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Liborio Parrino

Journal articles

Rositsa Poryazova, Esther Werth, Liborio Parrino, Mario Giovanni Terzano, Claudio L Bassetti (2011)  Cyclic alternating pattern in narcolepsy patients and healthy controls after partial and total sleep deprivation.   Clin Neurophysiol Mar  
Abstract: OBJECTIVE: To investigate the regulation NREM sleep at baseline and in morning recovery sleep after partial and total sleep deprivation (SD) in narcolepsy-cataplexy (NC) using cyclic alternating pattern (CAP). METHODS: Daytime sleep under either increased (no sleep in the previous night) or decreased sleep pressure (allowing 4h of sleep, 23:00-3:00h) was recorded in ten drug-free, HLA-positive, hypocretin deficient NC patients and ten age, gender and body mass index matched healthy controls. Baseline sleep was also recorded and used for comparison purposes. CAP parameters were scored and analyzed for each subject. RESULTS: Narcolepsy patients had significantly lower CAP rate, CAP index, CAP time, number of CAP cycles, A1 index and number of A1 cycles in comparison to healthy controls at baseline as well as after partial and total SD. In both narcolepsy patients and healthy control subjects there was a significant decrease in these parameters after partial and total SD but the changes followed a similar pattern. CONCLUSION: The persistence of baseline differences in CAP parameters between narcolepsy patients and healthy controls and their similar behavior after partial and total SD suggests similar homeostatic NREM sleep regulation but on a different level. SIGNIFICANCE: CAP analysis demonstrates that NREM sleep homeostasis although altered, is functional in narcolepsy patients.
M C Carra, P H Rompré, T Kato, L Parrino, M G Terzano, G J Lavigne, G M Macaluso (2011)  Sleep bruxism and sleep arousal: an experimental challenge to assess the role of cyclic alternating pattern.   J Oral Rehabil Feb  
Abstract: Summaryâ Rhythmic masticatory muscle activity (RMMA) is the characteristic electromyographic pattern of sleep bruxism (SB), a sleep-related motor disorder associated with sleep arousal. Sleep arousals are generally organised in a clustered mode known as the cyclic alternating pattern (CAP). CAP is the expression of sleep instability between sleep maintaining processes (phase A1) and stronger arousal processes (phases A2 and A3). This study aimed to investigate the role of sleep instability on RMMA/SB occurrence by analysing CAP and electroencephalographic (EEG) activities. The analysis was performed on the sleep recordings of 8 SB subjects and 8 controls who received sensory stimulations during sleep. Baseline and experimental nights were compared for sleep variables, CAP, and EEG spectral analyses using repeated measure ANOVAs. Overall, no differences in sleep variables and EEG spectra were found between SB subjects and controls. However, SB subjects had higher sleep instability (more phase A3) than controls (Pâ=â0·05). The frequency of phase A3 was higher in the pre-REM sleep periods (Pâ<â0·001), where peaks in RMMA/SB activity were also observed (Pâ=â0·05). When sleep instability was experimentally increased by sensory stimuli, both groups showed an enhancement in EEG theta and alpha power (Pâ=â0·04 and 0·02, respectively) and significant increases in sleep arousal and all CAP variables. No change in RMMA/SB index was found within either groups (RMMA/SB occurred in all SB subjects and only one control during the experimental night). These findings suggest that CAP phase A3 may act as a permissive window rather than a generator of RMMA/SB activity in predisposed individuals.
Sara Mariani, Elena Manfredini, Valentina Rosso, Martin O Mendez, Anna M Bianchi, Matteo Matteucci, Mario G Terzano, Sergio Cerutti, Liborio Parrino (2011)  Characterization of A phases during the Cyclic Alternating Pattern of sleep.   Clin Neurophysiol Mar  
Abstract: OBJECTIVE: This study aims to identify, starting from a single EEG trace, quantitative distinctive features characterizing the A phases of the Cyclic Alternating Pattern (CAP). METHODS: The C3-A2 or C4-A1 EEG leads of the night recording of eight healthy adult subjects were used for this analysis. CAP was scored by an expert and the portions relative to NREM were selected. Nine descriptors were computed: band descriptors (low delta, high delta, theta, alpha, sigma and beta); Hjorth activity in the low delta and high delta bands; differential variance of the EEG signal. The information content of each descriptor in recognizing the A phases was evaluated through the computation of the ROC curves and the statistics sensitivity, specificity and accuracy. RESULTS: The ROC curves show that all the descriptors have a certain significance in characterizing A phases. The average accuracy obtained by thresholding the descriptors ranges from 59.89 (sigma descriptor) to 72.44 (differential EEG variance). CONCLUSIONS: The results show that it is possible to attribute a significant quantitative value to the information content of the descriptors. SIGNIFICANCE: This study gives a mathematical confirm to the features of CAP generally described qualitatively, and puts the bases for the creation of automatic detection methods.
Sara Mariani, Anna M Bianchi, Elena Manfredini, Valentina Rosso, Martin O Mendez, Liborio Parrino, Matteo Matteucci, Andrea Grassi, Sergio Cerutti, Mario G Terzano (2010)  Automatic detection of a phases of the cyclic alternating pattern during sleep.   Conf Proc IEEE Eng Med Biol Soc 2010: 5085-5088  
Abstract: This study aimed to develop an automatic algorithm to detect the activation phases (A phases) of the Cyclic Alternating Pattern. The sleep EEG microstructure of 4 adult, healthy subjects was scored by a sleep medicine expert. Features were calculated from each of the six EEG bands (low delta, high delta, theta, alpha, sigma and beta), and three additional characteristics were computed: the Hjorth activity in the low delta and high delta bands, and the differential variance of the raw EEG signal. The correlation between couples of features was analyzed to find redundancies for the automatic analysis. The features were used to train an Artificial Neural Network to automatically find the A phases of CAP. The data were divided into training, validation and testing set, and the visual scoring provided by the clinician was used as the desired output. The statistics on the second by second classification show an average sensitivity equal to 76%, specificity equal to 83% and accuracy equal to 82%. The results obtained are encouraging, since an automatic classification of the A phases could benefit the practice in clinics, preventing the physician from the time-consuming activity of visually scoring the sleep microstructure over the whole eight-hour sleep recordings. Moreover, it would provide an objective criterion capable of overcoming the problems of inter-scorer variability.
Oliviero Bruni, Luana Novelli, Silvia Miano, Liborio Parrino, Mario Giovanni Terzano, Raffaele Ferri (2010)  Cyclic alternating pattern: A window into pediatric sleep.   Sleep Med 11: 7. 628-636 Aug  
Abstract: Cyclic alternating pattern (CAP) has now been studied in different age groups of normal infants and children, and it is clear that it shows dramatic changes with age. In this review we first focus on the important age-related changes of CAP from birth to peripubertal age and, subsequently, we describe the numerous studies on CAP in developmental clinical conditions such as pediatric sleep disordered breathing, disorders of arousal (sleep walking and sleep terror), pediatric narcolepsy, learning disabilities with mental retardation (fragile-X syndrome, Down syndrome, autistic spectrum disorder, Prader-Willi syndrome) or without (dyslexia, Asperger syndrome, attention-deficit/hyperactivity disorder). CAP rate is almost always decreased in these conditions with the exception of the disorders of arousal and some cases of sleep apnea. Another constant result is the reduction of A1 subtypes, probably in relationship with the degree of cognitive impairment. The analysis of CAP in pediatric sleep allows a better understanding of the underlying neurophysiological mechanisms of sleep disturbance. CAP can be considered as a window into pediatric sleep, allowing a new vision on how the sleeping brain is influenced by a specific pathology or how sleep protecting mechanisms try to counteract internal or external disturbing events.
I Chouvarda, V Rosso, M O Mendez, A M Bianchi, L Parrino, A Grassi, M Terzano, S Cerutti, N Maglaveras (2010)  EEG complexity during sleep: on the effect of micro and macro sleep structure.   Conf Proc IEEE Eng Med Biol Soc 2010: 5959-5962  
Abstract: This work investigates the relation between EEG complexity measures, in particular Fractal Dimension and Sample Entropy, and sleep structure, in terms of both macrostructure, i.e. sleep stages, and microstructure, i.e. phase A activation of CAP sleep. Activation phases are compared with the non-activation periods of non-REM sleep. The study suggests that complexity features can serve as consistent descriptors of sleep dynamics and can potentially assist in the classification of sleep stages.
I Chouvarda, V Rosso, M O Mendez, A M Bianchi, L Parrino, A Grassi, M Terzano, S Cerutti (2010)  Assessment of the EEG complexity during activations from sleep.   Comput Methods Programs Biomed Dec  
Abstract: The present study quantitatively analyzes the EEG characteristics during activations (Act) that occur during NREM sleep, and constitute elements of sleep microstructure (i.e. the Cyclic Alternating Pattern). The fractal dimension (FD) and the sample entropy (SampEn) measures were used to study the different sleep stages and the Act that build up the sleep structure. Polysomnographic recordings from 10 good sleepers were analyzed. The complexity indexes of the Act were compared with the non-activation (NAct) periods during non-REM sleep. In addition, complexity measures among the different Act subtypes (A1, A2 and A3) were analyzed. A3 presented a quite similar complexity independently of the sleep stage, while A1 and A2 showed higher complexity in light sleep than during deep sleep. The current results suggest that Act present a hierarchic complexity between subtypes A3 (higher), A2 (intermediate) and A1 (lower) in all sleep stages.
Maria Clotilde Carra, Guido M Macaluso, Pierre H Rompré, Nelly Huynh, Liborio Parrino, Mario Giovanni Terzano, Gilles J Lavigne (2010)  Clonidine has a paradoxical effect on cyclic arousal and sleep bruxism during NREM sleep.   Sleep 33: 12. 1711-1716 Dec  
Abstract: Clonidine disrupts the NREM/REM sleep cycle and reduces the incidence of rhythmic masticatory muscle activity (RMMA) characteristic of sleep bruxism (SB). RMMA/SB is associated with brief and transient sleep arousals. This study investigates the effect of clonidine on the cyclic alternating pattern (CAP) in order to explore the role of cyclic arousal fluctuation in RMMA/SB.
Liborio Parrino, Raffaele Ferri, Marco Zucconi, Francesco Fanfulla (2009)  Commentary from the Italian Association of Sleep Medicine on the AASM manual for the scoring of sleep and associated events: for debate and discussion.   Sleep Med 10: 7. 799-808 Aug  
Abstract: In 2007, the American Academy of Sleep Medicine (AASM) completed a new manual for the scoring of sleep and associated events. The AASM manual is divided into separate sections relative to the parameters reported for polysomnography. The present commentary, accomplished by a Task Force of the Italian Association of Sleep Medicine, focuses on sleep scoring data, arousal rules, movement and respiratory events. Comparisons with the previous Rechtschaffen and Kales system are detailed and a number of methodological weaknesses are pointed out. Major comments address the 30-s scoring epochs, the restrictive approach to arousals and EEG activating patterns, the incomplete quantification of motor events and the thresholds for the definition of hypopnea. Since the new AASM manual is an iterative process, proposals for discussion and re-examination of the agreed criteria with other national and international organizations are encouraged.
Liborio Parrino, Giulia Milioli, Fernando De Paolis, Andrea Grassi, Mario Giovanni Terzano (2009)  Paradoxical insomnia: the role of CAP and arousals in sleep misperception.   Sleep Med 10: 10. 1139-1145 Dec  
Abstract: The relationship between CAP parameters and subjective time perception during sleep in primary insomnia was investigated.
Liborio Parrino, Arianna Smerieri, Francesca Giglia, Giulia Milioli, Fernando De Paolis, Mario Giovanni Terzano (2008)  Polysomnographic study of intermittent zolpidem treatment in primary sleep maintenance insomnia.   Clin Neuropharmacol 31: 1. 40-50 Jan/Feb  
Abstract: Treatment of chronic insomnia with nightly hypnotics is efficacious, but discontinuation is recommended after 1 month, less than the average disease duration. This study was undertaken to determine the efficacy of intermittent administration.
M Ozone, T Yagi, H Itoh, Y Tamura, Y Inoue, N Uchimura, M Sasaki, T Shimizu, M G Terzano, L Parrino (2008)  Effects of zolpidem on cyclic alternating pattern, an objective marker of sleep instability, in Japanese patients with psychophysiological insomnia: a randomized crossover comparative study with placebo.   Pharmacopsychiatry 41: 3. 106-114 May  
Abstract: A placebo-controlled randomized crossover study to investigate the effects of zolpidem on sleep stability in Japanese insomniac patients was performed using the cyclic alternating pattern (CAP) rate, a polysomnographic marker that reflects sleep instability.
Arianna Smerieri, Liborio Parrino, Matteo Agosti, Raffaele Ferri, Mario Giovanni Terzano (2007)  Cyclic alternating pattern sequences and non-cyclic alternating pattern periods in human sleep.   Clin Neurophysiol 118: 10. 2305-2313 Oct  
Abstract: The CAP cycle is a module of activation (phase A) and inhibition (phase B) which repeats itself in sequences. The study aims at testing the hypothesis that the duration of CAP sequences is determined primarily by the number and not by the length of CAP cycles.
Mario Giovanni Terzano, Arianna Smerieri, Alessandra Del Felice, Francesca Giglia, Vincenzo Palomba, Liborio Parrino (2006)  Cyclic alternating pattern (CAP) alterations in narcolepsy.   Sleep Med 7: 8. 619-626 Dec  
Abstract: Narcolepsy is a sleep disorder with clinical symptoms attributed to a reduced activation of the arousal system. Cyclic alternating pattern (CAP) is the expression of rhythmic arousability during non-rapid eye movement (NREM) sleep. CAP parameters, arousals and conventional sleep measures were studied in narcoleptic patients with cataplexy.
Lino Nobili, Ivana Sartori, Michele Terzaghi, Francione Stefano, Roberto Mai, Laura Tassi, Liborio Parrino, Massimo Cossu, Giorgio Lo Russo (2006)  Relationship of epileptic discharges to arousal instability and periodic leg movements in a case of nocturnal frontal lobe epilepsy: a stereo-EEG study.   Sleep 29: 5. 701-704 May  
Abstract: We describe the case of a patient with nocturnal frontal lobe epilepsy, presenting with periodic leg movements during sleep and complaining of excessive daytime sleepiness. With the support of intracerebral electroencephalogram recordings and the corroboration of the postoperative outcome, periodic leg movements during sleep and excessive daytime sleepiness appeared to be associated to enhanced arousal instability induced by by recurrent epileptic discharges not detectable on scalp electroencephalogram.
Mario Giovanni Terzano, Fabio Cirignotta, Susanna Mondini, Luigi Ferini-Strambi, Liborio Parrino (2006)  Studio Morfeo 2: survey on the management of insomnia by Italian general practitioners.   Sleep Med 7: 8. 599-606 Dec  
Abstract: To carry out an observational epidemiological survey (Studio Morfeo 2) in order to define the management procedures of insomnia in a large Italian population presenting directly to the general practitioner (GP).
Liborio Parrino, Peter Halasz, Carlo Alberto Tassinari, Mario Giovanni Terzano (2006)  CAP, epilepsy and motor events during sleep: the unifying role of arousal.   Sleep Med Rev 10: 4. 267-285 Aug  
Abstract: Arousal systems play a topical neurophysiologic role in protecting and tailoring sleep duration and depth. When they appear in NREM sleep, arousal responses are not limited to a single EEG pattern but are part of a continuous spectrum of EEG modifications ranging from high-voltage slow rhythms to low amplitude fast activities. The hierarchic features of arousal responses are reflected in the phase A subtypes of CAP (cyclic alternating pattern) including both slow arousals (dominated by the <1Hz oscillation) and fast arousals (ASDA arousals). CAP is an infraslow oscillation with a periodicity of 20-40s that participates in the dynamic organization of sleep and in the activation of motor events. Physiologic, paraphysiologic and pathologic motor activities during NREM sleep are always associated with a stereotyped arousal pattern characterized by an initial increase in EEG delta power and heart rate, followed by a progressive activation of faster EEG frequencies. These findings suggest that motor patterns are already written in the brain codes (central pattern generators) embraced with an automatic sequence of EEG-vegetative events, but require a certain degree of activation (arousal) to become visibly apparent. Arousal can appear either spontaneously or be elicited by internal (epileptic burst) or external (noise, respiratory disturbance) stimuli. Whether the outcome is a physiologic movement, a muscle jerk or a major epileptic attack will depend on a number of ongoing factors (sleep stage, delta power, neuro-motor network) but all events share the common trait of arousal-activated phenomena.
Liborio Parrino, Robert J Thomas, Arianna Smerieri, Maria Cristina Spaggiari, Alessandra Del Felice, Mario Giovanni Terzano (2005)  Reorganization of sleep patterns in severe OSAS under prolonged CPAP treatment.   Clin Neurophysiol 116: 9. 2228-2239 Sep  
Abstract: To evaluate the immediate and long-term recovery processes of sleep and daytime vigilance in patients with sleep apnea syndrome (OSAS) after continuous CPAP treatment.
Mario Giovanni Terzano, Liborio Parrino, Enrica Bonanni, Fabio Cirignotta, Franco Ferrillo, Gian Luigi Gigli, Mariantonietta Savarese, Luigi Ferini-Strambi (2005)  Insomnia in general practice : a consensus report produced by sleep specialists and primary-care physicians in Italy.   Clin Drug Investig 25: 12. 745-764  
Abstract: Insomnia is an extremely common condition with major social and economic consequences worldwide. Two large epidemiological studies (Morfeo 1 and Morfeo 2) recently performed in Italy provided much-needed novel data on the impact of insomnia in patients whose primary healthcare is provided by general practitioners (GPs). These studies found that insomnia is managed relatively well by GPs in Italy, although diagnosis and treatment can be compromised because of the lack of standardised criteria. Although a number of consensus reports on insomnia have been published, these are mainly highly specific documents that are difficult to implement in general practice. To address this, a consensus group involving 695 GPs and over 60 specialists from the Italian Association of Sleep Medicine was established. The major objectives of the consensus study were to establish basic knowledge for the diagnosis and treatment of insomnia, and to produce guidelines for the management of insomnia by GPs. This is the first time that GPs have been directly involved in producing insomnia guidelines of this type, and this approach reflects their pivotal role in the diagnosis and management of this condition. Participants were carefully selected to ensure adequate representation of sleep specialists and GPs, with the group being headed by a steering committee and an advisory board. Guideline statements were selected following careful literature review and were voted on using formalised consensus procedures. This review describes current views on the diagnosis and management of insomnia from the perspective of the GP. In addition, the results of the consensus study are presented. They include recognition of the following principles: (i) insomnia is a genuine pathology that must be appropriately diagnosed and treated; (ii) when concomitant pathologies are present, additional significance should be given to treatment of insomnia since it can influence prognosis of coexistent disorders; (iii) appropriate treatment should consider the cause of insomnia as well as the characteristics of available pharmacological agents; (iv) with regard to hypnotic drugs, preference should be given to medications with a short half-life in order to limit residual effects; (v) non-benzodiazepine hypnotics are preferred to classic benzodiazepines as they have higher selectivity and present a lower risk of undesirable effects; (vi) tablets are preferable to liquid preparations as they are less likely to lead to dependence and to overdosing by the patient; and (vi) once treatment has been initiated, insomnia patients should be carefully followed up. These statements provide much needed criteria for better management of insomnia by GPs in Italy.
Mario Giovanni Terzano, Liborio Parrino, Arianna Smerieri, Fabrizio Carli, Lino Nobili, Stefania Donadio, Franco Ferrillo (2005)  CAP and arousals are involved in the homeostatic and ultradian sleep processes.   J Sleep Res 14: 4. 359-368 Dec  
Abstract: There is growing evidence that cyclic alternating pattern (CAP) and arousals are woven into the basic mechanisms of sleep regulation. In the present study, the overnight sleep cycles (SC) of 20 normal subjects were analyzed according to their stage composition, CAP rate, phase A subtypes and arousals. Individual SC were then divided into 10 normalized temporal epochs. CAP parameters and arousals were measured in each epoch and averaged in relation to the SC order. Subtypes A2 and A3 of CAP in non-rapid eye movement (NREM) sleep, and arousals, both in REM and NREM sleep when not coincident with a A2 or A3 phases, were lumped together as fast electroencephalographic (EEG) activities (FA). Subtypes A1 of CAP, characterized by slow EEG activities (SA), were analyzed separately. The time distribution of SA and FA was compared to the mathematical model of normal sleep structure including functions representing the homeostatic process S, the circadian process C, the ultradian process generating NREM/REM cycles and the slow wave activity (SWA) resulting from the interaction between homeostatic and ultradian processes. The relationship between SA and FA and the sleep-model components was evaluated by multiple regression analysis in which SA and FA were considered as dependent variables while the covariates were the process S, process C, SWA, REM-on and REM-off activities and their squared values. Regression was highly significant (P < 0.0001) for both SA and FA. SA were prevalent in the first three SC, and exhibited single or multiple peaks immediately before and in the final part of deep sleep (stages 3 + 4). The peaks of FA were delayed and prevailed during the pre-REM periods of light sleep (stages 1 + 2) and during REM sleep. SA showed an exponential decline across the successive SC, according to the homeostatic process. In contrast, the distribution of FA was not influenced by the order of SC, with periodic peaks of FA occurring before the onset of REM sleep, in accordance with the REM-on switch. The dynamics of CAP and arousals during sleep can be viewed as an intermediate level between cellular activities and macroscale EEG phenomena as they reflect the decay of the homeostatic process and the interaction between REM-off and REM-on mechanisms while are slightly influenced by circadian rhythm.
Robert J Thomas, Mario G Terzano, Liborio Parrino, J Woodrow Weiss (2004)  Obstructive sleep-disordered breathing with a dominant cyclic alternating pattern--a recognizable polysomnographic variant with practical clinical implications.   Sleep 27: 2. 229-234 Mar  
Abstract: To define the clinical and polysomnographic features of a distinct variant of obstructive sleep-disordered breathing that is remarkably mild during rapid eye movement (REM) sleep.
Mario Giovanni Terzano, Liborio Parrino, Fabio Cirignotta, Luigi Ferini-Strambi, Gianluigi Gigli, Giuseppa Rudelli, Sergio Sommacal (2004)  Studio Morfeo: insomnia in primary care, a survey conducted on the Italian population.   Sleep Med 5: 1. 67-75 Jan  
Abstract: To carry out an observational epidemiological survey (Studio Morfeo), to determine: (1) the frequency of insomnia in a large Italian population presenting directly to the general physician (GP); (2) the impact of insomnia on the quality of life, on the use of health-care resources and on co-morbidity.
Liborio Parrino, Franco Ferrillo, Arianna Smerieri, Maria Cristina Spaggiari, Vincenzo Palomba, Mariano Rossi, Mario Giovanni Terzano (2004)  Is insomnia a neurophysiological disorder? The role of sleep EEG microstructure.   Brain Res Bull 63: 5. 377-383 Jun  
Abstract: Unlike other sleep disorders, such as sleep-related breathing disorders and periodic limb movement (PLM), the nature and severity of which are quantified by specific respiratory and motor indexes, no apparent organ dysfunction underlies several cases of insomnia (in particular primary insomnia), which can be objectively diagnosed only through the structural alterations of sleep. Polysomnography (PSG) investigation indicates that insomnia is the outcome of a neurophysiological disturbance that impairs the regulatory mechanisms of sleep control, including sleep duration, intensity, continuity and stability. In particular, analysis of sleep microstructure has permitted to establish that etiologic factors of different nature (including depressive disorders) exert a common destabilizing action on sleep, which is reflected in an increase of cyclic alternating pattern (CAP) rate. These premises allow us to attribute a more objective identity to insomnia, which risks otherwise to be considered as an unexplainable mental complaint. In conclusion, PSG remains the "gold standard" for measuring sleep, and especially insomnia.
Péter Halász, Mario Terzano, Liborio Parrino, Róbert Bódizs (2004)  The nature of arousal in sleep.   J Sleep Res 13: 1. 1-23 Mar  
Abstract: 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.
Fabrizio De Carli, Lino Nobili, Manolo Beelke, Tsuyoshi Watanabe, Arianna Smerieri, Liborio Parrino, Mario Giovanni Terzano, Franco Ferrillo (2004)  Quantitative analysis of sleep EEG microstructure in the time-frequency domain.   Brain Res Bull 63: 5. 399-405 Jun  
Abstract: A number of phasic events influence sleep quality and sleep macrostructure. The detection of arousals and the analysis of cyclic alternating patterns (CAP) support the evaluation of sleep fragmentation and instability. Sixteen polygraphic overnight recordings were visually inspected for conventional Rechtscaffen and Kales scoring, while arousals were detected following the criteria of the American Sleep Disorders Association (ASDA). Three electroencephalograph (EEG) segments were associated to each event, corresponding to background activity, pre-arousal period and arousal. The study was supplemented by the analysis of time-frequency distribution of EEG within each subtype of phase A in the CAP. The arousals were characterized by the increase of alpha and beta power with regard to background. Within NREM sleep most of the arousals were preceded by a transient increase of delta power. The time-frequency evolution of the phase A of the CAP sequence showed a strong prevalence of delta activity during the whole A1, but high amplitude delta waves were found also in the first 2/3 s of A2 and A3, followed by desynchronization. Our results underline the strict relationship between the ASDA arousals, and the subtype A2 and A3 within the CAP: in both the association between a short sequence of transient slow waves and the successive increase of frequency and decrease of amplitude characterizes the arousal response.
Umberto Barcaro, Enrica Bonanni, Michelangelo Maestri, Luigi Murri, Liborio Parrino, Mario Giovanni Terzano (2004)  A general automatic method for the analysis of NREM sleep microstructure.   Sleep Med 5: 6. 567-576 Nov  
Abstract: To define a unified method for the automatic recognition and quantitative description of EEG phasic events of sleep microstructure occurring during NREM sleep, particularly arousals, phase A subtypes of cyclic alternating pattern and spindles.
Raffaele Manni, Michele Terzaghi, Ivana Sartori, Pierangelo Veggiotti, Liborio Parrino (2004)  Rhythmic movement disorder and cyclic alternating pattern during sleep: a video-polysomnographic study in a 9-year-old boy.   Mov Disord 19: 10. 1186-1190 Oct  
Abstract: We report on polysomnographic findings in a 9-year-old boy affected by rhythmic movement disorder. The subject's rhythmic movements were found to be intimately linked to unstable nonrapid eye movement N-REM sleep, as shown by their close association with the A phases of the cyclic alternating pattern. We examine the complex interactions between arousal mechanisms and rhythmic movements occurring during sleep.
Mario Giovanni Terzano, Mariano Rossi, Vincenzo Palomba, Arianna Smerieri, Liborio Parrino (2003)  New drugs for insomnia: comparative tolerability of zopiclone, zolpidem and zaleplon.   Drug Saf 26: 4. 261-282  
Abstract: 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 omega(1) and omega(2), which are located in different areas of the CNS. The sedative action of benzodiazepines is related to omega(1) receptors, whereas omega(2) 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 omega(1) receptors (sedative effect), whereas benzodiazepines also interact with omega(2) 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.
G Hajak, R Cluydts, H Allain, E Estivill, L Parrino, M G Terzano, J K Walsh (2003)  The challenge of chronic insomnia: is non-nightly hypnotic treatment a feasible alternative?   Eur Psychiatry 18: 5. 201-208 Aug  
Abstract: The adverse effects of insomnia on health and quality of life are matters receiving increasing attention. Yet, surveys have consistently shown that most people suffering from insomnia do not seek medical help, perhaps, in part, because of a concern of becoming dependent on hypnotic medication. The treatment of chronic insomnia poses a particular dilemma in that continuous hypnotic treatment is restricted in many countries to a maximum of 4 weeks, and behavioural treatment is not readily available. Non-nightly hypnotic treatment of chronic insomnia offers a promising alternative option for the many patients whose symptoms do not necessitate nightly drug intake, allaying fears of psychological dependence on medication and respecting regulatory constraints on hypnotic use while providing patients with adequate symptom relief. The practical feasibility and efficacy of this approach has been demonstrated with zolpidem using various treatment regimens and study designs. So far, six clinical trials have been completed on over 4000 patients. Published results show effective treatment of insomnia without any evidence of either adverse event associated with a discontinuous regimen or increased hypnotic use over the treatment period.
Mario Giovanni Terzano, Liborio Parrino, Maria Cristina Spaggiari, Vincenzo Palomba, Mariano Rossi, Arianna Smerieri (2003)  CAP variables and arousals as sleep electroencephalogram markers for primary insomnia.   Clin Neurophysiol 114: 9. 1715-1723 Sep  
Abstract: Polysomnographic (PSG) measures consistently reflect poor sleep quality and effective treatment in insomniac patients.
P Halász, M G Terzano, L Parrino (2002)  Spike-wave discharge and the microstructure of sleep-wake continuum in idiopathic generalised epilepsy.   Neurophysiol Clin 32: 1. 38-53 Jan  
Abstract: This review summarises all the evidences about the influence of different vigilance states on the occurrence of spike wave discharge (SWD) in idiopathic generalised epilepsy (IGE) patients. Numerous converging observations showed that full REM-sleep and alert wakefulness exert strong inhibition. A critical zone of vigilance which is a transitional state between waking and non-REM (NREM) sleep, and NREM sleep and REM sleep, has a promoting effect on the absence type spike wave discharge. Spike wave discharges are associated with phasic arousals without awakening and are attached to oscillation son the microstructural level of sleep, perpetuated by cyclic arousal events known as 'cyclic alternating pattern' (CAP), especially within the critical zone, but also along the whole sleep process. More specifically SWD seems to be attached to the 'A-phase' of CAP which is a reactive one and reflects synchronised NREM sleep EEG elements, like K-complexes, spindles and delta groups. The more slow wave elements are found in phase A--like in subtype A1--the more the coincidence with SWD occurs, and the more it is characterised by fast rhythms--as in subtype A2 and A3--the less the association with SWD could be observed. Since subtype A1 is associated with the first sleep cycle and with the descending branches of cycles, it is concluded that SWD appear in those dynamic moments of vigilance level oscillations which were characterised by strong sleep-like answers to arousal influences in high sleep pressure periods of sleep cyclicity. These data harmonize with another line of evidence suggesting that SWD represent the epileptic variant of the complex thalamocortical system function which is the substrate of NREM sleep EEG phenomena. In idiopathic generalised epilepsy there is a growing body of evidence that--as it was assumed by Gloor--spindles transform to SWD pattern. These data explain why those dynamic changes which evoke sleep responses are promoting for the occurrence of SWD. Adapting these data we offer a new interpretation to explain the strong activation effect of sleep deprivation in this kind of epilepsy. We assume that it is mainly due to the forced vigilance level oscillations, especially in morning, when elevated sleep pressure and circadian wake promoting forces, representing opposite tendencies, increase the amount of oscillations.
Raffaele Ferri, Liborio Parrino, Arianna Smerieri, Mario G Terzano, Maurizio Elia, Sebastiano A Musumeci, Salvatore Pettinato, Cornelis J Stam (2002)  Non-linear EEG measures during sleep: effects of the different sleep stages and cyclic alternating pattern.   Int J Psychophysiol 43: 3. 273-286 Mar  
Abstract: The objective of this work was to study the non-linear aspects of sleep EEG, taking into account the different sleep stages and the peculiar organization of its phasic events in ordered sequences (CAP) by applying a series of new non-linear measures (non-linear cross prediction or NLCP), which appear more reliable for the detection and characterization of non-linear structures in experimental data than the commonly used correlation dimension. Eight healthy subjects aged 18-20 years participated in this study. Polysomnography was performed in all subjects; signals were sampled at 128 Hz and stored on hard disk. The C3 or C4 derivation was used for all the subsequent computational steps, which were performed on EEG epochs (4096 data points) selected from sleep stage 2 (S2) and slow-wave sleep (SWS), in both CAP and non-CAP (NCAP) conditions. Also, epochs from sleep stage 1 (S1), REM and wakefulness preceding sleep were recorded. The dynamic properties of the EEG were assessed by means of the non-linear cross-prediction test, which uses three different 'model' time series in order to predict non-linearly the original data set (Pred, Ama, and Tir). Pred is a measure of the predictability of the time series, and Ama and Tir are measures of asymmetry, indicating non-linear structure. The non-linear measures applied in this study indicate that sleep EEG tends to show non-linear structure only during CAP periods, both during S2 and SWS. Moreover, during CAP periods, non-linearity can only be detected during the phase A1 subtypes (and partially A2) of CAP. The A3 phases show characteristics of non-stationarity and bear some resemblance to wakefulness. Based on the results of this study, sleep might be considered as a dynamically evolving sequence of different states of the EEG, which we could track by detecting non-linearity, mostly in association with CAP. Our results clearly show that detectable non-linearity in the EEG is closely related to the occurrence of the phase A of CAP.
Mario Giovanni Terzano, Liborio Parrino, Agostino Rosa, Vincenzo Palomba, Arianna Smerieri (2002)  CAP and arousals in the structural development of sleep: an integrative perspective.   Sleep Med 3: 3. 221-229 May  
Abstract: It is known that the number of arousals per hour of sleep increases linearly across life, while the amount of cyclic alternating pattern (CAP) undergoes a u-shaped evolution. The present study aimed at investigating the differences, overlaps and age-related distribution of arousals and CAP components, i.e. subtypes A1, A2, A3. The relationship between the phase A subtypes and the structural organization of sleep was also evaluated.
L Parrino, A Smerieri, M G Terzano (2001)  Combined influence of cyclic arousability and EEG synchrony on generalized interictal discharges within the sleep cycle.   Epilepsy Res 44: 1. 7-18 Apr  
Abstract: to analyze the activating role of cyclic alternating pattern (CAP) and EEG synchrony on generalized interictal paroxysms in the first part of the night, when all sleep patterns are represented.
I Eisensehr, L Parrino, S Noachtar, A Smerieri, M G Terzano (2001)  Sleep in Lennox-Gastaut syndrome: the role of the cyclic alternating pattern (CAP) in the gate control of clinical seizures and generalized polyspikes.   Epilepsy Res 46: 3. 241-250 Sep  
Abstract: Non-rapid eye movement (NREM) sleep contains periods of arousal instability (cyclic alternating pattern or CAP) and periods of arousal stability (non-CAP). During CAP, arousal oscillates between higher (phase A) and lower (phase B) levels of activation. We evaluated the relationship between CAP and the occurrence of epileptic events, i.e. clinical seizures and generalized interictal discharges, during sleep in 10 patients with Lennox-Gastaut syndrome (LGS). The macro- and microstructure of sleep of 10 attended overnight polysomnograms were analyzed. Compared with 10 age- and gender-matched controls, patients with LGS had significantly less stage 2 and REM sleep and higher amounts of CAP rate (68% vs. 33%; P<0.0001). The number of generalized polyspike bursts per hour of sleep was highest in slow wave sleep (226.5+/-57.6) and lowest in REM sleep (3.9+/-1.5). The polyspike burst frequency was significantly greater (P<0.017) during CAP (213.2+/-60.1) than during non-CAP (100.3+/-40), and within CAP, generalized polyspikes occurred more often (P=0.005) during phase A (461.1+/-127.2) than during phase B (6.1+/-1.9). The total amount of generalized polyspike bursts identified in NREM sleep correlated positively both with the number of A phases containing at least one generalized polyspike (P=0.005) and with the mean number of polyspikes within each of these A phases (P<0.0001). Nocturnal clinical seizures occurred in 8 of the 10 patients and showed a similar trend. We conclude from our results that CAP modulates the occurrence of both clinical seizures and generalized epileptic discharges in LGS by means of a gate-control mechanism: an independent spike generator is inhibited in phase B and non-CAP and bursts with its intrinsic activity in phase A.
L Parrino, A Smerieri, M Rossi, M G Terzano (2001)  Relationship of slow and rapid EEG components of CAP to ASDA arousals in normal sleep.   Sleep 24: 8. 881-885 Dec  
Abstract: Besides arousals (according to the ASDA definition), sleep contains also K-complexes and delta bursts which, in spite of their sleep-like features, are endowed with activating effects on autonomic functions. The link between phasic delta activities and enhancement of vegetative functions indicates the possibility of physiological activation without sleep disruption (i.e., arousal without awakening). A functional connection seems to include slow (K-complexes and delta bursts) and rapid (arousals) EEG events within the comprehensive term of activating complexes. CAP (cyclic alternating pattern) is the spontaneous EEG rhythm that ties both slow and rapid activating complexes together during NREM sleep. The present study aims at exploring the relationship between arousals and CAP components in a selected sample of healthy sleepers.
M G Terzano, L Parrino, A Smerieri (2001)  [Neurophysiological basis of insomnia: role of cyclic alternating patterns].   Rev Neurol (Paris) 157: 11 Pt 2. S62-S66 Nov  
Abstract: During non-REM (NREM) sleep it is possible to identify two complementary conditions of arousal stability and arousal instability. Unstable sleep, which can be detected in all stages, is expressed by the recurrence of arousal complexes (sequences of K-complexes, delta bursts, K-alpha, conventional arousals), which translate a brief (10-15 s) activation of the sleeping brain. These repetitive arousal complexes compose the cyclic alternating pattern (CAP). During stable NREM sleep, arousal complexes are rare or absent and the EEG lacks any cyclic pattern (non-CAP). CAP is a spontaneous feature of normal sleep as it is typically involved in stage changes and nocturnal motor activity. The physiological amount of CAP rate (ratio of CAP time to NREM sleep time) varies with age according to a U-shape curve. Within these ranges, sleep is perceived as continuous and restorative. Conversely, an excess of CAP rate fragments sleep and impairs its quality. Polysomnographic investigation reveals that untreated insomniac patients exhibit significantly higher values of CAP rate compared to healthy sleepers. Effective hypnotic treatment restores physiological amounts of CAP rate, with specific differences between the administered drugs. The sensitivity of CAP parameters to drug manipulation can provide circumscribed information on the hypnotic properties of active compounds.
R Ferri, L Parrino, A Smerieri, M G Terzano, M Elia, S A Musumeci, S Pettinato (2000)  Cyclic alternating pattern and spectral analysis of heart rate variability during normal sleep.   J Sleep Res 9: 1. 13-18 Mar  
Abstract: The natural arousal rhythm of non-rapid eye movement (NREM) sleep is known as the cyclic alternating pattern (CAP), which consists of arousal-related phasic events (Phase A) that periodically interrupt the tonic theta/delta activities of NREM sleep (Phase B). The complementary condition, i.e. non-CAP (NCAP), consists of a rhythmic electroencephalogram background with few, randomly distributed arousal-related phasic events. Recently, some relation between CAP and autonomic function has been preliminarily reported during sleep in young adults by means of spectral analysis of heart rate variability (HRV). The present study was aimed at analysing the effects of CAP on HRV in a group of normal children and adolescents. Six normal children and adolescents (age range 10.0-17.5 y) were included in this study. All-night polygraphic recordings were performed after adaptation to the sleep laboratory. Six 5-min epochs were selected from sleep Stage 2 and six from Stages 3 and 4 (slow-wave sleep), both in CAP and NCAP conditions. From such epochs, a series of parameters describing HRV was then calculated, in both time and frequency domains, on the electrocardiographic R-R intervals. Statistical comparison between CAP and NCAP epochs revealed a significant difference for most of the frequency domain parameters (increase of the low-frequency band, increase of the low-frequency/high-frequency ratio and decrease in the high-frequency band during CAP) both in Stage 2 and in slow-wave sleep. Our results demonstrate that the physiological fluctuations of arousal during sleep described as CAP are accompanied by subtle, but significant, changes in balance between the sympathetic and vagal components of the autonomic system.
L Parrino, A Smerieri, M Boselli, M C Spaggiari, M G Terzano (2000)  Sleep reactivity during acute nasal CPAP in obstructive sleep apnea syndrome.   Neurology 54: 8. 1633-1640 Apr  
Abstract: 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.
M G Terzano, L Parrino, M Boselli, A Smerieri, M C Spaggiari (2000)  CAP components and EEG synchronization in the first 3 sleep cycles.   Clin Neurophysiol 111: 2. 283-290 Feb  
Abstract: 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.
L Parrino, A Smerieri, M C Spaggiari, M G Terzano (2000)  Cyclic alternating pattern (CAP) and epilepsy during sleep: how a physiological rhythm modulates a pathological event.   Clin Neurophysiol 111 Suppl 2: S39-S46 Sep  
Abstract: 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.
Mario Giovanni Terzano, Liborio Parrino (2000)  Origin and Significance of the Cyclic Alternating Pattern (CAP). REVIEW ARTICLE.   Sleep Med Rev 4: 1. 101-123 Feb  
Abstract: This article reviews the 15 years of studies conducted on the cyclic alternating pattern (CAP), the electro- encephalogram (EEG) marker of arousal instability during sleep. Starting from the limits and drawbacks of conventional sleep parameters (macrostructure), investigation of the underground world (microstructure) is extensively carried out with particular attention to K-complexes and other arousal-related phasic events of non-rapid eye movement (NREM) sleep. The continuity between conventional and non-conventional arousals is stressed in the light of autonomic function and motor activity evidence. The similarities and differences between CAP and arousals are thoroughly illustrated as well as the putative biological bases of these phenomena. The oscillatory nature of CAP, the involvement of CAP in the modulation of EEG synchrony, the sleep-maintenance properties of CAP in response to arousing stimuli, the clinical applications of CAP parameters and the promising availability of automatic scoring systems are highlighted.
A C Rosa, L Parrino, M G Terzano (1999)  Automatic detection of cyclic alternating pattern (CAP) sequences in sleep: preliminary results.   Clin Neurophysiol 110: 4. 585-592 Apr  
Abstract: The analysis of cyclic alternating pattern (CAP) provides important microstructural information on arousal instability and on EEG synchrony modulation in the sleep process. This work presents a methodology for automatic classification of the micro-organization of human sleep EEG, using the CAP paradigm.
G M Macaluso, P Guerra, G Di Giovanni, M Boselli, L Parrino, M G Terzano (1998)  Sleep bruxism is a disorder related to periodic arousals during sleep.   J Dent Res 77: 4. 565-573 Apr  
Abstract: 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.
L Parrino, M Boselli, M C Spaggiari, A Smerieri, M G Terzano (1998)  Cyclic alternating pattern (CAP) in normal sleep: polysomnographic parameters in different age groups.   Electroencephalogr Clin Neurophysiol 107: 6. 439-450 Dec  
Abstract: The present study aimed at offering a standardized database for cyclic alternating pattern (CAP) parameters across representative ages of life.
M Boselli, L Parrino, A Smerieri, M G Terzano (1998)  Effect of age on EEG arousals in normal sleep.   Sleep 21: 4. 351-357 Jun  
Abstract: EEG arousals were quantified in 40 nocturnal polysomnographic recordings belonging to four age groups (teenagers: 10 to 19 years; young adults: 20 to 39 years; middle-aged: 40 to 59 years; elderly: > or = 60 years). Ten subjects (five males and five females) participated in each group. The subjects were healthy and sound sleepers. All sleep recordings were preceded by an adaptation night which aimed at excluding the presence of sleep-related disorders. The recordings were carried out in a partially soundproof recording chamber and in a standard laboratory setting. Arousal indices (AI), defined as the number of arousals per hour of sleep, were calculated for total sleep time (AI/TST) and for all the sleep stages. AI/TST increased linearly with age (r = 0.852; p < 0.00001): teenagers (13.8), young adults (14.7), middle-aged (17.8), elderly (27.1). An age-related positive linear correlation was found also for the arousal indices referred to NREM sleep (r = 0.811; p < 0.00001) and to stages 1 and 2 (r = 0.712; p < 0.00001), while in stages 3 and 4 and in REM sleep, arousal indices showed stable values across the ages. Overall, arousals lasted 14.9 +/- 2.3 seconds, with arousal duration stable across the ages (range of means: 13.3-16.6 seconds) and no relevant differences between NREM sleep (14.6 +/- 2.5 seconds) and REM sleep (16.2 +/- 5 seconds). The paper discusses the impact of age on arousals, the similarities between arousals and the phases d'activation transitoire, and the consideration that arousals are physiological components of sleep.
R Priest, M Terzano, L Parrino, P Boyer (1997)  Efficacy of zolpidem in insomnia.   Eur Psychiatry 12 Suppl 1: 5-14  
Abstract: The efficacy of zolpidem, a non benzodiazepine hypnotic agent with a short elimination half life, was reviewed, analysing more than 50 international clinical trials published since 1986. The hypnotic activity of zolpidem has been explored in different patient populations including normal volunteers, general practice outpatients and psychiatric out- or in-patients with varying sleep disorders; both transient and chronic. Assessment methods used have included objective and subjective measures of hypnotic efficacy for different treatment durations, with results confirming that 10 mg is superior to placebo. Zolpidem was shown to be superior in most trials on sleep parameters such as total sleep time, sleep onset latency and nocturnal awakenings, but total REM sleep and REM latency were usually unmodified. Zolpidem maintained normal sleep physiology as demonstrated by the preservation of slow wave stages and no, or minimal, effects on sleep architecture after abrupt discontinuation. Consequently, 10 mg is the recommended dose for the short-term treatment of insomnia in the non-elderly; in elderly patients 5 mg has been shown to be effective at inducing sleep whilst giving an optimum safety profile.
F Ferrillo, M Gabarra, L Nobili, L Parrino, G Schiavi, B Stubinski, M G Terzano (1997)  Comparison between visual scoring of cyclic alternating pattern (CAP) and computerized assessment of slow EEG oscillations in the transition from light to deep non-REM sleep.   J Clin Neurophysiol 14: 3. 210-216 May  
Abstract: Ten healthy volunteers (six men and four women) aged between 20 and 30 years underwent a nocturnal polygraphic recording on paper and on tape. Spectral analysis was accomplished and EEG sleep scored according to standard criteria and to the guidelines for the identification of cyclic alternating pattern (CAP). The initial 25 min of sleep, starting from the first clear-cut k-complex and ending within stage 4, was subdivided into five consecutive blocks of 5 min each. Using a zero-crossing technique, we evaluated the number of total power oscillations in each block and we tested the hypothesis of significant modifications of the number of total power oscillations and of their periodicity in the successive sessions. In addition, we measured the gap between the maximum and minimum values, respectively, of two successive half-waves making up each oscillation. The hypothesis of time-related trends of the values of the gaps was tested by means of linear regression techniques. Within the 25-min time span, the number of periodic oscillations and the number of CAP cycles showed significant increases. The amplitude gaps underwent a decreasing trend. The present data suggest that slow rhythmic oscillations expressed by CAP can be detected by means of spectral analysis. Their dynamics suggests a close relationship with the EEG synchronization processes.
M G Terzano, M F Monge-Strauss, F Mikol, M C Spaggiari, L Parrino (1997)  Cyclic alternating pattern as a provocative factor in nocturnal paroxysmal dystonia.   Epilepsia 38: 9. 1015-1025 Sep  
Abstract: 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.
L Parrino, M Boselli, M C Spaggiari, A Smerieri, M G Terzano (1997)  Multidrug comparison (lorazepam, triazolam, zolpidem, and zopiclone) in situational insomnia: polysomnographic analysis by means of the cyclic alternating pattern.   Clin Neuropharmacol 20: 3. 253-263 Jun  
Abstract: 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.
M G Terzano, L Parrino, M Boselli, M C Spaggiari, G Di Giovanni, A Smerieri (1997)  Sensitivity of cyclic alternating pattern to prolonged pharmacotherapy: a 5-week study evaluating zolpidem in insomniac patients.   Clin Neuropharmacol 20: 5. 447-454 Oct  
Abstract: To test the effects of a hypnotic drug administered on a regular basis, six adults (four women and two men; mean age 37 years) who complained of transient or short-term insomnia, took zolpidem 10 mg at bedtime for 4 consecutive weeks. The period of active treatment, preceded by a baseline placebo night, ended with a 4-night gradual tapering phase followed by 3 nights of placebo administration. After adaptation to the sleep laboratory, all subjects underwent five polysomnographic recordings; baseline placebo (night 1); 1st, 7th and 28th nights of hypnotic medication (nights 2, 3, and 4 respectively); 3rd placebo night after complete tapering (night 5) and completed a morning visual analogue scale (VAS) for evaluating sleep quality. The sleep recordings were scored according to the conventional procedures (macrostructure) and to the cyclic alternating pattern (CAP) rules (microstructure). Data analysis was based on a repeated-measures analysis of variance integrated by post-hoc comparisons. At the macrostructural level, significant overall modifications (p < 0.035) emerged only from slow-wave sleep (SWS). The amounts of SWS were enhanced along the entire drug period, but a significant difference was found only between the baseline night (10%) and the first night of drug administration (20%). At the microstructural level, CAP rate (the ratio of CAP time to non-rapid eye movement sleep time) showed overall significant variations throughout the entire protocol period (p < 0.0001). Compared with baseline night 1 (59%), the CAP rate was significantly lower on drug nights 2 (32%), 3 (37%), and 4 (38%). The increase in the CAP rate found on night 5 (43%) was still significantly below the baseline value. The VAS scores showed significant overall changes (p < 0.0001), with improved values during the active treatment period.
M G Terzano, L Parrino, M Boselli, M C Spaggiari, G Di Giovanni (1996)  Polysomnographic analysis of arousal responses in obstructive sleep apnea syndrome by means of the cyclic alternating pattern.   J Clin Neurophysiol 13: 2. 145-155 Mar  
Abstract: 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 quality's expense.
L Parrino, M G Terzano (1996)  Polysomnographic effects of hypnotic drugs. A review.   Psychopharmacology (Berl) 126: 1. 1-16 Jul  
Abstract: This review aims at providing a critical assessment of the effects of the most widely used benzodiazepine (flurazepam, flunitrazepam, temazepam, triazolam) and non-benzodiazepine (zopiclone and zolpidem) hypnotic drugs, based on the recording of polysomnographic variables. In the light of newly acquired neurophysiological data on the microstructure of sleep, this paper reconsiders the problem of insomnia and the current ideas on polysomnography and hypnotic drugs.
L Parrino, M Boselli, G P Buccino, M C Spaggiari, G Di Giovanni, M G Terzano (1996)  The cyclic alternating pattern plays a gate-control on periodic limb movements during non-rapid eye movement sleep.   J Clin Neurophysiol 13: 4. 314-323 Jul  
Abstract: 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 Association's 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.
M G Terzano, L Parrino, M Boselli, S Dell'Orso, M Moroni, M C Spaggiari (1995)  Changes of cyclic alternating pattern (CAP) parameters in situational insomnia under brotizolam and triazolam.   Psychopharmacology (Berl) 120: 3. 237-243 Aug  
Abstract: The standardized scoring criteria of sleep can serve as a rough tool for monitoring the effects of psychoactive compounds, both in normal sleepers and in insomniac patients. More sensitive information on the impact of perturbing factors and drugs during sleep is supplied by the cyclic alternating pattern (CAP) parameters. In particular, CAP rate, which measures the amount of arousal instability during NREM sleep, has been proved of high reliability in a variety of clinical and pharmacological settings. The present study aimed at evaluating the activity of brotizolam (Br) 0.25 mg and triazolam (Tr) 0.25 mg on both conventional and CAP parameters in a model of situational insomnia of intermediate severity. Six middle-aged healthy subjects (three males and three females, aged 40-55 years) with no complaints about sleep, underwent a polysomnographic investigation according to a double-blind crossover design: placebo without noise (night 1), placebo with noise (night 2), brotizolam or triazolam without noise (nights 3 and 5), brotizolam or triazolam with noise (nights 4 and 6). The unperturbed nights consisted of standard recording conditions in a sound-protected sleep laboratory, whereas situational insomnia was accomplished by means of continuous white noise at 55 dBA delivered throughout the night. Subjects received medication orally at bedtime. An interval of at least 48 h was secured between consecutive recordings in the same individual. Compared to baseline conditions, situational insomnia was characterized by a shorter amount of total sleep (-40 min) and by an extension of intrasleep awakenings (+62 min).(ABSTRACT TRUNCATED AT 250 WORDS)
M G Terzano, L Parrino, V Pietrini, D Mancia, M C Spaggiari, G Rossi, F Tagliavini (1995)  Precocious loss of physiological sleep in a case of Creutzfeldt Jakob disease: a serial polygraphic study.   Sleep 18: 10. 849-858 Dec  
Abstract: Creutzfeldt-Jakob disease (CJD) is a prion-related subacute encephalopathy producing widespread neuronal degeneration and spongiform pathological changes, especially in the neocortex. Progressive dementia, motor signs and electroencephalographic (EEG) alterations characterize the full stage of the disease. A series of eight 24-hour polygraphic recordings were carried out in the last 3 months of life of a 68-year-old female patient affected by CJD that was confirmed neuropathologically. Genetic classification demonstrated this patient to have a sporadic form of the disease. The polygraphic recordings demonstrated three types of EEG findings, as follows: 1) sustained pseudoperiodic discharges (SPD), characterized by long-lasting diffuse sequences of slow sharp waves or di- or triphasic slow waves recurring at 0.5- to 1.5-second intervals; 2) discontinuous pseudoperiodic discharges (DPD), consisting of runs of pseudoperiodic discharges (PD)(phase A) cyclically replaced at about 1-minute intervals with semi-rhythmic theta-delta activities (phase B); 3) non-rapid eye movement (NREM) sleep-like pattern, with dominant 0.5- to 4-Hz activities, less rhythmic than the EEG of phase B. Only these three EEG patterns occurred spontaneously during the repeated polygraphic sessions. The NREM sleep-like pattern was found only in the first recording, whereas the following polygraphic sessions were occupied exclusively by SPD or by a DPD pattern. SPD was associated with either a relatively high level of vigilance (along the first three recordings) or a state of alert-appearing silent immobility (following the fourth recording). During DPD, the patient was unable to accomplish any voluntary movement and fluctuated between levels of greater arousal (phase A) and lesser arousal (phase B). Just as in stage 2 coma, the fluctuations between phases A and B of DPD were synchronous with phasic modifications of muscle activity and neurovegetative functions. In particular, reinforcement of muscle tone and myoclonic spasms coincided with phase A, whereas heart rate deceleration and respiratory pauses or decrease in flow were synchronous with phase B. As EEG evolved toward the disappearance of DPD and finally to flatness, the phase-locked coordination among arousal, somatic and vegetative activities was progressively impaired and was replaced with an uncontrolled exaggeration of cardiorespiratory activity. The genetic, neuropathological and polysomnographic differences between CJD and another prion disease, fatal familial insomnia, are discussed.
M C Spaggiari, F Granella, L Parrino, C Marchesi, I Melli, M G Terzano (1994)  Nocturnal eating syndrome in adults.   Sleep 17: 4. 339-344 Jun  
Abstract: Ten adult subjects were referred to our sleep disorders center complaining of difficulty in maintaining sleep due to frequent and recurrent awakenings to eat or drink. All patients manifested more than one episode per night, characterized by compulsive food seeking and a return to sleep only after adequate food intake. Food-seeking drive was described as an urgent abnormal need to swallow food and was associated with an absence of real hunger. Six subjects showed an elective nighttime intake of carbohydrates, and in all cases only edible substances were injected. The patients were always fully awake during the episodes and could clearly recall them in the morning. Polysomnographic investigation showed low levels of sleep efficiency, a high number of awakenings and a strict relation between nocturnal eating episodes and nonrapid eye movement (NREM) sleep. The average length of each episode was 3.5 minutes. The "eating latency", that is the interval between awakening and chewing start, was shorter than 30 seconds in 50% of the episodes. No medical, hormonal or neurological disorders were found during clinical and laboratory investigations. Body mass index was abnormally high in six patients. Anorexia nervosa and bulimia were carefully excluded. Various psychiatric disturbances were found in nine subjects, who were nevertheless well-functioning adults. Concurrent dyssomniac disorders, such as narcolepsy or periodic leg movements occasionally associated with restless legs syndrome, were diagnosed in five patients.(ABSTRACT TRUNCATED AT 250 WORDS)
L Parrino, M C Spaggiari, M Boselli, G Di Giovanni, M G Terzano (1994)  Clinical and polysomnographic effects of trazodone CR in chronic insomnia associated with dysthymia.   Psychopharmacology (Berl) 116: 4. 389-395 Dec  
Abstract: Six middle aged subjects complaining of chronic insomnia associated with dysthymia were investigated in a 2-month single blind study: a 7-day placebo treatment period, followed by a 6-week phase with increasing doses of trazodone controlled release (CR) formulation (50 mg through days 8-10; 75 mg through days 11-13; 150 mg through days 14-49) and then a final 7-day withdrawal period under placebo. Medication was always administered at bedtime. Five polysomnographic recordings were accomplished by each subject (sleep 1: under baseline placebo; sleep 2-3-4; under active treatment; sleep 5: after drug discontinuation). A "blind" EEG reader analysed the traditional polysomnographic variables (macrostructure of sleep) and the amount and percentage ratio (CAP rate) of cyclic alternating pattern (CAP), the microstructural parameter that measures the instability of arousal during sleep. Visual analogue scales (VAS) for the evaluation of subjective sleep quality and the Hamilton rating scale for depression (HAM-D) were regularly assessed across the study. Statistical analysis was based on an ANOVA test with repeated measures completed by means of Bonferroni adjusted probabilities. No significant differences emerged from the macrostructural parameters referred to sleep initiation and maintenance, while significant overall modifications emerged from stage 2 (P < 0.0005), slow wave sleep (P < 0.0001), total CAP time (P < 0.0001) and CAP rate (P < 0.0001). Compared to the placebo baseline night, a significant increase of slow wave sleep (+40 min) and significant reductions of stage 2 (-67 min), CAP time (-90 min) and CAP rate (-23%) were already found on day 4 of treatment (sleep 2).(ABSTRACT TRUNCATED AT 250 WORDS)
M G Terzano, L Parrino (1994)  Effect of hypnotic drugs on sleep architecture.   Pol J Pharmacol 46: 5. 487-490 Sep/Oct  
Abstract: It is widely accepted that the conventional polysomnographic parameters (macrostructure of sleep) supply only rough information for clinical purposes. In particular, they often appear inadequate to support a diagnosis of insomnia or the effectiveness of a hypnotic compound. In the past years, attention has been focused on the microstructure of sleep, and especially on the periodic distribution of arousal-related phasic events known as Cyclic Alternating Pattern (CAP). This microstructural rhythm is not only a physiological component of normal NREM sleep, but it also appears highly sensitive in the detection of disturbing factors and drug manipulation. Regardless of the specific context, CAP always translates a condition of arousal instability during sleep. Accordingly, the higher the amount of CAP, the poorer the subjective quality of sleep. In young adults, the physiological amount of CAP Rate (percentage ratio of CAP time to NREM sleep time) ranges around 25%, while CAP Rate rises to 55% when sleep is perturbed by continuous white noise (situational insomnia). The analysis of CAP Rate within this framework of situational insomnia is recommended for evaluating the effects of hypnotic drugs under controlled experimental conditions. Therapeutical doses of zolpidem preserve the regular course of sleep both at the macro- and at the microstructural level, when sleep is recorded under basal conditions. In contrast, during acoustic perturbation, zolpidem reduces the pathological amounts of arousal instability by lowering the values of CAP Rate to 38%.(ABSTRACT TRUNCATED AT 250 WORDS)
Parrino, Spaggiari, Boselli, Barusi, Terzano (1993)  Effects of prolonged wakefulness on cyclic alternating pattern (CAP) during sleep recovery at different circadian phases.   J Sleep Res 2: 2. 91-95 Jun  
Abstract: Two separate groups of healthy subjects aged between 20 and 30 years underwent a random sequence of two non-consecutive polysomnographic recordings under standard conditions (night basal sleep) and after continuous sleep deprivation (recovery sleep). In the first group of 6 subjects (3 males and 3 females) recovery sleep occurred in the morning (after 24 h of prior waking); in the second group of 6 subjects (3 males and 3 females) recovery sleep occurred in the night (after 36 h of prior waking). In all cases the recording time was restricted to 500 minutes. Scoring was accomplished on conventional sleep variables and on Cyclic Alternating Pattern (CAP) parameters, while statistical analysis was based on a 2 x 2 ANOVA test. Compared to the night basal conditions, total sleep time and total NREM sleep were significantly longer in night recovery sleep and shorter in morning recovery sleep, respectively. No significant differences were found for sleep latency, intra-sleep awakenings, stage 2, REM sleep, NREM stages and slow-wave sleep. Total CAP time, CAP time in slow-wave sleep and all CAP rates were significantly higher in morning recovery sleep and lower in night recovery sleep. The enhanced amounts of CAP time and CAP rates during morning recovery sleep may be the outcome of two opposite forces, i.e. high sleep pressure versus maximum wake propensity. In contrast, the lower values of CAP during night recovery sleep suggest an in-phase associations between strong sleep pressure and the circadian clock.
M G Terzano, L Parrino (1993)  Clinical applications of cyclic alternating pattern.   Physiol Behav 54: 4. 807-813 Oct  
Abstract: 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.
M G Terzano, L Parrino (1992)  Evaluation of EEG cyclic alternating pattern during sleep in insomniacs and controls under placebo and acute treatment with zolpidem.   Sleep 15: 1. 64-70 Feb  
Abstract: In nonrapid eye movement (NREM) sleep, electroencephalographic cyclic alternating patterns (CAPS) express the organized complexity of arousal-related phasic events. As a translation of sustained instability of the arousal level, CAPS increase under perturbation and decrease under sleep-promoting conditions. After adaptation to the sleep lab, 18 subjects (12 with persistent psychophysiological insomnia and 6 without sleep complaints), all aged 40-60 years, underwent a random sequence of two nonconsecutive nocturnal recordings, one under placebo and one under an imidazopyridine hypnotic agent (zolpidem). The choice of this drug was oriented by its capability to warrant, at the selected dose of 10 mg, a physiological profile of sleep. Polysomnographic parameters and self-report of sleep quality by means of visual analogue scale (VAS) were assessed by analysis of variance followed by a Scheffé test when F statistics were significant. The placebo nights of controls showed a significantly longer duration of total sleep time (+60 minutes) compared with the placebo nights of insomniacs. However, no relevant differences emerged from the other traditional polysomnographic variables. Conversely, CAP rate (CAP time x 100/NREM sleep time) showed highly sensitive and consistent modifications. Under placebo, CAP rate was significantly higher among insomniacs compared with controls (62.2% vs. 38.5%). Under medication, CAP rate dropped to 26.8% in insomniacs, whereas it was only moderately reduced in controls (31%). CAP rate values paralleled the self-rating estimation of sleep quality, but the VAS means differed significantly only among insomniacs where a sharp average fall from 45 mm (placebo nights) to 15 mm (zolpidem nights) could be detected. Our findings suggest that CAP rate in sleep analysis can represent a useful tool for the diagnosis of insomnia and for gaining insight into the therapeutic efficacy of hypnotic-sedative drugs.
M G Terzano, L Parrino, S Anelli, M Boselli, B Clemens (1992)  Effects of generalized interictal EEG discharges on sleep stability: assessment by means of cyclic alternating pattern.   Epilepsia 33: 2. 317-326 Mar/Apr  
Abstract: Generalized interictal EEG discharges are influenced by a biphasic (phase A and B) modality of arousal control during non-rapid eye movement (REM) sleep termed cyclic alternating pattern (CAP). Each phase A and the following phase B compose a CAP cycle. The percentage ratio of total CAP time to total non-REM sleep time is the CAP rate, a sleep parameter that measures the instability and fragmentation of sleep. Since CAP exerts a powerful influence on generalized interictal EEG discharges during sleep, the polysomnograms of seven epileptic patients affected by a clinically active form of primary generalized epilepsy were matched with those of seven healthy volunteers of the same age and sex to assess the influence of interictal discharges on sleep organization. No remarkable differences emerged when the traditional polysomnographic parameters were compared between the two groups. However, the epileptic patients showed significantly higher CAP rate values (52.7 vs. 34.6%; p less than 0.003), indicating a greater arousal instability in the sleep records of these subjects. Within the epileptic group, the CAP cycles that included at least one interictal paroxysm were significantly longer than those without EEG discharges (31.2 vs. 25.4 s; p less than 0.007). The selective lengthening of CAP cycles is likely due to an exaggeration of the natural activating power of phase A when coupled with EEG paroxysms and an intensification of the inhibitory properties of the following phase B. The dynamic relationships and differences between spindles in animals, k-complexes, and slow-wave bursts in humans may have a functional linkage with epileptic phenomena during sleep.
M G Terzano, L Parrino, P G Garofalo, C Durisotti, C Filati-Roso (1991)  Activation of partial seizures with motor signs during cyclic alternating pattern in human sleep.   Epilepsy Res 10: 2-3. 166-173 Nov/Dec  
Abstract: Both interictal and ictal EEG phenomena are commonly activated by functional instability. The different non-REM sleep stages comprise long-lasting periods of cyclic alternating pattern (CAP) in which arousal fluctuates between 'A phases' of greater arousal and 'B phases' of less arousal, and periods in which vigilance maintains a tonic stability (non-CAP). Previous studies have revealed that phase A induces a marked enhancement of generalized EEG paroxysms, a minor though significant activation of focal lesional bursts, but no effect on rolandic functional spikes. Conversely, phase B exerts an inhibitory modulation, especially on bilateral interictal phenomena. Because of the opposite influence of phase A and phase B also on muscle tone, we assessed the amount and distribution of nocturnal partial motor seizures in 6 subjects affected by focal epilepsy. The polysomnograms included 45 motor seizures, 43 of which occurred during non-REM sleep. Nocturnal fits were significantly more frequent in stages 1 and 3 (P less than 0.0001). Among the non-REM seizures, 42 appeared in CAP (P less than 0.0001) and always in phase A. The transient arousal and the concomitant muscle tone activation expressed by phase A of CAP is likely to support the motor components of nocturnal seizures. Sleep analysis in terms of CAP and non-CAP provides a better understanding of the continuum from subclinical EEG paroxysms to clinical manifestations and of the relations between vigilance and seizure disorders.
M G Terzano, L Parrino, M C Spaggiari, R Barusi, S Simeoni (1991)  Discriminatory effect of cyclic alternating pattern in focal lesional and benign rolandic interictal spikes during sleep.   Epilepsia 32: 5. 616-628 Sep/Oct  
Abstract: 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.
M G Terzano, L Parrino, M C Spaggiari (1990)  Modifications of cyclic alternating pattern in sleep apnea syndrome.   Eur Neurol 30: 4. 235-240  
Abstract: Within non-rapid eye movement sleep, two complementary modalities of arousal organization may be identified: (1) the cyclic alternating pattern (CAP), correlated with successive upward (phase A) and downward (phase B) fluctuations of arousal and arousal-related vegetative functions, and (2) non-CAP, corresponding to a relative stability of arousal and vegetative activities. In a 62-year-old overweight and heavily snoring man, complaining of excessive daytime sleepiness, three consecutive polysomnograms displayed a highly frequent occurrence of nocturnal apneas (apnea index: 15), mostly obstructive and mixed, limited to non-rapid eye movement sleep stages 1 and 2. The apneic episodes, that never occurred during non-CAP, exclusively appeared during the inhibitory phase B of CAP, whereas the following breathing resumption was mainly induced by an activating phase A pattern. The crucial effect of arousal instability on respiratory control is emphasized.
M G Terzano, L Parrino, G Fioriti, B Orofiamma, H Depoortere (1990)  Modifications of sleep structure induced by increasing levels of acoustic perturbation in normal subjects.   Electroencephalogr Clin Neurophysiol 76: 1. 29-38 Jul  
Abstract: 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.
M G Terzano, L Parrino, S Anelli, P Halasz (1989)  Modulation of generalized spike-and-wave discharges during sleep by cyclic alternating pattern.   Epilepsia 30: 6. 772-781 Nov/Dec  
Abstract: Because arousal plays a critical role in activation of epileptic phenomena, we analyzed the behavior of interictal generalized spike-and-waves (S-W) during the two recently identified modalities of arousal control during NREM sleep: (a) the cyclic alternating pattern (CAP), expressed by successive biphasic (phase A and phase B) fluctuations of arousal; and (b) non-CAP (NCAP), characterized by prolonged stable periods of EEG and arousal level. Within the single NREM stages, phase A consists of clusters of phasic events associated with transient arousal activation, whereas phase B is represented by the periodic reappearance of the EEG background and reflects a rebound inhibitory condition. The polysomnograms of 10 subjects with a wide age range and affected by primary generalized epilepsy displayed significant differences (all at p less than 0.01) between the spike indexes (S-W/min) of CAP (2.9) and NCAP (1.3), of phase A (7.4) and phase B (0.3), and of NCAP and phase B. For distribution of S-W, a significant prevalence of EEG paroxysms was detected during CAP as compared with NCAP (68 vs. 32%, p less than 0.001), and 93% of all the interictal bursts that occurred in CAP occurred in phase A (p less than 0.001). Our data stress the arousal-dependent influence of CAP and NCAP on modulation of generalized epileptic mechanisms during sleep.
M G Terzano, L Parrino, G Fioriti, A Farolfi, B Orofiamma, J P Sauvanet (1988)  [Cyclic alternating pattern. A new approach to the pharmacology of sleep disorders].   Neurophysiol Clin 18: 5. 447-457 Sep  
Abstract: The Cyclic Alternating Pattern (CAP) is an intrinsic component of normal NREM sleep. This periodic activity is organized in biphasic 40-sec cycles clustered in sequences. CAP sequences are functionally correlated to long lasting arousal instability. CAP is induced by endogenous stimuli (change in sleep stage, body movements) but it is considerably increased by exogenous impulses (noise). CAP rate (CAPR) is a novel polysomnographic variable that measures the amount of CAP during sleep, and it may be calculated for total sleep time and total NREM sleep. We demonstrated that all-night exposure to a 45 dB(A) white noise induced a significant CAPR increase, correlated with impaired sleep quality, even without changes in sleep architecture. We hypothesized that administration of an hypnotic should attenuate this CAPR rise. This hypothesis was verified in a double-blind placebo study, in which 12 healthy young adults received zolpidem, a new imidazopyridine hypnotic. During the noise perturbed nights, zolpidem clearly demonstrated a protective effect on CAPR (mainly during slow wave sleep) and on sleep quality. CAPR appears to be a sensitive indicator of sleep quality, and the cumulative distribution of CAPR throughout the night represents a new method to evaluate the effects of an hypnotic in sleep.
M G Terzano, L Parrino, G Fioriti, A Farolfi, M C Spaggiari, S Anelli, T Arcelloni (1988)  Variations of cyclic alternating pattern rate and homeostasis of sleep organization: a controlled study on the effects of white noise and zolpidem.   Pharmacol Biochem Behav 29: 4. 827-829 Apr  
Abstract: The Cyclic Alternating Pattern (CAP) is a physiologic structure of normal non-REM (NREM) sleep, functionally correlated to long-lasting arousal instability. In 12 healthy volunteers, a continuous 45 dB (A) white noise induced no remarkable changes on the standard sleep parameters. However, compared to the baseline conditions, the acoustic perturbation determined a significant increase of the Cyclic Alternating Pattern Rate (CAPR), that measures the amount of CAP during sleep. Ten mg of zolpidem, a novel imidazopyridine hypnotic compound, did not modify the structure of unperturbed sleep, but induced a highly significant reduction of the increased values of CAP Rate due to white noise. The homeostatic function of CAP is stressed. CAPR appears to be a highly sensitive indicator of environmental modification during sleep.
M G Terzano, L Parrino, M C Spaggiari (1988)  The cyclic alternating pattern sequences in the dynamic organization of sleep.   Electroencephalogr Clin Neurophysiol 69: 5. 437-447 May  
Abstract: The cyclic alternating pattern (CAP) is a physiological component of normal NREM sleep, functionally correlated with long-lasting arousal oscillations. This EEG periodic activity, organized in sequences of two or more decasecond cycles, is detectable also in coma and in other neurologic disorders, appearing as a general modality of arousal organization. Within NREM sleep, the fluctuations of CAP alternate with sustained homogeneous EEG patterns, characterized by a greater stability of arousal and called non-CAP (NCAP). In 20 sleep records of 10 healthy young adults we analysed the chronological relationship between CAP and 3 fundamental states of arousal: wakefulness, NREM sleep, REM sleep. Sleep onset and sleep recoveries after nocturnal awakenings were closely linked to CAP sequences, indicating a functional linkage between cyclic fluctuations of arousal and the beginning of any sleep behavioural state. On the basis of their temporal relationship with CAP sequences, the waking to sleep and the waking transitions appeared a symmetrical events in the organization of arousal, whereas the NREM to REM transitions and the REM to NREM transitions occurred as asymmetrical events. Moreover, almost 50% of all NREM stage changes were accompanied by CAP sequences. The EEG and dynamic features of CAP sequences show morphological and behavioural analogies with some phasic phenomena (i.e., phase d'activation transitoire or micro-arousals) and EEG patterns reported in the literature (e.g., tracé alternant; phase transitionnelles; tracé intermittent). Our data suggest a functional correlation between the control mechanisms of CAP and the organization of sleep.
V Pietrini, M G Terzano, G D'Andrea, L Parrino, A R Cananzi, F Ferro-Milone (1987)  Acute confusional migraine: clinical and electroencephalographic aspects.   Cephalalgia 7: 1. 29-37 Mar  
Abstract: Twelve patients with episodes of acute confusional migraine (ACM) are reported. Prolonged agitation and mental confusion characterized the headache attacks, occurring mostly among adolescents. The ictal EEG showed diffuse, slow abnormalities and a peculiar pattern known as FIRDA (frontal intermittent rhythmic delta activity). Neuroradiologic examinations and laboratory tests were unremarkable. After the acute stage, EEG gradually tended to show normalization. Apart from the noticeable similarities to the "juvenile head trauma syndrome", the authors assume that ACM represents a peculiar clinical form among the different types of migraine associated with disorders of higher mental functions.
M G Terzano, L Parrino, G Fioriti, M C Spaggiari, A Piroli (1986)  Morphologic and functional features of cyclic alternating pattern (CAP) sequences in normal NREM sleep.   Funct Neurol 1: 1. 29-41 Jan/Mar  
Abstract: The Cyclic Alternating Pattern (CAP) is an EEG biphasic periodic activity of normal NREM sleep, generally organized in sequences of two or more cycles and correlated to long-lasting fluctuations in the level of arousal. The remaining NREM sleep is characterized by prolonged stationary activities or non-CAP (NCAP). Criteria for the detection of morphology and reactivity of CAP and NCAP segments are defined in the sleep recordings of 10 healthy young adults. Standard sleep variables and CAP rates, referred to the ratio of CAP time to Total NREM sleep time (CAPR/NREM) and to each NREM sleep stage, were scored for statistical inferences and correlations. CAPR/NREM may be considered an additional non-redundant sleep variable which determines the measure of arousal instability during NREM sleep. The relationship between CAP and the biphasic behavior of microarousals is discussed.
L Parrino, V Pietrini, M C Spaggiari, M G Terzano (1986)  Acute confusional migraine attacks resolved by sleep: lack of significant abnormalities in post-ictal polysomnograms.   Cephalalgia 6: 2. 95-100 Jun  
Abstract: We observed acute confusional migraine (ACM) attacks in two adolescents, and in both cases the episodes ended when the patients fell asleep spontaneously. Laboratory and neuroradiologic examinations were unremarkable. The post-ictal polysomnograms displayed a regular quality and duration of the physiologic components of sleep. Random posterior slow waves occurred only during the nocturnal awakenings and REM periods. The observation that sleep may resolve migraine attacks is emphasized. ACM is characterized by peculiar and relatively quickly reversible clinical manifestations and EEG abnormalities. The lack of significant abnormalities in post-ictal polysomnograms corresponds to a functional integrity of the brainstem structures involved in the global organization of sleep and may represent a useful laboratory feature in the diagnosis of ACM.
M G Terzano, L Parrino, A Mazzucchi, G Moretti (1986)  Confusional states with periodic lateralized epileptiform discharges (PLEDs): a peculiar epileptic syndrome in the elderly.   Epilepsia 27: 4. 446-457 Jul/Aug  
Abstract: The histories of seven patients over the age of 60 years are reported. They all suffered from recurrent and prolonged episodes of confusional state associated with psychic and neurologic manifestations. All episodes were accompanied by the occurrence of periodic lateralized epileptiform discharges (PLEDs) on the EEG, which became normal when the ictal episodes subsided either spontaneously or after administration of diazepam i.v. Although PLEDs may correspond to severe hemispheric lesions, serial computed tomography (CT) scan and laboratory investigations detected significant abnormalities in only one case, that of a patient with a progressive dementing outcome. In the other six patients, follow-up neuropsychological controls indicated moderate impairment of higher cortical functions according to the hemisphere involved by PLEDs. Administration of carbamazepine (CBZ) proved rather effective in preventing the recurrence of the ictal episodes. For its clinical, EEG, and prognostic features, this condition may represent a peculiar nonconvulsive status epilepticus in the elderly.
M G Terzano, D Mancia, M R Salati, G Costani, A Decembrino, L Parrino (1985)  The cyclic alternating pattern as a physiologic component of normal NREM sleep.   Sleep 8: 2. 137-145  
Abstract: The cyclic alternating pattern (CAP) is a long-lasting periodic activity consisting of two alternate electroencephalogram (EEG) patterns. This variation in EEG is closely related to fluctuations in the level of arousal that characterize two different functional states in the arousal control mechanism. We studied 20 sleep records of 10 healthy subjects to see if CAP appears under physiologic conditions. During NREM sleep, CAP corresponded to a periodic succession of spontaneous phasic phenomena recurring within every stage, i.e., intermittent alpha rhythm, K-complex sequences, and reactive slow wave sequences. The following analyses were performed. Each EEG specific alternating pattern, defined as a cycle, was subdivided into two phases depending on the arousal response to stimulation. Average cycle length, average duration of each phase, and average ratio phase/cycle were calculated. CAP rate defined as (CAP time/Sleep time) was calculated for total sleep time (TST), (Cap time/TST); for NREM sleep, (CAP time/Total NREM); and for each NREM sleep stage. CAP is the EEG translation of the reorganization of the sleeping brain challenged by the modification of environmental conditions.
M G Terzano, L Parrino, G C Manzoni, D Mancia (1983)  Seizures triggered by blinking when beginning to speak.   Arch Neurol 40: 2. 103-106 Feb  
Abstract: A patient had seizures triggered by spontaneous blinking associated with the act of beginning to speak. Diffuse paroxysmal discharges in the EEG appeared when the patient was blinking in darkness or in bright light. Closing the eyes voluntarily, on command, or as a reflex reaction produced this response very infrequently. During intermittent photic stimulation the epileptic discharges were accompanied by myoclonic jerks. The act of beginning to speak was linked with spontaneous blinking and EEG changes and was accompanied consistently by seizures. These were characterized by a peculiar stuttering and an absencelike impairment of consciousness. Seizures have been controlled well using clonazepam and valproic acid.
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