Jan Kleiman

Autonomic activity during human sleep as a function of time and sleep stage.

While there is a developing understanding of the influence of sleep on cardiovascular autonomic activity in humans, there remain unresolved issues. In particular, the effect of time within the sleep period, independent of sleep stage, has not been investigated. Further, the influence of sleep on central sympathetic nervous system (SNS) activity is uncertain because results using the major method applicable to humans, the low frequency (LF) component of heart rate variability (HRV), have been contradictory, and because the method itself is open to criticism. Sleep and cardiac activity were measured in 14 young healthy subjects on three nights. Data was analysed in 2‐min epochs. All epochs meeting specified criteria were identified, beginning 2 h before, until 7 h after, sleep onset. Epoch values were allocated to 30‐min bins and during sleep were also classified into stage 2, slow wave sleep (SWS) and rapid eye movement (REM) sleep. The measures of cardiac activity were heart rate (HR), blood pressure (BP), high frequency (HF) and LF components of HRV and pre‐ejection period (PEP). During non‐rapid eye movement (NREM) sleep autonomic balance shifted from sympathetic to parasympathetic dominance, although this appeared to be more because of a shift in parasympathetic nervous system (PNS) activity. Autonomic balance during REM was in general similar to wakefulness. For BP and the HF and LF components the change occurred abruptly at sleep onset and was then constant over time within each stage of sleep, indicating that any change in autonomic balance over the sleep period is a consequence of the changing distribution of sleep stages. Two variables, HR and PEP, did show time effects reflecting a circadian influence over HR and perhaps time asleep affecting PEP. While both the LF component and PEP showed changes consistent with reduced sympathetic tone during sleep, their pattern of change over time differed.

Nature's clocks and human mood: the circadian system modulates reward motivation

Existing literature on reward motivation pays scant attention to the fact that reward potential of the environment varies dramatically with the light/dark cycle. Evolution, by contrast, treats this fact very seriously: In all species, the circadian system is adapted to optimize the daily rhythm of environmental engagement. We used 3 standard protocols to demonstrate that human reward motivation, as measured in the dynamics of positive affect (PA), is modulated endogenously by the circadian clock. Under naturalistic conditions, 13.0% of PA variance was explained by a 24-hr sinusoid. In a constant routine protocol, 25.0% of PA variance was explained by the unmasked circadian rhythm in core body temperature (CBT). A forced desynchrony study showed PA to align with CBT in exhibiting circadian periodicity independent of a 28-hr sleep/wake cycle. It is concluded that the circadian system modulates reward activation, and implications for models of normal and abnormal mood are discussed.

The influence of sleep onset on the diurnal variation in cardiac activity and cardiac control.

Heart rate (HR), blood pressure (BP) and autonomic nervous system (ANS) activity vary diurnally, with a reduction in HR and BP, and a shift to vagal dominance during the dark phase. However, the cause of these changes, particularly the relative influence of sleep and circadian mechanisms, remains uncertain. The present study assessed the effect of sleep onset on HR, BP, high frequency (HF) component of heart rate variability (HRV), low frequency/high frequency (LF/HF) ratio and pre‐ejection period (PEP). Sleep onset was dissociated from circadian influences by having subjects go to sleep at two different circadian phases, their normal time of sleep onset (normal sleep onset, NSO), and after a delay of 3 h (delayed sleep onset, DSO). The assumption was that changes caused by sleep onset would occur in association with sleep onset, irrespective of its timing, while circadian effects would have a consistent circadian phase and be independent of when sleep onset occurred. Thirteen and 17 subjects were run in the NSO and DSO conditions, respectively. Following a 1‐h adaptation period, data collection began 2 h before subjects’ normal time of sleep onset and continued until morning awakening. The lights were turned out after 2 h in the NSO condition and 5 h in the DSO condition. Subjects were required to maintain a supine position throughout the experimental sessions. The night‐time decrease in HR was found to be due to both sleep onset and a circadian influence, with the circadian component being more prominent. In contrast, the fall in BP was largely due to a sleep onset effect. Increased vagal activity, as reflected in the HF component and a shift to vagal dominance in the LF/HF ratio, appeared to be primarily a function of the sleep system, while sympathetic activity, as assessed by PEP, reflected a circadian influence.

Cardiac activity during sleep onset

Alterations in a number of measures of cardiac activity were examined during sleep onset in 6 participants over 3 experimental nights. Each sleep onset was divided into four consecutive phases: wakefulness, mixed alpha and theta activity, stage 2 NREM sleep with arousals, and stable stage 2 sleep. The variables measured were heart rate (HR), respiratory sinus arrhythmia (RSA), pre-ejection period (PEP) and T-wave amplitude (TWA). Respiration rate (RR) was also measured. HR and RR were lower in stable Stage 2 sleep compared with wakefulness, whereas PEP, TWA and RSA did not change significantly. During the second and third phases of sleep onset, HR decreased at each transition into sleep and increased following each spontaneous arousal. This increase resolved rapidly, with a return to sleep levels by 12 beats after the arousal. HR changes are discussed with reference to RSA, PEP, TWA and the concept of a waking reflex.

The cardiorespiratory activation response at an arousal from sleep is independent of the level of CO2

Arousal from sleep is associated with transient cardiorespiratory activation. Traditionally, this response has been understood to be a consequence of state‐dependent changes in the homeostatic control of ventilation. The hypothesis predicts that the magnitude of ventilatory and cardiac responses at an arousal will be a function of the intensity of concurrent respiratory stimuli (primarily PCO2). Alternatively, it has been proposed that increased cardiorespiratory activity is due to reflex activation. This hypothesis predicts that the magnitude of the cardiorespiratory response will be independent of respiratory stimuli. To compare these hypotheses we measured minute ventilation (Vi), heart rate (HR) and blood pressure (BP) during wakefulness and stage 2 sleep, while manipulating PetCO2. Further, we assessed the magnitude of the response of these variables to an arousal from sleep at the various levels of PetCO2. The subjects were male aged 18–25 years. PetCO2 was manipulated by clamping it at four levels during wakefulness [wake eucapnic, sleep eucapnic (Low), and sleep eucapnic +3 mmHg (Medium) and +6 mmHg (High)] and three levels during sleep (Low, Medium and High). The average number of determinations for each subject at each level was 14 during wakefulness and 25 during sleep. Arousals were required to meet American Sleep Disorders Association criteria and were without body movement. The results indicated that average increases in Vi, HR and BP at arousal from sleep did not significantly differ as a function of the level of PetCO2 present at the time of the arousal (all P > 0.05). Further, the magnitude of the ventilatory response to an arousal was significantly less than the values predicted by the homeostatic hypothesis (P < 0.05). We conclude that, in normal subjects, the cardiorespiratory response to an arousal from sleep is not because of a homeostatic response, but of a reflex activation.

The effect of flow limitation on the cardiorespiratory response to arousal from sleep under controlled conditions of chemostimulation in healthy older adults.

The influence of flow limitation on the magnitude of the cardiorespiratory response to arousal from sleep is of interest in older people, because they experience considerable flow limitation and frequent arousals from sleep. We studied older flow‐limiting subjects, testing the hypothesis that the cardiorespiratory activation response would be larger when arousal occurred during flow limitation, compared to no flow limitation, and chemical stimuli were controlled. In 11 older adults [mean ± standard deviation (SD) age: 68 ± 5 years] ventilation was stabilized using continuous positive airway pressure, and flow limitation was induced by dialling down the pressure. Partial pressure of end‐tidal carbon dioxide (PetCO2) was maintained by titration of the inspired CO2 and hyperoxia was maintained using 40% O2 balanced with nitrogen. Flow limitation at the time of arousal did not augment cardiovascular activation response (heart rate P = 0.7; systolic blood pressure P = 0.6; diastolic blood pressure P = 0.3), whereas ventilation was greater following arousals during flow limitation compared to no flow limitation (P < 0.001). The pre–post‐arousal differences in ventilation reflected significant pre‐arousal suppression (due to flow limitation) plus post‐arousal activation. In summary, the cardiovascular response to arousal from sleep is not influenced by flow limitation at the time of arousal, when chemical stimuli are controlled in older adults. This finding may contribute to the decreased cardiovascular burden associated with sleep‐disordered breathing reported in older adults, although our data do not exclude the possibility that flow limitation in the presence of mild hypoxic hypercapnia could increase the cardiovascular response to arousal.

The effect of presleep anxiety on respiratory instability during sleep

Ventilation falls at sleep onset as a consequence of the inactivation of a wakefulness specific input to the respiratory system. The magnitude of the difference in ventilation between wakefulness and sleep is thought to be positively related to respiratory instability during subsequent sleep. It is also known that psychological arousal can result in hyperventilation. The present paper evaluates the hypothesis that the mechanism producing hyperventilation to arousing stimuli during wakefulness is the same as that inactivated at sleep onset It was predicted that the magnitude of the fall in ventilation and subsequent respiratory instability would be a function of the subjects presleep arousal level. To test the prediction, presleep cognitive arousal was manipulated in Experiment 1, while anxiety level was varied in Experiment Z Neither manipulation produced hyperventilation immediately before sleep, or affected the magnitude of the fall in ventilation at sleep onset. Experiment 3 reassessed the hypothesis in subjects selected as hyperventilators on the basis of an anxiety-provoking task presented in the afternoon. However, while subjects hyperventilated in response to the manipulation in the afternoon, they did not do so immediately before sleep. It was concluded that the respiratory response to anxiety-provoking situations is inhibited in preparation for sleep and that the subsequent fall in ventilation at sleep onset is a consequence of an independent mechanism.