Maria Cristina Spaggiari

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.

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.

Cyclic alternating pattern (CAP) and epilepsy during sleep: how a physiological rhythm modulates a pathological event

OBJECTIVES Epileptic susceptibility is triggered by the sleeping condition. However, both ictal and interictal events are not equally affected by the different sleep states. Besides the well-known dichotomy between non-REM sleep (high activation) and REM sleep (low activation), epileptic phenomena are deeply sensitive to the ongoing level of arousal. METHODS During non-REM sleep the arousal level can be either unstable, as expressed by the repetitive sequences of the cyclic alternating pattern (CAP), or stable, as reflected by non-CAP. Phase A (arousal complex) and phase B (post-arousal rebound response) are the two basic components of the CAP cycle, which presents a 20-40 s periodicity. Three subtypes of A phases can be recognized: the A1 subtypes, which are thoroughly composed of K-complexes and delta bursts, and subtypes A2 and A3 dominated by moderate (A2) or prominent (A3) EEG desynchrony. RESULTS As a manifestation of unstable sleep, CAP offers a favorable background for the occurrence of nocturnal motor seizures that in most cases arise in concomitance with a phase A. In primary generalized epilepsy (PGE) and in lesional epilepsies with fronto-temporal focus, activation of interictal discharges is high during CAP reaching the climax during phase A and the strongest inhibition during phase B. A lack of modulation is observed instead in epilepsy with benign rolandic spikes. In PGE, the interictal bursts are mostly associated with the highly synchronized phase A1 subtypes. CONCLUSIONS The analysis of sleep microstructure based on CAP parameters offers a sensitive framework for exploring the linkage between dynamic EEG events and epileptic phenomena.

CAP components and EEG synchronization in the first 3 sleep cycles.

OBJECTIVE There is consolidated evidence that stage changes in sleep are closely related to spontaneous EEG fluctuations centered on the 20-40 periodicity of the cyclic alternating pattern (CAP). The present investigation aimed at assessing the involvement of the different components of CAP in the process of build-up, maintenance and demolition of deep non-REM (NREM) sleep. METHODS CAP parameters were quantified in the first 3 sleep cycles (SC1, SC2, SC3), selected from polysomnographic recordings of 25 healthy sound sleepers belonging to an extensive age range (10-49 years). Only ideal SCs were selected, i.e. the ones uninterrupted by intervening wakefulness and in which all stages were represented and linked in a regular succession of a descending branch, a trough and an ascending branch. RESULTS Among the first 3 SCs, a total amount of 45 (SC1, 16; SC2, 13; SC3, 16) met the inclusion requirements. SCI contained the highest amount of slow wave sleep (43.7 min) and the lowest values of CAP rate (31.6%). The number of phase A1 subtypes remained unmodified across the 3 SCs (SC1, 48; SC2, 48; SC3, 48), whereas both subtypes A2 (SC1, 9; SC2, 14; SC3, 14) and A3 (SC1, 2; SC2, 8; SC3, 10) increased significantly (P<0.028 and P<0.0001, respectively). The A1 subtypes composed more than 90% of all the A phases collected in the descending branches and in the troughs, while the A2 and A3 subtypes were the major representatives (64.3%) of the A phases occurring in the ascending branches. CONCLUSIONS Within the dynamic organization of sleep, the non-random distribution of CAP sequences, with their succession of slow (subtypes A1) and rapid (subtypes A2 and A3) EEG shifts, seem to be responsible for sculpturing EEG synchrony under the driving and alternating forces of NREM and REM sleep.

Multidrug comparison (lorazepam, triazolam, zolpidem, and zopiclone) in situational insomnia: Polysomnographic analysis by means of the cyclic alternating pattern

Since homogeneous samples of insomniacs are difficult to recruit for pharmacotherapy studies, normal sleepers can be used to assess the protective effect of hypnotic drugs, under standardized nonconducive conditions. In particular, a noisy environment is a typical cause of situational insomnia that can be counteracted by a sedative-hypnotic agent. Six healthy middle-aged subjects (three men and three women), with no complaints about sleep, underwent a completely randomized double-blind series of 10 nocturnal polysomnograms with at least 72-h washout intervals. All subjects received a single dose of placebo, zolpidem 10 mg, zopiclone 7.5 mg, lorazepam 1 mg, and triazolam 0.25 mg both under basal and under perturbed conditions. For each individual, five recordings were carried out under basal conditions (sound pressure level not higher than 30 dB) and five recordings under acoustically perturbed conditions (continuous white noise at 55 dB). Sleep quality was assessed by means of a visual analogue scale (VAS). All recordings were scored according to conventional rules (macro-structure) and cyclic alternating pattern (CAP) methodology (microstructure). Statistical analysis was based on a repeated measures analysis-of-variance design integrated by Bonferroni adjusted probabilities. Under placebo, situational insomnia was confirmed by the significant increase in sleep fragmentation (intrasleep wakefulness) and by the significant enhancement of arousal instability (CAP parameters). In contrast to macrostructural information, CAP parameters were highly sensitive in detecting the perturbing effects of noise (mean CAP rate under placebo, 57%) and the protective action of hypnotic drugs during perturbation (mean CAP rate under active medication, 41%). Microstructural analysis enabled us to discriminate hypnotic drugs from placebo, nonbenzodiazepine compounds from benzodiazepine agents, and zopiclone from zolpidem. The latter, in fact, induced the lowest values of CAP rate both under basal (30%) and under noisy (39%) conditions and determined a significant decrease in electroencephalogram arousals. All CAP parameters were significantly correlated with the visual-analogue-scale scores for sleep quality. The use of CAP methodology in a highly standardized model of situational insomnia can be a valid alternative to conventional sleep scoring for the investigation of drug effects on disturbed sleep.

Cyclic Alternating Pattern as a Provocative Factor in Nocturnal Paroxysmal Dystonia

Summary: Purpose: We made a polygraphic study of 6 patients with nocturnal paroxysmal dystonia (NPD) in which the cyclic alternating pattern (CAP) parameters were compared with those of a group of age‐ and sex‐matched controls.

Discriminatory Effect of Cyclic Alternating Pattern in Focal Lesional and Benign Rolandic Interictal Spikes During Sleep

Summary: Twenty epileptic patients (10 male and 10 female) were polygraphically recorded during nocturnal sleep. Ten subjects, with a wide age range, were affected by focal lesional epilepsy, and 10 were children affected by benign epilepsy with rolandic spikes (BERS). In five cases a bihemispheric expression of the focal lesional bursts emerged occasionally during the night recordings. The behavior of interictal electroencephalographic (EEG) paroxysms were analyzed with respect to the two arousal states of non‐rapid‐eye‐movement (REM) sleep: (a) the cyclic alternating pattern (CAP), expressed by biphasic EEG periodic activities and related to long‐lasting fluctuations between greater (phase A) and lesser (phase B) arousal levels; and (b) the non‐CAP (NCAP), manifested by EEG stationarities that reflect a sustained relative stability of arousal. The CAP/NCAP modality affected the spiking activity and distribution of the focal lesional EEG paroxysms, which appeared enhanced during CAP and which were mostly collected in phase A. The even more powerful influence of CAP and especially phase A on the secondary bisynchronous bursts suggests a crucial integration among thalamocortical circuits, arousal modulation, and epileptic generalization mechanisms. Conversely, in the BERS recordings no significant differences emerged throughout CAP and NCAP. The intense activity of the rolandic foci induced by sleep as such could be explained on the basis of the greater dependence of these functional cortical EEG abnormalities on the degree of synchronization during sleep.

Sleep reactivity during acute nasal CPAP in obstructive sleep apnea syndrome

Objective: To measure the readjustments of sleep macro- and microstructure in patients with obstructive sleep apnea syndrome (OSAS) after acute nasal continuous positive airway pressure (NCPAP) treatment. Background: The conventional polysomnographic analysis (macrostructure of sleep) does not necessarily provide the best measures of sleep disruption associated with OSAS. In contrast, microstructural methods of analyzing sleep (i.e., arousals and cyclic alternating pattern) may improve evaluation of patients with OSAS. Method:— Ten patients with OSAS were monitored polygraphically before and during the first night of NCPAP therapy. The results were compared with those of 10 age- and sex-matched controls without sleep-related breathing disorders. Each nocturnal recording was followed by daytime observation using the multiple sleep latency test and Visual Analogue Scale (VAS). Results: The first night of ventilatory therapy was characterized by a remarkable expansion of stages 3 and 4 and of REM sleep. In addition, NCPAP suppressed the presence of cyclic alternating pattern (CAP) in REM sleep and induced an impressive rebound of arousals and of certain CAP variables—i.e., CAP rate, CAP time, number of CAP cycles—which dropped well below the physiologic values expressed by controls. A normal duration of phases A and B was re-established starting the first treatment night. When we matched sleep variables with the indices of daytime function, a significant correlation emerged only between the variations of CAP rate and VAS scores. In particular, improvement of daytime sleepiness was less evident when the ventilatory-induced drop of CAP rate was more pronounced. Conclusions: The application of CAP variables to the microstructural analysis of sleep may expand our knowledge regarding sleep and respiration.