Lung Biology in Health & Disease Volume 223 Sleep in Children: Developmental Changes in Sleep Patterns 2nd Edition

Sleep in Children

LUNG BIOLOGY IN HEALTH AND DISEASE

Executive Editor Claude Lenfant Former Director, National Heart, Lung, and Blood Institute National Institutes of Health Bethesda, Maryland

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Immunologic and Infectious Reactions in the Lung, edited by C. H. Kirkpatrick and H. Y. Reynolds The Biochemical Basis of Pulmonary Function, edited by R. G. Crystal Bioengineering Aspects of the Lung, edited by J. B. West Metabolic Functions of the Lung, edited by Y. S. Bakhle and J. R. Vane Respiratory Defense Mechanisms (in two parts), edited by J. D. Brain, D. F. Proctor, and L. M. Reid Development of the Lung, edited by W. A. Hodson Lung Water and Solute Exchange, edited by N. C. Staub Extrapulmonary Manifestations of Respiratory Disease, edited by E. D. Robin Chronic Obstructive Pulmonary Disease, edited by T. L. Petty Pathogenesis and Therapy of Lung Cancer, edited by C. C. Harris Genetic Determinants of Pulmonary Disease, edited by S. D. Litwin The Lung in the Transition Between Health and Disease, edited by P. T. Macklem and S. Permutt Evolution of Respiratory Processes: A Comparative Approach, edited by S. C. Wood and C. Lenfant Pulmonary Vascular Diseases, edited by K. M. Moser Physiology and Pharmacology of the Airways, edited by J. A. Nadel Diagnostic Techniques in Pulmonary Disease (in two parts), edited by M. A. Sackner Regulation of Breathing (in two parts), edited by T. F. Hornbein Occupational Lung Diseases: Research Approaches and Methods, edited by H. Weill and M. Turner-Warwick Immunopharmacology of the Lung, edited by H. H. Newball Sarcoidosis and Other Granulomatous Diseases of the Lung, edited by B. L. Fanburg Sleep and Breathing, edited by N. A. Saunders and C. E. Sullivan Pneumocystis carinii Pneumonia: Pathogenesis, Diagnosis, and Treatment, edited by L. S. Young Pulmonary Nuclear Medicine: Techniques in Diagnosis of Lung Disease, edited by H. L. Atkins Acute Respiratory Failure, edited by W. M. Zapol and K. J. FaIke

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Gas Mixing and Distribution in the Lung, edited by L. A. Engel and M. Paiva High-Frequency Ventilation in Intensive Care and During Surgery, edited by G. Carlon and W. S. Howland Pulmonary Development: Transition from Intrauterine to Extrauterine Life, edited by G. H. Nelson Chronic Obstructive Pulmonary Disease: Second Edition, edited by T. L. Petty The Thorax (in two parts), edited by C. Roussos and P. T. Macklem The Pleura in Health and Disease, edited by J. Chre´tien, J. Bignon, and A. Hirsch Drug Therapy for Asthma: Research and Clinical Practice, edited by J. W. Jenne and S. Murphy Pulmonary Endothelium in Health and Disease, edited by U. S. Ryan The Airways: Neural Control in Health and Disease, edited by M. A. Kaliner and P. J. Barnes Pathophysiology and Treatment of Inhalation Injuries, edited by J. Loke Respiratory Function of the Upper Airway, edited by O. P. Mathew and G. Sant’Ambrogio Chronic Obstructive Pulmonary Disease: A Behavioral Perspective, edited by A. J. McSweeny and I. Grant Biology of Lung Cancer: Diagnosis and Treatment, edited by S. T. Rosen, J. L. Mulshine, F. Cuttitta, and P. G. Abrams Pulmonary Vascular Physiology and Pathophysiology, edited by E. K. Weir and J. T. Reeves Comparative Pulmonary Physiology: Current Concepts, edited by S. C. Wood Respiratory Physiology: An Analytical Approach, edited by H. K. Chang and M. Paiva Lung Cell Biology, edited by D. Massaro Heart–Lung Interactions in Health and Disease, edited by S. M. Scharf and S. S. Cassidy Clinical Epidemiology of Chronic Obstructive Pulmonary Disease, edited by M. J. Hensley and N. A. Saunders Surgical Pathology of Lung Neoplasms, edited by A. M. Marchevsky The Lung in Rheumatic Diseases, edited by G. W. Cannon and G. A. Zimmerman Diagnostic Imaging of the Lung, edited by C. E. Putman Models of Lung Disease: Microscopy and Structural Methods, edited by J. Gil Electron Microscopy of the Lung, edited by D. E. Schraufnagel Asthma: Its Pathology and Treatment, edited by M. A. Kaliner, P. J. Barnes, and C. G. A. Persson Acute Respiratory Failure: Second Edition, edited by W. M. Zapol and F. Lemaire Lung Disease in the Tropics, edited by O. P. Sharma Exercise: Pulmonary Physiology and Pathophysiology, edited by B. J. Whipp and K. Wasserman Developmental Neurobiology of Breathing, edited by G. G. Haddad and J. P. Farber

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Mediators of Pulmonary Inflammation, edited by M. A. Bray and W. H. Anderson The Airway Epithelium, edited by S. G. Farmer and D. Hay Physiological Adaptations in Vertebrates: Respiration, Circulation, and Metabolism, edited by S. C. Wood, R. E. Weber, A. R. Hargens, and R. W. Millard The Bronchial Circulation, edited by J. Butler Lung Cancer Differentiation: Implications for Diagnosis and Treatment, edited by S. D. Bernal and P. J. Hesketh Pulmonary Complications of Systemic Disease, edited by J. F. Murray Lung Vascular Injury: Molecular and Cellular Response, edited by A. Johnson and T. J. Ferro Cytokines of the Lung, edited by J. Kelley The Mast Cell in Health and Disease, edited by M. A. Kaliner and D. D. Metcalfe Pulmonary Disease in the Elderly Patient, edited by D. A. Mahler Cystic Fibrosis, edited by P. B. Davis Signal Transduction in Lung Cells, edited by J. S. Brody, D. M. Center, and V. A. Tkachuk Tuberculosis: A Comprehensive International Approach, edited by L. B. Reichman and E. S. Hershfield Pharmacology of the Respiratory Tract: Experimental and Clinical Research, edited by K. F. Chung and P. J. Barnes Prevention of Respiratory Diseases, edited by A. Hirsch, M. Goldberg, J.-P. Martin, and R. Masse Pneumocystis carinii Pneumonia: Second Edition, edited by P. D. Walzer Fluid and Solute Transport in the Airspaces of the Lungs, edited by R. M. Effros and H. K. Chang Sleep and Breathing: Second Edition, edited by N. A. Saunders and C. E. Sullivan Airway Secretion: Physiological Bases for the Control of Mucous Hypersecretion, edited by T. Takishima and S. Shimura Sarcoidosis and Other Granulomatous Disorders, edited by D. G. James Epidemiology of Lung Cancer, edited by J. M. Samet Pulmonary Embolism, edited by M. Morpurgo Sports and Exercise Medicine, edited by S. C. Wood and R. C. Roach Endotoxin and the Lungs, edited by K. L. Brigham The Mesothelial Cell and Mesothelioma, edited by M.-C. Jaurand and J. Bignon Regulation of Breathing: Second Edition, edited by J. A. Dempsey and A. I. Pack Pulmonary Fibrosis, edited by S. Hin. Phan and R. S. Thrall Long-Term Oxygen Therapy: Scientific Basis and Clinical Application, edited by W. J. O’Donohue, Jr. Ventral Brainstem Mechanisms and Control of Respiration and Blood Pressure, edited by C. O. Trouth, R. M. Millis, H. F. Kiwull-Scho¨ne, and M. E. Schla¨fke A History of Breathing Physiology, edited by D. F. Proctor Surfactant Therapy for Lung Disease, edited by B. Robertson and H. W. Taeusch

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The Thorax: Second Edition, Revised and Expanded (in three parts), edited by C. Roussos Severe Asthma: Pathogenesis and Clinical Management, edited by S. J. Szefler and D. Y. M. Leung Mycobacterium avium–Complex Infection: Progress in Research and Treatment, edited by J. A. Korvick and C. A. Benson Alpha 1–Antitrypsin Deficiency: Biology . Pathogenesis . Clinical Manifestations . Therapy, edited by R. G. Crystal Adhesion Molecules and the Lung, edited by P. A. Ward and J. C. Fantone Respiratory Sensation, edited by L. Adams and A. Guz Pulmonary Rehabilitation, edited by A. P. Fishman Acute Respiratory Failure in Chronic Obstructive Pulmonary Disease, edited by J.-P. Derenne, W. A. Whitelaw, and T. Similowski Environmental Impact on the Airways: From Injury to Repair, edited by J. Chre´tien and D. Dusser Inhalation Aerosols: Physical and Biological Basis for Therapy, edited by A. J. Hickey Tissue Oxygen Deprivation: From Molecular to Integrated Function, edited by G. G. Haddad and G. Lister The Genetics of Asthma, edited by S. B. Liggett and D. A. Meyers Inhaled Glucocorticoids in Asthma: Mechanisms and Clinical Actions, edited by R. P. Schleimer, W. W. Busse, and P. M. O’Byrne Nitric Oxide and the Lung, edited by W. M. Zapol and K. D. Bloch Primary Pulmonary Hypertension, edited by L. J. Rubin and S. Rich Lung Growth and Development, edited by J. A. McDonald Parasitic Lung Diseases, edited by A. A. F. Mahmoud Lung Macrophages and Dendritic Cells in Health and Disease, edited by M. F. Lipscomb and S. W. Russell Pulmonary and Cardiac Imaging, edited by C. Chiles and C. E. Putman Gene Therapy for Diseases of the Lung, edited by K. L. Brigham Oxygen, Gene Expression, and Cellular Function, edited by L. Biadasz Clerch and D. J. Massaro Beta2-Agonists in Asthma Treatment, edited by R. Pauwels and P. M. O’Byrne Inhalation Delivery of Therapeutic Peptides and Proteins, edited by A. L. Adjei and P. K. Gupta Asthma in the Elderly, edited by R. A. Barbee and J. W. Bloom Treatment of the Hospitalized Cystic Fibrosis Patient, edited by D. M. Orenstein and R. C. Stern Asthma and Immunological Diseases in Pregnancy and Early Infancy, edited by M. Schatz, R. S. Zeiger, and H. N. Claman Dyspnea, edited by D. A. Mahler Proinflammatory and Antiinflammatory Peptides, edited by S. I. Said Self-Management of Asthma, edited by H. Kotses and A. Harver Eicosanoids, Aspirin, and Asthma, edited by A. Szczeklik, R. J. Gryglewski, and J. R. Vane Fatal Asthma, edited by A. L. Sheffer Pulmonary Edema, edited by M. A. Matthay and D. H. Ingbar

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Inflammatory Mechanisms in Asthma, edited by S. T. Holgate and W. W. Busse Physiological Basis of Ventilatory Support, edited by J. J. Marini and A. S. Slutsky Human Immunodeficiency Virus and the Lung, edited by M. J. Rosen and J. M. Beck Five-Lipoxygenase Products in Asthma, edited by J. M. Drazen, S.-E. Dahle´n, and T. H. Lee Complexity in Structure and Function of the Lung, edited by M. P. Hlastala and H. T. Robertson Biology of Lung Cancer, edited by M. A. Kane and P. A. Bunn, Jr. Rhinitis: Mechanisms and Management, edited by R. M. Naclerio, S. R. Durham, and N. Mygind Lung Tumors: Fundamental Biology and Clinical Management, edited by C. Brambilla and E. Brambilla lnterleukin-5: From Molecule to Drug Target for Asthma, edited by C. J. Sanderson Pediatric Asthma, edited by S. Murphy and H. W. Kelly Viral Infections of the Respiratory Tract, edited by R. Dolin and P. F. Wright Air Pollutants and the Respiratory Tract, edited by D. L. Swift and W. M. Foster Gastroesophageal Reflux Disease and Airway Disease, edited by M. R. Stein Exercise-Induced Asthma, edited by E. R. McFadden, Jr. LAM and Other Diseases Characterized by Smooth Muscle Proliferation, edited by J. Moss The Lung at Depth, edited by C. E. G. Lundgren and J. N. Miller Regulation of Sleep and Circadian Rhythms, edited by F. W. Turek and P. C. Zee Anticholinergic Agents in the Upper and Lower Airways, edited by S. L. Spector Control of Breathing in Health and Disease, edited by M. D. Altose and Y. Kawakami Immunotherapy in Asthma, edited by J. Bousquet and H. Yssel Chronic Lung Disease in Early Infancy, edited by R. D. Bland and J. J. Coalson Asthma’s Impact on Society: The Social and Economic Burden, edited by K. B. Weiss, A. S. Buist, and S. D. Sullivan New and Exploratory Therapeutic Agents for Asthma, edited by M. Yeadon and Z. Diamant Multimodality Treatment of Lung Cancer, edited by A. T. Skarin Cytokines in Pulmonary Disease: Infection and Inflammation, edited by S. Nelson and T. R. Martin Diagnostic Pulmonary Pathology, edited by P. T. Cagle Particle–Lung Interactions, edited by P. Gehr and J. Heyder Tuberculosis: A Comprehensive International Approach, Second Edition, Revised and Expanded, edited by L. B. Reichman and E. S. Hershfield Combination Therapy for Asthma and Chronic Obstructive Pulmonary Disease, edited by R. J. Martin and M. Kraft

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Sleep Apnea: Implications in Cardiovascular and Cerebrovascular Disease, edited by T. D. Bradley and J. S. Floras Sleep and Breathing in Children: A Developmental Approach, edited by G. M. Loughlin, J. L. Carroll, and C. L. Marcus Pulmonary and Peripheral Gas Exchange in Health and Disease, edited by J. Roca, R. Rodriguez-Roisin, and P. D. Wagner Lung Surfactants: Basic Science and Clinical Applications, R. H. Notter Nosocomial Pneumonia, edited by W. R. Jarvis Fetal Origins of Cardiovascular and Lung Disease, edited by David J. P. Barker Long-Term Mechanical Ventilation, edited by N. S. Hill Environmental Asthma, edited by R. K. Bush Asthma and Respiratory Infections, edited by D. P. Skoner Airway Remodeling, edited by P. H. Howarth, J. W. Wilson, J. Bousquet, S. Rak, and R. A. Pauwels Genetic Models in Cardiorespiratory Biology, edited by G. G. Haddad and T. Xu Respiratory-Circulatory Interactions in Health and Disease, edited by S. M. Scharf, M. R. Pinsky, and S. Magder Ventilator Management Strategies for Critical Care, edited by N. S. Hill and M. M. Levy Severe Asthma: Pathogenesis and Clinical Management, Second Edition, Revised and Expanded, edited by S. J. Szefler and D. Y. M. Leung Gravity and the Lung: Lessons from Microgravity, edited by G. K. Prisk, M. Paiva, and J. B. West High Altitude: An Exploration of Human Adaptation, edited by T. F. Hornbein and R. B. Schoene Drug Delivery to the Lung, edited by H. Bisgaard, C. O’Callaghan, and G. C. Smaldone Inhaled Steroids in Asthma: Optimizing Effects in the Airways, edited by R. P. Schleimer, P. M. O’Byrne, S. J. Szefler, and R. Brattsand IgE and Anti-lgE Therapy in Asthma and Allergic Disease, edited by R. B. Fick, Jr., and P. M. Jardieu Clinical Management of Chronic Obstructive Pulmonary Disease, edited by T. Similowski, W. A. Whitelaw, and J.-P. Derenne Sleep Apnea: Pathogenesis, Diagnosis, and Treatment, edited by A. I. Pack Biotherapeutic Approaches to Asthma, edited by J. Agosti and A. L. Sheffer Proteoglycans in Lung Disease, edited by H. G. Garg, P. J. Roughley, and C. A. Hales Gene Therapy in Lung Disease, edited by S. M. Albelda Disease Markers in Exhaled Breath, edited by N. Marczin, S. A. Kharitonov, M. H. Yacoub, and P. J. Barnes Sleep-Related Breathing Disorders: Experimental Models and Therapeutic Potential, edited by D. W. Carley and M. Radulovacki Chemokines in the Lung, edited by R. M. Strieter, S. L. Kunkel, and T. J. Standiford Respiratory Control and Disorders in the Newborn, edited by O. P. Mathew The Immunological Basis of Asthma, edited by B. N. Lambrecht, H. C. Hoogsteden, and Z. Diamant

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Oxygen Sensing: Responses and Adaptation to Hypoxia, edited by S. Lahiri, G. L. Semenza, and N. R. Prabhakar Non-Neoplastic Advanced Lung Disease, edited by J. R. Maurer Therapeutic Targets in Airway Inflammation, edited by N. T. Eissa and D. P. Huston Respiratory Infections in Allergy and Asthma, edited by S. L. Johnston and N. G. Papadopoulos Acute Respiratory Distress Syndrome, edited by M. A. Matthay Venous Thromboembolism, edited by J. E. Dalen Upper and Lower Respiratory Disease, edited by J. Corren, A. Togias, and J. Bousquet Pharmacotherapy in Chronic Obstructive Pulmonary Disease, edited by B. R. Celli Acute Exacerbations of Chronic Obstructive Pulmonary Disease, edited by N. M. Siafakas, N. R. Anthonisen, and D. Georgopoulos Lung Volume Reduction Surgery for Emphysema, edited by H. E. Fessler, J. J. Reilly, Jr., and D. J. Sugarbaker Idiopathic Pulmonary Fibrosis, edited by J. P. Lynch III Pleural Disease, edited by D. Bouro´s Oxygen/Nitrogen Radicals: Lung Injury and Disease, edited by V. Vallyathan, V. Castranova, and X. Shi Therapy for Mucus-Clearance Disorders, edited by B. K. Rubin and C. P. van der Schans Interventional Pulmonary Medicine, edited by J. F. Beamis, Jr., P. N. Mathur, and A. C. Mehta Lung Development and Regeneration, edited by D. J. Massaro, G. Massaro, and P. Chambon Long-Term Intervention in Chronic Obstructive Pulmonary Disease, edited by R. Pauwels, D. S. Postma, and S. T. Weiss Sleep Deprivation: Basic Science, Physiology, and Behavior, edited by Clete A. Kushida Sleep Deprivation: Clinical Issues, Pharmacology, and Sleep Loss Effects, edited by Clete A. Kushida Pneumocystis Pneumonia: Third Edition, Revised and Expanded, edited by P. D. Walzer and M. Cushion Asthma Prevention, edited by William W. Busse and Robert F. Lemanske, Jr. Lung Injury: Mechanisms, Pathophysiology, and Therapy, edited by Robert H. Notter, Jacob Finkelstein, and Bruce Holm Ion Channels in the Pulmonary Vasculature, edited by Jason X.-J. Yuan Chronic Obstructive Pulmonary Disease: Cellular and Molecular Mechanisms, edited by Peter J. Barnes Pediatric Nasal and Sinus Disorders, edited by Tania Sih and Peter A. R. Clement Functional Lung Imaging, edited by David Lipson and Edwin van Beek Lung Surfactant Function and Disorder, edited by Kaushik Nag

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Pharmacology and Pathophysiology of the Control of Breathing, edited by Denham S. Ward, Albert Dahan and Luc J. Teppema Molecular Imaging of the Lungs, edited by Daniel Schuster and Timothy Blackwell Air Pollutants and the Respiratory Tract: Second Edition, edited by W. Michael Foster and Daniel L. Costa Acute and Chronic Cough, edited by Anthony E. Redington and Alyn H. Morice Severe Pneumonia, edited by Michael S. Niederman Monitoring Asthma, edited by Peter G. Gibson Dyspnea: Mechanisms, Measurement, and Management, Second Edition, edited by Donald A. Mahler and Denis E. O’Donnell Childhood Asthma, edited by Stanley J. Szefler and Sfren Pedersen Sarcoidosis, edited by Robert Baughman Tropical Lung Disease, Second Edition, edited by Om Sharma Pharmacotherapy of Asthma, edited by James T. Li Practical Pulmonary and Critical Care Medicine: Respiratory Failure, edited by Zab Mosenifar and Guy W. Soo Hoo Practical Pulmonary and Critical Care Medicine: Disease Management, edited by Zab Mosenifar and Guy W. Soo Hoo Ventilator-Induced Lung Injury, edited by Didier Dreyfuss, Georges Saumon, and Rolf D. Hubmayr Bronchial Vascular Remodeling In Asthma and COPD, edited by Aili Lazaar Lung and Heart–Lung Transplantation, edited by Joseph P. Lynch III and David J. Ross Genetics of Asthma and Chronic Obstructive Pulmonary Disease, edited by Dirkje S. Postma and Scott T. Weiss Reichman and Hershfield’s Tuberculosis: A Comprehensive, International Approach, Third Edition (in two parts), edited by Mario C. Raviglione Narcolepsy and Hypersomnia, edited by Claudio Bassetti, Michel Billiard, and Emmanuel Mignot Inhalation Aerosols: Physical and Biological Basis for Therapy, Second Edition, edited by Anthony J. Hickey Clinical Management of Chronic Obstructive Pulmonary Disease, Second Edition, edited by Stephen I. Rennard, Roberto Rodrı´guez-Roisin, Ge´rard Huchon, and Nicolas Roche Sleep in Children, Second Edition: Developmental Changes in Sleep Patterns, edited by Carole L. Marcus, John L. Carroll, David F. Donnelly, and Gerald M. Loughlin Sleep and Breathing in Children, Second Edition: Developmental Changes in Breathing During Sleep, edited by Carole L. Marcus, John L. Carroll, David F. Donnelly, and Gerald M. Loughlin

The opinions expressed in these volumes do not necessarily represent the views of the National Institutes of Health.

Sleep in Children Second Edition Developmental Changes in Sleep Patterns

Edited by

Carole L. Marcus

University of Pennsylvania School of Medicine Philadelphia, Pennsylvania, USA

John L. Carroll

University of Arkansas for Medical Sciences Little Rock, Arkansas, USA

David F. Donnelly

Yale University School of Medicine New Haven, Connecticut, USA

Gerald M. Loughlin

Weill Medical College of Cornell University New York, New York, USA

Informa Healthcare USA, Inc. 52 Vanderbilt Avenue New York, NY 10017 # 2008 by Informa Healthcare USA, Inc. Informa Healthcare is an Informa business No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 1-4200-6080-5 (Hardcover) International Standard Book Number-13: 978-1-4200-6080-5 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequence of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a notfor-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data Sleep in children : developmental changes in sleep patterns / edited by Carole Marcus . . . [et al.]. —2nd ed. p. ; cm. — (Lung biology in health and disease ; v. 223-) Includes bibliographical references and index. ISBN-13: 978-1-4200-6080-5 (hardcover : alk. paper) ISBN-10: 1-4200-6080-5 (hardcover : alk. paper) 1. Sleep. 2. Children—Sleep. 3. Respiratory insufficiency in children. I. Marcus, Carole L. II. Series. [DNLM: 1. Sleep—physiology. 2. Child Development—physiology. 3. Child. 4. Respiration. 5. Sleep Disorders—physiopathology. W1 LU62 v.223- 2008 / WL 108 S6115 2008] QP425.S662 2008 612.8’21083—dc22 2007035094 For Corporate Sales and Reprint Permissions call 212-520-2700 or write to: Sales Department, 52 Vanderbilt Avenue, 16th floor, New York, NY 10017. Visit the Informa Web site at www.informa.com and the Informa Healthcare Web site at www.informahealthcare.com

Introduction

Sleep is the only medicine that gives me ease. Sophocles (496–406 BC), Philoctetes Philoctetes, a play written and presented by Sophocles in 409 BC, is based on the adventures, or rather misadventures, of the hero Philoctetes, who was the son of the mythological king of Thessaly. He had been deported by the Greeks on an island where he suffered physically and psychologically. It is while commenting on his fate that he stated, “Sleep is the only medicine that gives me ease.” Of course, at that time, no one knew much about the biology of sleep, but it appears that it was already recognized that (good) sleep is an effective regulator of many biological and mental functions. Today, sleep research and sleep medicine have clearly demonstrated that sleep is a determinant of good health. Impaired or disordered sleep is associated with numerous conditions, some quite serious like sleep apnea and/or hypertension, among others. We have learned that infants, children, and adolescents are, as adults, affected by sleep disorders; this is a critical problem because physiological and mental functions develop during the early years of life. The younger the age, the more the sleep required. We also have learned that adolescents of school age will be at risk of learning, health, behavioral, and mood impairments if they do not have enough sleep (8 to 9.5 hours) or if their sleep is disordered. At the same time, we have also learned through extensive research that sleep is a complex process and that sleep patterns evolve during the years of physical growth and maturation. In addition, during these years, many physiological functions develop—respiratory, circulatory, and endocrine. In 2000, the series of monographs Lung Biology in Health and Disease introduced a volume titled Sleep and Breathing in Children. The editors, Drs. Gerald M. Loughlin, John L. Carroll, and Carole L. Marcus, aimed to emphasize the importance of the interactions of sleep and breathing during the developmental journey from infancy to adolescence. The authors and editors underscored the need for further research to understand and

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Introduction

hopefully to eventually correct the disordered patterns of sleep and breathing in early life so that these disorders would not spill into, and worsen, during adult life. Since then, a considerable amount of research has been done and our knowledge on the development of sleep and breathing and the relationship— perhaps interdependency—between these two functions has markedly increased. Thus, it is with thanks and gratitude that the series of monographs Lung Biology in Health and Disease welcomes the publication of this new volume, Sleep in Children: Developmental Changes in Sleep Patterns. Although the title is partly similar to that of the Loughlin et al. volume, the scope of the two volumes is very different. This current edition is in two volumes; one focuses on developmental changes in sleep patterns and the other on developmental changes in breathing during sleep. The editors of this new monograph, Drs. Carole L. Marcus, John Carroll, David Donnelly, and Gerald Loughlin, have reached out to experts from several countries and institutions to present a complete state of our current knowledge. The readership of these volumes will undoubtedly be stimulated by the new developments presented by the authors and will appreciate that it brings us closer to helping infants and children suffering from disordered sleep and breathing. As the executive editor of this series of monographs, I am thankful for their valuable contribution. Claude Lenfant, M.D. Gaithersburg, Maryland, U.S.A.

Foreword

Human infants at birth spend more time asleep than awake, but for a long time limited attention was given to the sleep of children. Interestingly, it was while observing sleeping infants that Aserinski and Kleitman (1) noticed periods of sleep characterized by bursts of eye movements with seemingly half-opened eyes. These researchers decided to place electrodes and monitor eye movements. This experiment lead to the discovery of two types of eye movements during sleep, one fast and the other slow, with the fast eye movements occurring episodically several times during sleep. William C. Dement (2), a student in the Kleitman laboratory, continued the work started by Aserinski and placed EEG electrodes alongside the eye electrodes to investigate infant sleep, thus discovering REM sleep in humans. During such monitoring, it was noted that bursts of rapid eye movements were associated with irregular breathing and short respiratory pauses. The question arose: why? Was control of vital functions different during periods of wake and sleep? Much work has been done since these discoveries in the mid-1950s. We have a better understanding of the physiology of sleep and the mechanisms that underlie the two different sleep states. We have also integrated sleep and wake within the 24-hour cycle, which led, for example, to distinguishing hormones whose secretory patterns are circadian dependent from those that are sleep dependent, such as growth hormone. We have deciphered differences in the control of some vital functions, such as the dependence of respiratory rhythm on central chemosensitivity during slow wave sleep (the “quiet sleep” of infants). We have begun to understand the mechanism behind congenital central hypoventilation syndrome. Our progress in understanding the mechanisms underlying sleep and wakefulness and in understanding the progressive “buildup” of sleep during the nocturnal period has led to better approaches to sleep-related disorders, as well as better diagnostics and treatment options. I recall an occasion in 1972 (3) when I had to tell the mother of a 12-year-old girl who had failed to improve following adenotonsillectomy that the only treatment available for her newly diagnosed obstructive sleep apnea syndrome (OSAS) was a tracheostomy. I also recall the joy of

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Foreword

mother and daughter in the fall of 1981 when I contacted them to indicate that there was a potential new treatment, developed in Australia, called “nasal continuous positive airway pressure” (CPAP) (4). Colin Sullivan sent one of his technicians to show us how to make a mask by hand, but it was a young craniofacial otolaryngologist, Nelson Powell, who helped us pull things together. We used a homemade CPAP device made by a small firm in South San Francisco that could probably have powered a small motorcycle. Carleen, since my encounter with her in 1972, underwent every treatment advance for OSAS and finally became free of medical care after a maxillomandibular advancement. Another patient, a three-year-old boy, at first misdiagnosed with atonic seizures due to his “drop attacks,” still requires one or two short naps daily despite modafinil and sodium oxybate. Despite his narcolepsy-cataplexy syndrome, he completed his Ph.D. this year, but vigilantly watches his food intake to avoid losing the battle of inappropriate weight gain. The discovery that narcolepsy-cataplexy was related to the destruction of hypocretin/orexin neurons located in the lateral hypothalamus, as predicted by Von Economo (5) in the mid-1920s, has allowed both a better understanding of the different clinical features of the syndrome and better treatment of symptoms. Pediatric sleep medicine is an integral part of pediatrics. All children sleep, and sleep mechanisms may trigger or worsen many disorders seen in daily pediatric practice. Difficulty falling asleep, sleep terrors, sleepwalking, and enuresis are common complaints, but so are problems associated with sleep disorders such as nasal allergies, enlarged adenoids and tonsils, difficulties in school, attention deficit hyperactivity disorder, and even orthodontic treatment. When to recommend adenotonsillectomy or to avoid nocturnal headgear as an orthodontic treatment? Sleep medicine is young, and we do not necessarily have all the answers, but we have much to contribute. We can respond better to the needs of children with a better understanding of issues and problems associated with pediatric sleep medicine. Medical students rotating through pediatric departments should be exposed to the basics of sleep medicine, and all pediatricians should be exposed to it during their residency. This book has many chapters authored by experts on the subject, and it contains important information for all health professionals dealing with children. The different chapters with their many vignettes and well-constructed bibliographies will help in responding to questions from parents and their children. It will be helpful to many in their regular practice, and not simply to those interested in pediatric sleep medicine. Christian Guilleminault, M.D., D.M., Biol.D. Stanford University Palo Alto, California, U.S.A.

Foreword

vii

References 1. Aserinsky E, Kleitman N. Regularly occurring periods of eye motility, and concomitant phenomena, during sleep. Science 1953; 118:273,274. 2. Dement WC, Kleitman N. Cyclic variations in EEG during sleep and their relation to eye movements, body motility, and dreaming. Electroencephalogr Clin Neurophysiol 1957; 9:673–690. 3. Guilleminault C, Dement WC, Monod N. Mort Subite du Nourrisson, apne´e lors du sommeil: nouvelle hypothe`se. Nouv Presse Med 1973; 2:1355–1358. 4. Sullivan CE, Issa FG, Berthon-Jones M, et al. Reversal of obstructive sleep apnoea by continuous positive airway pressure applied through the nares. Lancet 1981; 1:862–865. 5. Von Economo C. Sleep as a problem of localization. J Nerv Men Dis 1930; 71: 249–259.

Preface

Depending on age, infants and children spend one- to two-thirds of their life asleep. Despite this, very little attention was paid until recently to understanding both normal sleep and sleep-related abnormalities during development. However, the last few years have seen burgeoning research and publications in this area. Important developments have occurred in the field since the publication of the first edition of this book in 2000. Thus, the book has been totally revised. The basis of the book remains rigorously conducted scientific research. The chapters have been authored by an international group of outstanding scientists. As several clinical pediatric sleep books have been published since the first edition of this book, we have shifted the focus of the book away from some of the more clinically oriented chapters toward developmental physiology. In addition, we have divided the book into two volumes to accommodate the increased amount of literature that is now available. One volume concentrates on sleep alone, and the other on breathing during sleep. It should be noted, however, that not all chapters could be so neatly categorized, and thus the two volumes are synergistic. This volume is devoted to sleep per se, and its changes with development. There are profound changes in sleep and circadian rhythm during growth and maturation. Sleep is particularly important in children because of its putative role in consolidating memory and other neurocognitive functions, and the parents of a young child can easily describe the effects of sleep deprivation. This volume covers normal changes in sleep during development, important behavioral aspects of sleep, cultural effects on sleep, and nonrespiratory sleep-related disorders. The concluding section reviews new techniques that are currently being used in sleep-related research. The success of the book depends, of course, on the quality of the individual contributors. We therefore want to thank the many authors who have contributed to the book. They are all leaders in the field and, as such, have many demands on their time. Nevertheless, as the reader will appreciate, they have devoted time and energy into writing outstanding chapters.

ix

Preface

x

We would like to dedicate this book to the children and families who have willingly participated in sleep research experiments. Without them, this book would not exist. We thank Mary Anne Cornaglia for her invaluable assistance with the book preparation. Carole L. Marcus John L. Carroll David F. Donnelly Gerald M. Loughlin

Contributors

Candice A. Alfano Children’s National Medical Center, The George Washington University School of Medicine, Washington, D.C., U.S.A. Kristin T. Avis University of Alabama Birmingham, Birmingham, Alabama, U.S.A. Jules Verne University of Picardy, Amiens, France

Ve´ronique Bach

University of Cincinnati College of Medicine, Cincinnati,

Dean W. Beebe Ohio, U.S.A.

University La Sapienza, Rome, Italy

Oliviero Bruni

Mary A. Carskadon Warren Alpert Medical School of Brown University, Providence, Rhode Island, U.S.A. Jules Verne University of Picardy, Amiens, France

Karen Chardon

Lilia Curzi-Dascalova

INSERM U 676, Paris, France

Patricia Franco Pediatric Sleep Unit, Hôpital Debrousse and INSERM U 628, University of Lyon 1, Lyon, France Lee T. Gettler

University of Notre Dame, Notre Dame, Indiana, U.S.A.

Fiorenza Giganti

University of Florence, Florence, Italy

Jose´ Groswasser University Children Hospital Reine Fabiola, Free University of Brussels, Brussels, Belgium Ronald M. Harper David Geffen School of Medicine, UCLA, Los Angeles, California, U.S.A.

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Contributors

Susan Higgins Pediatric Sleep Unit, Hôpital Debrousse and INSERM U 628, University of Lyon 1, Lyon, France Ineko Kato

Nagoya City University, Nagoya, Japan

Suresh Kotagal

Mayo Clinic, Rochester, Minnesota, U.S.A.

Rajesh Kumar David Geffen School of Medicine, UCLA, Los Angeles, California, U.S.A. Daniel S. Lewin Children’s National Medical Center, The George Washington University School of Medicine, Washington, D.C., U.S.A. Jean-Pierre Libert Jian-Sheng Lin

Jules Verne University of Picardy, Amiens, France

INSERM U 628, University of Lyon 1, Lyon, France

Gerald M. Loughlin Weill Medical College of Cornell University, New York, New York, U.S.A. Paul M. Macey David Geffen School of Medicine, UCLA, Los Angeles, California, U.S.A. Thornton B. A. Mason II The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, U.S.A. James J. McKenna U.S.A.

University of Notre Dame, Notre Dame, Indiana,

Jodi A. Mindell St. Joseph’s University, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, U.S.A. Enza Montemitro Allan I. Pack

Universita di Roma “La Sapienza”, Rome, Italy

University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A.

Aude Raoux Pediatric Sleep Unit, Hôpital Debrousse and INSERM U 628, University of Lyon 1, Lyon, France Avi Sadeh The Adler Center for Research in Child Development and Psychopathology, Department of Psychology, Tel Aviv University, Tel Aviv, Israel Piero Salzarulo

University of Florence, Florence, Italy

Contributors

xiii

Sonia Scaillet University Children Hospital Reine Fabiola, Free University of Brussels, Brussels, Belgium Mark S. Scher

Case Western Reserve University, Cleveland, Ohio, U.S.A.

Arthur S. Walters New Jersey Neuroscience Institute, Seton Hall University School of Graduate Medical Education, Edison, New Jersey, U.S.A. Marco Zucconi Sleep Disorders Centre, Department of Neurology, H San Raffaele Institute, Milan, Italy

Contents

Introduction Claude Lenfant . . . . . . . . iii Foreword Christian Guilleminault . . . . . v Preface . . . . . . . . . . . . . . . . . . . . . . . . . ix Contributors . . . . . . . . . . . . . . . . . . . . . . xi 1.

2.

Neurophysiological Basis and Behavior of Early Sleep Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lilia Curzi-Dascalova, Fiorenza Giganti, and Piero Salzarulo I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. General Principles of Sleep-Wake Control . . . . . . . . . . . . III. Sleep Development During Early Ontogenesis: Animal Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. Development of Behavioral States During Human Ontogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . V. The Development of Sleep-Wake Rhythm . . . . . . . . . . . VI. Early Sleep-Wake Regulation . . . . . . . . . . . . . . . . . . . . VII. Awakening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ontogeny of EEG Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mark S. Scher I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Caveats Concerning Neurophysiologic Interpretation of State . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . III. General Comments on Recording Techniques and Instrumentation for Neonates and Infants . . . . . . . . . . . IV. Maturation of Electrographic Patterns in the Neonate . . V. Midline Theta/Alpha Activity ................... VI. Maturation of Noncerebral Physiologic Behaviors That Define State in the Preterm Infant . . . . . . . . . . . . VII. Assessment of State Organization in the Full-Term Infant VIII. Sleep Ontogenesis—State Maturation from Fetal Through Infancy Periods . . . . . . . . . . . . . . . . . . . . . . IX. Ontogeny of Autonomic Behaviors During Sleep . . . . . .

xv

1 1 2 6 11 22 24 24 27 39 39 40 41 42 46 47 50 54 57

xvi

Contents X. Brain Adaptation to Stress as Reflected in Sleep Reorganization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XI. Computer-Assisted Analyses of EEG Sleep Organization in Neonates and Infants . . . . . . . . . . . . . . XII. Sleep Ontogenesis and Neural Plasticity . . . . . . . . . . . . XIII. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3.

4.

5.

Maturation of Sleep Patterns During Infancy and Childhood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Avi Sadeh I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Consolidation of Nocturnal Sleep . . . . . . . . . . . . . . . . . III. Sleep Onset and Sleep Duration . . . . . . . . . . . . . . . . . . IV. Sleep State Organization . . . . . . . . . . . . . . . . . . . . . . . V. Factors Influencing Sleep Maturation . . . . . . . . . . . . . . VI. Maturation of Sleep and Cognitive Function in Children . . VII. Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Maturation of Processes Regulating Sleep in Adolescents Mary A. Carskadon I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Circadian Timing System . . . . . . . . . . . . . . . . . . III. Sleep-Wake Homeostasis (Process S) . . . . . . . . . IV. A Model Relating These Processes to the Adolescent Sleep Delay . . . . . . . . . . . . . . . . . . . V. What About Young Adults? . . . . . . . . . . . . . . . . VI. Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . .

....

60 61 64 66 66 77 77 78 79 81 83 85 87 87 95

. . . . . 95 . . . . . 98 . . . . 102 . . . .

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Characteristics of Arousal Mechanisms from Sleep in Infants and Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Patricia Franco, Ineko Kato, Enza Montemitro, Jose´ Groswasser, Sonia Scaillet, Susan Higgins, Aude Raoux, and Jian-Sheng Lin I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. The Hierarchy of the Arousal Process ............ III. Definitions and Scoring Methodologies . . . . . . . . . . . . IV. The Determination of Arousal Thresholds . . . . . . . . . . V. Factors Influencing Arousability . . . . . . . . . . . . . . . . . VI. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

105 106 107 108 115 115 116 117 120 120 128 128

Contents 6.

7.

8.

9.

Thermoregulation During Sleep in Infants: A Functional Interaction with Respiration . . . . . . . . . . . . . . Jean-Pierre Libert, Karen Chardon, and Ve´ronique Bach I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Neonatal Thermoregulation . . . . . . . . . . . . . . . . . . . . III. Sleep and Thermoregulation ................... IV. Sleep, Thermoregulation, and Respiration . . . . . . . . . . V. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Behavioral Influences on Sleep in Children and Adolescents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kristin T. Avis and Jodi A. Mindell I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Infants, Toddlers, and School-Aged Children ....... III. Adolescence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cultural Influences on Infant and Childhood Sleep Biology, and the Science That Studies It: Toward a More Inclusive Paradigm II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . James J. McKenna and Lee T. Gettler I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Culture and Childhood Sleep . . . . . . . . . . . . . . . . . . . III. Conventional Western Understandings of “Healthy, Normal” Infant and Childhood Sleep: Where Did They Come From? Is One Form of Sleep as Good as Any Other? . . . . . . . . . . . . . . . . . . . . . . . . . IV. Infant-Parent or Child Cosleeping: “The Political Third Rail?” Why So Controversial? . . . . . . . . . . . . . . V. Conclusions/Recommendations/Afterthoughts—Getting Mothers and Infants Together for Nighttime Sleep and Breast-feeding: Still Crazy After All These Years . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pediatric Parasomnias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thornton B. A. Mason II and Allan I. Pack I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Disorders of Arousal from NREM Sleep . . . . . . . . . . . III. Parasomnias Usually Associated with REM Sleep . . . .

xvii

135 135 137 144 150 153 154

159 159 159 168 175 175

183 183 185

192 205 210 215 223 223 223 229

xviii

Contents IV. Other Parasomnias . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

10.

11.

12.

233 238

...........................

243

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. . . . . . . .

243 244 244 249 251 254 256 257

Sleep in Children with Neurologic Disease .............. Marco Zucconi and Oliviero Bruni I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Sleep in Children with Pervasive Developmental Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . III. Sleep in Other Forms of Mental Retardation . . . . . . . . IV. Nocturnal Frontal Lobe Epilepsy and Abnormal Motor Behaviors of Epileptic Origin: Differentiation from Parasomnias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V. Achondroplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VI. Neuromuscular Diseases . . . . . . . . . . . . . . . . . . . . . . VII. Cerebral Palsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VIII. Headaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IX. Use of Melatonin in Children with Neurologic Disorders ........................ References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

261

Narcolepsy in Childhood Suresh Kotagal I. Introduction . . . . II. Epidemiology . . . III. Pathophysiology . IV. Clinical Features . V. Diagnosis . . . . . . VI. Management ... VII. Conclusions . . . . References . . . . .

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Sleep and Psychiatric Disorders in Children: A Complex Reciprocal Relationship . . . . . . . . . . . . . . . . . . . Daniel S. Lewin and Candice A. Alfano I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Sleep and Anxiety Disorders . . . . . . . . . . . . . . . . . . . III. Sleep and Depression . . . . . . . . . . . . . . . . . . . . . . . . IV. Sleep and ADHD . . . . . . . . . . . . . . . . . . . . . . . . . . . V. Sleep and Developmental Disorders . . . . . . . . . . . . . . VI. Case Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . VII. Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

261 262 264 268 274 276 278 280 282 285 297 297 299 301 303 305 306 310 310

Contents 13.

14.

15.

16.

Restless Legs Syndrome and Periodic Limb Movements in Sleep in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Arthur S. Walters I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Epidemiology of Adult and Childhood RLS ........ III. Essential Clinical Features of Adult RLS .......... IV. Nonessential Features of Adult Restless Legs Syndrome ...................... V. Essential Clinical Criteria for Childhood RLS . . . . . . . VI. Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . VII. Relationship of Childhood RLS to Growing Pains . . . . VIII. Relationship of Childhood RLS to ADHD . . . . . . . . . . IX. Treatment Options . . . . . . . . . . . . . . . . . . . . . . . . . . X. Treatment of Restless Legs and Periodic Limb Movements of Sleep in Children . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gastroesophageal Reflux During Sleep . . . . . . . . . . . . . . . . . Gerald M. Loughlin I. Sleep, Gastroesophageal Function and Dysfunction . . . II. Sleep-Related Clinical Manifestations of GER . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Assessing Neurobehavioral Outcomes in Childhood Sleep-Disordered Breathing: A Primer for Nonneuropsychologists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dean W. Beebe I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Psychometric Terms . . . . . . . . . . . . . . . . . . . . . . . . . III. Psychometric Issues in Child Assessment . . . . . . . . . . IV. The State of the Field Circa 2006 ............... V. Concluding Comments ....................... References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Structural and Functional Magnetic Resonance Imaging as a Research Tool in Pediatric Sleep Research . . . . . . . . . . . Ronald M. Harper, Paul M. Macey, and Rajesh Kumar I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Structural Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . III. Functional Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . IV. Analytic Procedures . . . . . . . . . . . . . . . . . . . . . . . . . V. Physiological Data Acquisition . . . . . . . . . . . . . . . . . .

xix

317 317 318 319 319 321 322 323 324 326 329 330 335 335 338 341

345 345 346 354 360 363 363 367 367 367 373 375 378

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Contents VI. Movement Control . . . . . . . . . . . . . . . . . . . . . . . . . . VII. Imaging Resources and Shared Access . . . . . . . . . . . . VIII. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Index . . . . 385

379 379 380 380

1 Neurophysiological Basis and Behavior of Early Sleep Development

LILIA CURZI-DASCALOVA INSERM U 676, Paris, France

FIORENZA GIGANTI and PIERO SALZARULO University of Florence, Florence, Italy

I.

Introduction

Behavioral states [namely, wakefulness, slow-wave or non–rapid eye movement sleep (NREM), and paradoxical or rapid eye movement (REM) sleep] in infants are one of the most remarkable functions of the central nervous system (CNS) and good indicators of normal or abnormal development. Behavioral states are constellations of physiological and behavioral variables that become stable over time and occur repeatedly in all infants (1). Consequently, changes in these variables as state development progresses can be discussed only in reference to age-specific modulations in sleep parameter concordance. Since the landmark descriptions of cyclic modifications of respiratory, motor, and EEG behaviors in sleeping infants (2,3), it is well known that states of vigilance modulate vital functions. The concept of states has made it possible to group movements and physiological parameters into definable entities, whose gradual organization during nervous system maturation can be studied (4–6). This chapter is limited to a general discussion of the developmental aspects of the neurophysiological basis of sleep. Autonomic functions (respiration and cardiovascular control), development of the rest-activity cycle, thermoregulation, and 1

2

Curzi-Dascalova et al.

endocrine factors, which are all closely linked to states, will be discussed in other chapters. After briefly reviewing the CNS structures involved in states control and their development, we will discuss available data on wakefulness and sleep states during development from the fetal period to early childhood. Developmental studies of sleep-wake patterns are of utmost importance. They contribute to the understanding of CNS maturation and function and may provide answers to many fundamental, but still unsettled, questions regarding the functional role(s) of sleep. II.

General Principles of Sleep-Wake Control

Sleep is a coordinated process involving simultaneous or quasi-simultaneous changes in sensory, motor, autonomic, hormonal, and cerebral processes. The control mechanisms of these changes are manifested at every level of biological organization, from genes and intracellular mechanisms to networks of cell populations and the entire CNS (7). Sleep is controlled by mutually inhibitory or excitatory interactions between arousing or activating systems on the one hand and hypnogenic or deactivating systems on the other. However, none of the changes occurring with sleep are exclusively coupled with sleep (8). The main three behavioral states, i.e., wakefulness, NREM, and REM sleep, all obey these principles, although they are known to be each controlled by specific mechanisms. Sleep and waking states are produced by the activity of excitatory and inhibitory neurons located in several brainstem and forebrain centers, which are organized into ‘‘systems’’ or ‘‘networks,’’ each of which is responsible for controlling a given state. Figure 1 shows the main brain structures involved in sleep-wake regulation. In general, the occurrence of each sleep state involves two neuronal networks. One, the ‘‘executive’’ network, is responsible for sleep phenomenology (each state-characteristic phenomenon may depend on a specific network). The other, called the ‘‘permissive’’ network, triggers sleep (7–12). Neurochemical mechanisms underlie the neuronal and receptor functions involved in sleep. As with the first described cholinergic and aminergic neurons, many other neurotransmitter systems modulate the REM-NREM oscillator and may interact with aminergic and cholinergic control (13–16). The regulation of sleep is considered a dual interaction of circadian and homeostatic processes, which are explained later. Whereas the nature of the sleep homeostat remains partially unclear, a detailed model of a genetically controlled suprachiasmatic cell has been established, especially in mammalians. Genes transcribe and translate to proteins shortly after certain neurons became active. They are reliably involved in 24-hour rhythmicity and in state-dependent processes (17,18). Recent studies suggest that clock genes directly influence sleep states and are implicated in sleep disorders (18,19). Sleep interacts with immune and endocrine systems (20,21) and facilitates memory consolidation (22,23). REM and NREM sleep have been unambiguously identified in mammals and birds (8).

Neurophysiological Basis and Behavior of Early Sleep Development

3

Figure 1 Diagram of the main brain structures involved in behavioral states control. Abbreviations: NREM, non–rapid eye movement; REM, rapid eye movement; EEG, electroencephalogram. Source: From Refs. 7, 9–11.

A.

REM Sleep

Since the historical investigations of Dement, from N. Kleitman’s laboratory (24), and Jouvet (13), REM sleep, also called ‘‘paradoxical’’ sleep, is the beststudied sleep pattern. It is the first state that is developed during ontogenesis. REM sleep can be understood as the result of interactions between an executive network and a permissive network (12). Converging data suggest that reticular neurons in the pons and spinal cord play a key role in REM sleep regulation. Jouvet and coworkers devised a model in which the executive REM system includes REM-on neurons specific to each of the REM parameters (12,13). In adult humans and animals, REM sleep is associated with muscular atony, pontogeniculo-occipital (PGO) spikes, rapid eye movements, small facial movements, and cortical activation with a paradoxical wakefulness-like electroencephalogram (EEG) pattern. The characteristic signs of REM sleep are further modulated at different CNS levels (7,16). The REM-on system would work as a pacemaker if it were isolated, i.e., it is continuously active when the inhibitory

4

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systems are not functional. Cessation of aminergic REM-off system firing lifts the inhibition of REM-on neurons, thus ‘‘permitting’’ the REM-on executive system to function. In addition, REM sleep is characterized by sympathetic activation (irregular heart rate and increased blood pressure, respiratory rate, and pupil diameter), as well as by augmented metabolism and oxygen consumption. Its duration may depend on the size of available energy stores (25). It is considered the (nonexclusive) state of dreaming. B.

NREM Sleep

NREM sleep lacks the visible motility of rapid eye movements and twitches. In human adults, it is divided into stages 1 through 4, defined by a slowing of brain EEG waves and an increase in the arousal threshold. NREM stages 3–4 are also named slow-wave sleep (SWS). The term SWS is frequently used to indicate NREM sleep in animals. NREM is the consequence of the inhibition of one or more of the influences that produce arousal (see sec. II.D). Similar to REM sleep, NREM sleep may involve an executive system and a permissive system. Activity of the executive NREM sleep system is identified on the basis of only two criteria, namely, sleep spindles and slow high-voltage EEG activity. Sleep spindles are produced mainly by the thalamic reticular nucleus. Slow ‘‘synchronized’’ electrical activity has been found at various cortical and subcortical levels; however, the slow-wave characteristic of NREM sleep is strongly dependent on the integrity of the neocortex and results from pyramidal cell hyperpolarization. An isolated thalamic reticular nucleus continues to exhibit rhythmic oscillations, suggesting that it acts as a pacemaker subject to inhibitory influences from the permissive system (26). The inhibitory SWS system includes neurons responsive to acetylcholine (mesencephalo-pontine nuclei and basal forebrain), histamine (posterior hypothalamus), and noradrenaline (locus coeruleus). Many aspects of the SWS system are under thermoregulatory control. SWS is characterized by a high parasympathetic tone and a decrease in general metabolism and body temperature, accompanied by the augmented synthesis of brain proteins and replenishment of energetic reserves to prepare for subsequent waking and REM sleep (22). C.

Between-Sleep State Transition

Transition between NREM and REM sleep consists in more or less progressive changes in the constellation of characteristics of the preceding state to those of the ongoing state. Although sleep during transitions between NREM and REM sleep exhibits features of both main states, it is described as an independent, individualized mode of CNS functioning. The duration and the order of sleep parameter modifications during the switch from REM to NREM sleep, and vice versa, depend on the variables taken into consideration and the age (27). Transitional sleep (TS) is probably present in mammals in general and has been

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linked to the activity seen in cerveau isole´ preparations (28). TS was first studied in the 1960s and 1970s (29). Work conducted more recently has demonstrated a variety of more or less progressive changes in neurotransmitter release during TS (30). Studies of TS have shown modifications in neuron activation at various CNS levels in animals (30,31), in autonomic nervous system control of vital functions (32), in the threshold of excitability (28), and in mental content as assessed by dream analysis (33). A recent study by Brandenberger et al. (21) demonstrates that in human adults, the autonomic and hormonal background of sleep state 2 (an NREM state) is characterized by a ‘‘quiet’’ period preparing slow-wave NREM sleep and an ‘‘active’’ period preceding REM sleep. Transition between sleep states in early human ontogenesis will be discussed in section IV.B. D.

Waking and Sleep Onset Promotion

Waking results from the conjunction of sleep inhibition with generalized neuronal activation. (34). It is mainly characterized by cortical activation (lowamplitude, fast EEG) and by behavioral arousal (movements and high postural muscles tonus). Wakefulness is supported by multiple, partially redundant neuronal systems that use different neurotransmitters, among these noradrenaline, histamine, and orexin (8,16). Investigations related to the recent identification of orexin (also known as hypochretin), a wakefulness-promoting peptide, denotes once more the role of gene expression in signaling systems that are subjected to behavioral states (18). The waking network is activated by endogenous and exogenous stimuli (Fig. 2). Sleep inhibition seems to be produced by systems specific to each of these states (7,34). Sleep-promoting neurons, mainly GABAergic, have been described in brainstem, thalamus, basal forebrain, and preoptic area. An anti-waking system is probably located in the anterior hypothalamus, an area also involved in the control of many vital functions (thermoregulation, reproduction, etc.). The antiwaking system may integrate information about the general condition of the body and the size of energy stores; sleep onset may be a preventive mechanism influenced by circadian rhythms controlled by biological clocks (7,22). Advances in biochemical techniques made during the last 20 years have led to intensive research, the results of which support the hypothesis that the awake brain produces diffusible ‘‘sleep-promoting substances’’ that induce sleep (14,18). Several such substances have been identified (see chap. 4 on hormonal control of sleep). Several models of the process involved in circadian wake-sleep regulation have been developed. Two of these models can be applied to the development of sleep characteristics during early human ontogenesis. The two-process model constructed by Achermann et al. (35) on the basis of EEG slow-wave activity emphasizes interactions between circadian (C) and homeostatic (S) processes and will be discussed below in section VI.

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Figure 2 Diagram of the sleep-waking regulation. This diagram presents five neuronal networks: waking, NREM sleep, REM sleep, anti-waking, and biological clock. The main known neuromediators are indicated by abbreviations (underlined). Note the anti-waking (sleep onset) is triggered by 5-HT, an element of the waking system. Abbreviations: NREM, non–rapid eye movement; REM, rapid eye movement; NA, noradrenalin; Ach, acetylcholine; ORX, orexin/hypocretin; 5-HT, serotonin; HA, histamine; GLU, glutamate; GABA, gamma-amino-butyric acid; GLY, glycine. Source: From Ref. 34.

Finally, many investigations suggest that wake-sleep alternation, as well as nearly all the functions of the organism, are modulated by a ‘‘clock’’ in the suprachiasmatic nuclei of the hypothalamus. In mammalians, the circadian oscillator is based on an intracellular molecular feedback loop involving time-ofday-dependent gene transcription, protein synthesis, and the suppression of transcription by the protein products of the genes that have been transcribed. At birth, circadian sleep-wake rhythms are fundamentally different as compared with those in adulthood. Maturation of circadian rhythms in humans is discussed below (see sec. V). III.

Sleep Development During Early Ontogenesis: Animal Studies

States are defined by the cyclic concordance of certain specific patterns of physiological variables, including cerebral electrical activity (EEG), motor activity, autonomic functions, and behavior. The neural structure underlying each of these variables must reach a certain degree of development before the corresponding state can appear. Behavioral states are present before birth. Data regarding prenatal morphological and neurochemical development of the main cerebral structures (Fig. 1) involved in sleep control are scant and fragmentary. The degree of brain structure maturity at a given prenatal or early postnatal age varies in different animal species. In any case, the relationship between structural

Neurophysiological Basis and Behavior of Early Sleep Development

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maturation and function is complex and nonlinear. The relationship between brain structural maturation and sleep may be bidirectional. Many studies have implicated active, REM sleep as having an important role in some brain area development. In general, active (REM) sleep has been more extensively studied than quiet (NREM) sleep. A.

Development of Brain Structures Involved in Sleep Control

In macaque monkeys, the neurons in the cerebral cortex and all other cerebral structures except the cerebellum and hippocampus are present before E100 (E, days of gestation) of the 165-day gestational period. The neurons in the locus coeruleus, raphe nuclei, and basal forebrain nuclei are generated before E50. However, axon overproduction and elimination continue until birth, and synapse density continues to increase (in the cortex) between birth and two months of age (with a peak between two and four months). Synapse density declines during the next three years, and the total number of neurons (in the visual cortex) is 16% higher in newborn than in adult animals. In humans, the cerebral cortex neurons are produced between E40 and E125 of the 265-day gestation (36,37), and studies of the visual cortex found that synapse density peaked between 8 and 12 months after birth, reaching a level about 60% greater than that in adults (38). Cortical neurons are generated from E14 to E20 in rats (21 days of gestation) and from E30 to E57 in cats (65 days of gestation). Thus, generation of cortical neurons occurs at an earlier gestational age (GA) in primates than in rodents and cats (37). Circadian timing systems develop prenatally, and the suprachiasmatic nuclei, the site of circadian clock, are present by midgestation in primates (39). Although the development of the cholinergic and monoaminergic neurotransmitters involved in sleep control begins prenatally, it continues in a significant measure during the first postnatal months in all the species studied. A developmental decrease of REM sleep between 12 and 21 days of age in rats is accompanied by an important hypertrophy of cholinergic cells in the pedunculopontine nucleus at 15 to 16 days, followed by a decrease by 20 to 21 days (40) and development of choline acetyltransferase activity in rat laterodorsal tegmental nucleus (41). Development time curves for neurotransmitters vary from one neurotransmitter to the next and from one brain region to the next. Receptor concentrations sometimes increase at a rate that exceeds the capacity of the neurons to produce their neurotransmitters. The regions that mature earliest are usually the medulla and pons, followed by the midbrain, thalamus, and hypothalamus and then by the cerebral cortex and striatum (42). This pattern reflects the earlier neurogenesis of the caudal as opposed to the rostral part of the brain. Data have been reported on the ontogenesis in the brain of neuropeptides that may be sleep factors. Somatostatin (SRIF), known to promote REM sleep (43), is detectable in the macaque cortex at E120, i.e., after completion of neuron generation and migration. SRIF levels increase prenatally, reaching a peak around birth, and in adults are only 15–30% of those at birth. Similar increases

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between E100 and near term have been observed in baboons, but there was no subsequent decline during adulthood. Vasoactive intestinal peptide (VIP) enhances both NREM and REM sleep in rats and selectively increases REM sleep in cats. This neuropeptide, which is widely distributed in the mammalian nervous system, influences cell division, neuronal survival, and neurodifferentiation (44). VIP is detectable in the cortex of primates at E120, and its levels increase 4- to 11-fold between E120 and near term; in adults, VIP levels in the various cortical regions are only 5–9% of those found at birth (37). Cholecystokinin (CCK-8) may promote NREM sleep, especially postprandial sleep. In the human brain, high levels of CCK have been found in several cortical areas, in the hypothalamus, and in the cerebellum. In the cortex of nonhuman primates, CCK immunoreactive cells colocalize with GABA cells. In macaques, CCK is detectable at E120 and increases sharply until E165 and then decreases in adulthood. In rat cortex, CCK concentrations seem to increase gradually during ontogenesis. Delta-sleep-inducing peptide (DSIP) has been detected in fetal guinea pig hypothalamus at E38 (37). Neuropeptide Y (NPY), known to produce behavioral signs of sedation and significant EEG synchronization (45), is also one of the most abundant peptides in the cerebral cortex of mammalians. NPY levels in baboon visual cortex have been studied throughout ontogenesis and found to increase gradually between E100 and adulthood. In contrast, the number of NPY immunopositive cells decrease in macaque visual cortex between E110 and adulthood (37). Orexin/hypocretin expression studied in rat increases from postnatal day 1 to adulthood (46). Developmental changes of orexin/hypocretin and their receptors are complex, specific to each area of the rat hypothalamus (47). All these substances act as neurotransmitters or neuromodulators in the developing brain and have been studied chiefly in the cortex. The fact that they are all detectable during embryonic life suggests that they might be functional before birth. However, data on correlations between neurotransmitter, neuropeptide and protein ontogenesis, and intrauterine fetal behavior are currently lacking. A behavioral state effect on cerebral metabolic rate has been described in ovine fetus near term. The REM state is characterized by an increase in oxygen and glucose uptake, compared with that of the NREM state (48). Czikk et al. (49) found that cerebral leucine uptake significantly increases during the high-voltage electrocortical/NREM state in the same ovine fetus near term. Sleep in early life may play a crucial role in brain development (50). REM sleep deprivation in adolescent rats disrupts the maturational processes that underlie developmental synaptic plasticity (51) and the balance between inhibitory and excitatory mechanisms in the visual cortex (52). REM-deprived rats aged 7 to 14 days showed significant decreases in brain mass and stained positively for programmed cell death. It is well established that myelination starts in the spinal cord and then progresses to the brainstem and forebrain. Thus, REM sleep mechanisms located in the brainstem are the first to mature and be ready to function (53).

Neurophysiological Basis and Behavior of Early Sleep Development B.

9

Development of Behavioral States in Animals

Distinct behavioral states have been described in chronically instrumented fetuses. In guinea pig fetuses, Astic et al. (54) recorded paradoxical sleep beyond 41 days of gestation, with a peak at 50 days of gestation, i.e., at the time of the first appearance of SWS. Paradoxical (REM) sleep then decreased until birth (65 days of gestation), while SWS increased. The timing of the fetal sleep cycle was not correlated with that of the maternal sleep cycle. REM and NREM states were found in lambs between 120 and 140 days of gestation (normal length of gestation, 150 days) (48, 49, 55–58). In a study using rest-activity and heart rate evaluation, Belich et al. (59) documented the cyclic occurrence of three states in rabbit fetuses beyond 25 days of gestation. Two distinct EEG states have been described in baboon fetuses recorded from 143 to 153 days of gestation (normal length of gestation, 175 to 185 days). State 1 (quiet sleep) was distinguishable from state 2 (active sleep) based on the presence of ‘‘trace´ alternant.’’ Epoch duration was shorter in state 1 than in state 2, and a smaller percentage of time was spent in state 1 than in state 2 (60). Several studies starting in the early 1960s found that newborn animals exhibited a number of different behavioral states, which were first identified on the basis of the intensity and pattern of motor activity (61). Behavioral observation and polysomnographic recording in chronically implanted kittens and rat pups showed that three main behavioral states were recognizable during the first few days of life. These states were designated (1) wakefulness (defined by moving and eating behavior), (2) quiet sleep (short periods of quiescence), and (3) active, or paradoxical, seismic REM sleep characterized by neck muscle atony, rapid eye movements, and generalized ‘‘seismic’’ movements. In these species characterized by marked immaturity at birth, EEG findings were similar in all three states (62–64). In contrast, in guinea pigs and sheep, whose brain is relatively mature at birth, the characteristics of the three main states, including EEG patterns, were similar during the first days of life and in adulthood (63,65). Active and quiet sleep, defined on the basis of the concordance of the electrocorticogram, electrooculogram (EOG), and nuchal electromyogram (EMG), were found in preterm lambs born at 133 to 135 days of gestation. Compared with full-term lambs (147 days of gestation), the preterm lambs spent more time in active, REM sleep (66). In rats and cats, the establishment of adult-like EEG characteristics of quiet sleep occurs around the third week of life and may be facilitated by weaning (63,67). However, some earlier data suggested that brain electrical oscillations characteristic of sleep states occurred in pups with relatively immature brain (57,68,69). Finding sleep state characteristics may depend on methods of parameter detection as well as on environmental conditions during recording and behavior observation (69–71). In spite of the presence of epochs with an opposition between the main REM-NREM characteristics (muscle tonus, rapid eye movements, body movement aspects), some authors do not accept that the REM-NREM epochs (in animals) during infancy are near similar to REM and NREM sleep in adulthood. On the basis of the lesions of anterior raphe nuclei, locus coeruleus, and nucleus

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subcoeruleus, Adrien et al. (72) concluded that monoaminergic systems are not involved in sleep control at birth in cats and rats. Three hypotheses have been put forward to explain some of the data obtained by the authors and some from the literature demonstrating sleep state characteristics in earlier ontogenesis: (1) The few (10%) remaining terminals may be sufficient to trigger and maintain NREM sleep and, to some extent, REM sleep. (2) Sleep maturation in immature mammals may occur via nonmonoaminergic mechanisms. (3) Active sleep may be different from adult REM sleep, including in terms of its underlying mechanisms (72,73). A study by Frank et al., based on the effect of REM sleep-inhibiting drugs in neonatal rats (74), supports the last hypothesis. In a series of recent controversial articles, these authors have named sleep in the early postnatal period as presleep and argued that ‘‘presleep is not a homolog of REM sleep and instead represents a common precursor to REM and NREM sleep’’ (75). Numerous older and recent data from the literature demonstrate that REM sleep occupies a larger proportion of time in newborns than in adults. The rate of age-related modifications in states depends on the degree of maturation at birth (Fig. 3). During the first days of life, REM sleep contributes to most of the total

Figure 3 Percentage of behavioral states during the first month of life (chronic polygraphic studies) in rat pups and kittens (immature brain at birth) and guinea pig (mature brain at birth) between 1 and 28 days of life. Abbreviations: Discont, discontinuous; EEG, electroencephalogram; SWS, slow-wave sleep, NREM sleep, non–rapid eye movement sleep; W, wakefulness; REM, rapid eye movements sleep; FT, full-term newborn; d, age in days. Source: From Ref. 76.

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sleep time in animals with very immature brains at birth (e.g., rats) versus 15–20% in guinea pigs. The amount of REM sleep declines during the first three weeks of life (5,77,78). However, at three weeks of age, the amount of REM sleep in kittens, rat pups, and guinea pig pups remains twice that in adult animals (63). REM sleep in rats continues to decline between 23 and 40 days of age (79). In conclusion, the first steps of the differentiation of behavioral states seem dependent on the degree of brain maturation; in several species characterized by greater brain maturity at birth, concordance between REM and NREM state characteristics may be established during fetal life or during the first few days after birth. Interestingly, starting very early during animal and human ontogenesis, the control of vital functions during active sleep is very similar to that during REM sleep in adults (6). EEG characteristics and time spent in different sleep states continue to mature progressively between birth and puberty. The mechanisms involved in the regulation of the main states during early ontogenesis in animals remain controversial. IV.

Development of Behavioral States During Human Ontogenesis

A. Fetal Life

The perception of cyclic fetal movements, an experience that evokes a strong emotional response in many mothers, is one of oldest criteria for assessing fetal well-being. Historically, the gathering of knowledge on fetal behavior has been dependent on advances in techniques and ethical considerations related to the study of fetuses. Prechtl (80) has described the history of fetal states assessment in great detail. Advances in real-time ultrasonography made since 1980 have demonstrated that the human fetus exhibits behavioral states that are similar to those in neonates. Estimates of the time of the first appearance of behavioral states in utero have varied according to the parameter and state scoring method used. Using continuous observation and fetal heart rate recording, Prechtl and coworkers defined four fetal behavioral states: (1) F1, characterized by a slow regular heart beat, with startles but no eye movements; (2) 2F, with an irregular heartbeat, eye movements, and occasional gross body movements; (3) 3F, with a fast regular heart rate and eye movements but no body movements; and (4) 4F, with a fast irregular heart rate, eye movements, and continual body movements (80). The first studies by Prechtl and coworkers found evidence of behavioral state development in human fetuses between 36 and 38 weeks GA (81). However, Visser et al. (82) reported correlations between heart rate, eye movement, and gross body movement patterns in normal fetuses at 30 to 32 weeks GA. In a study involving the simultaneous use of three real-time ultrasound scanners, Okai et al. (83) documented stable periods of REM and NREM of more than three minutes’ duration between 28 and 31 weeks GA and also found a strong correlation between the occurrence of rapid eye movements and breathing movements after 27 weeks GA.

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Fetal behavior is characterized by state-specific patterns of complex motor activity (80) and by ‘‘breathing’’ movements that occur mainly during state 2F or REM sleep. Interestingly, thoracic and abdominal fetal respiratory movements usually occur out of phase during state 2F, a characteristic also found during active sleep in newborns (6,84,85). Fetal states are independent of maternal behavioral states (86). Groom et al. (87) studied 30 low-risk fetuses at 38 to 40 weeks GA and again at about 2 weeks postnatal age. Behavioral states were assigned similarly on the basis of the HR pattern and the presence or absence of eye and gross body movements. The proportions of active, quiet, and indeterminate sleep were virtually identical in fetuses and neonates. Studies involving monitoring of fetal EEG activity and heart rate variability recording in healthy fetuses during normal labor demonstrated two alternating sleep states identical to those observed in newborns (88,89). Prolonged real-time ultrasonography is now avoided. On the basis of previous fetal state classification, some more recent studies bring new arguments on the influence of different fetal behavioral states on fetal cerebral hemodynamic patterns (90,91). In conclusion, the bulk of data shows that differentiated behavioral states appear in utero early during the third trimester of gestation. Fetal states are similar to those observed in newborns of the same postconceptional age, as far as criteria possible to monitor in fetuses are considered (see sec. IV.B). B.

Early Postnatal Ontogenesis: From Premature to Full-Term Newborns

The pioneers of behavioral state studies in newborns, including Roffwarg (92), Dreyfus-Brisac (93), Monod et al. (94), Parmelee (95), Prechtl (96), Wolff and Farber (97), and Anders et al. (98), have argued from the outset that specific terms were needed to designate states in newborns because EEG and behavioral characteristics differed between adults and newborns. On the basis of the results of polysomnography studies, they agreed to distinguish two major sleep states in early infancy, namely, active sleep (state 2) and quiet sleep (state 1), to which they subsequently added indeterminate (undifferentiated) sleep. As befitted careful neurophysiologists, they defined the main state-related modifications of various parameters and used combinations of several of these parameters to define states. Thus, whereas the classification of sleep states in adults was developed solely on the basis of EEG patterns (99), polygraphic recording became the gold standard for state classification and developmental physiology studies in neonates. However, attempts at state classification based on a single parameter (movement or heart rate) have also been made (100). Successful polysomnography in newborns requires that a number of technical criteria be met (70): (1) the person in charge of the recording be trained in neonatal care; (2) the data be interpreted by a person conversant with agerelated EEG characteristics in premature and full-term newborns (70,101,102);

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Figure 4 Example of digitized recordings in a 34-week PCA, healthy premature baby. Abbreviations: w, week; HE, PCA, postconceptional age; EEG, electroencephalogram; LEOG, left electrooculogram; REOG, right electrooculogram; Eye, eye movements recorded using a piezo transducer (sleep watch, respironics); O1C3 and O2C4, EEG recordings; CHIN, chin electromyograph; ECG, electrocardiogram; RR, cardiotachography based on instantaneous heart-rate measurement; FLW, nasobuccal airflow detected by thermistors; THO and ABD, thoracic and abdominal respiratory movements detected by strain gauges); RHM and ACTI1, right hand and left leg movements, respectively, detected by a piezo transducer and a commercial (Alice 4) actimeter; SaO2, oxygen saturation; sec, time in seconds; QS, quiet sleep, characterized by both a discontinuous EEG pattern and absence of eye movements; AS, active sleep characterized by a continuous EEG pattern and presence of rapid eye movements (observed and better detected by piezo recording); IS, indeterminate sleep (similar to that observed during transition between AS and QS in either direction), with a continuous EEG pattern but no rapid eye movements). Source: From Ref. 70.

(3) piezoelectric transducers rather than EOG be used for eye movement detection because of the very low amplitude of retino-corneal electrical potential differences in neonates (Fig. 4); (4) chin EMG recording may be unsuccessful because of the possibility of low amplitude activity at this level; (5) extremely lightweight transducers be used for leg movement detection. Use of recording methods that are not suited to newborns causes errors in sleep state identification. When the technician is experienced in neonatal polysomnography, the baby usually falls asleep before the end of electrode placement. Sleep state scoring data are dependent on a number of methodological factors, including (1) the nature of the variables chosen for state definition (Fig. 4, Table 1), (2) whether or not the characteristics of these variables are quantified

Discont.



AS

Cont.: DþY, or D, or semidiscont.

þ

State

EEG

Eye movements

Regular or irregular

þ/ (20%)

þþ (5.2%)



þþþ (20%)

þþþ (22%)



Irregular

AS

35–36

þþ (7%)

þ/ (20%)

Regular or irregular

QS



þþþ (22%)



Irregular

AS

37–38

Discont. or semidiscont.

Cont.: DþY, or D þþ

QS

AS

35–36

þþ (10%)

þ/ (20%)

Regular or irregular

QS

þþþ

Cont.: Y, or, DþY or D

AS

37–41

þþ (14%)



Irregular

AS

39–41



þ (3%)

þ/ (20%)

Regular or irregular

QS

Trace´ alternant

QS

Some authors (100) used variable/nonvariable heart rate as a state criterion; however, no quantified data are available. Note that about 20% of quiet sleep is spent with inhibited tonic chin EMG. Body movements decrease in amount with age. The number of pluses is a relative indication of eye or body movement density. For irregular respiration definition and amount, see Ref. 70. a No quantitative data available for younger infants. b In parentheses: percentage of 20 seconds spent with this parameter. Abbreviations: PCA, postconceptional age, calculated from the first day of the last menstrual period; Cont., continuous EEG trace; Discont., discontinuous EEG trace; D, delta EEG activity; Y, theta EEG activity. Source: From Ref. 70.

Body movements

b

Tonic chin EMGb

Respiratory rate

QS

Irregular

AS

State

a

31–34a

PCA in wk

(B) Ancillary Variables for Sleep State Scoring

QS

27–34a

PCA in wk

(A) Major Variables for Sleep State Scoring

Table 1 Summary of the Major Variables and Ancillary Variables That Have Been Used for Sleep State Scoring at Various Conceptional Ages

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or scored on the basis of their general ‘‘gestalt’’ aspect (e.g., what is regular vs. irregular breathing), (3) the minimum duration used to define the state, (4) the predefined duration of parameter discrepancies that can be kept within the ongoing state (state smoothing), (5) the criteria used to define the onset of a given state, and (6) the criteria used to define termination of a given state. Although scoring is done epoch by epoch, the stability of concordance between parameters throughout successive epochs of the major states (wakefulness and crying, active sleep, quiet sleep) is required before a recording period can be assigned to a given state. The onset of a major state is defined as the presence of the corresponding constellation of state-specific criteria for one minute (103,104), three minutes (96,100), or four minutes (4). Discrepancies among parameters lasting less than 60 seconds are included within the state (70,103,105), whereas a longer-lasting discrepancy (>60 seconds) or occurrence of a constellation specific to another state defines termination of the state. Periods with discrepancies between the main state criteria are scored as undifferentiated or indeterminate or ambiguous sleep. Transitional sleep (TS) (27,103) is the term used to designate periods of transition from one main state to another; its duration can be less than 60 seconds Table 1 summarizes the main and secondary criteria used to define active and quiet sleep in newborns. In addition to the consensual active sleep versus quiet sleep concept (98), many authors use the classification developed in the late 1960s by Prechtl and coworkers in full-term newborns. This classification, which does not use the EEG pattern as a state criterion, distinguishes five behavioral states (1,96) as follows: (1) state 1, eyes closed, regular respiration, no movements; (2) state 2, eyes closed, irregular respiration, no gross movements; (3) state 3, eyes open, no gross movements; (4) state 4, eyes open, gross movements, no crying; and (5) state 5, eyes open or closed, crying. The basic procedure for recording and scoring behavioral states is the same whether a chart polygraph or a computerized data acquisition system is used. For references on the computerized method for state parameter analysis in newborns, see the studies by Scher et al. (106) and chapter 2, ‘‘Ontogeny of EEG Sleep,’’ in this book. Periods of active and quiet sleep of more than three minutes’ duration, defined on the basis of concordance between EEG and REM criteria, exist in neurologically normal premature newborns of more than 27 (105) or 28 weeks PCA (107), although marked inter- and intraindividual differences occur. On the basis of REMs versus the presence of EEG discontinuity scoring, Vecchierini et al. (108) and Scher et al. (109) recently found sleep state cyclicity for a majority of neonates between 25 and 30 weeks GA. In premature babies, active sleep and quiet sleep are characterized by striking differences in EEG activity [continuous in active sleep vs. discontinuous in quiet sleep (Fig. 4)] and rapid eye movements (present in active sleep and absent in quiet sleep). Over time, slow-wave burst duration increases slightly and the amplitude of background EEG activity between the slow-wave bursts on discontinuous tracings steps up significantly,

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Figure 5 Duration in minutes (min) of between-sleep state transitions in 35 premature babies of 30–36 week post-conceptional age. AS and QS have been defined by the concordance between REMs and EEG criteria (See Fig. 4 for state definition). Abbreviations: AS, active sleep; QS, quiet sleep; REMs, rapid eye movements; EEG, electroencephalogram. Source: From Ref. 27.

finally producing the trace´ alternant pattern characteristic of quiet sleep near normal term (101,110). During the first postterm few weeks of life, the trace´ alternant pattern is replaced by a slow-wave high-voltage pattern (111–114). Between 30 and 36 weeks PCA, the duration of active to quiet sleep transition is significantly longer than the quiet to active transition, independent of GA (Fig. 5). The sequence of modification in parameters is invariable: REM cessation is the first change in active to quiet sleep transition, and REM appearance is the last change in quiet to active transition (27). Monod et al. (103) described a complex pattern of between-state transition in full-term newborns using chin EMG and body movement parameters in addition to EEG recording (103). Between 27 and 34 weeks PCA, indeterminate sleep contributes a mean of 30% of the total sleep time. Indeterminate sleep is defined on the basis of discordance between the two main criteria defining active and quiet sleep. Indeterminate sleep diminishes significantly at 35 to 36 weeks PCA and then remains stable until term (104). Beyond 31 to 34 weeks PCA, a significantly larger percentage of time is spent in active than in quiet sleep (104,105). Near term, 55–65% of the sleep time is spent in active sleep versus about 20% in quiet sleep (Fig. 6). The duration of sleep states can vary widely across successive sleep cycles in a given infant (70,109). In contrast to adults, premature and full-term newborns fall asleep in active sleep. The first active sleep period, following a period of wakefulness, is usually characterized by a shorter duration and a slower EEG

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Figure 6 Percentage of the total sleep time spent in active, REM sleep; quiet, NREM sleep; and IS. (Left) Daytime sleep in newborns from 27 to 41 w GA. (Right) Nighttime sleep in infants from 1 to 24 m of postnatal age. The data on NREM sleep from the study by Louis et al. (117) include the amount of St 2–4, and the data on IS are the sum of IS and St 1, according to the state scoring system developed by Retchtschaffen and Kales (99). Abbreviations: EEG, electroencephalogram; REM, rapid eye movement; NREM, non– rapid eye movement; PNA, postnatal age; IS, indeterminate sleep; AS, active sleep; St 1, state 1; St 2–4, states 2 to 4; GA, gestational age; w, week, m, month. Source: Adapted from Refs. 103, 104 (left) and from Ref. 115 for 1- to 6-month-old infants and from Refs. 116 and 117 for 9- to 24-month-old infants (right).

pattern compared with the next active sleep period, occurring after a quiet sleep period. Sleep cycles, defined as an active sleep and a quiet sleep period with the interpolated indeterminate sleep period, are shorter before 35 weeks GA, with a mean duration of 45 to 50 minutes according to the study. From 35 to 36 weeks GA to term, the sleep cycle duration is about 55 to 65 minutes (Fig. 7), which is similar to that observed during the first few months of life (104,105,116). Artificial ventilation per se does not modify sleep structure in premature babies who are neurologically normal and clinically stable (105,107,109). Sleep organization is unaffected by maintenance-dose caffeine in 33 to 34 weeks PCA in premature infants (119). Bertelle et al. (120) found that the Neonatal Individualized Developmental Care Assessment Program (NIDCAP), as described by Als et al. (121), promoted sleep duration and sleep stability in the neonate. Data and review of the literature (122) did not confirm the influence of some NIDCAP element on sleep in preterm infants. Sleep organization in premature

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Figure 7 Mean sleep cycle duration in minutes at different ages. Data from different laboratories are connected by a dark line. (Left): Daytime sleep in newborns from 27 to 41 weeks PCA or GA. (Right): Nighttime sleep in infants from 1.5 to 24 m of PNA and in children aged about 5 y. Abbreviations: PCA, postconceptional age; GA, gestational age; PNA, postnatal age; m, months; y, years. Source: Adapted from Refs. 104, 105 (left); Refs. 117, 118 (right).

babies reaching normal term (123,124) and in full-term, small-for-GA newborns (125) does not differ from that observed in full-term controls. In general, both in the literature and in our own experience, sleep state differentiation was documented earlier during ontogenesis in studies performed after the 1980s (104,107,126,127) than in those done previously (96,128). This differentiation is probably ascribable to the improvements made in neonatal care in industrialized countries during the last few decades. In conclusion, differentiated active sleep and quiet sleep are observed starting at 27 weeks PCA in neurologically normal and clinically stable premature infants, concordance between REMs and specific EEG patterns being observed beyond 25 weeks PCA. Until 34 weeks PCA, about 30% of the sleep time is spent in indeterminate sleep. Beyond 35 to 36 weeks GA, indeterminate sleep decreases significantly and sleep structure becomes very similar to that observed during the first month of postterm life. Thus, 27 weeks and 35 to 36 weeks PCA appear as turning points in the ontogenesis of human sleep (Fig. 6, Table 2). Knowledge of early state differentiation is important because (1) a number of physiological parameters are correlated to sleep states in young babies (6,85,129,130) and (2) a number of abnormalities in newborns occur primarily in one or the other of the two main sleep states (abnormal respiratory events are more common during active sleep, whereas EEG abnormalities are more readily detected during quiet sleep).

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Table 2 Main Steps in Sleep-Wake Maturation Sleep-wake cycle

Sleep structure

Ultradian rhythm during the fetal period and first days of life

Emergence of AS/QS at 27-wk gestational age AS increases, IS decreases; cycle duration increases (40–45 to 55–60 min) at 34–35 wk gestational age Emergence of sleep spindles between 1.5 and 3 mo Significant decrease in REM sleep with concomitant increase in NREM sleep: emergence of stages 1, 2 and 3, 4 between 3 and 5 mo Disappearance of REM sleep onset from 3 to 9 mo Nycthemeral organization of SWS and REM sleep between 9 and 12 mo Lengthening of the sleep cycle to adult level between 2 and 6 yr

Emergence of circadian rhythmicity during the first weeks of life (free running cycle of 25 hr)

Entrainment to 24-hr cycle after 3 mo Consolidation of nocturnal sleep from 6 mo of age Disappearance of naps between 3 and 6 yr of life

Abbreviations: AS, active sleep; QS, quiet sleep; IS, indeterminate sleep; REM, rapid eye movement; NREM, non–rapid eye movement; SWS, slow-wave sleep.

C.

The First Year of Life

After the first month of postnatal life, the global amount of sleep as well as of different sleep states show evident changes (Table 2). Studies aimed to trace the development of sleep states in the first year of life based on 24-hour polygraphic recordings (117, 131–134) showed that the global amount of sleep decreases with age, that quiet sleep increases, and that active sleep and indeterminate or ambiguous sleep decrease (Fig. 6). In particular, the global amount of sleep decreases from about 13 hours at term age to 10 hours at the end of the first year of life, quiet sleep increases from about 5 hours to about 7 hours, and active and indeterminate sleep decrease, respectively, from about 5 hours to about 1.5 hours and from about 3 hours to about 1 hour (Fig. 8). A distinct development occurs between day and night periods. The reduction of active sleep during the 24-hour period is mainly due to the decrease of the active sleep episodes during the day, whereas the global amount during the night does not change. On the contrary, the global amount of quiet sleep slightly decreases during the day, while markedly increasing during the night because of the increase of the mean duration of the phases. As far as indeterminate sleep is concerned (Fig. 6), a decreasing trend with age, with no particular distribution across 24-hour periods (131), is observed. The almost complete disappearance of

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Figure 8 Waking and sleep states amounts in the 24-hour period according to the age. Abbreviations: W, waking; QS, quiet sleep; PS, paradoxical sleep or REM, rapid eye movement sleep; Amb S, ambiguous sleep or IS, indeterminate sleep. Source: From Ref. 131.

this form of sleep at the end of the first year of life is an expression of the progressive maturation of the CNS (131). In addition, the reduction of indeterminate sleep also has an impact on the increasing organization of the sleep episode. Indeed, a study (135) analyzing the internal structure of the sleep cycle (i.e., the quiet sleep–active sleep sequence) during the first year of life showed an increase with age of the mean duration of the cycles because of the presence of slow-wave sleep within quiet sleep episodes and the near disappearance of indeterminate sleep within the cycle, whereas the proportion of active sleep did not change. The lengthening of sleep cycles during the second semester of life (Fig. 7) and the decrease in sleep ‘‘out of the cycle’’ lead to the increased proportion of total time spent in cycle (TCT) on total sleep time (TST) (135). During the first 12 months of age, the distribution of sleep states across the night changes, approaching what is observed in the adult. From 4 months of age the longer quiet sleep episodes tend to be located in the first part of the night, whereas at 12 months active sleep in the last part of the night is not yet prevalent. Indeed, the active sleep amount does not change with age in any epochs of the nocturnal period, and in the second semester of life the longest active sleep episodes are not yet located at the end of the night (131). Although features of quiet sleep develop later than that of active sleep (136), quiet sleep reaches the adult-like night distribution before active sleep.

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Across early epochs of postnatal life, some turning points in steps of sleep development can be underscored. During the second month, the trace´ alternant disappears (111,112,137) and spindles take place (138–140), the burst density of eye movements reaches a plateau level (141), and the difference of the heart rate values between quiet sleep and active sleep becomes more evident (142,143). Around the fifth month, the duration and the structure of quiet sleep episodes (144) become similar to those of the adult. The increase in duration does not involve all quiet sleep episodes, but mainly those containing slow-wave activity (145), which is present in alternating episodes of quiet sleep with a periodicity of about 100 minutes. At this epoch of life, two different periodicities exist within sleep episodes (144): one related to the sleep state cycle every 50 minutes, and the other related to the slow EEG activity that appears every 100 minutes. To summarize the main sleep modifications that occur during the first 12 months of life, at the end of the first year infant sleep acquires new modalities of functioning and new phenomena and loses some others. In particular, the sleep features are more and more similar to those of the adult, with nocturnal sleep composed of one or two episodes and few diurnal naps composed mainly of NREM sleep. As in adult sleep, SWS is more prevalent during the first part of the night and the eye movement activity within REM episodes is organized in bursts. D.

From Two to Five Years

Polygraphic studies analyzing sleep modification after two years of life are rare (117,146). In particular, 24-hour home polygraphic recordings of sleep in infants, observed longitudinally from 3 to 24 months, showed, at 2 years of life, a further reduction of REM sleep during the diurnal period, with sleep episodes essentially composed of SWS. As far as the nocturnal period is concerned, a significant increase in sleep efficiency and in the length of the REM period was reported, whereas the total sleep time and number of awakenings decreased (Fig. 9). A recent longitudinal study (147) analyzing sleep throughout actigraphy, in infants from 3 months to 3 years of life, reported a well-organized sleep by 12 months and a progressive increase with age in sleep continuity and in sleep efficiency, without a significant difference between boys and girls. In particular, the analysis of motor activity during sleep revealed a moderate stability of body motility across time. The sleep onset and sleep duration instability across time found by the authors could, instead, reflect the sensibility of sleep schedules and parental interventions. On the contrary, the discontinuity of the number of awakenings reported in this period of age probably reflects sleep maturational changes. Modifications in sleep parameters were also observed at later ages. In a recent study, Acebo and colleagues (148), investigating sleep-wake patterns from actigraphy recordings and maternal reports in healthy children aged one to five years, reported that 12-month-old infants had the earliest start of bedtime, the longest time in bed, and the longest sleep duration. In contrast, rise time, sleep end time, and nocturnal sleep (an average of 8.7 hour at night) were stable

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Figure 9 Evolution with age of the different behavioral stages as percentages of total 24-hour home recordings. Diurnal (left) and nocturnal (right) periods were defined based on the light-off and light-on times given by the parents. Note that waking and REM sleep are negatively correlated, especially during the daytime. Abbreviations: IS, indeterminate sleep; St 1, state 1 of NREM sleep; St 2, State 2 of NREM sleep; SWS, slow-wave sleep; REM, rapid eye movement; TRT, total recorder time; m, post-term age in months, NREM, non–rapid eye movement. Source: From Ref. 117.

across ages. Mother reports underestimate night wake time and night wake episodes, reporting lower values than those observed with actigraphy recordings. The same study showed that children of families with low socioeconomic status get up later, remain longer in bed, and have more night awakenings and higher night-to-night variability than children of families with high socioeconomic status. V.

The Development of Sleep-Wake Rhythm

Although the circadian pacemaker is probably functional in the fetal period (149–151), circadian rhythmicities are scarcely developed in the newborns. At birth, several physiological and behavioral variables show ultradian rhythms (152–158) that become longer during the first months of life. Many factors seem to be involved in the entrainment of circadian rhythmicity. The maternal influence has been shown to be involved in the fetal circadian rhythmicity of heart rate (159), whereas in the newborn, external factors such as light-dark alternation (160–162) and care practices (163,164) seem to influence the time of establishment of a circadian modulation of several physiological and behavioral variables.

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In neonates observed in the first months of life, short sleep and waking episodes alternate across the 24-hour period (158,165). Daytime sleep episode lengths assessed by behavioral observations vary between 20 and 40 minutes (166). The duration of sleep episodes measured by polygraphic recordings are shown in Figure 7. The uninterrupted period of waking lasts about 7 minutes, with an interindividual range between 3 and 21 minutes (166). During the first months of life, sleep polygraphic recordings across 24 hours showed numerous sleep episodes that tend to be longer during the nocturnal period (132). On the contrary, by one month of age, periods of prolonged wakefulness are preferentially located in the early evening hours (165,167,168). It is interesting to note that the development of monophasic sleep-wake rhythm in infants is paralleled by the difficulty in falling asleep in a delimited period of 24 hours. This phenomenon, which Lavie (169) has previously shown in the adult, has been recently also observed in preterm (170) and full-term infants across the first year of life (171). The occurrence at very early ages of a peak of wakefulness in the night for preterm infants and in the evening for full-term infants (corresponding to the time of lowest sleep propensity in the adult) looks like an example of the precocious mechanism that regulates the temporal distribution of sleep and waking. By three to four months of age, the entrainment of sleep-wake rhythm to the 24-hour cycle emerges (165,167,168). The duration of longest sustained sleep increases with age and is mainly located during the night (172), whereas the longest sustained waking is mainly located during the day (165). The longest sustained sleep period increases progressively from about 3.5 hours at 3 months to 6 hours at 6 months. Also, the longest sustained waking period increases from about 2 hours at 3 months to 3.5 hours at 6 months (133). Circadian rhythms of heart rate, body movements, body temperature, cortisol, and melatonin are present from the first months of life, and the amplitude of these rhythms increases by three months of age (154,156,173–175). Some of these rhythms could play an important role in the development of the sleep-wake cycle. In particular, the circadian rhythmicity of body temperature observed by Guilleminault et al. (155) from 10 weeks of postnatal age onward could be parallel to the change from a more polyphasic sleep-wake rhythm to a less polyphasic one, as proposed by Giganti and colleagues (193). Also, the melatonin secretion cycle seems to influence the sleep-wake rhythm. In six- to eight-month-old infants, higher melatonin secretion rates during the evening hours were associated with an earlier onset of nocturnal sleep episode, whereas a delayed peak was associated with a more fragmented nocturnal sleep (156). Feeding rhythms have no noticeable impact on sleep-wake rhythms (while they could contribute to reinforce the existing ones), as was demonstrated by the study of infants continuously fed from birth (176,177). On the contrary, feeding rhythm seems important for the circadian rhythmicity of cardiac rate (178).

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Early Sleep-Wake Regulation

Experiments involving manipulation of sleep in the adult, such as sleep deprivation, sleep extension, or shifting of sleep, demonstrate that NREM sleep, and more specifically the intensity of slow-wave sleep, is largely dependent on the duration of the prior wakefulness. This observation suggested the existence of a homeostatic process, designated process S, which becomes more intense as the duration of prior wakefulness increases and less intense as the duration of sleep increases. In the adults, SWS is abundant immediately after sleep onset and recurs during each cycle with decreasing intensity from one cycle to the next (179). In infants, no studies have used the paradigm that evaluates the effect of previous sleep deprivation. However, few studies did attempt to evaluate the time course of slow EEG activity across the sleep episode during the first year of life (180–182). A sketch of a decreasing trend of slow activity was found already at early ages from the second week on (180). Moreover, looking at naturally existing wake episodes of different lengths before a sleep episode, a close relation was found between the duration of waking and the intensity of EEG synchronization, i.e., slow-wave activity (183). This relation is a further argument for an early regulation of the homeostatic nature of the sleep process. The existence of sleep cycles with alternate slow waves in the second semester of life complicates the decreasing trend of SWS (180,184). These results point at also taking into account the basic structure of the sleep on which delta waves are superimposed. An open question is the existence of ‘‘signs’’ of homeostatic control before term age. In conclusion, a sketch of the homeostatic control of sleep can be inferred from the EEG slow-wave trends across the sleep episode observed from the first week of life on. However, to conclude for a true homeostatic control, we would need experiments that manipulate the sleep-wake rhythm and evaluate the effect on EEG activity trends. Also, to conclude about the working of the ‘‘two-process model’’ at early ages, we would need a combined homeostatic and circadian time course of EEG and other physiological variables such as temperature. A second process was considered important, i.e., the circadian one interacting with the process S, to regulate sleep-wake rhythm (179,185). No coexisting data have been collected for babies. Fagioli et al. (186) have proposed a tentative model (Fig. 10). VII.

Awakening

Awakening is an event of special interest for developmental studies, as suggested by both the high frequency in the first epochs of life and its subsequent decline. In addition, an excessive number or duration of awakenings (night waking) is well known in the clinical domain. Quite recently, several papers and meetings have been devoted to this topic (187).

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Figure 10 (Upper panel ): Process S and Process C time course in adults and resulting sleep-wake organisation: waking and sleep resulting respectively from the intersection of declining S process (black) curve and the threshold L (grey, lower sinusoidal curve) and from the intersection of the increasing S process curve and the threshold H (grey, upper sinusoidal curve) are represented by white and black rectangles in the upper part of the figure. (Lower panel ) Process S and C and sleep-wake organization in infants according to the hypotheses. Source: From Refs. 185, 186.

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Awakening (behavioral) should be distinguished from arousal, a term often used as a synonym. Arousal represents the short-lasting activation of the CNS, which is manifested either by the EEG fast activity or by an increase in muscle tonus and body movements; arousal events are often shown in sleep-related respiratory disturbances (187). Physiological mechanisms that precede awakening have been described. The sleep state preceding awakening is mainly REM (active) sleep in infants as well as in young adults (188–190). This result indirectly suggests that similar mechanisms could facilitate the transition from sleep to waking. Similar activation level in active (REM) sleep and waking could facilitate the ‘‘gating’’ role of REM sleep. The analysis of the time course of individual physiological and behavioral activities has shown that awakening is the result of progressive changes. The level of EEG activation increases some minutes before the full behavioral awakening from quiet sleep, but it does not change during active sleep (191). Tach and Ljiowska (192) have reported an increase of motor activity before awakening in infants aged one to six months. More systematic investigation of epochs preceding the awakenings for both quiet sleep and active sleep are needed, starting from preterm infants up to at least the end of the first year of life. A study of the development of awakenings during the 24-hour period in preterm and near-term infants showed that the number of awakenings does not change, but that their mean duration increases significantly (193). The increase is observed mainly during the day and is accounted for by those awakenings starting with crying. At later ages, the awakenings decrease across the first year of life mainly at nighttime (117,132), without any further change in the second year of life (117). The trend toward a decrease in the number of awakenings during the first year of life has been reported by several studies performed during nighttime only (115,189,194,195) (Fig. 11) and parallels the process of nighttime sleep consolidation (134). Where there is a high consistency in the literature concerning the trend with age in the occurrence of awakenings, some discrepancies are observed concerning the developmental trend of awakening duration. As previously suggested by Fagioli et al. (186), the difference in the minimal duration for states’ scoring can explain these results. In particular, according to Hoppenbrouwers et al. (115), the mean duration of awakenings slightly increases with age, whereas Louis et al. (117) and Ficca et al. (189) observed no changes. Only Navelet and coworkers (195), using the longest minimum duration to define the waking state (5 minutes), found an evident decrease with age. The periodicity of awakening is about 100 minutes for those coming from active (REM) sleep across the whole first year of life, but it is greater for those coming from quiet (NREM) sleep, reaching nearly the double (about 200 minutes) from six months onward (186).

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Figure 11 Number of night awakenings (y axis) as a function of age (x axis) reported in five studies. Source: From Ref. 186.

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2 Ontogeny of EEG Sleep MARK S. SCHER Case Western Reserve University, Cleveland, Ohio, U.S.A.

I.

Introduction

Electrographic and polygraphic recordings of newborns and infants have been performed for over half a century (1). Pioneering studies by multiple researchers worldwide offer neurophysiologic information concerning the developing central nervous system (2–9). Earlier investigations predated the creation of the modern neonatal intensive care unit (NICU). However, these seminal works described for the first time electrographic patterns and other physiologic behaviors that define rudimentary state of the preterm neonate, and state maturation with increasing postmenstrual ages (PMAs) to term. Given the higher rate of neonatal mortality, particularly in the premature infant, the clinical neurophysiologist had a more limited consultative role in the neurologic care of the sick neonate. With the creation of the modern-day tertiary care NICU, more sophisticated medical care now includes technological advances in physiologic recordings at bedside. Currently, the neonatal neurologist has a more interactive role as a neurointensive care consultant, combining clinical examination assessments with interpretations of neurophysiologic and neuroimaging studies for the dual purpose of diagnostic and prognostic input for the neonatal intensivist. 39

40

Scher

With the decline of neonatal morbidity and mortality, renewed attention has been directed toward the neurologic performance of the high-risk newborn during both the acute and convalescent periods in the days to weeks after birth. Given the immature clinical repertoire of the newborn and infant, as well as limited access to neonates in a busy intensive care setting, EEG-polygraphic studies can augment the neurologist’s ability to document functional brain maturation as well as the presence and severity of encephalopathic states. Serial EEG-sleep analyses can also have impact on the clinician’s ability to offer appropriate interventional therapies when altered functional brain maturation is detected (i.e., dysmaturity) (10). This degree of monitoring is particularly relevant for the very low-birth weight neonate who carries a substantially long-term risk for neurocognitive and neurobehavioral morbidities (11–15). Quantitative estimates of brain dysmaturity using computer analyses are being refined as research tools to develop objective measures for the detection of pervasive expressions of encephalopathy to better predict outcome (16). Neonatal survivors can then be evaluated after discharge at successively older ages to document continued brain maturation during infancy and later childhood by using serial neurophysiologic analyses. The documentation of maturation of neonatal and infant behaviors requires careful evaluation of both waking and sleep states. Combined neurophysiologic and noncerebral monitoring can more completely assess functional brain maturation throughout the neuraxis. The clinician utilizing skilled visual analyses will be able to apply knowledge of sleep ontogeny to the evaluation of different pediatric populations who are at risk for developmental delay (17), as suggested by altered behaviors during sleep or wakefulness. Computer-assisted analytical tools also augment our abilities to examine physiologic relationships between cerebral and noncerebral measures and to explore associations with neuroimaging, neurogenetic, and neurodevelopmental outcome measures (16,18,19). It has been recently suggested that the extensive but largely phenomenological visual analyses of neonatal EEG-sleep be integrated with computational analyses. This union of investigative techniques by visual and automated strategies can critically evaluate brain organization and maturation in conjunction with future translational and comparative studies related to brain ontogeny (20,21). II.

Caveats Concerning Neurophysiologic Interpretation of State

Knowledge of specific caveats can assist the neurophysiologist in applying an understanding of sleep analysis to developmental assessment from neonatal through infancy periods. Maturational changes on EEG-polygraphic studies are noted at successively older ages after birth, taking into account the weeks of maturity at birth. Recommendations by the American Academy of Pediatrics (22)

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suggest that the term postmenstrual age (PMA) replace the term postconceptional age. Such recommendations emphasize standardized terminology when defining ages and comparing outcomes of fetuses and newborns. Neurophysiologic maturity of a neonate can be estimated within two weeks for the preterm infant (i.e.,