High-amplitude theta wave bursts during REM sleep and cataplexy in hypocretin-deficient narcoleptic mice

Neurons that release hypocretin (HCRT; orexin) peptides control wake–sleep states and autonomic functions, and are lost in patients with narcolepsy with cataplexy. Bursts of high‐amplitude electroencephalographic (EEG) activity have been reported during behavioural arrests and rapid eye movement sleep (REMS) episodes at sleep onset in HCRT‐deficient narcoleptic mice. Quantitative information on these EEG phenomena is lacking. We aimed to quantify EEG frequency, occurrence rate, daily rhythm and cardiovascular correlates of high‐amplitude EEG bursts during REMS and cataplexy. Twenty HCRT‐deficient mice and 15 congenic wild‐type controls were instrumented with electrodes for sleep recordings and a telemetric blood pressure transducer. Short (1–2 s) high‐amplitude bursts of pointed theta waves (7 Hz) occurred during either REMS or cataplexy in 80% of HCRT‐deficient mice without any significant accompanying modification in systolic blood pressure or heart period. Theta bursts were significantly more likely to occur during the dark period and in the last third of REMS episodes. Similar EEG events were detected in a significantly lower fraction (27%) of wild‐type mice and with a significantly lower occurrence rate (0.8 versus 5 per hour of REMS). These data demonstrate that occurrence of high‐amplitude theta bursts is facilitated during REMS and cataplexy in narcoleptic mice. Analysis of EEG frequency and daily and intra‐episode patterns of event occurrence do not support interpretation of theta bursts as temporally displaced pre‐REMS spindles. Facilitation of high‐amplitude theta bursts may thus represent a novel neurophysiological abnormality associated with chronic HCRT deficiency.     

Cardiovascular variability as a function of sleep–wake behaviour in narcolepsy with cataplexy

Hypocretin/orexin signalling varies among sleep–wake behaviours, impacts upon cardiovascular autonomic control and is impaired in patients with narcolepsy with cataplexy (NC). However, evidence concerning disturbed cardiovascular autonomic control in NC patients is contrasting, and limited mainly to waking behaviour. We thus investigated whether control of cardiovascular variability is altered in NC patients during wakefulness preceding sleep, light (1–2) and deep (3–4) stages of non‐rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep. Polysomnographic recordings and finger blood pressure measurements were performed on nine drug‐free male NC patients and nine matched healthy control subjects during spontaneous sleep–wake behaviour in a standardized laboratory environment. Indices of autonomic function were computed based on spontaneous fluctuations of systolic blood pressure (SBP) and heart period (HP). During wakefulness before sleep, NC patients showed significant decreases in indices of vagal HP modulation, cardiac baroreflex sensitivity and amplitude of central autonomic (feed‐forward) cardiac control compared with control subjects. During NREM sleep, the negative correlation between HP and subsequent SBP values was greater in NC patients than in control subjects, suggesting a greater contribution of central autonomic commands to cardiac control. Collectively, these results provide preliminary evidence that autonomic control of cardiac variability by baroreflex and central autonomic (feed‐forward) mechanisms is altered in NC patients during spontaneous sleep–wake behaviour, and particularly during wakefulness before sleep.     

Sympathetic and cardiovascular activity during cataplexy in narcolepsy

Autonomic nervous system activity changes have been described during cataplexy as playing a role in triggering it. To confirm these previous findings, we investigated the time course of sympathetic and cardiovascular activities during cataplexy. We made for the first time microneurographic recordings of 10 cataplectic episodes in three patients with hypocretin‐deficient narcolepsy. During microneurography, muscle sympathetic nerve activity (MSNA) was recorded simultaneously with heart rate (HR), respiratory movements, arterial finger blood pressure (BP), electroencephalography, electro‐oculogram and superficial electromyogram. Results showed no significant autonomic changes before the onset of the cataplectic episodes. Cataplexy was associated with a significant increase in MSNA and BP compared with baseline, whereas HR was markedly decreased. An irregular breathing pattern mainly characterized by apnea typically occurred during the attacks. In conclusion, our findings did not show significant changes in autonomic activity prior to cataplexy onset, ruling out a triggering role of the autonomic system. However, cataplexy was associated with co‐activation of sympathetic and parasympathetic autonomic systems, a pattern reminiscent of that reported during the vigilance reaction in animals.     

Sleep efficiency and neurophysiological patterns in middle‐aged men are associated with cognitive change over their adult life course

Disrupted sleep is a contributing factor to cognitive ageing, while also being associated with neurodegenerative disorders. Little is known, however, about the relation of sleep and the gradual cognitive changes over the adult life course. Sleep electroencephalogram (EEG) patterns are potential markers of the cognitive progress. To test this hypothesis, we assessed sleep architecture and EEG of 167 men born in the Copenhagen Metropolitan Area in 1953, who, based on individual cognitive testing from early (~18 years) to late adulthood (~58 years), were divided into 85 subjects with negative and 82 with positive cognitive change over their adult life. Participants underwent standard polysomnography, including manual sleep scoring at age ~58 years. Features of sleep macrostructure were combined with a number of EEG features to distinguish between the two groups. EEG rhythmicity was assessed by spectral power analysis in frontal, central and occipital sites. Functional connectivity was measured by inter‐hemispheric EEG coherence. Group differences were assessed by analysis of covariance (p < 0.05), including education and severity of depression as potential covariates. Subjects with cognitive decline exhibited lower sleep efficiency, reduced inter‐hemispheric connectivity during rapid eye movement (REM) sleep, and slower EEG rhythms during stage 2 non‐REM sleep. Individually, none of these tendencies remained significant after multiple test correction; however, by combining them in a machine learning approach, the groups were separated with 72% accuracy (75% sensitivity, 67% specificity). Ongoing medical screenings are required to confirm the potential of sleep efficiency and sleep EEG patterns as signs of individual cognitive progress.     

Blunted cardiovascular responses to acute psychological stress predict low behavioral but not self‐reported perseverance

Emerging evidence relates attenuated physiological stress reactions to poor behavioral regulation. However, only a small number of behaviors such as impulsivity and risk taking have been explored. Nevertheless, one opportunistic study suggested that blunted reactivity might relate to poor perseverance. The present study examined the relationship between cardiovascular reactivity to acute active psychological stress and self‐reported and behavioral perseverance. Participants (N = 64) completed a self‐report perseverance questionnaire before heart rate (HR) and blood pressure (BP) were measured at rest and in response to 4‐min active (paced auditory serial addition; PASAT) and passive (cold pressor) stress tests. This was followed by an unsolvable Euler puzzle tracing task, with the time spent and number of attempts endeavoring to solve the puzzle recorded as behavioral perseverance measures. Blunted systolic and diastolic BP reactivity to the PASAT was associated with fewer attempts at the impossible puzzle, and lower diastolic BP PASAT reactivity related to less time persevering at the puzzle. Moreover, attenuated diastolic BP and HR PASAT reactivity predicted poorer perseverance at keeping one's hand in the iced water of the cold pressor task. There was no association between reactivity and self‐reported perseverance. These preliminary findings add to the evidence that implicates blunted reactivity as a physiological marker of poor behavioral regulation, and this may indicate why individuals with blunted reactivity are at increased risk of developing negative health outcomes (e.g., obesity and addictions).     

CSF Histamine Contents in Narcolepsy,Idiopathic Hypersomnia and Obstructive Sleep Apnea Syndrome

Study Objective:

To (1) replicate our prior result of low cerebrospinal fluid (CSF) histamine levels in human narcolepsy in a different sample population and to (2) evaluate if histamine contents are altered in other types of hypersomnia with and without hypocretin deficiency.

Design:

Cross sectional studies.

Setting and Patients:

Sixty-seven narcolepsy subjects, 26 idiopathic hypersomnia (IHS) subjects, 16 obstructive sleep apnea syndrome (OSAS) subjects, and 73 neurological controls were included. All patients were Japanese. Diagnoses were made according to ICSD-2.

Results:

We found significant reductions in CSF histamine levels in hypocretin deficient narcolepsy with cataplexy (mean ± SEM; 176.0 ± 25.8 pg/mL), hypocretin non-deficient narcolepsy with cataplexy (97.8 ± 38.4 pg/mL), hypocretin non-deficient narcolepsy without cataplexy (113.6 ± 16.4 pg/mL), and idiopathic hypersomnia (161.0 ± 29.3 pg/mL); the levels in OSAS (259.3 ± 46.6 pg/mL) did not statistically differ from those in the controls (333.8 ± 22.0 pg/mL). Low CSF histamine levels were mostly observed in non-medicated patients; significant reductions in histamine levels were evident in non-medicated patients with hypocretin deficient narcolepsy with cataplexy (112.1 ± 16.3 pg/mL) and idiopathic hypersomnia (143.3 ± 28.8 pg/mL), while the levels in the medicated patients were in the normal range.

Conclusion:

The study confirmed reduced CSF histamine levels in hypocretin-deficient narcolepsy with cataplexy. Similar degrees of reduction were also observed in hypocretin non-deficient narcolepsy and in idiopathic hypersomnia, while those in OSAS (non central nervous system hypersomnia) were not altered. The decrease in histamine in these subjects were more specifically observed in non-medicated subjects, suggesting CSF histamine is a biomarker reflecting the degree of hypersomnia of central origin.

Citation:

Kanbayashi T; Kodama T; Kondo H; Satoh S; Inoue Y; Chiba S; Shimizu T; Nishino S. CSF histamine contents in narcolepsy, idiopathic hypersomnia and obstructive sleep apnea syndrome. SLEEP 2009;32(2):181–187.     

Blood Pressure and Heart Rate During Continuous Experimental Sleep Fragmentation in Healthy Adults

Study Objectives:

This paper aims to determine whether experimental arousals from sleep delay the sleep related fall in cardiovascular activity in healthy adults.

Design:

We report the results of 2 studies. The first experiment manipulated arousals from sleep in young adults. The second compared the effect of frequent arousals on young and middle-aged adults. The influence of arousals were assessed in 2 ways; (1) the fall in cardiovascular activity over sleep onset and the early sleep period, and (2) the underlying sleep levels during the sleep periods in between arousals.

Setting:

Both experiments were conducted in the sleep laboratory of the Department of Psychology, The University of Melbourne, Australia.

Participants:

There were 5 male and 5 female healthy individuals in each experiment between the ages of 18–25 years (Experiment 1) and 38–55 years (Experiment 2).

Interventions:

Participants in Experiment 1 were aroused by auditory stimuli every (i) 2 min, (ii) 1 min, and (iii) 30 sec of sleep for 90 min after the first indication of sleep. In a control condition, participants slept undisturbed for one NREM sleep cycle. Experiment 2 compared the control with the 30-sec condition in the young adults and in an additional group of middle-aged adults.

Measurements and Results:

The dependent variables were blood pressure (BP) and heart rate (HR). In Experiment 1, sleep fragmentation at higher frequencies retarded the fall in BP over sleep onset but did not affect the underlying sleep levels. Experiment 2 showed that there were no age differences on the effect of arousals on changes in BP and HR during sleep.

Conclusions:

This paper supports the hypothesis that repetitive arousals from sleep independently contribute to elevations in BP at night.

Citation:

Carrington MJ; Trinder J. Blood pressure and heart rate during continuous experimental sleep fragmentation in healthy adults. SLEEP 2008;31(12):1701–1712.     

Topography of homeostatic sleep pressure dissipation across the night in young and middle‐aged men and women

Decline in slow‐wave activity (SWA) across the night is believed to reflect dissipation of the homeostatic sleep drive. This study evaluated the effects of age, sex and topography on SWA dissipation. The sleep electroencephalogram of 48 young [22 women, 26 men; mean = 23.3 years; standard deviation (SD) = 2.4] and 39 middle‐aged (21 women, 18 men; mean = 51.9 years; SD = 4.6) healthy volunteers was analysed. Spectral analysis (0.5–22.0 Hz) was performed per non‐rapid eye movement period for Fp1, F3, C3, P3 and O1. SWA (1.0–5.0 Hz) dissipation was modelled using linear and exponential decay functions applied to each age and sex subgroup data set for each derivation. The relative adequacy of both functions was compared using Akaike’s information criterion. Results suggest that the exponential model provides a better data fit than the linear fit independently of age, gender and brain location. In women, age reduced the span (distance between the y intercept and the asymptote) of SWA decay in Fp1, F3, P3 and O1. In men, however, the effect of age on the span of SWA decay was limited to Fp1 and F3. In all age and sex subgroups, anterior regions showed a higher span than posterior regions. The asymptote was lower in anterior regions in young but not in middle‐aged subjects. These results suggest that the homeostatic process operates on a larger scale in anterior regions. Importantly, ageing reduced the scale of homeostatic dissipation in both sexes, but this effect was more widespread across the brain in women.     

Acute Cardiovascular Changes with Obstructive Events in Children with Sleep Disordered Breathing

Study Objectives:

Obstructive apneas in adults are associated with acute changes in blood pressure (BP) and heart rate (HR) that may contribute to poor cardiovascular outcome. Children with sleep disordered breathing (SDB) are similarly at risk for cardiovascular complications. We aimed to test the hypothesis that BP and HR are augmented during obstructive events in children equivalent to levels reported in adults.

Design:

Beat-by-beat mean arterial pressure (MAP) and HR were analyzed over the course of obstructive events (pre, early, late, and post-event) during NREM and REM sleep and compared using 2-way ANOVA with post hoc analyses.

Setting:

Pediatric sleep laboratory.

Patients or Participants:

30 children (15M/15F) aged 7–12 y referred for investigation of SDB

Interventions:

N/A

Measurements and Results:

All children underwent overnight polysomnography with continuous BP recording. MAP and HR increased significantly from late to post event in both sleep states (mean ± SEM, NREM: MAP, 74 ± 3 to 93 ± 3 mm Hg; HR, 76 ± 2 to 97 ± 2 bpm. REM: MAP, 76 ± 3 to 89 ± 3 mm Hg; HR, 76 ± 2 to 91 ± 2 bpm. P < 0.05 for all). NREM sleep state and arousal from sleep were significant independent predictors of the magnitude of cardiovascular change from late to post event (P < 0.05 for all).

Conclusions:

Children with SDB experience significant changes in HR and BP during obstructive events with magnitudes that are similar to levels reported in adults. These changes are more pronounced during NREM sleep and with arousal. These acute cardiovascular changes may have important implications for poor cardiovascular outcome in children with OSA as repetitive cardiovascular perturbations may contribute to the development of hypertension.

Citation:

O''Driscoll DM; Foster AM; Ng ML; Yang JSC; Bashir F; Nixon GM; Davey MJ; Anderson V; Walker AM; Trinder J; Horne RSC. Acute cardiovascular changes with obstructive events in children with sleep disordered breathing. SLEEP 2009;32(10):1265-1271.     

Depressive symptoms and cardiovascular reactivity to laboratory behavioral stress

Although a growing literature associates depressive symptoms with cardiovascular disease (CVD), the mechanisms underlying this association have not been clearly determined. The cardiovascular reactivity (CVR) hypothesis suggests that chronically elevated CVR during psychological distress can confer disease risk via vascular alterations. This investigation is a quantitative review of studies that evaluated the association of depressive symptoms with CVR. Atotal of 60 hypotheses were tested: 21 tests involved systolic blood pressure (SBP), 21 involved diastolic blood pressure (DBP), and 18 involved heart rate (HR). The aggregate effect size for the relation between depressive symptoms and HR reactivity was moderate (d = 0.37); aggregate effect sizes were small for SBP reactivity (d = 0.13) and DBP reactivity (d = 0.17). Effect sizes involving SBP reactivity were homogenous, whereas effect sizes involving DBP and HR reactivity were higher for studies that examined participants with CVD. These findings provide partial support for the associations of depressive symptoms with CVR.     

Effect of arm-cranking on leg blood flow and noradrenaline spillover during leg exercise in man

Controversy exists whether recruitment of a large muscle mass in dynamic exercise may outstrip the pumping capacity of the heart and require neurogenic vasoconstriction in exercising muscle to prevent a fall in arterial blood pressure. To elucidate this question, seven healthy young men cycled for 70 minutes at a work load of 5540%VO_2max. At 30 to 50 minutes, arm cranking was added and total work load increased to (mean ± SE) 82 ± 4% of Vo_2max. During leg exercise, leg blood flow average 6.15 4.511 minutes^-1, mean arterial blood pressure 137 ± 4 mmHg and leg conductance 42.3 ± 2.2 ml minutes^-1 mmHg^-1. When arm cranking was added to leg cycling, leg blood flow did not change significantly, mean arterial blood pressure increased transiently to 147 ± 5 mmHg and leg vascular conductance decreased transiently to 33.5 ± 3.1 ml minutes^-1 mmHg^-1. Furthermore, arm cranking doubled leg noradrenaline spillover. When arm cranking was discontinued and leg cycling continued, leg blood flow was unchanged but mean arterial blood pressure decreased to values significantly below those measured in the first leg exercise period. Furthermore, leg vascular conductance increased transiently, and noradrenaline spillover decreased towards values measured during the first leg exercise period. It is concluded that addition of arm cranking to leg cycling increases leg noradrenaline spillover and decreases leg vascular conductance but leg blood flow remains unchanged because of a simultaneous increase in mean arterial blood pressure. The decrease in leg vascular conductance observed when arm cranking increased mean arterial blood pressure could be regarded more as a measure to prevent overperfusion than a measure to maintain arterial blood pressure.     

Insomnia symptoms and subsequent cardiovascular medication: a register‐linked follow‐up study among middle‐aged employees

Sleep disturbances have been associated with an increased risk of cardiovascular disease outcomes. The associations of insomnia with hypertension and dyslipidaemia, the main modifiable cardiovascular risk factors, are less studied. We especially lack understanding on the longitudinal effects of insomnia on dyslipidaemia. We aimed to examine the associations of insomnia symptoms with subsequent prescribed medication for hypertension and dyslipidaemia using objective register‐based follow‐up data. Baseline questionnaire surveys among 40–60‐year‐old employees of the City of Helsinki, Finland, were conducted in 2000–2002 (n = 6477, response rate 67%, 78% women) and linked to a national register on prescribed reimbursed medication 5–7 years prior to and 5 years after baseline. Associations between the frequency of insomnia symptoms (difficulties in initiating and maintaining sleep, non‐restorative sleep) and hypertension and dyslipidaemia medication during the follow‐up were analysed using logistic regression analysis (odds ratios with 95% confidence intervals). Analyses were adjusted for pre‐baseline medication, sociodemographic and work‐related factors, health behaviours, mental health, and diabetes. Frequent insomnia symptoms were reported by 20%. During the 5‐year follow‐up, 32% had hypertension medication and 15% dyslipidaemia medication. Adjusting for age, gender and pre‐baseline medication, frequent insomnia symptoms were associated with hypertension medication (odds ratio 1.57, 95% confidence interval 1.23–2.00) and dyslipidaemia medication (odds ratio 1.59, 95% confidence interval 1.19–2.12). Occasional insomnia symptoms were also associated with cardiovascular medication, though less strongly. Further adjustments had negligible effects. To conclude, insomnia should be taken into account in the prevention and management of cardiovascular disease and related risk factors.     

When to measure resting values in studies of children's cardiovascular reactivity

Investigations suggesting that the order of obtaining resting and cardiovascular reactivity measurements moderates values have provided inconsistent results and have not analyzed data from children; the generalizability of results is uncertain. In this investigation, all children enrolled in the eighth-grade classrooms of the public schools of an entire county (n=451) participated in standardized reactivity assessments. The order of resting and reactivity measurements was randomized by examination day (a total of 19 days). Analyses indicated that all comparisons of order effects on mean resting blood pressure and heart rate, as well as reactivity (both change from resting and absolute values and both mean and maximal values), were nonsignificant. Results indicate that measurement order is not always a necessary consideration in studies of reactivity; the conditions under which measurement order is a consideration requires clarification.Dr. Joseph K. Murphy passed away in March of 1994.     

Between- and within-race variation in acute cardiovascular responses to alcohol: Evidence for genetic determination in normal males in three races

Cardiovascular responses (changes in heart rate, systolic and diastolic blood pressure) of 103 normal young adult males (46 European, 30 Japanese, 27 Chinese) to a test drink of alcohol were analyzed. The two Oriental groups did not differ in their mean responses (measured as postdrink value minus baseline value). When these two groups were pooled as Orientals, they differed very significantly from Europeans in their responses. Each of the three groups showed marked between-individual variability in alcohol response for each cardiovascular parameter, in the absence of obvious environmental differences. Repeated-measures ANOVA on these and other data, plus a direct genetic study in mice of the heritability of alcohol-induced change in heart rate, indicates that the broad-sense heritability of such changes in humans is in the region 0.3 to 0.5.This research was supported by the National Institute on Alcohol Abuse and Alcoholism (AA 01761-03) and the Natural Sciences and Engineering Council of Canada.     

Thoracic impedance and pulmonary atrial natriuretic peptide during head-up tilt induced hypovolaemic shock in humans

Head up and down tilts were used for manipulating the central blood volume in eight volunteers. During head-up tilt thoracic electrical impedance (TI) increased from 36.7 (33.9–52.1) ohm (mean and range) to 41.9 (36.9–59.2) ohm, heart rate from 60 (49–72) to 80 (65–90) beats min^-1 (P < 0.05) and decreased again to 57 (48–67) beats min^-1 accompanying a fall in mean arterial pressure from 86 (76–97) to 54 (41–79) mmHg and in cardiac output from 9.2 (5.9–12.1) to 6.9 (3.4–8.8) 1 min-¹ (n= 7, P < 0.07). Central venous pressure did not change significantly. Pulmonary arterial mean, 6 (3–12) mmHg, and wedge pressures, 4 (1–9) mmHg, decreased to 4 (1–11) and 1 (0–7) mmHg, respectively, and mixed, 78 (77–79%), and central venous oxygen saturations, 72 (71–73)%, fell to 62 (46–75) and 54 (44–58)%, respectively (P < 0.05). Atrial natriuretic peptide (ANP) was determined from blood of the superior vena cava and pulmonary and brachial arteries. Pulmonary artery ANP, 18.4 (7.5–30.7) pmol l^-1, was higher than in vena cava, 13.3 (5.2–20.9) pmol 1^_1 (P < 0.05). At the time of presyncope, pulmonary artery ANP decreased from 20.8 (37.4–10.1) to 13.7 (19.7-5.7) pmol l^-1, in vena cava from 13.8 (23.1–7.1) to 10.2 (17.9-6.7) pmol l^-‘ and in the brachial artery from 16.9 (34.1–5.2) to 11.3 (18.5-5.1) pmol l“¹ (P < 0.05). Head-down tilt did not affect the recorded variables significantly. Thoracic electrical impedance, pulmonary artery pressure and venous oxygen saturations were sensitive indices of the central blood volume as reflected in the release of atrial natriuretic peptide from the right side of the heart.     

Sleep and resting‐state functional magnetic resonance imaging connectivity in middle‐aged adults and the elderly: A population‐based study

Sleep problems increase with ageing. Increasing evidence suggests that sleep problems are not only a consequence of age‐related processes, but may independently contribute to developing vascular or neurodegenerative brain disease. Yet, it remains unclear what mechanisms underlie the impact sleep problems may have on brain health in the general middle‐aged and elderly population. Here, we studied sleep's relation to brain functioning in 621 participants (median age 62 years, 55% women) from the population‐based Rotterdam Study. We investigated cross‐sectional associations of polysomnographic and subjectively measured aspects of sleep with intrinsic neural activity measured with resting‐state functional magnetic resonance imaging on a different day. We investigated both functional connectivity between regions and brain activity (blood‐oxygen‐level‐dependent signal amplitude) within regions, hierarchically towards smaller topographical levels. We found that longer polysomnographic total sleep time is associated with lower blood‐oxygen‐level‐dependent signal amplitude in (pre)frontal regions. No objective or subjective sleep parameters were associated with functional connectivity between or within resting‐state networks. The findings may indicate a pathway through which sleep, in a ‘real‐life’ population setting, impacts brain activity or regional brain activity determines total sleep time.