Liborio Parrino

The nature of arousal in sleep

The role of arousals in sleep is gaining interest among both basic researchers and clinicians. In the last 20 years increasing evidence shows that arousals are deeply involved in the pathophysiology of sleep disorders. The nature of arousals in sleep is still a matter of debate. According to the conceptual framework of the American Sleep Disorders Association criteria, arousals are a marker of sleep disruption representing a detrimental and harmful feature for sleep. In contrast, our view indicates arousals as elements weaved into the texture of sleep taking part in the regulation of the sleep process. In addition, the concept of micro‐arousal (MA) has been extended, incorporating, besides the classical low‐voltage fast‐rhythm electroencephalographic (EEG) arousals, high‐amplitude EEG bursts, be they like delta‐like or K‐complexes, which reflects a special kind of arousal process, mobilizing parallely antiarousal swings. In physiologic conditions, the slow and fast MA are not randomly scattered but appear structurally distributed within sleep representing state‐specific arousal responses. MA preceded by slow waves occurs more frequently across the descending part of sleep cycles and in the first cycles, while the traditional fast type of arousals across the ascending slope of cycles prevails during the last third of sleep. The uniform arousal characteristics of these two types of MAs is supported by the finding that different MAs are associated with an increasing magnitude of vegetative activation ranging hierarchically from the weaker slow EEG types (coupled with mild autonomic activation) to the stronger rapid EEG types (coupled with a vigorous autonomic activation). Finally, it has been ascertained that MA are not isolated events but are basically endowed with a periodic nature expressed in non‐rapid eye movement (NREM) sleep by the cyclic alternating pattern (CAP). Understanding the role of arousals and CAP and the relationship between physiologic and pathologic MA can shed light on the adaptive properties of the sleeping brain and provide insight into the pathomechanisms of sleep disturbances. Functional significance of arousal in sleep, and particularly in NREM sleep, is to ensure the reversibility of sleep, without which it would be identical to coma. Arousals may connect the sleeper with the surrounding world maintaining the selection of relevant incoming information and adapting the organism to the dangers and demands of the outer world. In this dynamic perspective, ongoing phasic events carry on the one hand arousal influences and on the other elements of information processing. The other function of arousals is tailoring the more or less stereotyped endogenously determined sleep process driven by chemical influences according to internal and external demands. In this perspective, arousals shape the individual course of night sleep as a variation of the sleep program.

Sleep Bruxism is a Disorder Related to Periodic Arousals During Sleep

There is evidence that sleep bruxism is an arousal-related phenomenon. In non-REM sleep, transient arousals recur at 20- to 40-second intervals and are organized according to a cyclic alternating pattern. Polysomnographic recordings from six subjects (two females and four males) affected by sleep bruxism (patients) and six healthy age-and gender-matched volunteers without complaints about sleep (controls) were analyzed to: (1) compare the sleep structure of bruxers with that of non-complaining subjects; and (2) investigate the relations between bruxism episodes and transient arousals. Patients and controls showed no significant differences in conventional sleep variables, but bruxers showed a significantly higher number of the transient arousals characterized by EEG desynchronization. Bruxism episodes were equally distributed between non-REM and REM sleep, but were more frequent in stages 1 and 2 (p < 0.0001) than in slow-wave sleep. The great majority of bruxism episodes detected in non-REM sleep (88%) were associated with the cyclic alternating pattern and always occurred during a transient arousal. Heart rate during the bruxism episodes (69.3 ± 18.2) was significantly higher (p < 0.0001) than that during the pre-bruxing period (58.1 ± 15.9). Almost 80% of all bruxism episodes were associated with jerks at the anterior tibial muscles. The framework of the cyclic alternating pattern offers a unified interpretation for sleep bruxism and arousal-related phenomena.

The cyclic alternating pattern plays a gate-control on periodic limb movements during non-rapid eye movement sleep

Periodic limb movements in sleep (PLMS) is a disorder characterized by a cyclic pattern of motor phenomena and EEG changes (mostly arousals), both recurring at approximately 20- to 40-s intervals. The periodicity of the PLMS phenomena recalls the physiological EEG arousal rhythm of non-rapid eye movement (NREM) sleep known as the cyclic alternating pattern (CAP). During CAP, arousals and arousal-equivalent features do not appear as isolated events but periodically intrude (phase A) between intervals of background EEG activity (phase B). Though the A phases can be expressed by a variety of EEG patterns, each with a different arousal impact on polygraphic parameters, overall CAP is a sequence of biphasic cycles reflecting a condition of unstable sleep. Twelve middle-aged PLMS subjects complaining of poor sleep were polygraphically compared with 12 age-matched and gender-matched healthy volunteers (controls). With respect to controls, the PLMS recordings showed an enhancement of the more powerful arousals and presented significantly increased amounts of CAP time (+45 min) and CAP rate (+15%). Of all the jerks detected in NREM sleep, 92% occurred in CAP, with the great majority of limb movements (96%) associated with phase A. Ninety-four percent of the nocturnal jerks coupled with phase A started jointly with the onset of the phase or when the latter had already begun. In particular, most of the myoclonic events (67%) occurred in the first 2.5 s of the A phase. The CAP cycles coupled with periodic movements were significantly longer than those without motor events (+6.4 s). Compared to the American Sleep Disorders Associations rules for scoring EEG arousals, the CAP framework offers a more extensive insight into PLMS. In effect, the present study indicates an entrainment of nocturnal myoclonus by means of CAP and sheds light on the complex interactions between arousal mechanisms and motor phenomena during sleep.

New drugs for insomnia: comparative tolerability of zopiclone, zolpidem and zaleplon.

Insomnia affects 30–35% of people living in developed countries. The impact of insomnia on daytime functioning and its relationship with medical and psychiatric illnesses necessitate early treatment to prevent insomnia becoming persistent and to avoid the development of complications. However, pharmacological strategies must achieve a balance between sedative and adverse effects.In the last 30 years, benzodiazepines have been the preferred drugs for the treatment of insomnia. Benzodiazepines act nonselectively at two central receptor sites, named ω1 and ω2, which are located in different areas of the CNS. The sedative action of benzodiazepines is related to ω1 receptors, whereas ω2 receptors are responsible for their effects on memory and cognitive functioning. According to their pharmacokinetic profile, benzodiazepines can be classified into three groups: short half-life (<3 hours), medium half-life (8–24 hours) and long half-life (>24 hours).The newer non-benzodiazepine agents zopiclone, zolpidem and zaleplon have a hypnosedative action comparable with that of benzodiazepines, but they display specific pharmacokinetic and pharmacodynamic properties. These three ‘Z’ agents all share a short plasma half-life and limited duration of action. In addition, these agents are selective compounds that interact preferentially with ω1 receptors (sedative effect), whereas benzodiazepines also interact with ω2 receptors (adverse effects on cognitive performance and memory). Zaleplon is characterised by an ultrashort half-life (approximately 1 hour). Zolpidem and zopiclone have longer half-lives (approximately 2.4 and 5 hours, respectively). These properties, together with the low risk of residual effect, may explain the limited negative influences of these agents on daytime performance. Psychomotor tasks and memory capacities appear to be better preserved by non-benzodiazepine agents than by benzodiazepines. When present, cognitive deficits almost exclusively coincide with the peak plasma concentration. In particular, impairment can emerge in the first hours after drug administration, whereas psychomotor and memory tests carried out 7–8 hours later (i.e. in the morning) generally show no relevant alterations.As with benzodiazepines, the three ‘Z’ non-benzodiazepine agents should be used for a limited period, even in chronic relapsing conditions. Further evaluation is needed of the safety of hypnosedative medications in the long-term management of insomnia.

Cyclic alternating pattern (CAP): The marker of sleep instability

Cyclic alternating pattern CAP is the EEG marker of unstable sleep, a concept which is poorly appreciated among the metrics of sleep physiology. Besides, duration, depth and continuity, sleep restorative properties depend on the capacity of the brain to create periods of sustained stable sleep. This issue is not confined only to the EEG activities but reverberates upon the ongoing autonomic activity and behavioral functions, which are mutually entrained in a synchronized oscillation. CAP can be identified both in adult and children sleep and therefore represents a sensitive tool for the investigation of sleep disorders across the lifespan. The present review illustrates the story of CAP in the last 25 years, the standardized scoring criteria, the basic physiological properties and how the dimension of sleep instability has provided new insight into pathophysiolology and management of sleep disorders.

Clinical applications of cyclic alternating pattern.

Sleep-related disorders are revisited in the light of the physiological modality of NREM sleep expressed by the cyclic alternating pattern (CAP). Owing to its fluctuating properties on vigilance, muscle tone, and vegetative activities, CAP represents a highly favorable condition for the occurrence of interictal generalized and focal lesional EEG discharges, for motor seizures, and for periodic jerks in nocturnal myoclonus. All these manifestations are significantly associated with the components of activation during CAP, i.e., the A phases. On the contrary, the B phases of CAP appear chronologically linked to inhibitory phenomena in epileptic patients and in nocturnal myoclonus. The two phases of CAP seem especially involved in sleep apnea syndrome, where respiration is interrupted during a phase B and restored during a phase A. CAP rate, that measures the effort of the brain to maintain sleep, is increased by all conditions that induce vigilance instability such as noise, clinical insomnia, interictal EEG paroxysms, nocturnal seizures, periodic leg movements, and in certain extreme pathologic conditions such as Creutzfeldt-Jakob disease and stage 2 coma.

CYCLIC ALTERNATING PATTERN (CAP) IN NORMAL SLEEP : POLYSOMNOGRAPHIC PARAMETERS IN DIFFERENT AGE GROUPS

OBJECTIVES The present study aimed at offering a standardized database for cyclic alternating pattern (CAP) parameters across representative ages of life. METHODS CAP parameters were quantified in 40 healthy sleepers and polygraphically investigated in a partially sound-proof recording chamber under a standard laboratory setting. Four age groups were investigated (teenagers: 10-19 years; young adults: 20-39 years; middle-aged: 40-59 years; elderly: 60 years). Each group included 10 subjects (5 males and 5 females). Nocturnal recordings were accomplished after adaptation to the sleep laboratory that also served to rule out the presence of sleep-related disorders. The study indicated that CAP is a natural phenomenon of NREM sleep, with specific age-related characteristics across the life cycle. RESULTS CAP rate in NREM sleep, defined as the percentage ratio of total CAP time to total NREM sleep time, showed a U-shape profile with minimum in young adults (31.9%), maximum in the elderly group (55.3%), and intermediate values in teenagers (43.4%) and in middle-aged subjects (37.5%). The longest duration of CAP cycles was found among the older subjects (31 s). The highest amounts of subtypes A1 were identified in teenagers (n = 261), while the highest amounts of A2 and A3 subtypes occurred in the elderly group (n = 183). Across the ages, the level of arousal mostly fluctuated in stages 1 and 3, whereas stage 4 emerged as the most stable NREM stage. Overall, stage 2 better reflected the CAP values referred to as total NREM sleep. CONCLUSIONS The periodic arousal fluctuations reflected by CAP are a natural phenomenon of NREM sleep with specific age-related variations across the life cycle.

POLYSOMNOGRAPHIC ANALYSIS OF AROUSAL RESPONSES IN OBSTRUCTIVE SLEEP APNEA SYNDROME BY MEANS OF THE CYCLIC ALTERNATING PATTERN

Obstructive sleep apnea syndrome (OSAS) is characterized by multiple interruptions of airflow between periods of arousals. A key feature of OSAS is the 20- to 40-s cyclic pattern of electrophysiologic parameters. The periodicity of the OSAS-related phenomena is reminiscent of the natural electroencephalographic (EEG) arousal rhythm of non-rapid eye movement (NREM) sleep known as the cyclic alternating pattern (CAP). Morphologically, CAP consists of transient arousals (phase A) that periodically interrupt the tonic theta/delta activities of NREM sleep (phase B). Functionally, CAP translates a condition of sustained arousal instability oscillating between a greater arousal level (phase A) and a lesser arousal level (phase B). CAP is also related to the controls of the motor and autonomic mechanisms. On the basis of the information simultaneously derived from EEG activities, muscle tone, and neurovegetative responses, it is possible to distinguish three subtypes of A phases corresponding to different levels of arousal power: A1 (dominated by EEG synchronization and weak activation of polygraphic variables); A2 (mixture of EEG synchronization/desynchronization and intermediate activation of polygraphic variables); and A3 (dominated by EEG desynchronization and strong activation of polygraphic variables). Unlike standard criteria, CAP parameters offer a more suitable perspective for evaluating sleep pathologies in which brief and frequent arousals appear as a prominent feature. The present study aimed at (a) assessing CAP parameters in OSAS patients and (b) investigating the reciprocal interactions between CAP and the cyclic variations in respiratory rate. Twelve obese middle-aged OSAS subjects complaining of daytime sleepiness were polygraphically compared with age-matched and gender-matched volunteers in good health and with no complaints about sleep and wakefulness (controls). In OSAS patients, conventional parameters showed predictable decrements in total sleep time, slow wave sleep, and REM sleep and increases in stage 1 and nocturnal awakenings. Sleep fragmentation was associated with a significant enhancement of CAP and of the A phases with longer and more desynchronized EEG patterns (especially A3). The increase of A3 subtypes permitted scoring and detecting CAP also in REM sleep. The great majority of respiratory pauses (96% in NREM and 80% in REM sleep) were coupled with CAP. All CAP-related respiratory events rose in close temporal connection with a phase B, while effective breathing was always recovered during phase A (especially A2 and A3 subtypes). These data suggest that (a) phase B of CAP offers a vulnerable background for upper airway collapse and for attenuation of biochemical and neural mechanisms in the control of the ventilatory drive and (b) survival in OSAS patients is effected by the enhancement of the strongest components of the natural arousal rhythm at sleep qualitys expense.

CAP variables and arousals as sleep electroencephalogram markers for primary insomnia.

OBJECTIVE Polysomnographic (PSG) measures consistently reflect poor sleep quality and effective treatment in insomniac patients. METHODS The PSG findings of 47 patients (18 M and 29 F, 42.5+/-10 years) meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for a diagnosis of primary insomnia were compared with those of 25 age- and gender-balanced healthy subjects (controls) without sleep complaints. After one adaptation night to the sleep lab, each patient underwent two randomized double-blind PSG recordings. Twenty-four patients followed a placebo-drug sequence and 23 a drug-placebo succession. Active treatment consisted of widely used hypnotic drugs, i.e. zolpidem, triazolam, zopiclone, brotizolam. Conventional PSG measures, electroencephalogram (EEG) arousals and CAP variables (including phase A subtypes) were quantified and statistically analyzed. RESULTS Compared to controls, insomniac patients under placebo showed a significant increase of CAP rate, subtypes A1 and A2, EEG arousals, nocturnal wakefulness and stage 1, associated with reduced values of total sleep time and slow wave sleep (stages 3 and 4). In insomniac patients, sleep quality was significantly improved by hypnotic treatment. Compared to placebo, active medication significantly reduced CAP rate, subtypes A1 and A2, but had only marginal effects on subtypes A3 and on EEG arousals. Under hypnotic treatment total sleep time, nocturnal awakenings, stage 1 and slow wave sleep recuperated normal values. The most significant correlation between sleep quality and PSG variables was found for CAP rate (P<0.0001). CONCLUSIONS PSG investigation extended to CAP variables and EEG arousals can be an important procedure for the diagnosis of primary insomnia and evaluation of treatment efficacy.

Modifications of sleep structure induced by increasing levels of acoustic perturbation in normal subjects

In each non-REM (NREM) sleep stage, the aggregation of the arousal-related phasic events permits identification of periods of arousal fluctuation (cyclic alternating pattern or CAP) and periods of long-lasting arousal stability (non-CAP or NCAP). As the ratio CAP time to NREM sleep time (CAP/NREM) measures the instability of arousal during sleep, any perturbing event determines an increase of CAP/NREM. On the basis of these premises, 6 healthy volunteers underwent 5 sleep recordings at increasing intensities of sound pressure level (basal condition followed by continuous white noise at 45 dBA, 55 dBA, 65 dBA and 75 dBA, respectively). Besides a remarkable enhancement of CAP/NREM (P less than 0.00001), acoustic perturbation induced a significant linear increase of waking time after sleep onset, stage 2, NREM sleep, stage shifts and a significant linear decrease of stage 4, deep sleep, REM sleep and total sleep time. At each step of environmental disturbance, the values of the CAP ratio were consistent with the gradual changes of sleep organization. Although the Multiple Sleep Latency Test was unremarkable during the day following the sleep recording, CAP/NREM was significantly correlated with the personal evaluation of sleep quality (P less than 0.01). Through this model of transient situational insomnia it was possible to outline different degrees of subjective complaint depending on 3 ranges of CAP/NREM. A crucial role of CAP in the pathophysiological mechanisms of clinical insomnia is hypothesized.