disordered breathing and nocturnal hypoventilation are currently not cited as an important symptom in these children, we present three cases who all had an abnormal breathing during sleep. In view of the consequences associated with sleep apnea and hypoventilation, we advise to perform a polysomnography in children with MECP2 duplication. Different treatment modalities (ENT surgery, CPAP, and non‐invasive ventilation) can be applied to successfully treat these conditions.     

Circadian and wake-dependent modulation of fastest and slowest reaction times during the psychomotor vigilance task

Performance on the psychomotor vigilance task (PVT) sensitively reflects a circadian modulation of neurobehavioral functions, as well as the effect of sleep pressure developing with duration of time awake, without being confounded by a learning curve. Sixteen healthy volunteers underwent two 40-h constant posture protocols in a balanced crossover design. During these protocols, either low sleep pressure conditions were attained by an alternating cycle of 150 min of wakefulness and 75 min of sleep (NAP) protocol, or high sleep pressure conditions were achieved by total sleep deprivation (SD) protocol. During scheduled wakefulness in both protocols, the PVT was carried out every 225 min. Quantitative analysis of the lapses, slowest (90th percentile) and fastest (10th percentile) reaction times (RTs) during the protocols, indicated that the lapses and slowest RTs were sensitive to changes in homeostatic sleep pressure. Our data indicate that the difference between the fastest and slowest RTs (interpercentile range 10th–90th percentile) was particular sensitive to detect very early effects of growing sleep pressure. On the other hand, decrements in PVT performance which were related to circadian phase did not depend significantly on any categorization (such as percentiles of the RTs).