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Understanding and Treating Sleep Disturbances in Autism: A Multi-Disciplinary Approach [1 ed.]
 9781787759916, 9781787759923

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Understanding and Treating Sleep Disturbances in Autism

in the same series Understanding and Treating Anxiety in Autism A Multi-Disciplinary Approach

Edited by Stephen M. Edelson and Jane Botsford Johnson Foreword by Dr. David Amaral ISBN 978 1 78775 152 1 eISBN 978 1 78775 153 8

Understanding and Treating Self-Injurious Behavior in Autism A Multi-Disciplinary Perspective

Edited by Stephen M. Edelson and Jane Botsford Johnson Foreword by Temple Grandin ISBN 978 1 84905 741 7 eISBN 978 1 78450 189 1

by the same authors Infantile Autism The Syndrome and Its Implications for a Neural Theory of Behavior by Bernard Rimland, PhD 50th Anniversary Updated Edition

Edited by Stephen M. Edelson Forewords by Temple Grandin, PhD, and Margaret L. Bauman, MD ISBN 978 1 84905 789 9 eISBN 978 1 78450 057 3

Siblings The Autism Spectrum Through Our Eyes

Jane Johnson and Anne Van Rensselaer ISBN 978 1 84905 829 2 eISBN 978 0 85700 281 5

UNDERSTANDING AND TREATING SLEEP DISTURBANCES IN AUTISM A MULTI-DISCIPLINARY APPROACH EDITED BY STEPHEN M. EDELSON AND JANE BOTSFORD JOHNSON

FOREWORD BY BETH ANN MALOW, MD, MS

First published in Great Britain in 2022 by Jessica Kingsley Publishers An imprint of Hodder & Stoughton Ltd An Hachette Company 1 Copyright © Jessica Kingsley Publishers 2022 Foreword copyright © Beth Ann Malow 2022 The right of Stephen M. Edelson and Jane Botsford Johnson to be identified as the Author of the Work has been asserted by them in accordance with the Copyright, Designs and Patents Act 1988. Front cover image source: Starkow. The cover image is for illustrative purposes only, and any person featuring is a model. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means without the prior written permission of the publisher, nor be otherwise circulated in any form of binding or cover other than that in which it is published and without a similar condition being imposed on the subsequent purchaser. A CIP catalogue record for this title is available from the British Library and the Library of Congress ISBN 978 1 78775 992 3 eISBN 978 1 78775 991 6 Printed and bound in Great Britain by CPI Group Jessica Kingsley Publishers’ policy is to use papers that are natural, renewable and recyclable products and made from wood grown in sustainable forests. The logging and manufacturing processes are expected to conform to the environmental regulations of the country of origin. Jessica Kingsley Publishers Carmelite House 50 Victoria Embankment London EC4Y 0DZ www.jkp.com

CONTENTS

FOREWORD 7 Beth Ann Malow, MD, MS, Professor of Neurology and Pediatrics, Burry Chair in Cognitive Childhood Development, Director of Sleep Disorders Division, Vanderbilt University Medical Center INTRODUCTION 9 Stephen M. Edelson, PhD, Autism Research Institute, San Diego

1. Pharmacotherapy for Sleep Problems in Autism Spectrum Disorder

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Tomoya Hirota, MD, Department of Psychiatry and Behavioral Sciences, University of California San Francisco, UCSF Benioff Children’s Hospital Oakland, Michelle S. Nakaishi, CPNP, UCSF Benioff Children’s Hospital Oakland, Katherine Whitley, MS, UCSF Benioff Children’s Hospital Oakland, and Robert L. Hendren, DO, Department of Psychiatry and Behavioral Sciences, University of California San Francisco

2. The Role of Clinical Polysomnography in the Evaluation of Sleep Difficulties in Patients on the Autism Spectrum

37

Kenneth C. Sassower, MD, Massachusetts General Hospital, Harvard Medical School, and Margaret L. Bauman, MD, Boston University School of Medicine

3. Sleep Disorders in Autism: The Role of Pain and Serotonin

51

Manuel F. Casanova, MD, University of South Carolina School of Medicine Greenville, Department of Pediatrics, Division of Developmental Behavioral Pediatrics, PrismaHealth System, Greenville, Emily L. Casanova, PhD, University of South Carolina School of Medicine Greenville, and Estate M. Sokhadze, PhD, University of South Carolina School of Medicine Greenville

4. Diet, Nutrition, Sleep and those with Autism Spectrum Disorder

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Kelly McCracken Barnhill, MBA, CN, CCN, The Johnson Center for Child Health and Development, Texas

5. Sleep and Sensory Processing

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Virginia Spielmann, PhD, MSOT, STAR Institute for Sensory Processing Centennial, Colorado, Marco Leão, MS, OT, AcademiaPediatrica.com, Porto, Portugal, and Shelly J. Lane, PhD, OTR/L, FAOTA, Colorado State University

6. Behavioral Interventions for Sleep Problems Lauren J. Moskowitz, PhD, St. John’s University, New York, and V. Mark Durand, PhD, University of South Florida St. Petersburg

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CONCLUSION 137 Stephen M. Edelson, PhD, Autism Research Institute, San Diego SUBJECT INDEX 139 AUTHOR INDEX 141

Foreword Beth Ann Malow, MD, MS, Professor of Neurology and Pediatrics, Burry Chair in Cognitive Childhood Development, Director of Sleep Disorders Division, Vanderbilt University Medical Center

“There is a time for many words, and there is also a time for sleep.” – Homer, The Odyssey

As a neurology sleep specialist in the 1990s, I was fascinated by the ways sleep impacted every aspect of brain health. I was intrigued when one of my patients with difficult-to-control epilepsy became seizure free after his obstructive sleep apnea was treated with continuous positive airway pressure (CPAP), which led to my publishing a case series and eventually a randomized clinical trial on the topic. Similarly, strokes, migraines, and even cognitive function, were all adversely affected by poor sleep. Sleep also affects neurodevelopmental conditions. After my children were diagnosed on the autism spectrum in the early 2000s, I was encouraged to pursue the field of sleep and autism, which at the time was only beginning to emerge. I embraced this challenge, not only because it was intellectually stimulating to work with others as pioneers in this new area, but also because I recognized how badly sleep therapeutics—whether behavioral or pharmacological—were needed. Sleep not only affects physical health in autism, but also daytime behavior. At a time when pharmacological treatments for challenging behaviors were not readily available (they are still lacking, especially those without concerning adverse effects), improving sleep was, and remains, an important avenue for improving physical health, mental health, daytime behavior, and child and family quality of life. When my oldest son was diagnosed on the autism spectrum, the prevalence of this condition was about 1 in 200; it has now increased to 1 in 44.

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More than 700,000 children with autism will enter adulthood in the upcoming decade, and sleep problems (which affect 50–80%) do not resolve with age. The commonality of autism, the high prevalence of sleep problems, and the significant benefits of treatment will continue to propel this field forward. My hope is that others will be inspired by the work presented in this text, and research funders will recognize the need to support the work that lies ahead.

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Introduction Stephen M. Edelson, PhD, Autism Research Institute, San Diego

For an individual on the autism spectrum, poor sleep can have a profound impact on almost every aspect of life. Sleep disturbances can lead to a state of chronic sleep deprivation, and recent research suggests that reduced amounts of sleep may contribute to lower levels of functioning and greater severity of symptoms in people with autism (Carmassi et al., 2019; MacDuffie et al., 2020; Wintler et al., 2020). One study did suggest that sleep problems simply co-occur with autistic traits during early childhood rather than precede them (Verhoeff et al., 2018). Critical and rapid brain growth occurs during infancy and early childhood, and much neurodevelopment occurs during sleep (Tham, Schneider & Broekman, 2017). An infant needs approximately 12–14 hours of sleep each day, and a young child needs roughly 10–12 hours. Unfortunately, those with autism often sleep for significantly fewer hours than neurotypical children (Elrod & Hood, 2015; Malow et al., 2006). In addition to its crucial role in neural development, it is central to healthy immune and metabolic functioning (Besedovsky, Lange & Haack, 2019; Potter et al., 2016), as well as optimal cognition and the appropriate expression of emotions (Goldstein & Walker, 2014; Shellhaas et al., 2017). Immune function, metabolism, cognition and emotional control are frequently impaired in individuals with autism spectrum disorder (ASD). Two of the most challenging behaviors that are common in this population—aggression and self-injurious behavior—have also been associated with sleep disturbances (Edelson, 2021; Edelson & Johnson, 2016). Other impairments associated with sleep deprivation include problems with anxiety (Moskowitz & Edelson, 2021; Sullivan et al., 2021), social interactions (Merikanto et al., 2019) and sensory sensitivities (Tzischinsky et al., 2018).

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Sleep disturbances take several forms. A survey of 2,327 caregivers conducted by the Autism Research Institute (ARI) from 2015 to 2017 found that 47 percent had difficulty falling asleep, 39 percent woke up in the middle of the night and 35 percent typically woke up in the early morning hours. Interestingly, about a quarter, or 27 percent, suffered from one of these sleep issues; a little over half, or 57 percent, suffered from two; and 16 percent suffered from all three sleep issues. Although Dr. Bernard Rimland did not discuss sleep disturbances in his seminal book Infantile Autism: The Syndrome and its Implications for a Neural Theory of Behavior, he would often describe his son’s sleep issues during his lectures. Basically, Mark slept very little as an infant and cried most of the time while awake. In fact, when Dr. Rimland and his wife showed Mark’s pediatrician a graph of the times he would sleep and cry over a 24-hour period, the doctor did not believe them. Many parents worldwide have written to ARI over the past 50-plus years describing their child’s severe sleep problems. Obviously, sleep issues can take a significant toll on the entire family. Many parents literally take turns watching their children throughout the day and the entire night. Numerous factors contribute, including autonomic and biomedical dysregulation (see Chapters 1, 3 and 5), nutritional deficiencies (see ­Chapter 4), sensory sensitivities (see Chapter 5) and environmental influences (see ­Chapters 1 and 6). The six chapters in this book summarize the research into these issues. The different perspectives of the authors provide valuable insights into various causes of sleep disturbances in this population and offer strong evidence that an integrated, multi-disciplinary approach can often lead to successful treatment.

Brief Overview of the Chapters Chapter 1 describes known biochemical impairments associated with autism—for example, alterations in serotonin, melatonin and gamma aminobutyric acid (GABA)—and their relationship to sleep disturbances. Various assessments that can provide insight into medical, psychiatric, sensory, behavioral and environmental contributors are also summarized. In addition, research on numerous pharmacological treatments, including 10

Introduction

antidepressants, antihistamines, antipsychotics and alpha agonists, is discussed. Complementary and integrated treatments such as amino acids, biofeedback, exercise and massage are also covered. Chapter 2 presents an overview of electrical patterns in the brain that are characteristic of certain sleep disturbances. Specific physiological factors associated with sleep disturbances, including heart rate and limb movements, are also described. Other problems associated with sleep issues are discussed, including bruxism (teeth grinding and clenching) and parasomnias (e.g., night terrors and sleep walking). The chapter concludes with general guidance for primary care physicians on how to properly assess various sleep problems in their clients. Chapter 3 explores discomfort and pain, two commonly reported reasons for sleep disturbances in autism. The authors note that serotonin levels are often dysregulated in autism, a well-replicated finding, and normal serotonin is well-known to help induce sleep in the general population. Interestingly, serotonin is also related to pain perception. The interrelationship between these factors is discussed with respect to sleep problems associated with autism. Chapter 4 looks at the role of nutrition, summarizing evidence showing that a healthful diet is important for good sleep. Numerous contributors to a proper night’s sleep are discussed, including macro- and micronutrients, as well as foods that affect hormonal balance. The benefits of certain dietary programs, such as the Mediterranean Diet, are also explored. Chapter 5 offers one of the few extensive reviews on sensory processing and integration in relation to associated sleep disturbances. The authors describe how the nervous system, especially the autonomic nervous system (ANS), is instrumental for sleep. The ANS is divided into two branches, including the sympathetic nervous system (responsible for an increase in arousal) and the parasympathetic nervous system (responsible for a decrease in arousal), and the authors detail how both systems are known to be impaired in autism. Another contributor to sleep problems, dysfunctional circadian rhythm, is also discussed. Various sensory-related interventions known to improve sleep are detailed as well. Chapter 6 discusses “sleep hygiene”—a term used to describe a behavioral approach to treating sleep disturbances. This involves developing a bedtime 11

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routine to increase or decrease certain activities and behaviors. The authors explain why a functional behavioral assessment is first recommended to identify the possible antecedents and consequences of a sleep problem. Sleep behavior can then be treated by promoting certain calming behaviors, such as taking a bath or reading a book prior to bedtime, and fading and extinguishing stimulating behaviors such as social interaction, computer screen time and the ingestion of stimulants such as chocolate and caffeinated sodas. As this book demonstrates, a great deal is known about the sleep problems associated with autism. It is our hope that by compiling this knowledge into a single resource, we can aid clinicians in conducting thoughtful and detailed analyses that will point the way toward successful treatment.

References Besedovsky, L., Lange, T. & Haack, M. (2019). The sleep-immune crosstalk in health and disease. Physiological Reviews, 99(3), 1325–1380. DOI: 10.1152/physrev.00010.2018 Carmassi, C., Palagnini, L., Caruso, D., Masci, I., Nobili, L., et al. (2019). Systematic review of sleep disturbances and circadian sleep desynchronization in autism spectrum disorder: Toward an integrative model of a self-reinforcing loop. Frontiers in Psychiatry, 10, 366. DOI: 10.3389/fpsyt.2019.00366 Edelson, S. M. (2021). Comparison of autistic individuals who engage in self-injurious behavior, aggression, and both behaviors. Pediatric Reports, 13, 558–565. DOI: 10.3390/pediatric13040066 Edelson, S. M. & Johnson, J. B. (2016). Understanding and Treating Self-Injurious Behavior in Autism. London: Jessica Kingsley Press. Elrod, M. G. & Hood, B. S. (2015). Sleep differences among children with autism spectrum disorders and typically developing peers: A meta-analysis. Journal of Developmental and Behavioral Pediatrics, 36(3), 166–177. DOI: 10.1097/DBP.0000000000000140 Goldstein, A. N. & Walker, M. P. (2014). The role of sleep in emotional brain function. Annual Review of Clinical Psychology, 10, 679–708. DOI: 10.1146/annurev-clinpsy-032813-153716 MacDuffie, K. E., Shen, M. D., Dager, S. R., Styner, M. A., Kim, S. H., et al. (2020). Sleep onset problems and subcortical development in infants later diagnosed with autism spectrum disorder. American Journal of Psychiatry, 177(6), 518–525. DOI: 10.1176/appi.ajp.2019.19060666 Malow, B. A., Marzec, M. L., McGrew, S. G., Wang, L., Henderson, L. M. et al. (2006). Characterizing sleep in children with autism spectrum disorders: A multidimensional approach. Sleep, 29(12), 1563–1571. DOI: 10.1093/sleep/29.12.1563 Merikanto, I., Kuula, L., Makkonen, T., Salmela, L., Raikkonen, K. & Pesonen, A. (2019). Autistic traits are associated with decreased activity of fast sleep spindles during adolescence. Journal of Clinical Sleep Medicine, 15(3), 401–407. DOI: 10.5664/jcsm.7662 Moskowitz, L. J. & Edelson, S. M. (2021). Introduction. In S. M. Edelson & J. B. Johnson (eds.), Understanding and Treating Anxiety in Autism. London: Jessica Kingsley Publishers. Potter, G. D. M., Skene, D. J., Arendt, J., Cade, J. E., Grant, P. J. & Hardie, L. J. (2016). Circadian rhythm and sleep disruption: Causes, metabolic consequences, and countermeasures. Endocrine Reviews, 37(6), 584–608. DOI: 10.1210/er.2016-1083 Shellhaas, R. A., Burns, J. W., Hassan, F., Carlson, M. D., Barks, J. D. E. & Chervin, R. D. (2017). Neonatal sleepwake analyses predict 18-month neurodevelopmental outcomes. Sleep, 40(11), zsx144. DOI: 10.1093/ sleep/zsx144

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Introduction Sullivan, E. C., Halstead, E. J., Ellis, J. G. & Dimitriou, D. (2021). Anxiety, insomnia, and napping predict poorer sleep quality in an autistic adult population. International Journal of Environmental Research and Public Health, 18(18), 9883. DOI: 10.3390/ijerph18189883 Tham, E. K. H., Schneider, N. & Broekman, B. F. P. (2017). Infant sleep and its relation with cognition and growth: A narrative review. Nature and Science of Sleep, 9, 13–149. DOI: 10.2147/NSS.S125992 Tzischinsky, O., Meiri, G., Manelis, L., Bar-Sinai, Flusser, H., et al. (2018). Sleep disturbances are associated with specific sensory sensitivities in children with autism. Molecular Autism, 9, 22. DOI: 10.1186/ s13229-018-0206-8 Verhoeff, M. E., Blanken, L. M. E., Kocevska, D., Mileva-Seitz, V. R., Jaddoe, V. W. V., et al. (2018). The bidirectional association between sleep problems and autism spectrum disorder: A population-based cohort study. Molecular Autism, 9, 8. DOI: 10.1186/s13229-018-0194-8 Wintler, T., Schoch, H., Frank, M. G. & Peixoto, L. (2020). Sleep, brain development, and autism spectrum disorders: Insights from animal models. Journal of Neuroscience Research, 98(6), 1137–1149. DOI: 10.1002/ jnr.24619

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CHAPTER 1

Pharmacotherapy for Sleep Problems in Autism Spectrum Disorder Tomoya Hirota, MD, Department of Psychiatry and Behavioral Sciences, University of California San Francisco, UCSF Benioff Children’s Hospital Oakland, Michelle S. Nakaishi, CPNP, UCSF Benioff Children’s Hospital Oakland, Katherine Whitley, MS, UCSF Benioff Children’s Hospital Oakland, and Robert L. Hendren, DO, Department of Psychiatry and Behavioral Sciences, University of California San Francisco

Introduction Although the prevalence estimates vary depending on the study designs (sampling and ascertainment methods), existing studies consistently report that sleep problems are more prevalent in individuals with autism spectrum disorder (ASD) and other developmental disorders, ranging from 50 percent to 80 percent, compared with those with typical development (Couturier et al., 2005; Krakowiak et al., 2008; Reynolds et al., 2019). Studies report the association of sleep problems with increased internalizing (emotional) problems, externalizing behaviors (aggression, for example) and self-injurious behaviors in those with ASD (Goldman et al., 2009). These findings imply that sleep disturbance is transdiagnostic and linked to various forms of psychopathology, thereby suggesting that treatment of sleep problems may help to mitigate the emotional and behavioral challenges families and youth with ASD may experience. As discussed elsewhere in this book, behavioral management is the mainstay intervention of sleep problems in this population; however, it is true that some individuals require adjunct medication treatment in real-world clinical practice. In fact, a study conducted in 1,518 children with ASD aged 4–10 years who were enrolled in the Autism Treatment Network registry 15

UNDERSTANDING AND TREATING SLEEP DISTURBANCES IN AUTISM

revealed that 46 percent of these children were taking medication for sleep (Malow et al., 2016). Therefore, this chapter highlights themes related to sleep problems with a focus on pharmacological approaches. In the first section, we will briefly review the neurobiology of sleep in individuals with ASD to deepen readers’ understanding of how medication treatment can address proposed abnormalities in sleep physiology in this population. We will highlight assessments of sleep problems in ASD in clinical settings and then treatment strategies as well as considerations prior to the start of medication in the next two sections. These sections will be followed by two sections focusing on up-todate evidence of the safety and efficacy of pharmacological interventions and complementary and integrative medicine for sleep problems. We will also provide case vignettes in this chapter to deepen readers’ understandings of real-world clinical challenges and strategies taken in assessing and treating sleep problems in this population.

Physiology/Neurobiology of Sleep in ASD In this section, we will briefly describe important findings pertaining to sleep physiology to provide a rationale for the use of medication for sleep problems in this population. Previous research has indicated a critical role of neurobiological alterations in the onset and exacerbation of sleep problems in individuals with ASD (Cortesi et al., 2010; Richdale & Schreck, 2009). In particular, disrupted expression of several neurotransmitters, such as gamma-aminobutyric acid (GABA), serotonin and melatonin, described in the cause of ASD are also implicated in the regulation of the sleep-wake cycle.

GABA GABA is the principal inhibitory neurotransmitter in the central nervous system. A decrease in GABAergic inhibition may contribute to insomnia. The GABAergic system is critical to cortical development (Varju et al., 2001) and has been strongly implicated in ASD and insomnia due to the overlapping molecular mechanisms (Ballester et al., 2020). For example, the variations, 16

Pharmacotherapy for Sleep Problems in ASD

including mutation, of genes encoding GABA are found to be associated with ASD and insomnia (Shao et al., 2003).

Serotonin Serotonin or 5-hydroxytryptamine (5-HT) is another neurotransmitter involved in ASD and the regulation of the sleep-wake cycle (Ballester et al., 2020). Dysregulation of the serotonergic signaling system, such as increased levels of blood serotonin (hyperserotonemia), altered serotonin synthesis and degradation, and genetic mutations in serotonin pathways (e.g., transporter gene SLC6A4), is reported in individuals with ASD (Veatch, Maxwell-Horn & Malow, 2015). Studies have found that serotonin contributes to the promotion of wakefulness and inhibits rapid eye movement (REM) sleep (Monti, 2011).

Melatonin Melatonin is a naturally occurring hormone involved in coordinating the body’s sleep-wake cycle, inhibited by light and released by the pineal gland (Bruni et al., 2015). It is synthesized from serotonin. Several studies have described abnormal melatonin regulation in ASD (Nir et al., 1995; Tordjman et al., 2005). In a study that measured levels of a metabolite of melatonin, children and adolescents with ASD had reduced nocturnal production of melatonin in comparison with those without ASD (Tordjman et al., 2005). Although extant research has focused on comparing the levels of neurobiological alterations between individuals with ASD and those without ASD, there may be individual differences in how these neurotransmitters contribute to sleep problems in an individual with ASD.

Assessment of Sleep Difficulty in ASD Although the primary purpose of this chapter is to provide readers with further understanding of pharmacological approaches for sleep problems, it is important to first highlight the significance of an adequate sleep assessment. Sleep problems in youth with ASD often stem from a multifactorial etiology, while the primary cause of insomnia in neurotypical youth is behaviorally 17

UNDERSTANDING AND TREATING SLEEP DISTURBANCES IN AUTISM

based (Armstrong, Quinn & Dadds, 1994). Thus, a thorough sleep evaluation in those with ASD should include behavioral, environmental, genetic, medical, sensory and psychiatric screenings if they are identified to be screen-positive for sleep problems.

Behavioral and Environmental Assessment When the screening for insomnia is positive, additional behavioral and environmental screening questions are necessary. In addition to gathering a weekly routine (naps, activities, nutritional intake) and bedtime sleep routine, the history should also include where the youth sleeps, who else sleeps in the bedroom, how the bedroom is set up and any environmental factors that may impact sleep (i.e., lighting, noise level, temperature, pets, parental sleeping behaviors) (Kotagal & Broomall, 2012). Assessing the parents’ mental health may also be necessary; anxious or depressed parents may be less able to institute consistent sleep routines for the youth. Parental resources can also play a factor in the ability to afford and obtain interventions. Additionally, it is important to assess if there are any reinforcing actions that may reward the current sleeping challenges. Another important environmental factor contributing to sleep problems in individuals with ASD is the use of electronics. In one study, a parent-report questionnaire on the child’s media use revealed that children with ASD who used media as part of the bedtime routine had significantly greater sleep onset latency than those who did not (39.8 vs 16.0 minutes) (Mazurek et al., 2016). Similarly, children who were exposed to media with violent content within the 30-minute period before bedtime experienced significantly greater sleep onset delays and shorter overall sleep duration.

Genetic Assessment Children with specific genetic syndromes like Fragile X syndrome, Angelman syndrome, Rett syndrome, Williams syndrome, Kleine-Levin syndrome and Smith-Magenis syndrome are more susceptible to sleep problems (Arnulf, Rico & Mignot, 2012; Siegel & Smith, 2010).

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Pharmacotherapy for Sleep Problems in ASD

Medical Assessment It is essential to perform a complete medical assessment before any consideration for medication treatment to rule out common medical disorders that contribute to sleep problems. These disorders can include, but are not limited to, gastrointestinal, seizure, asthma, pain, sleep-related breathing disorders (SRBDs) and nutrition problems. For example, obstructive sleep apnea is one of the SRBDs that could more frequently occur in individuals with ASD compared to those who are typically developing (Youssef et al., 2013). Additionally, feeding problems that often co-occur in children with ASD can lead to nutritional problems, including iron deficiency (Ahearn et al., 2001). Iron deficiency/low serum ferritin level is reported to be associated with restless leg syndrome and periodic limb movements in sleep that could negatively impact sleep in this population (Youssef et al., 2013). Lastly, a review of medications and over-the-counter supplements is another essential part of medical assessment since some medications and over-the-counter medications/supplements can contribute to sleep issues.

Sensory Assessment Another area to assess is sensory over-responsivity, which is very common in children with ASD, ranging from 56 to 70 percent (Baranek et al., 2006). This reaction is characterized by distress from sensory stimuli such as light, sound, smell and tactile experiences, potentially leading to sleep problems with a correlation between sleep problems and sensory over-responsivity in individuals with ASD (Mazurek & Petroski, 2015).

Psychiatric Assessment Psychiatric diagnoses, such as anxiety, attention-deficit hyperactivity disorder (ADHD), depression and disruptive behaviors, that commonly co-occur in those with ASD can also have an impact on sleep. For example, people with ASD and co-occurring anxiety may have difficulties regulating arousal and thus have trouble falling asleep due to increased physiological arousal and autonomic activity. The statement above is corroborated by the study finding reporting a positive correlation between anxiety and sleep problems 19

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(bedtime resistance, sleep onset delay, sleep duration, sleep anxiety and night awakenings) in children with ASD (Mazurek & Petroski, 2015). In addition, a trauma history should be obtained during the psychiatry assessment as trauma-related symptoms such as hyper-arousal, nightmares, and intrusive thoughts can disrupt sleep onset and maintenance. ADHD is another psychiatric disorder that frequently co-occurs with ASD and that could impact sleep quality in individuals with ASD given potential bidirectional relationships between ADHD and sleep problems (Konofal, Lecendreux & Cortese, 2010). When assessing sleep in those with ASD and ADHD, it is also important to pay close attention to the medication the child takes for ADHD symptoms. Stimulant medications used to treat ADHD may also cause insomnia, and clonidine, non-stimulant medication, could help treat ADHD and insomnia (Hvolby, 2015). Lastly, depression is a disorder accompanied by impaired sleep; about 80 percent of those with depression suffer from insomnia and 15–35 percent from hypersomnia (Steiger & Pawlowski, 2019). Although no studies have shed light on the associations of depression and sleep in people with ASD, it is very likely that depressive symptoms have a similar impact on sleep in this population (Mayes et al., 2011).

Treatment Strategies of Pharmacotherapy for Insomnia in ASD While behavioral intervention is the first choice in treating insomnia in ASD, some people do not adequately benefit from this form of intervention. Due to the severity of insomnia and its negative impact on overall functioning in individuals with ASD, medication treatment should then be considered.

Considering Medication (When to Consider Medication and When to Refer to Prescribers) If behavioral strategies are not fully working or the severity of symptoms is at a critical level, pharmacologic treatment is warranted (Malow et al., 2012). Additionally, if all root medical causes have been found, ruled out or addressed, medication should be discussed. When first discussing the possibility of starting a medication, clinicians should inquire of both the youth and caregivers about behavioral adjustments that have been made, their efficacy 20

Pharmacotherapy for Sleep Problems in ASD

and if there are any safety issues or concerns (e.g., self-injurious behavior or injury toward others). Furthermore, clinicians should inquire whether the child’s sleep disturbances are negatively affecting their well-being overall and interfering with the ability to make progress in school and/or therapy.

Initiating Medication (What to Talk About and How with Patients and Caregivers) First, clinicians need to acknowledge the youth’s and caregivers’ worries about starting medication. Some may have concerns related to misunderstandings of medications used for sleep problems. Their misunderstandings may stem from the nomenclature of psychotropics frequently used for sleep problems. For example, while trazodone is commonly used for sleep problems, it is classified as an antidepressant, leading to confusion for some parents unless they are provided sufficient education on medication treatment. Clinicians need to understand what symptoms they want to treat with medication (whether symptoms are disrupted sleep alone or if there are other associated symptoms) and clearly outline realistic and quantifiable treatment goals (Bruni et al., 2017). Clinicians should obtain a thorough medication history including prescription and non-prescription or over-the-counter medications from caregivers. This includes asking if patients are medication naïve or have tried a couple of medications already, as this is an important factor that may predict treatment outcomes. Education plays a critical role in starting medication. It is important to explain to the caregiver that the evidence for medication for insomnia in youth with ASD is limited and medications are often used off-label. Furthermore, it is necessary to provide psychoeducation on the safety of medications, including side effects. Some caregivers are particularly concerned about sedation and carry-over effects the next morning, as they may affect the child’s school performance. Although the purpose of medication use is to treat insomnia, clinicians need to acknowledge that unnecessary sedation may end up causing more harm than good. Other side effects can include increased appetite, weight gain, low blood pressure, a slower than normal heart rate, irritability, dry mouth, transient sedation and REM sleep suppression (Relia & Ekambaram, 2018). Also, it is important to note to caregivers that children 21

UNDERSTANDING AND TREATING SLEEP DISTURBANCES IN AUTISM

can build a tolerance to a few of the medications (Rana, Kothare & DeBassio, 2021). The caregiver and child need to be advised against suddenly stopping a medication as the abrupt discontinuation of certain medications may cause the child to experience rebound side effects that could diminish the child’s willingness to try another medication needed for sleep problems. Lastly, clinicians should discuss with caregivers the medication forms, including whether tablets, capsules or liquid might be best, as some children with ASD have sensitivity issues that narrow the choices of medications. It is also important for clinicians to discuss a timeline for monitoring the child’s progress and what other considerations may be necessary if the child does not fully respond to the medication. A follow-up appointment to re-assess the sleep is generally required within a few weeks of initiating a medication (Malow et al., 2012). Just as one or more short-term visits may be needed, a long-term follow-up appointment (after 1 year, for example) is necessary to monitor the child’s response to the medication; the same steps employed when starting and increasing a child’s medication must be repeated at the long-term appointment as well. Lastly, prescribers can consider consulting with a sleep specialist if sleep problems don’t improve with the use of medication or when the sleep difficulties are especially severe and causing daytime difficulties or putting the child’s safety at risk in the night while the child is awake (Malow et al., 2012).

Case Vignette 1: Sarah Sarah is a 7-year-old girl with ASD, intellectual disability and ADHD. She is hyperactive and has major difficulties regulating her emotions both day and night. In some situations, she could exhibit dangerous behaviors, becoming physically aggressive towards others, or could run off into the middle of the street without paying attention to traffic. During primary care clinic visits, she was not able to sit still and would have a tantrum when it was time to leave the clinic. Sarah also had major difficulties falling and staying asleep every night. Several stimulant medications were trialed in primary care for ADHD; however, none of them was effective and they increased her agitation, leading to a referral to child psychiatry.

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Pharmacotherapy for Sleep Problems in ASD

While it was the parents’ and therapist’s priority to first address her hyperactivity and disruptive daytime behaviors, the psychiatry practitioner began with addressing Sarah’s sleep challenges. The goal was to see whether better sleep would improve her daytime behavior. A trial of melatonin was unsuccessful, but her sleep substantially improved with clonidine. Atomoxetine was added for continued daytime hyperactivity. Despite the initial improvement in sleep problems with clonidine, her response to this medication stopped a few months later. A thorough sleep history revealed that Sarah was waking up early on the days (i.e., 4 am) when her mother would leave for work early. Further psychiatric assessment revealed severe separation anxiety. Thus, the practitioner recommended a selective serotonin reuptake inhibitor (SSRI) antidepressant, escitalopram, for her anxiety. Two weeks after the initiation of escitalopram treatment, Sara’s anxiety substantially decreased, and she started sleeping through the night, waking consistently at reasonable hours in the morning. Improvement in her anxiety and sleep resulted in a decrease in her aggressive and impulsive behaviors.

Pharmacotherapy While the European Medicines Agency approves the use of extended-release melatonin for pediatric insomnia, there are no medications approved for this purpose by the Food and Drug Administration (FDA) in the United States. Thus, readers need to be mindful that the majority of medications described in this section are used off-label; these medication classes include melatonin, alpha agonists, sedating antidepressants, antihistamines, antipsychotics, benzodiazepines and others.

Melatonin Commercially available melatonin formulations tend to vary in purity and strength (Kratochvil & Owens, 2009). There are now several different delivery forms on the market including capsules, tablets, gummies, solutions, lotions and vaping suspensions. Some of the melatonin gummies also include additional supplements like lemon balm extract, L-theanine or chamomile. Pediatric prolonged-release melatonin (PedPRM) is a novel age-appropriate

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formulation under development for sleep disorders in children with neurodevelopmental disabilities who have difficulty swallowing (mini-tablet). It has been designed to gradually release melatonin, parroting the physiological secretion profile in the body that produces sustained plasma levels for up to 8–10 hours. PedPRM is approved for use in several European countries, where melatonin is a prescription drug. It is not approved for pediatric insomnia in the US; however, several immediate and controlled-release melatonin preparations can be purchased online. A recently conducted randomized controlled trial (RCT) with 195 study participants demonstrated the long-term efficacy and safety of PedPRM for insomnia in children (2–17 years old) with ASD and rare neurogenetic disorders (Rett’s disorder, tuberous sclerosis, Smith-Magenis syndrome and Angelman syndrome) with or without ADHD comorbidity (Maras et al., 2018). In this multi-center—including Europe and the United States—52-week study, PedPRM treatment demonstrated improvements in sleep time, ability to fall asleep, nightly awakenings and sleep quality compared with baseline in comparison to a placebo. The prolonged-release melatonin was generally safe, and the most frequent treatment-related adverse events were fatigue (5.3%) and mood swings (3.2% of patients). A systematic review of 13 RCTs with melatonin in children with neurodevelopmental disorders, including ASD, also supported the use of melatonin when parent-directed sleep management interventions fail. While the results of this meta-synthesis suggest that no single intervention is effective across all sleep problems in children with ASD, melatonin, behavioral interventions and parent education/education program interventions were the most effective at helping with the multiple domains of sleep problems compared with other interventions (Cuomo et al., 2017). Practically, a dose of 1–3 mg is recommended to be administered 30–60 minutes before intended bedtime (Rossignol & Frye, 2011). However, if a circadian rhythm issue is identified, a lower dose (0.5–1 mg) administered earlier (3–4 hours before bedtime) is recommended (Bruni et al., 2015). Titration strategies have not been scientifically established; however, in one of the literature reviews the recommended melatonin dose was increased by 1 mg every 2 weeks (Grigg-Damberger & Ralls, 2013). The maximum dose is usually thought to be 9–10 mg. Studies have demonstrated good tolerability of melatonin; most studies published to date have not reported any serious 24

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safety concerns (Rzepka-Migut & Paprocka, 2020). Generally reported adverse effects include morning drowsiness, increased enuresis, headache, dizziness and hypothermia (Rzepka-Migut & Paprocka, 2020).

Alpha Agonists Alpha agonists have become more common as an off-label medication for the treatment of sleep disorders and anxiety over time. Prescription trends in groups of young people (aged 4–18 years, n = 282,875) evaluated from 2009 to 2011 in the US revealed that approximately 68 percent obtained alpha agonists (shorter acting agents) as an off-label treatment for ASD and ADHD, based largely on results from clinical studies without FDA approval (Fiks et al., 2015). According to the findings, about 12 percent of people were prescribed alpha agonists for sleep challenges and anxiety (Fiks et al., 2015). The two most common alpha agonists employed off-label to treat insomnia in autism are clonidine and guanfacine. By stimulating presynaptic neurons, clonidine, an antihypertensive agent and a central and peripheral a­ lpha-adrenergic agonist, reduces noradrenergic outflow from axion terminals in a neuron (Jamadarkhana & Gopal, 2010). Guanfacine is a selective alpha 2A adrenergic receptor agonist that enhances noradrenergic transmission and connection in the prefrontal cortex (PFC) by activating postsynaptic alpha2A receptors in the PFC (Wang et al., 2007).

Clonidine In two open-label retrospective research investigations in youth (aged 4–16 years) with ASD and other neurodevelopmental challenges, clonidine (dosing range: 0.05–0.225 mg/day) improved sleep latency as well as difficulty staying asleep with reasonable tolerability and minimal adverse effects (Ingrassia & Turk, 2005; Ming et al., 2008). Low blood pressure, a slower than normal heart rate, irritability, dry mouth and REM sleep suppression are all possible side effects; stopping higher doses of clonidine suddenly can result in a significant rise in blood pressure and REM sleep rebound (Ingrassia & Turk, 2005; Pelayo & Yuen, 2012). There are some study constraints, such as the lack of RCTs that may yield more solid scientific findings and more understanding of its clinical utility and safety profile in ASD (Rana et al., 2021). 25

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Guanfacine Although considered less sedative than clonidine anecdotally, guanfacine is used for sleep problems in individuals with ASD. In the pediatric age group, immediate-release guanfacine (dosing range: 0.5–2 mg/day) is commonly given off-label for sleep disruptions (Fiks et al., 2015; Hollway & Aman, 2011). Yet a recent RCT of extended-release guanfacine (guanfacine ER), which has FDA approval for the treatment of ADHD, found that guanfacine ER did not significantly aid sleep patterns in youth with ASD (Politte et al., 2018). In another RCT of guanfacine ER, furthermore, polysomnography revealed a reduction in overall sleep time (Rugino, 2014).

Antidepressants Antidepressants are the most common class of psychotropics prescribed for people with ASD (Mandell, et al., 2008). In general, antidepressants may influence sleep promotion by influencing the activity of non-GABA neurotransmitters (e.g., histamine, acetylcholine, serotonin) involved in the regulation of sleep and wakefulness (Kratochvil & Owens, 2009). The use of antidepressants for insomnia could be considered in the presence of concurrent mood or anxiety symptoms. Hopefully, by treating the underlying mood or anxiety disorder, sleep can be improved. In addition, by improving sleep, a mood or anxiety disorder may also improve. Although antidepressants are frequently used in clinical practice for insomnia, there is a lack of methodologically rigorous research supporting the use of antidepressants for insomnia in adults or typically developing children (Kratochvil & Owens, 2009). Trazodone, a 5-hydroxytryptamine agonist, is the most commonly used antidepressant for treating pediatric insomnia. It both inhibits the binding of serotonin and blocks histamine receptors, which has suppressing effects on REM and may increase slow-wave sleep. The common side effects are “feeling sleepy and dazed” in the morning. Although uncommon, there is a risk of priapism (prolonged erection of the penis) in doses in the 50–150 mg range. Its efficacy has been studied in adults; however, there is a scarcity of data on the efficacy and safety of trazodone in children and adolescents. Mirtazapine is an a2-adrenergic 5-HT receptor agonist that can cause 26

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a high degree of sedation at low doses. Studies have shown its efficacy in decreasing sleep-onset latency, increasing sleep duration and reducing waking after sleep onset in adults with and without major depression (Kratochvil & Owens, 2009). It is known to have little effect on REM. In a naturalistic open-label study of 25 people with ASD and other pervasive developmental disorders (age 4–23 years old), 35 percent responded with many improvements after four weeks of treatment in a variety of symptoms (aggression, self-injury, irritability, hyperactivity, anxiety, depression and insomnia) (Posey et al., 2004). While mirtazapine did not improve core symptoms of social or communication impairment, there were minimal side effects that included increased appetite and weight gain, irritability and transient sedation. Although there are a few studies demonstrating its efficacy for anxiety in children and adolescents (Mrakotsky et al., 2008), no studies have examined its efficacy primarily for pediatric insomnia. Doxepin is a tricyclic anti-depressant that inhibits the reuptake of serotonin and norepinephrine, with cholinergic, histaminergic, and α1-adrenergic receptor blockade. At lower doses, doxepin is considered functioning mostly as a histaminergic blockade (McCall & McCall, 2012) and is FDA-approved for adult insomnia. In a retrospective chart review of typically developing children 2 to 17 years of age with pediatric insomnia who failed treatment with melatonin and behavioral interventions, they were trialed on doxepin doses of 2 mg up to 10 mg and showed improvement in sleep with minimal side effects; 7 percent showed increased aggression or enuresis (Shah et al., 2020).

Antihistamines Antihistamines are the most common non-prescription medication used to treat sleep disorders in a survey completed by pediatricians from the American Academy of Pediatrics (Owens, Rosen & Mindell, 2003). Despite being widely used in the US and parts of the world, there is little evidence to convey whether they can be advantageous in treatment for youth with sleep difficulties (Bruni et al., 2019). Only a limited number of RCTs have provided the efficacy of antihistamine medication for transient insomnia in neurotypical youth (Russo, Gururaj & Allen, 1976). Data on the efficacy and

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safety of antihistamines for those with ASD and other neurodevelopmental disorders are scarce (Bruni et al., 2019). Medical and psychiatric providers frequently recommend diphenhydramine, an old antihistamine also known as a first-generation antihistamine, for altered sleep, dosed between 0.5 mg/kg and 25 mg/day. It competes to inhibit histamine at the histamine (H1) receptor in the central as well as the peripheral nervous system, leading to sedative and hypnotic effects (Pelayo & Yuen, 2012). Side effects may include drowsiness and anticholinergic effects, such as blurry vision, constipation, dry mouth, difficulty urinating, fever, elevated heart rate or disorientation (Hollway & Aman, 2011; Wang et al., 2007). Niaprazine, a piperazine derivative that also works as an antihistamine (dosing range: 1 mg/kg/day three times a day), exhibited success in ameliorating sleep disruptions in young people with ASD as well as mild to moderate intellectual disability in a European open-label investigation; however, it is not licensed for use in the United States (Rossi, Posar & Parmeggiani, 1999). Hydroxyzine, a medication derived from piperazine, is being used off-label to treat insomnia in current clinical settings with some success. In a review of antihistamines in youth, the sedative effect from an old H1-antihistamine, including hydroxyzine, was considered beneficial for those experiencing severe pruritis from urticaria or atopic dermatitis (Simons, 2002). Although no studies have examined the efficacy of hydroxyzine for the treatment of sleep problems in people with ASD, the findings from studies with typically developing youth may be applicable to those with ASD who suffer from pruritis and resultant insomnia. Young people are more vulnerable than adults to the adverse effects of antihistamines, and they are at a greater risk for developing central nervous system stimulant effects such as excitability (Simons, 2002). Therefore, paradoxical responses to medications used to alleviate insomnia in youth, particularly with ASD, should be closely monitored given that they are often sensitive to pharmacological agents. Literature on the use of antihistamines for sleep problems in ASD is scarce and thus needed.

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Antipsychotics Antipsychotics are divided into two classes: typical (or first-generation) and atypical (or second-generation), depending on their pharmacology. Two atypical antipsychotics, risperidone and aripiprazole, which primarily modulate dopamine and serotonin, are the only medications that have FDA approval for the treatment of irritability and aggression associated with ASD. Typical antipsychotics are not commonly prescribed for this population due to the higher likelihood of side effects, such as muscle stiffness and tremor. However, as reported in a meta-analysis of adult studies, the use of atypical antipsychotics may be appropriate to address sleep problems only when those medications are administered for the comorbid conditions (irritability, aggression, self-injurious behaviors, for example) that could benefit from their primary actions (Thompson et al., 2016). Despite insufficient evidence for atypical antipsychotics for insomnia, practitioners have been anecdotally using them for their sedating effect when other treatment modalities failed (Sateia et al., 2017). One small (n = 13) controlled study comparing quetiapine, which is one of the atypical antipsychotics that have a sedating effect, with a placebo failed to demonstrate statistically significant differences between the two groups; however, participants who received 25 mg of quetiapine at bedtime showed a trend toward improvement of total sleep time and sleep latency (Tassniyom et al., 2010). Further, limited evidence exists for the use of antipsychotics for treating sleep problems in individuals with ASD. In an open-label trial, 11 children aged 13–17 years with ASD who received lowdose quetiapine primarily for their aggression demonstrated reductions in both aggressive behaviors and sleep problems (Golubchik, Sever & Weizman, 2011). Other antipsychotics, such as risperidone and aripiprazole, which are FDA-approved medications for irritability and aggression in ASD, potentially address sleep problems in those with ASD directly through their sedative effects and indirectly via mitigating the emotional and behavioral problems that often impact their sleep. The side effects of antipsychotics include, but are not limited to, appetite increase, weight gain, metabolic side effects, extrapyramidal symptoms (muscle rigidity, tremor, akathisia/restlessness and pacing, for example) and sedation.

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Benzodiazepines Compared to the use of these agents in adult populations, benzodiazepines (BZDs) are much less frequently prescribed for pediatric insomnia mainly due to their side effects, including cognitive impairment, carry-over effects on daytime sleepiness and addiction potential (physical and psychological dependence). The mechanism of action is primarily to bind GABA-type A chloride receptors, and the inhibitory action of GABA on the central nervous system causes sedative, muscle-relaxing, anticonvulsant and anxiolytic effects (Johnston, 1996). Additionally, some people experience paradoxical reactions, characterized by increased talkativeness, excitement, restlessness/ pacing and emotional instability. Children are considered more vulnerable to these paradoxical reactions in comparison to adults; however, the underlying mechanisms accounting for these reactions remain unclear (Mancuso, Tanzi & Gabay, 2012). Related to this book chapter, paradoxical reactions to BZDs in children with ASD have also been reported (Marrosu et al., 1987). The literature on their use for sleep problems in ASD is scarce. Clonazepam is the only one that was reported to be effective for REM sleep behavior disorder (Thirumalai, Shubin & Robinson, 2002). It was also found to be effective in treating REM sleep behaviors in children with other developmental disabilities, and for nocturnal biting in children with developmental disabilities (Hollway & Aman, 2011). Clonazepam has a long half-life (> 18 hours), and thus providers need to be attentive to potential carry-over effects on next-day sleepiness.

Gabapentin Gabapentin is an anticonvulsant medication, designed as a precursor of GABA that easily enters the brain and increases brain synaptic GABA (Czapinski, Blaszczyk & Czuczwar, 2005). In a retrospective chart review at one pediatric sleep clinic in the US, gabapentin ameliorated sleep-onset and sleep-maintenance insomnia in 78 percent of children (mean age 7.2 years of age) with neurodevelopmental disorders (Robinson & Malow, 2012). The average starting dose of gabapentin was 5 mg/kg to a maximum dose of 15 mg/kg per day. Gabapentin showed good tolerability in this study: only six children reported adverse effects, including agitation or feeling “wired.” 30

Pharmacotherapy for Sleep Problems in ASD

Case Vignette 2: Alvin Alvin is an 11-year-old male with ASD who was diagnosed with insomnia and other specified impulse control and conduct disorders. After seeing no improvement in sleep from melatonin and learning that he experienced a paradoxical response to diphenhydramine at bedtime, his pediatrician recommended that his mother try him on clonidine for insomnia and daytime disruptive behavior related to impulse control challenges. His mother agreed to start Alvin on 0.05 mg of clonidine. Unfortunately, he had to stop due to nightmares and increased irritability. Following this, his pediatrician recommended escitalopram (antidepressant/anti-anxiety medication) for sleep and potential comorbid anxiety that might be driving his insomnia and disruptive behavior. A trial of this medication was unsuccessful, as he started engaging in more impulsive, self-injurious behavior that put his safety at risk (he hit one eye hard enough to require an ophthalmology exam and surgery). Therefore, the pediatrician referred him to our psychiatry clinic. Given Alvin’s sensitivity to medications, the increased severity of his self-injurious behavior, his significant sleep deprivation and his mother’s deteriorating sleep and emotional stability related to his challenges, the psychiatric nurse practitioner (NP) recommended a trial of risperidone. The NP explained the risks, benefits and alternatives. His mother questioned why her son would take an antipsychotic for sleep and behavioral problems. The NP empathetically listened to her concerns and explained that risperidone works by targeting specific neurotransmitters that support the reduction of aggressive behavior, and that its sedative side effect can improve sleep. The NP gave the mother clear instructions on how to monitor for improvement in Alvin’s sleep and daytime behavior after starting, while also looking for any unwanted side effects. The NP reviewed the frequency and schedule for follow-up visits in the psychiatry clinic, and explained when to expect to see improvement and what to look for as signs of recovery. Following this thorough psychoeducation on medication treatment, Alvin’s mother provided informed consent to risperidone treatment. He started with a low dose (0.25 mg), which the NP gradually increased while carefully monitoring his sleep and disruptive behavior, as well as

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potential negative side effects such as weight gain. Four weeks after starting risperidone, the NP noticed a significant improvement in Alvin’s sleep and overall behavior, as captured by his mother’s and teacher’s reports. He initially gained weight, but his mother successfully managed that side effect by increasing his physical activity and providing healthy meals, as recommended by the NP.

Complementary and Integrative Medicine Complementary, alternative and integrative therapies for insomnia in children include supplements, herbal remedies, amino acids, relaxation and meditation, guided imagery, yoga, hypnosis, biofeedback, aromatherapy, relaxation, massage, acupuncture and exercise. These approaches are tried by many parents of children with insomnia (Cohen et al., 2018), but most have inconsistent or no published trial results. Valerian root may help promote the length and quality of deep and restorative sleep, as well as reduce the length of time it takes to fall asleep at night, but inconsistent results are reported according to a recent meta-analysis (Shinjyo, Waddell & Green, 2020). Other supplements and herbs that do not have results from published studies include St. John’s Wort, kava, passionflower and herbal extracts such as chamomile, saffron, lavender, lemon balm and hops. They may help promote feelings of relaxation and calm that facilitate sleep. As described earlier in this chapter and elsewhere in this book, GABA is involved in sleep and theoretically may be helpful for the treatment of sleep disorders in children, as it has demonstrated benefits in adults (Ballester et al., 2020). L-tryptophan may also be of theoretical benefit to children as it has shown benefit in adults. While 5-hydroxytryptophan plays an important role in the regulation of emotion, behavior, sleep and other physiological functions, and is mentioned as a sleep aid, no clinical trials have been published related to its treatment for sleep difficulty in neurodevelopmental disorders, so dosing, safety and comparative efficacy are unknown. Cannabidiol (CBD) has been proposed for the treatment of sleep disorders in children with ASD (Khan et al., 2020) with anecdotal reports, but conclusive studies have not yet been published. Potential agents include CBD and hemp oil, potentially in combination with tetrahydrocannabidiol.

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Conclusions and Future Directions Insomnia is one of the most troubling symptoms of ASD and it can be challenging to treat. Potential treatments range from good sleep hygiene, to supplements, herbs, amino acids and CBD, and to mild and stronger medications. Studies for all of these agents in children, especially children with ASD, are limited and deserve greater study that includes the nature of the sleep difficulty. As psychiatric and psychological conditions often co-occur in individuals with ASD and these conditions can lead to or exacerbate sleep problems, clinicians can consider referrals to mental health professionals in such cases. The referral can result in proper psychiatric assessment and interventions, including medication treatment.

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Pharmacotherapy for Sleep Problems in ASD Marrosu, F., Marrosu, G., Rachel, M. G. & Biggio, G. (1987). Paradoxical reactions elicited by diazepam in children with classic autism. Functional Neurology, 2(3), 355–361. PMID: 2826308. Mayes, S. D., Calhoun, S. L., Murray, M. J. & Zahid, J. (2011). Variables associated with anxiety and depression in children with autism. Journal of Developmental and Physical Disabilities, 23, 325–337. DOI: https://doi. org/10.1007/s10882-011-9231-7 Mazurek, M. O. & Petroski, G. F. (2015). Sleep problems in children with autism spectrum disorder: Examining the contributions of sensory over-responsivity and anxiety. Sleep Medicine, 16(2), 270–279. DOI: https://doi.org/10.1016/j.sleep.2014.11.006 Mazurek, M. O., Engelhardt, C. R., Hilgard, J. & Sohl, K. (2016). Bedtime electronic media use and sleep in children with autism spectrum disorder. Developmental Behaviour Pediatrics, 37(7), 525–531. DOI: 10.1097/ DBP.0000000000000314 McCall, C. & McCall, W. V. (2012) What is the role of sedating antidepressants, antipsychotics, and anticonvulsants in the management of insomnia? Sleep Disorders, 14, 494–502. DOI: https://doi.org/10.1007/ s11920-012-0302-y Ming, X., Brimacombe, M., Chaaban, J., Zimmerman-Bier, B. & Wagner, G. C. (2008). Autism spectrum disorders: Concurrent clinical disorders. Journal of Child Neurology, 23(1), 6–13. DOI: https://doi. org/10.1177/0883073807307102 Monti, J. M. (2011). Serotonin control of sleep-wake behavior. Sleep Medicine Reviews, 15(4), 269–281. DOI: https://doi.org/10.1016/j.smrv.2010.11.003 Mrakotsky, C., Masek, B., Biederman, J., Raches, D., Hsin, O., et al. (2008). Prospective open-label pilot trial of mirtazapine in children and adolescents with social phobia. Journal of Anxiety Disorders, 22(1), 88–97. DOI: https://doi.org/10.1016/j.janxdis.2007.01.005 Nir, I., Meir, D., Zilber, N., Knobler, H., Hadjez, J., et al. (1995). Brief report: Circadian melatonin, thyroid-stimulating hormone, prolactin, and cortisol levels in serum of young adults with autism. Journal of Autism and Developmental Disorders, 25, 641–654. DOI: https://doi.org/10.1007/BF02178193 Owens, J. A., Rosen, C. L. & Mindell, J. A. (2003). Medication use in the treatment of pediatric insomnia: Results of a survey of community-based pediatricians. Pediatrics, 111(5), 628–635. DOI: https://doi. org/10.1542/peds.111.5.e628 Pelayo, R. & Yuen, K. (2012). Pediatric sleep pharmacology. Child and Adolescent Psychiatric Clinics of North America, 21(4), 861–883. DOI: https://doi.org/10.1016/j.chc.2012.08.001 Politte, L. C., Scahill, L., Figueroa, J., McCracken, J. T., King, B., et al. (2018). A randomized, placebo-controlled trial of extended-release guanfacine in children with autism spectrum disorder and ADHD symptoms: An analysis of secondary outcome measures. Neuropsychopharmacology, 43, 1772–1778. DOI: https://doi.org/10.1038/s41386-018-0039-3 Posey, D. J., Guenin, K. S., Kohn, A. E., Swiezy, N. B. & McDougle, C. J. (2004). A naturalistic open-label study of mirtazapine in autistic and other pervasive developmental disorders. Journal of Child and Adolescent Psychopharmacology, 11(3), 267–277. DOI: https://doi.org/10.1089/10445460152595586 Rana, M., Kothare, S. & DeBassio, W. (2021). The assessment and treatment of sleep abnormalities in children and adolescents with autism spectrum disorder: A review. Journal of the Canadian Child and Adolescent Psychiatry, 30(1), 25–35. PMCID: PMC7837521 Relia, S. & Ekambaram, V. (2018). Pharmacological approach to sleep disturbances in autism spectrum disorders with psychiatric comorbidities: A literature review. Medical Sciences, 6(4), 94. DOI: https:// doi.org/10.3390/medsci6040095 Reynolds, A. M., Soke, G. N., Sabourin, K. R., Hepburn, S., Katz, T., et al. (2019). Sleep problems in 2- to 5-year-olds with autism spectrum disorder and other developmental delays. Pediatrics, 143(3), e2-180492. DOI: https://doi.org/10.1542/peds.2018-0492 Richdale, A. L. & Schreck, K. A. (2009). Sleep problems in autism spectrum disorders: Prevalence, nature & possible biopsychosocial aetiologies. Sleep Medicine Reviews, 13(6), 403–411. DOI:  https://doi. org/10.1016/j.smrv.2009.02.003 Robinson, A. A. & Malow, B. A. (2012). Gabapentin shows promise in treating refractory insomnia in children. Journal of Child Neurology, 28(12), 1618–1621. DOI: https://doi.org/10.1177/0883073812463069 Rossi, P. G., Posar, A. & Parmeggiani, A. (1999). Niaprazine in the treatment of autistic disorder. Journal of Child Neurology, 14(8), 547–550. DOI: https://doi.org/10.1177/088307389901400814 Rossignol, D. A. & Frye, R. E. (2011). Melatonin in autism spectrum disorders: A systematic review and meta-analysis. Developmental Medicine and Child Neurology, 53(9), 783–792. DOI: https://doi. org/10.1111/j.1469-8749.2011.03980.x

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UNDERSTANDING AND TREATING SLEEP DISTURBANCES IN AUTISM Rugino, T. A. (2014). Effect on primary sleep disorders when children with ADHD are administered guanfacine extended release. Journal of Attention Disorders, 22(1), 14–24. DOI:  https://doi. org/10.1177/1087054714554932 Russo, R. M., Gururaj, V. J. & Allen, J. E. (1976). The effectiveness of diphenhydramine HCI in pediatric sleep disorders. The Journal of Clinical Pharmacology, 16(5–6), 284–288. DOI:  https://doi. org/10.1002/j.1552-4604.1976.tb02406.x Rzepka-Migut, B. & Paprocka, J. (2020). Efficacy and safety of melatonin treatment in children with autism spectrum disorder and attention-deficit/hyperactivity disorder. From Behavior to Pathology: The Underlying Mechanisms in Children with ASD, 10(4), 219. DOI: https://doi.org/10.3390/brainsci10040219 Sateia, M. J., Buysse, D. J., Krystal, A. D., Neubauer, D. N. & Heald, J. L. (2017). Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: An American academy of sleep medicine clinical practice guideline. Journal of Clinical Sleep Medicine, 13(2), 307–349. DOI: https://doi.org/10.5664/ jcsm.6470 Shah, Y. D., Stringel, V., Pavkovic, I. & Kothare, S. V. (2020). Doxepin in children and adolescents with symptoms of insomnia: A single-center experience. Journal of Clinical Sleep Medicine, 16(5). DOI: https:// doi.org/10.5664/jcsm.8338 Shao, Y., Cuccaro, M. L., Hauser, E. R., Raiford, K. L., Menold, M. M., et al. (2003). Fine mapping of autistic disorder to chromosome 15q11-q13 by use of phenotypic subtypes. AJHG, 72(3), 539–548. DOI: https:// doi.org/10.1086/367846 Shinjyo, N., Waddell, G. & Green, J. (2020). Valerian root in treating sleep problems and associated disorders: A systematic review and meta-analysis. Journal of Evidence-Based Integrative Medicine, 25. DOI: 10.1177/2515690X20967323 Siegel, M. S. & Smith, W. E. (2010). Psychiatric features in children with genetic syndromes: Toward functional phenotypes. Child and Adolescent Psychiatric Clinics of North America, 19(2), 229–261. DOI: https:// doi.org/10.1016/j.chc.2010.02.001 Simons, F. E. R. (2002). H1-antihistamines in children. Clinical Allergy and Immunology, 17, 437–464. PMD: 12113226 Steiger, A. & Pawlowski, M. (2019). Depression and sleep. Molecular Science, 20(3), 607. DOI: https://doi. org/10.3390/ijms20030607 Tassniyom, K., Paholpak, S., Tassniyom, S., Kiewyoo, J. (2010). Journal of the Medical Association of Thailand, 93(6), 729–734. PMID: 20572379 Thirumalai, S. S., Shubin, R. A. & Robinson, R. (2002). Rapid eye movement sleep behavior disorder in children with autism. Journal of Child Neurology, 17(3), 173–178. DOI: https://doi.org/10.1177/088307380201700304 Thompson, W., Quay, T. A. W., Rojas-Fernandez, C., Farrel, B. & Bjerre, L. M. (2016). Atypical antipsychotics for insomnia: A systematic review. Sleep Medicine, 22, 13–17. DOI: https://doi.org/10.1016/j. sleep.2016.04.003 Tordjman, S., Anderson, G. M., Pichard, N., Charbuy, H. & Touitou, Y. (2005). Nocturnal excretion of 6-sulphatoxymelatonin in children and adolescents with autistic disorder. Biological Psychiatry, 57(2), 134–138. DOI: https://doi.org/10.1016/j.biopsych.2004.11.003 Varju, P., Katarova, Z., Madarász, E. & Szabó, G. (2001). GABA signalling during development: New data and old questions. Cell and Tissue Research, 305, 239–246. DOI: https://doi.org/10.1007/s004410100356 Veatch, O. J., Maxwell-Horn, A. C. & Malow, B. A. (2015). Sleep in autism spectrum disorders. Current Sleep Medicine Reports, 1(2), 131–140. DOI: 10.1007/s40675-015-0012-1 Wang, M., Ramos, B. P., Paspalas, C. D., Shu, Y., Simen, A., et al. (2007). α2A-Adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell, 129(2), 397–410. DOI: https://doi.org/10.1016/j.cell.2007.03.015 Youssef, J., Singh, K., Huntington, N., Becker, R. & Kothare, S. V. (2013). Relationship of serum ferritin levels to sleep fragmentation and periodic limb movements of sleep on polysomnography in autism spectrum disorders. Pediatric Neurology, 49(4), 274–278. DOI: https://doi.org/10.1016/j.pediatrneurol.2013.06.012

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CHAPTER 2

The Role of Clinical Polysomnography in the Evaluation of Sleep Difficulties in Patients on the Autism Spectrum Kenneth C. Sassower, MD, Massachusetts General Hospital, Harvard Medical School, and Margaret L. Bauman, MD, Boston University School of Medicine

Introduction In this chapter, we will discuss electrographic “sleep signatures” in relation to certain sleep disturbances associated with autism and related disorders. Although in-lab sleep evaluations are considered to be the gold standard when evaluating sleep disturbances, home sleep measures can be used to assess certain sleep-related issues, such as breathing, degrees of autonomic activation and heart rate variability. Both approaches will be discussed.

Overview Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction, delayed and disordered communication, repetitive patterns of behavior and isolated areas of interest (American Psychiatric Association, 2013). Multiple lines of evidence have suggested that both children and adults with ASD tend to demonstrate more sleeping difficulties when compared to typically developing persons or to individuals with other handicapping conditions (Couturier et al., 2005). The prevalence rates for sleep difficulties in ASD have been estimated to range between 44 and 83 percent (Richdale, 1999). Nocturnal sleep fragmentation or disruption may lead to daytime sleepiness, increased neurobehavioral irritability and agitation, attention deficit,

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and/or exacerbation of underlying depressive and/or anxiety symptoms. Improving sleep consolidation and continuity may help to improve daytime alertness and attention, attenuate symptoms of neurobehavioral irritability and control depressive and/or anxiety symptoms. Additionally, enhancing the sleep of patients with ASD may help improve the sleep of parents and other family members. Polysomnography is one approach that can help to identify sleep-related issues in ASD. It is a technique that involves the use of a polygraph to make a continuous record during sleep of multiple physiological variables such as breathing, oxygen saturations, heart rate and rhythm, chin and limb muscle activity, brain wave activity and sleep staging. This technology may reveal information that can provide clues to effective treatments, and can thus play a key role in improving the quality of life of individuals with ASD and their caregivers.

Uses and Limitations of Polysomnography The most common sleep disorders in children with ASD include problems in sleep initiation, re-initiation and maintenance, also known as initial and middle insomnia, respectively (Hering et al., 1999; Honomichl et al., 2002; Wiggs & Stores, 2004; Williams, Sears & Allard, 2004). Difficulties with sleep initiation do not typically require a formal polysomnographic evaluation. However, when children and adults with ASD demonstrate problems with sleep re-initiation or maintenance, an overnight sleep study evaluation may be informative. Sleep difficulties that may benefit from formal polysomnography include sleep-disordered breathing with associated snoring; nocturnal limb movements just prior to or during sleep initiation; abnormal arousal behaviors during both non-REM and REM sleep; excessive daytime sleepiness; non-­ restorative sleep; and sleep-related seizures. Additional symptoms that may warrant polysomnography include recurrent stereotyped episodic behaviors that may be seizure-related, sleep-related bruxism, and sleep fragmentation due to the presence of gastroesophageal reflux disorder (GERD) and/or other forms of gastrointestinal dysfunction (Richdale, 1999). Questions have been raised as to whether formalized diagnostic sleep studies with additional neurophysiological monitoring, including an 38

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extended electroencephalogram (EEG) or measures of heart-rate variability, might be able to identify a neurophysiological and electrographic “sleep signature” that could assist in the early detection of individuals on the spectrum, or, alternatively, help to correlate these markers with respect to the severity of sleep involvement. To date, there have been relatively few formal sleep study evaluations on either children or adults on the spectrum reported in the literature. Formal sleep studies involving patients with ASD could substantially improve the interpretation of subjective clinical symptoms and expand our understanding of the underlying neurophysiologic basis for many of these conditions, which are often erroneously attributed to anxiety-ridden and sleep-deprived caregivers (Malow, Marzec et al., 2006). It must be noted that there are multiple obstacles to conducting such tests. Potential methodological obstacles in performing formal sleep study evaluations on patients with ASD may include tactile defensiveness with respect to electrode placement; lowered pain threshold when applying scalp EEG electrodes (needed to reduce impedances and to aid in the interpretation of EEG data); poor tolerance of an unfamiliar sleep environment (often without contact with a familiar family member or caregiver); inherent frustrations on the part of the patient, who may be non-verbal; and the refusal of insurers to cover the cost of testing. These factors should be taken into consideration when recommending a sleep evaluation. While overnight in-lab sleep evaluations are still considered the gold standard with regard to diagnosing numerous sleep conditions, home evaluations are recommended under certain special clinical conditions. For instance, sleep apnea tests can be performed in the home at any time of the night and measure several important respiratory parameters by assessment of nasal airflow, respiratory effort, snoring and oxygen saturations. These studies may also include monitoring of changes in cardiac rate and rhythm through the electrocardiogram (ECG), as well as assessment of body position (which may be particularly helpful in cases of supine-related apnea). In addition, there are several devices that may be used to monitor movements during sleep, such as accelerometers and/or movement monitors. Accelerometers, in the form of an actigraph, can be a valuable method of objectively measuring sleep parameters and average sleep activity over a period of days to weeks and are non-invasive. The actigraph is a small device 39

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that is worn like a wristwatch and is considered to be more accurate than patient self-report or sleep diaries. Movement monitors can be helpful when evaluating possible periodic limb movements during sleep. These monitors can also be employed to examine the efficacy, or lack of efficacy, of various sleep-related interventions. There are also specialized home sleep evaluations that assess autonomic nervous system activity during sleep. Common physiological measures include heart rate variability and peripheral arterial tonometry (Pillar et al., 2002; Yalamanchali et al., 2013).

Sleep Conditions Requiring Sleep Evaluation A wide range of sleep problems associated with ASD may be detectable through polysomnography. Some disorders can only be accurately diagnosed by clinical polysomnography, while others can be identified through home testing.

Difficulty Breathing during Sleep Several studies have reported breathing disturbances in individuals with ASD. This can be a result of oxygen desaturation, apnea associated with arousal and awakening, or chronic sleep deprivation. Breathing problems can also be due to hypotonia, oromotor dyspraxia, enlarged tonsils and adenoids, and/ or obesity (Tomkies et al., 2019). Sleep-disordered breathing can lead to cardiovascular and metabolic dysfunction, as well as various neuropsychiatric and neurobehavioral disorders. Many individuals with ASD also suffer from medical comorbidities that can exacerbate sleep apnea, such as hypertension, diabetes and thyroid dysfunction. Through in-lab and home sleep testing, and by assessment of diminished nasal airflow and either thwarted or absent respiratory effort, one can determine if a person is suffering from sleep apnea. Alternatively, test results may not indicate overt apnea but rather shallow breathing (hypopneas), or even subclinical obstructions with associated sleep arousals (i.e., more suggestive of an upper airway resistance syndrome). 40

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Adenotonsillar hypertrophy (i.e., abnormal growth of the pharyngeal tonsil and palatine tonsils) is likely the single most common cause of sleep apnea in children, and treatments such as tonsillectomy and adenoidectomy are relatively safe and effective. However, such operations require a good deal of pre-operative preparation (Murata et al., 2020). Additional strategies that can improve airflow and breathing during sleep include sleeping in a lateral recumbent position, i.e., three-quarters prone. Weight reduction may also lead to improvements in airflow. Some treatments, such as positive airway pressure therapy—which involves using a device to pump air into the individual’s lung—may be difficult for people with ASD. In such instances, alternative treatment options such as wearing an oro-dental appliance may be helpful, but this can be costly and particularly difficult for children on the spectrum to manage on a daily basis.

Periodic Limb Movements during Sleep Studies have reported an increased rate of body and limb movements in children on the autism spectrum as compared to neurotypical children (Naito et al., 2019). These lower limb movements typically have a characteristic pattern or cycle, and usually occur every 5–90 seconds during the first 1–2 hours of light non-REM sleep. There are some reports of relatively long duration of these nocturnal limb movements, lasting as long as 3 or more hours in children with ASD (Naito et al., 2019). It is not clear whether these atypical movements are a variation of periodic limb movements or may actually be a unique form of nocturnal limb movement. Body and limb movements can be monitored during an overnight sleep evaluation, and motion can be measured using an accelerometer or an actigraph. Movement of the anterior tibialis (i.e., large muscle in the lower limb) is often monitored using electromyography (EMG, which measures muscle electrical activity) and is typically represented as either phasic or tonic bursts of activity. There is some controversy in the medical literature as to whether such sleep disturbances are caused by body and limb movements, or whether these movements reflect varying levels of hyper-arousability (i.e., lowered 41

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arousal threshold during sleep) throughout the night (El-Ad & Chervin, 2000). (Hyper-arousability and sleep disturbances will be addressed later in this chapter.) Based on clinical experience (K.S.), treatments involving anti-myoclonic medications such as dopamine receptor agonists and muscle relaxants are not very effective, particularly when body and limb movements occur during REM sleep.

Non-REM Parasomnias Increased levels of arousal in individuals with ASD have been reported during non-REM stage III sleep (i.e., “slow-wave” deep sleep). This stage is often associated with night terrors, sleepwalking and confusional arousals—that is, not knowing where you are or what you are doing when you wake up (Petit et al., 2007). Polysomnographic measurements recorded during stage III sleep indicate diffuse, high-amplitude, hypersynchronous, delta slowing waves (1–4 Hz). These can also be characterized by abrupt changes in frequencies from deep to light stages of sleep, in addition to an increase in spontaneous EEG activity, which may result in wakefulness. It can often be difficult to clinically distinguish between high activity or arousal levels during non-REM deep sleep and a predisposition to sleep-­ related complex partial seizure disorder. Overnight diagnostic sleep evaluations may help to more accurately determine the underlying cause. The presence of sleep-activated focal epileptiform discharges on an EEG would suggest a partial seizure disorder.

REM-Related Parasomnias REM-associated parasomnias, such as dream enactment and agitated movements, are not often observed in neurotypical children and young adults, but they are relatively common in the elderly population. They have also been reported in children and young adults on the autism spectrum (Thirumalai, Shubin & Robinson, 2002). Patients with possible REM-related parasomnia are often referred to a sleep laboratory for an overnight diagnostic assessment. Both upper and lower limb EMG are usually employed, in addition to an extended EEG. 42

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During this evaluation, the presence of “REM without atonia” indicates REM motor disinhibition. Under ordinary circumstances, REM sleep is characterized by a marked attenuation of submental EMG tone and phasic anterior tibialis EMG activity. However, in cases of REM motor disinhibition, polysomnographic measurements include phasic and/or tonic bursts of increased submental EMG tone and/or phasic bursts of upper and lower limb EMG activity. These movements occur in the absence of any focal or generalized epileptiform discharges as evidenced by sleep EEG monitoring. When dream-enactment behaviors and agitated movements occur during REM motor disinhibition, some researchers suggest that this may be a sign of a neurodegenerative process such as Parkinson’s disease. It is well known that adults with Parkinson’s disease, or “Parkinson’s plus,” can suffer from REM motor disinhibition. However, there is no clear evidence to date to support a similar neurodegenerative process occurring in those on the autism spectrum who also suffer from this REM sleep behavior disorder. (See Starkstein et al.’s (2015) report on Parkinson’s disease in ASD adults.) Maybe ASD adults have not been adequately evaluated. There is a serious concern that ASD adults are receiving less than adequate health care and screening. Potential treatments for REM disinhibition include low-dosage benzodiazepine, over-the-counter melatonin, specialized melatonin receptor agonists and dopamine agonist medications.

Sleep-Related EEG Abnormalities Studies have suggested that sleep-related EEG abnormalities occur in upwards of 40 percent of children on the autism spectrum, whereas the incidence of sleep-related seizures is notably lower (4–6%) (Malow, 2004). Neurotypical children with interictal focal or generalized epileptiform discharges during sleep have often been given anti-epileptic medications. Questions frequently arise as to whether to treat patients on the autism spectrum who experience EEG abnormalities but who do not exhibit clear clinical paroxysms. “Spike suppressants,” such as valproic acid or lamotrigine, have occasionally been prescribed. Mood stabilization is one of the reported benefits from these anti-epileptic agents, and these medications may have both a primary role

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in suppressing EEG spikes, and a secondary role with respect to mood stabilization and enhancement for those on the autism spectrum.

Related Autism Conditions with Characteristic Sleep EEG Patterns There are certain characteristic sleep EEG and polysomnographic patterns associated with disorders of differing etiologies that may exhibit the clinical features of autism, including Angelman syndrome, Landau-Kleffner syndrome and reduplicaton syndrome (or interstitial 15 q.11.2–q.13) (Sassower, 2016). Approximately 80 percent of those with Angelman syndrome have abnormal EEGs and suffer from epilepsy. The onset of seizures in these individuals usually occurs within the first 3 years of life with a reported prevalence rate of sleep dysfunction varying widely from 20 percent to 80 percent. EEG findings include “notched delta” waves evident bifrontally, diffuse theta waves with posterior localization, and posterior spikes and slow waves that occur in association with eye movements. There is a rich admixture of seizure subtypes in Angelman syndrome that may include generalized tonic-clonic convulsions, atypical absences, atonic seizures and myoclonic seizures. Landau-Kleffner syndrome is an acquired epileptic aphasia, which may, in many cases, demonstrate sleep-activated epileptiform discharges and lead to behaviors associated with autism. EEG abnormalities may include unilateral slow-wave focus, bilateral independent spike-wave discharges and continuous spike-wave discharges during slow sleep (i.e., non-REM stage III sleep). Reduplication syndrome (or interstitial 15 q.11.2–q.13) is a relatively new condition associated with autism (Arkilo et al., 2016). It is characterized by clinical symptoms and behaviors commonly displayed by individuals with ASD in addition to mild facial abnormalities and striking sleep EEG findings. The syndrome may account for 1–3 percent of all autism spectrum cases. Genomic studies have documented subtle microscopic micro-deletions and micro-duplications (i.e., copy number variants, or CNVs) in this reduplication syndrome (Arkilo et al., 2016). EEG findings from these individuals are very striking and may include diffuse superimposed attenuated “fast” activity (beta) waves during both wakefulness and sustained non-REM sleep, i.e., resembling an “alpha-delta” sleep pattern. Similar EEG findings of diffuse superimposed attenuated beta activity and an “alpha-delta” sleep pattern 44

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have been described in the setting of certain psychotropic agent use, such as the benzodiazepines and barbiturates (Sassower, 2016).

Paroxysmal Non-Epileptiform Behaviors As described above, sleep-related epilepsy has been reported in individuals with ASD and related conditions. There are also cases of non-sleep-related episodic behaviors that may occur without any significant electrographic correlates. These events are often referred to as paroxysmal non-epileptiform activity (Gabriels et al., 2005). With respect to Angelman syndrome, there are many reported cases of electroclinical seizures with abnormal EEGs. In addition, there may be cases of non-epileptic myoclonus and diffuse tremulousness without significant EEG correlates. This can first be seen in children with Angelman syndrome but has been more commonly reported in older individuals with Angelman syndrome (Pollack et al., 2018).

Hyper- and Hypo-Arousability Some sleep researchers suggest that the presence of periodic limb movements during sleep may reflect an underlying hyper-arousability and/or hypo-arousability (El-Ad & Chervin, 2000). Hyper-arousability (i.e., lowered arousal threshold) has been reported in some individuals on the autism spectrum. This condition is usually detected during in-lab diagnostic sleep evaluations with extended EEG array, and is identified by increased heart rate variability and/or an increase in spontaneous sleep EEG arousals. Based on polysomnographic observations, hyper-arousability during sleep is typically characterized by abrupt changes (usually increases) in EEG frequencies that last for at least 3 seconds. While psychotropic drugs have been reported to attenuate hyper-arousability, there is a dearth of well-controlled research on these medications. “Alpha-delta” sleep or alpha sleep patterns may reflect hyper-arousability or a lowered arousal threshold. This pattern is sometimes associated with “non-restorative sleep,” which refers to tiredness after waking up from a full night of sleep.

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Sleep-Related Bruxism There have been numerous reports of forceful teeth-clenching and teeth-grinding in children and adults on the autism spectrum. Such behaviors can impact occlusion of the jaw and mastication (Muthu & Prathibha, 2008). During overnight sleep studies, polysomnographic recordings reveal the presence of phasic submental EMG activity along with high-amplitude repetitive movements emanating from bilateral temporal regions. There is also a diffuse distribution of EEG activity that can mimic seizure-like events. To reduce temporo-mandibular joint dysfunction, dental treatment approaches are utilized. These include oro-dental appliances (“nightguard”) and implanting stainless steel crowns on primary molars. Given the similar pathogenetic mechanisms between these involuntary movements and periodic limb movements during sleep, some researchers suggest prescribing low-dosage dopamine agonist medications.

Sleep Arousals in GERD and Esophagitis In some individuals with ASD, increases in sleep EEG arousals and awakenings can be attributed to GERD and esophagitis, both of which are particularly common in patients on the spectrum (Wasilewska & Klukowski, 2015). GERD often causes difficulty with sleep onset (Buie et al., 2010). Polysomnographic recordings in addition to an overnight pH probe can be utilized to measure sleep EEGs in relation to alterations in gastric pH. When results of gastrointestinal studies indicate GERD or esophagitis, endoscopy with the use of a PH probe may be of particular benefit (Buie et al., 2010). EEG arousals may result from gastric discomfort and/or pain symptoms stemming from gastric acids ascending up the esophagus and into the throat upon lying down. Treatments may include anti-reflux medications and surgery in addition to emerging nutrition-related approaches such as zinc carnosine and treating the microbiome.

Comorbid Conditions That May Impact Sleep Consolidation Overnight diagnostic sleep evaluations consist of assessing a person’s neuro­ physiological and electrographic “sleep signature.” However, other factors may be directly or indirectly associated with abnormal brain activity. 46

The Role of Clinical Polysomnography

Anxiety is one common comorbidity associated with autism, affecting as much as 79 percent of this population (Kent & Simonoff, 2017). Intercurrent anxiety symptoms may relate to hyper-arousability during sleep and are inferred by the presence of increased “spontaneous” EEG arousals or “alpha sleep patterns.” Anxiolytic medications given over a period of time may prove beneficial in this situation. Many individuals with ASD suffer from circadian rhythm dysfunction, which is referred to as “delayed sleep phase.” In this condition, sleep is delayed 2 or more hours in relation to normal sleep patterns. Potential treatment options may include behavioral attempts at sleep phase advancement (chrono­therapy) and the use of melatonin and melatonin receptor agents at night; ambient sun or bright-light exposure in the morning can also be considered.

The Role of the Clinician As noted previously, sleep disturbances are extremely common among people of all ages who are on the autism spectrum. Given the prevalence of sleep disorders within this population, it is an area that should be explored by primary care physicians as well as specialists as part of their assessments of their ASD patients. Questions should address the ease of sleep onset, any difficulties with nighttime awakenings and evidence of fatigue during the day (Malow, McGrew, et al., 2006). The cause of this high prevalence of sleep disorders is largely unknown. Hypotheses include 1) factors in the home environment that are not conducive to good sleep, 2) biological or genetic abnormalities that alter brain neurobiology, 3) behavioral or psychological disorders, or 4) potential medical comorbidities that may be associated with respiratory compromise and/or lightened sleep and/or pain or discomfort. A detailed sleep history should be obtained and should include information regarding bedtime routines and behaviors, the presence of snoring or noisy breathing, eating/feeding patterns, the presence of constipation or diarrhea, frequency of otitis media or other illnesses, and the level of daily energy and physical endurance. Psychological factors should also be explored. Possible disorders that could contribute to sleep disturbances include anxiety, depression, stress or attention deficit hyperactivity disorder. 47

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Interventions will depend on the symptoms described. However, many ASD individuals may not present with symptoms that easily direct the practitioner to the correct diagnosis. An example might be a non-verbal patient who presents with episodic self-injurious behavior (SIB), who is later found to have GERD. When diagnosed and treated, the SIB decreases dramatically and, in some cases, disappears (Buie et al., 2010). Interventions may commonly include behavioral approaches to promote predictable bedtime routines. Pharmacological interventions may also be considered. There is evidence that melatonin can be effective in promoting sleep onset and it appears to have few if any long-term negative side effects. However, there are limited studies to support the use of melatonin or other pharmacological products to promote and/or sustain sleep onset in the ASD population. Nonetheless, a number of medications have been used with vary­ ing success, including clonidine, trazodone, fluvoxamine, mirtazepine and clomipramine, as well as some anticonvulsant medications. Referrals to specialists should be considered in some cases. Given the high prevalence rate of gastrointestinal disorders associated with ASD, a referral to a gastroenterologist should be considered for a patient who has difficulty with sleep onset or sustaining sleep, even in the absence of obvious gastrointestinal symptoms. Consultation with an otolaryngologist should also be considered if there is any suggestion of breathing difficulties and/ or enlarged tonsils and adenoids. Allergies may be a factor in some patterns of disturbed sleep and should, in some cases, be evaluated in some detail. If nighttime urinary incontinence is reported, a referral to a urologist may be useful, since some disorders associated with incontinence, such as “spastic bladder,” are treatable. If medications and referrals to specialists prove unsuccessful, and disordered sleep patterns persist or worsen, a referral to a sleep specialist and studies including polysomnography should be considered. While sleep-pattern disruptions are often seen through the lens of episodic behavioral dysregulation frequently associated with ASD, it is critical that potential medical comorbidities be ruled out before assuming that the behaviors in question are “just part of the autism diagnosis.” Studies directed to more specifically investigate biological factors related to sleep may need to be explored.

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Conclusion Sleep disorders are common in those with ASD and can severely impact their quality of life and the well-being of their caregivers. In many cases, it is possible to identify these disorders through polysomnographic testing. Moreover, a number of sleep disorders can be effectively treated. While clinical polysomnography can be challenging to perform, it is possible in many cases. For some conditions, home testing is also an option, but for complex and challenging sleep dysregulation for individuals with ASD, polysomnography should be considered.

References American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorders, 5th edn. Arlington, VA: APA. Arkilo, D., Devinsky, O., Mudigoudar, B., Boronat, S., Jennesson, M., et al. (2016). Electroencephalographic patterns during sleep in children with chromosome 15 q11.2–13.1 duplications (Dub 15 q.). Epilepsy & Behaviour, 57, 133–136. Buie, T., Campbell, D. B., Fuchs, G. J., Furuta, G. T., Levy, J., et al. (2010). Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASD: A consensus report. Pediatrics, 125(suppl. 1), S1–S18. Couturier, J. L., Speechley, K. N., Steele, M., Norman, R., Stringer, B., et al. (2005). Parental perception of sleep problems in children of normal intelligence with pervasive developmental disorders: Prevalence, severity, and pattern. The Journal of the American Academy of Child & Adolescent Psychiatry, 44, 815–822. El-Ad, B. & Chervin, R. D. (2000). The case of a missing PLM. Sleep, 23(4), 1–2. Gabriels, R. L., Cuccaro, M. L., Hill, D. E., Ivers, B. J. & Goldson, E. (2005). Repetitive behaviors and autism: Relationships with associated clinical features. Developmental Disabilities Research Reviews, 26, 169–181. Hering, E., Epstein, R., Elroy, S., Iancu, D. R. & Zelnick, N. (1999). Sleep patterns in autistic children. Journal of Developmental & Behavioral Pediatrics, 29, 143–147. Honomichl, R. D., Goodlin-Jones, B. L., Burnham, M., Gaylor, E. & Anders, T. F. (2002). Sleep patterns of children with pervasive developmental disorders. The Journal of Autism and Developmental Disorders, 32, 553–561. Kent, R. & Simonoff, E. (2017). Prevalence of anxiety in autism spectrum disorders. In C. M. Kerns, E. A. Storch & J. J. Wood (eds.), Anxiety in Children and Adolescents with Autism Spectrum Disorder: Evidence-Based Assessment and Treatment. Cambridge, MA: Academic Press. Malow, B. A. (2004). Sleep disorders, epilepsy, and autism. Mental Retardation and Developmental Disabilities Research Reviews, 10, 122–125. Malow, B. A., Marzec, M. L., McGrew, S. G., Wang, L., Henderson, L. M., et al. (2006). Characterizing sleep in children with autism spectrum disorders: A multidimensional approach. Sleep, 29(12), 1563–1571. Malow, B. A., McGrew, S. G., Harvey, M., Henderson, L. M. & Stone, W. L. (2006). Impact of treating sleep apnea in a child with autism spectrum disorder. Pediatric Neurology, 34, 325–328. Murata, E., Kato-Nishimura, K., Taniike, M. & Mohri, I. (2020). Evaluation of the validity of psychological preparation for children undergoing polysomnography. Journal of Clinical Sleep Medicine, 16(2), 167–174. Muthu, M. S. & Prathibha, K. M. (2008). Management of a child with autism and severe bruxism: A case report. Journal of Indian Society of Pedodontics and Preventive Dentistry, 26(2), 82–84. DOI: https://doi. org/10.4103/0970-4388.41623 Naito, N., Kikuchi, M., Yoshimura, Y., Kumazaki, H., Kitagawa, S., et al. (2019). Atypical body movements during night and young children with autism spectrum disorder: A pilot study. Scientific Reports, 9, 6999. DOI: https://doi.org/10.1038/s41598-019-43397-y Petit, D., Touchette, E., Tremblay, R. E., Boivin, M. & Montplaisir, J. (2007). Dyssomnias and parasomnias in early childhood. Pediatrics, 119(5), e1016–e1025.

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UNDERSTANDING AND TREATING SLEEP DISTURBANCES IN AUTISM Pillar, G., Bar, A., Shlitner, A., Schnall, R., Shefy, R., et al. (2002). Autonomic arousal index: Automated detection based on peripheral arterial tonometry. Sleep, 25(5), 541–547. Pollack, S. F., Grocott, O. R., Parkin, K. A., Larson, A. M. & Thibert, R. L. (2018). Myoclonus in Angelman syndrome. Epilepsy & Behavior, 82, 170–174. DOI: https://doi:10.1016/j.yebeh.2018.02.006 Richdale, A. L. (1999). Sleep problems in autism: Prevalence, cause, and intervention. Developmental Medicine & Child Neurology, 41, 60–66. Sassower, K. C. (2016). Sleep EEG, epilepsy and polysomnogram and autism and autism variants: Highlights of 2016 “Autism: Challenges and Solutions” International Conference in Moscow. Journal of Autism and Epilepsy, 1(1), 1002. Starkstein, S., Dragovic, M., Brockman, S., Wilson, M., Bruno, V. & Merello, M. (2015). The impact of emotional distress on motor blocks and festination in Parkinson’s disease. The Journal of Neuropsychiatry and Clinical Neuroscienced, 27(2), 121–126. DOI: 10.1176/appi.neuropsych.13030053 Thirumalai, S. S., Shubin, R. A. & Robinson, R. (2002). Rapid eye movement sleep behavior disorder in children with autism. Journal of Child Neurology, 17, 173–178. Tomkies, A., Johnson, R. F., Shah, G., Caraballo, M., Evans, P., et al. (2019). Obstructive sleep apnea in children with autism. Journal of Clinical Sleep Medicine, 15(10), 1469–1476. Wasilewska, J. & Klukowski, M. (2015). Gastrointestinal symtoms and autism spectrum disorder: Links and risks—a possible new overlap syndrome. Pediatric Health, Medicine and Therapeutics, 6, 153–166. DOI: https://doi:10.2147/PHMT.S85717 Wiggs, L. & Stores, G. (2004). Sleep patterns and sleep disorders in children with autism spectrum disorders: Insights using parent report and actigraphy. Developmental Medicine & Child Neurology, 46, 372–380. Williams, P. G., Sears, L. L. & Allard, A. (2004). Sleep problems in children with autism. Journal of Sleep Research, 13, 265–268. Yalamanchali, S., Farajian., V., Hamilton, C., Pott, T. R., Samuelson, C. G., et al. (2013). Diagnosis of obstructive sleep apnea by peripheral arterial tonometry. JAMA Otolaryngology Head & Neck Surgery, E1–E8. DOI: https://doi:10.1001/jamato.2013.5338

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CHAPTER 3

Sleep Disorders in Autism The Role of Pain and Serotonin Manuel F. Casanova, MD, University of South Carolina School of Medicine Greenville, Department of Pediatrics, Division of Developmental Behavioral Pediatrics, PrismaHealth System, Greenville, Emily L. Casanova, PhD, University of South Carolina School of Medicine Greenville, and Estate M. Sokhadze, PhD, University of South Carolina School of Medicine Greenville

Summary Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders that commonly present with comorbid conditions. Among these comorbidities sleep problems are particularly common, with a prevalence rate that varies from 60 to 80 percent of ASD individuals. Symptoms (e.g., difficulties falling asleep, frequent awakening, early morning wakening) tend to be chronic, occur daily and vary widely in severity. Factors that can cause sleep disorders include physical disturbances, medical disorders, abnormalities in melatonin physiology and psychiatric disorders. Among medical issues, chronic pain is the number one cause of insomnia in the general population. Moreover, in some cases, pain causes anxiety and together they act synergistically to disrupt sleep. Serotonin modulates pain-signaling processes through its inhibitory role in pain perception. Serotonin also induces sleep and is a chemical precursor for the hormone melatonin. Unsurprisingly, many studies have found abnormalities of serotonin levels in ASD. Recognizing the role of pain and serotonin in sleep disorders may be the first step toward instituting appropriate therapy. In some cases, melatonin supplements along with lifestyle changes and occupational therapy may prove effective in establishing proper sleep hygiene.

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Introduction When Jimmy was born it seemed like he never slept. He was fidgety all night and cried non-stop at the top of his lungs. His parents thought that something was bothering him. It was troublesome for them to think that he could be in pain. Indeed, while crying, Jimmy would clench his fists, curl up his legs and remain in a cramped and contracted position. Breastfeeding was difficult and burping exacerbated his outbursts. Attempts at comforting him just made matters worse. He did not like being touched and, even as a baby, he would push against those trying to hold him. By pushing against those carrying him, he would often end up with his head hanging downward. Since he seemed to be at peace in this position, his parents used to call him “batboy.” Jimmy could not sleep, and neither could his parents. The whole family felt stressed and frustrated. Multiple visits to the pediatrician only prompted snide comments about the anxiety of first-time parents. The official medical diagnosis was colic, and his parents were told not to worry: the pediatrician reassured them, “His colics will likely disappear by 6 months of age.” Unfortunately, Jimmy never outgrew his “colics”; rather, time brought a plethora of new symptoms, including repetitive behaviors and seizures. As the years went by it was worrisome to his parents that he could hear sounds, yet never reacted when called by his name. In the end, as Jimmy grew older, all of his problems, including those related to sleep, only grew. Whether he was restless, anxious or suffered pain that kept him from falling asleep, the causes remained hidden from everybody as he was non-verbal. In Jimmy’s case a diagnosis of autism was ascertained by a multispecialty clinic when he was 4 years of age. According to the pediatrician, sleep problems were easily explained by his autism. However, recommendations for lifestyle interventions and sleep aids proved worthless. Jimmy’s sleep disorder persisted until it was discovered that the problem was apparently prompted by what was perceived as overstimulation. An in-house sensory swing that allowed his mother to swing along with Jimmy proved almost miraculous for inducing sleep. This was especially the case when he was wrapped in several blankets and held in a tight squeeze. In the long run, desensitization massages by a physical therapist proved most effective in calming him down and ultimately allowing him to sleep. 52

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Sleep Disorders Sleep disorders or somnipathies are a group of medical disorders that are becoming increasingly common within the general population. According to the American Sleep Association (2021), more than one third of US adults, or between 50 and 70 million individuals, report having a sleep disorder. Side effects of sleep deprivation, such as fatigue, mood swings and heart disease, affect the overall health, safety and quality of life of those affected. It is therefore unsurprising that sleep deprivation, especially in the context of high-stress and high-risk workplaces, has been cited as a factor in some of the biggest disasters in recent history, including the meltdown at the nuclear plant at Three Mile Island (1979), the nuclear accident at Chernobyl (1986), the NASA space shuttle Challenger explosion (1986) and the Exxon Valdez oil spill (1989). Indeed, everyday drowsiness and consequent fatigue provide a serious risk not only to the health of affected individuals, but also to those around them. In the United States alone, drowsy driving is believed to be responsible for over 1,500 fatalities every year. This ominous statistic makes early detection and treatment of sleep disorders all the more urgent. Sleep disorders have been a recognized malady since the ancient Greeks. Democritus, the Greek philosopher who formulated the atomic theory of the universe, believed that poor nutrition was the main cause of insomnia. In the Middle Ages, the British physician and anatomist Thomas Willis described restless leg syndrome and wrote that “the diseased are no more able to sleep, than if they were in a place of greatest torture” (Vein Center of North Texas, 2021; see also Consens & Chervin, 2008). Throughout most of recorded history disturbances of sleep were considered a symptom of other diseases rather than a primary medical disorder. In the United States sleep disorders were only recognized as an independent category in the second edition of the Diagnostic and Statistical Manual (DSM) in 1965. According to the latest iteration of the DSM, for a sleep disturbance to qualify as a medical disorder it must be severe enough to provide daytime impairment of occupational, social, behavioral and/or educational functioning. In addition, for a sleep disturbance to qualify as a medical disorder, any co-existing condition(s) must be specified (APA, 2013). This qualification stresses the fact that sleep disorders are highly comorbid with other longstanding medical disorders such as chronic pain and diabetes. Unsurprisingly, 53

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affected patients exhibit significant distress and are dissatisfied with the quantity and/or quality of sleep. Difficulties happen repeatedly throughout the week and may last for months despite adequate opportunities for sleep. Presently, there are about 70 recognized sleep disorders, the most prevalent being insomnia, sleep apnea, narcolepsy, restless leg syndrome and rapid eye movement (REM) sleep behavior disorder. Adults need about 8–9 hours of sleep daily, but children need a lot more. Those aged 1–3, for example, need 12–14 hours, while those aged 3–6 need 10–12 hours. If we, meaning all neurodiverse individuals, are deprived of sleep our threshold for stress is lowered, we become inattentive and forgetful, creativity is impaired and our sociability (i.e., our ability to make friends) suffers. Chronic sleep restriction leads to emotional dysregulation and increases the risk for depression. Problems with sleep may give rise to hypertension and an increase in food consumption, obesity and cardiac mortality. In addition, sleep problems may be associated with behavioral issues, including inattention and hyperactivity.

Sleep Disorders and Autism Basic sleep patterns are present during the fetal period, but they change as the brain develops and ages. Neurodevelopmental disorders are characterized by maldevelopment of the central nervous system. It is therefore understandable that some children with neurodevelopmental disorders may be prone to a disrupted sleep pattern. The medical literature recognizes this fact in an abundance of reports indicating a high prevalence of sleep problems in specific neurodevelopmental syndromes such as Fragile X, Down, Rett, Angelman and Prader-Willi (Angriman et al., 2015). Unsurprisingly, neurodevelopmental disorders account for 35 percent of patients referred to clinics for sleep disorders (Stores, 1992). The medical literature reports a prevalence rate of 60–80 percent among individuals diagnosed with autism (Baker et al., 2013; Posar & Visconti, 2020; Souders, Zavodny & Eriksen, 2017). It is significant that the cited prevalence figures are higher than for any other neurodevelopmental condition. The high prevalence may indicate that sleep problems may unfold as a side effect of the core neuropathological processes underlying autism. In this regard, the 54

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same dysregulated mechanisms that lead to impaired social skills, inflexible behaviors, and speech and language difficulties may also cause sleep difficulties. Indeed, according to some researchers, “sleep disorders can also be related to the severity of core symptoms of ASD, including social cognition and communication, stereotypic behavior, and hypersensitivity to the environment” (Posar & Visconti, 2020, p.278). It is therefore unsurprising that sleep problems seem to exacerbate core symptoms of the autistic disorder (Schreck, Mulick & Smith, 2004), resulting in increased repetitive behaviors, insistence on sameness, higher autism severity scores and more social skill deficits. Symptoms of sleep disorder in ASD tend to run a chronic course, often developing in childhood and lasting throughout adolescence. Symptoms appear to be more prevalent among those who are higher functioning. Researchers believe that this bias in symptom expression may, in part, correlate with a person’s capability for managing life skills, including the ability to understand and communicate those problems that affect them. Regardless of this, symptoms of sleep difficulties are similar across both low and high functioning individuals (Goldman et al., 2012). These symptoms vary from mild to severe and include difficulty falling asleep (it takes them an average of 11 more minutes to fall asleep than for neurotypicals), waking up early and never falling back to sleep, and being restless/anxious. The end result is a decrease in total sleep time and low sleep efficiency (i.e., the time a person sleeps as compared to the total time they spend in bed) (Malow et al., 2006; Souders et al., 2009). What are the consequences of insufficient sleep? During the daytime, ASD individuals who suffer from sleep problems tend to feel grumpy, exhibit a predisposition to maladaptive behaviors, experience learning problems and have poorer developmental outcomes (Abel et al., 2018). Like neurotypicals, sleep problems often lead to other comorbidities (e.g., cardiac conditions or obesity, which may itself propitiate sleep apnea and insomnia), increased emergency department visits and more common mental health problems. Furthermore, as in Jimmy’s case, these symptoms go on to affect parents, increasing both their stress levels and disturbing their own sleep patterns. Infants spend most of their sleep in the REM stage, but this gradually decreases with time, reaching about 20–25 percent of total sleep time in adults. By comparison, people with autism seem to spend 15 percent of their 55

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time in REM sleep. REM sleep is important for learning and consolidating memories. Insufficient REM sleep predisposes a person to negative thinking, irritability, emotional volatility and migraines (note: sleep disorders are one of the most common and frustrating symptoms of migraines; www. sleepfoundation.org/articles/rem-sleep-deprivation-and-migraines). Some researchers believe that the reported REM deficiency in ASD reflects an abnormality of neuronal organization during brain development (see the section on serotonin and sleep). In this regard it is noteworthy that disruption of the serotonergic system, and its consequent alterations in brain function and behavior, is a crucial determinant of some neurodevelopmental disorders including autism and Down syndrome (Whitaker-Azmitia, 2001).

Serotonin Serotonin is a chemical that signals information between cells, primarily those that are found in the central nervous system and digestive tract. In addition, within the blood, serotonin is found in platelets where secretion induces both platelet aggregation and contraction of blood vessel walls. When found in low concentrations, serotonin mediates the blood vessel dilation that can trigger migraine attacks in susceptible patients (Table 3.1). Table 3.1 Serotonin-related symptoms Decreased serotonin

Increased serotonin

Anxiety Negative thinking Depression Pain Migraine Constipation Insomnia

Agitation or restlessness Shivering Confusion Diarrhea

Serotonin is also considered a natural stabilizer for mood (including depression, anxiety, panic and obsessive-compulsive behaviors), digestion (helps regulate gastric acid as well as mucus secretion) and socialization (mediates responses to social norms) (Figure 3.1). It is the chemical precursor of melatonin, a hormone that helps regulate the entire sleep-wake cycle. Researchers 56

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have used whole blood serotonin and plasma melatonin as potential biomarkers for autism and as potential targets for treatment (Gabriele, Sacco & Persico, 2014). Tryptophan

Serotonin

Peripheral effects (produced in the gut and stored in the platelets)

Central effects (produced almost exclusively in the raphe nucleus of the brainstem)

Migraine Sleep Anxiety Depression Aggression Food intake

Vasoconstriction/vasodilation Immune system Insulin secretion Lipogenesis

Serotonin is synthesized by two tryptophan hydroxylase enzymes separately active in the brain and in the periphery. The functions of these enzymes are differentially regulated and can therefore be targeted individually. In the case of migraines, serotonin from both sources may be involved (Walther & Bader, 2003).

Figure 3.1 Peripheral and central actions of serotonin

Many decades of research have supported a link between the serotonergic system and autism (Gabriele et al., 2014; Schain & Freedman, 1961). Elevated levels of serotonin have consistently been found in blood/platelets of individuals with autism as well as their relatives. Dietary manipulation meant to deplete serotonin exacerbates repetitive behaviors and elevates feelings of anxiety and unhappiness in people with autism. Indeed, too much serotonin causes mild to severe symptoms in any individual, but in autism they seem to be exacerbated. The presence of muscle rigidity, confusion, agitation, tremors, diarrhea, shivering and sweating, especially when a patient’s medications have been changed, may attest to the presence of a serotonergic abnormality.

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These symptoms have to be kept in mind as difficulties in communication may prevent a person with autism from voicing proper concerns.

Serotonin and Sleep Recently, my group has proposed that sensory abnormalities in autism are the result of aberrantly constructed cortical modules called minicolumns (Casanova and Casanova 2019; Casanova et al., 2002). These abnormalities result in a hyperexcitable cortex with consequent manifestations of seizures and sensory abnormalities (see Casanova, 2013b). The overall findings are similar to those exhibited by migraineurs (see Casanova, 2013a). The physiological basis of the macrocolumn is defined, in part, by the balance of activity between glutamate and serotonin (5HT) neurotransmission (Blue and Johnston, 1995; Xu, Sari & Zhou, 2004). Prenatal exposure to alcohol, selective serotonin reuptake inhibitors (SSRIs) and excess serotonin (monoamine oxidase inhibitors (MAO-A) and MAO-A knockout mice) deleteriously affect the postnatal development of cortical barrel formation (Powrozek and Zhou, 2005; Xu et al., 2004). The effects appear to be mediated by the transient expression of functional serotonin transporter in the axons of thalamocortical fibers.1 Knockout mice for the serotonin transporter show a complete lack of macrocolumnar structures (barrels) despite the absence of visible alterations in either the density of synapses or the length of synaptic contacts in layer IV (Persico et al., 2001). Serotonergic projections to the marginal zone make synaptic contacts with Cajal-Retzius cells. Disturbing the normal development of these connections lowers reelin levels and alters columnar development (Janusonis, Gluncic & Rakic, 2004). Some of the behavioral symptoms of autism, specifically the repetitive behaviors, are strongly related to serotonergic (5HT) dysfunction (Hollander et al., 2000). It has also been reported that sumatriptan, a 5-HT1d receptor agonist and an antimigraine medication, improved symptoms of autism and migraine in patients who suffered from both disorders (Hollander

1

It has been postulated that abnormal minicolumnar organization in ASD is associated with altered thalamocortical connections and dysfunction of the arousal-modulating system of the brain (Casanova et al., 2002; Hutsler & Casanova, 2014).

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et al., 2000).2 Although sumatriptan is primarily a 5-HT1d receptor agonist, it may also bind to other subtypes of 5HT receptors (Adham et al., 1997). Double-­blind studies of serotonin reuptake inhibitors, clomipramine (Gordon et al., 1993) and fluvoxamine (McDougle et al., 1998), as well as open-label studies of fluoxetine (Mehlinger, Scheftner & Poznanski, 1990) and sertraline (Steingard et al., 1997), have documented efficacy in treating various symptoms of autism. Depletion of 5HT precursor tryptophan has been shown to induce a worsening of autistic symptoms in some but not all patients (McDougle et al., 1996). It is not surprising that taking tryptophan has been of some use in treating insomnia, thus it has been called a “natural sleeping aid.”3

Pain and Sleep Many individuals on the autism spectrum have sensory abnormalities that can either numb or sensitize them.4 In a population study of 208 autistic children 20–54 months of age referred to a habilitation center for early intervention, parents reported a large prevalence of pain and hearing abnormalities (44% exhibited over-reactivity to sound while 40% exhibited under-reactivity to pain; Klintwall, Holm & Eriksson, 2011). Those diagnosed as typically autistic (nuclear autism with no learning disability) had the highest number of affected modalities. Those children classified as belonging to an “autistic features” subgroup had the lowest number of affected modalities. These sensory abnormalities manifest themselves early in childhood, thus offering some of the first signs of autism risk and a possible target for intervention. People with autism have comorbidities that can increase pain severity. Lack of restful or restorative sleep may accentuate pain regardless of its origin. Interrupted sleep is physically debilitating and, at the same time, emotionally exhausting. It leaves one with little energy to fight any perceived pain signals. Without proper sleep the immune system becomes hyperactive 2 3 4

Not coincidentally, individuals taking sumatriptan commonly report changes in their sleep patterns. The body uses tryptophan to make melatonin and serotonin. Food supplements of tryptophan were removed from the market because of an unusual side effect called eosinophilia-myalgia syndrome. See Casanova (2017).

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in such a way as to promote inflammation. According to a randomized controlled study, “Insufficient sleep quantity may facilitate and/or exacerbate pain through elevations of IL-6. In disorders where sleep disturbances are common, insufficient sleep quantity itself may establish and maintain its co-occurrence with pain and increased inflammation” (Haack, Sanchez & Mullington, 2007, p.1145). Anxiety disorders, common in autism, intensify pain severity and make it longer lasting. Also, pain, by itself, is a common symptom of an anxiety disorder, particularly that of a generalized type. A recent study published in March 2018 in the European Journal of Neuroscience showed that an autistic individual’s anticipation of pain was indirectly correlated to scores in an empathy quotient questionnaire, thus linking anxiety (pain anticipation) to social impairment (Gu, Zhou & Anagnostou, 2018). Pain that is perceived as normal by a neurotypical person may be overwhelming for people with autism. In some cases, a way to protect oneself from pain is to withdraw from social interactions. Chronic pain5 is a common cause of disability within our society. A study (NCCIH, 2015) from the 2012 National Health Interview Survey found that approximately 11 percent or 25 million adults in America experience chronic pain. Compounding the problem, those with chronic pain also had worse health status and a confluence of multiple symptoms. Men and women differ regarding their sensitivity to pain and response to pharmacological and non-pharmacological interventions (Bartley & Fillingim, 2013). In some cases, use of certain medications (e.g., ergotamines, tryptans) for prolonged periods of time may exacerbate and prolong pain. In addition, pain perception is modified by sociodemographic features like self-perceived health status, lifestyle habits and psychological distress. Those with autism may be predisposed to chronic pain and lower quality of life (Asztély et al., 2019).

5

Chronic pain is usually defined as pain that persists or progresses for longer than 12 weeks despite treatment. Sleeping with chronic pain is difficult, leading to more awakenings during the night as well as less efficient sleep.

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Treatment The cause for sleep difficulties in ASD is multifactorial and may vary from one person to another. Sleep problems seem to involve a complex interaction of biological, psychological, social/environmental and familial factors (Devnani & Hegde, 2015). In this regard, treatment needs to be individually targeted. Standard of care guidelines for sleep disorders should address several different problems: recognize and treat comorbidities, implement a standardized review of systems,6 institute diagnostic assessment and follow-ups within multi-disciplinary health care settings, provide guidelines for appropriate referrals to specialists, avoid polypharmacy and make available appropriate transition services.7 When taking a history of sleep in ASD it is necessary to clarify whether the problems are due to night terrors, sleep walking and/or confusional arousals. These conditions usually occur during the first half of the night during deep. In some cases, sleep abnormalities are due to restless leg syndrome. This condition has been associated with low blood iron levels.8 Other important points during history taking include medication usage (e.g., antiepileptic, psychotropic), and the presence of concomitant medical conditions such as epilepsy, gastroesophageal reflux, dental problems, eczema, asthma exacerbations and mood disorders—all of which may contribute to poor sleep. The presence of agitation, confusion, rapid heart rate, dilated pupils and loss of muscle coordination in a person with autism may point toward a serotonin syndrome or toxicity. These symptoms may manifest themselves within hours after taking new medications or changing the dosage of drugs one is already taking. This seems to be a common occurrence when combining drugs such as SSRIs, monoamine oxidase inhibitors and opioid medications. People with autism seem more susceptible to the side effects 6 7 8

https://meded.ucsd.edu/clinicalmed/ros.htm See Casanova (2015). Some studies claim that iron deficiency and anemia are common in children with ASD. Low iron levels when combined with advanced maternal age is associated with a five-fold increase in the chance for autism. In these cases, the level of iron deficiency is not related to the severity of autistic symptoms. You should consider iron deficiency if you are feeling tired and weak, your work or school performance diminishes, you experience difficulties in maintaining body temperature, have mood changes, suffer from multiple infections and/or have an inflamed tongue. Your threshold for investigating this possibility should be lower if you are dealing with a baby that was born prematurely (more than 3 weeks before term) or has a low birth weight.

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of these medications and the adverse reactions are the most common cause for withdrawing from therapy. Parents and caregivers should be aware of the black box warning instituted by the US Food and Drug Administration (FDA) for SSRIs. These drugs may lead to excessive emotional arousal and behavioral activation in children. Indeed, in young people their usage may lead to increased risk of suicidal thinking, feeling and behavior. The manifestation of any of these symptoms in someone with autism should lead to urgent consultation and intervention by a physician. Besides withdrawal of any offending medication, treatment may include benzodiazepines, cyproheptadine (a drug that inhibits serotonin production) and intravenous fluids. With proper treatment, symptoms may disappear in less than 24 hours. Melatonin, a hormone derived from serotonin, has proven of some benefit in treating sleep problems associated with ASD. A pediatrician will prescribe 0.5 mg 30–45 minutes before bedtime and titrate up rapidly, but usually to no more than 10 mg. There is an extended-release form for those who have problems staying asleep. Common side effects include daytime drowsiness, a morning “hangover” effect, nausea, headaches and dizziness. Clonidine, used primarily to treat high blood pressure, has also been used for insomnia as it has a strong sedative effect; similarly some antidepressants (trazodone, mirtazapine, atypical antipsychotics) may be of some benefit. An interdisciplinary unit on pain offers the best treatment opportunities for chronic pain. They offer therapy that is adept for multiple purposes, involving cognitive-behavioral strategies like relaxation training, biofeedback and stress management techniques, and physical reconditioning. It is important to identify and treat co-existing comorbidities (e.g., sleep problems, anxiety). Medications will often be needed, but in the case of chronic pain opioids are avoided. They may cause addiction, depress respiration and, in the case of irritable bowel syndrome, exacerbate any attendant constipation. If opioids are needed, a special multi-disciplinary clinic may be in the best position to recommend newer medications of kappa opioid agonists and atypical benzodiazepine antagonists. When considering treatment options start by establishing healthy sleeping practices. Establish how much caffeine and other dietary stimulants the child may be taking. Avoid prolonged naps during the day, especially those after 4 pm. Provide adequate exposure to light and perform a good amount 62

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of exercise to release energy. Use the bedroom primarily for sleep and sleep only. Do winding down activities, and no roughhousing should be engaged in before going to bed. When necessary, or if found pleasant, use massage and/or other relaxation techniques. White noise in the room helps some people. Eliminate TV and computers in the bedroom (as they can entice the patient to go to them during the night). No heavy meals before bedtime. Some individuals may benefit from sleeping with a weighted blanket (see Casanova, 2014). Establish a bedtime routine with a visual schedule—write a social story to illustrate how to go to bed.

References Abel, E. A., Schwichtenberg, A. J., Brodhead, M. T. & Christ, S. L. (2018). Sleep and challenging behaviors in the context of intensive behavioral intervention for children with autism. Journal of Autism and Developmental Disorders, 48(11), 3871–3884. Adham, N., Bard, J. A., Zgombick, J. M., Durkin, M. M., Kucharewicz, S., et al. (1997). Cloning and characterization of the guinea pig 5-HT1F receptor subtype: A comparison of the pharmacological profile to the human species homolog. Neuropharmacology, 36(45), 569–576. American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders, 5th edn. Arlington, VA: APA. https://doi.org/10.1176/appi.books.9780890425596 American Sleep Association. (2021). Sleep Statistics—Data about Sleep and Sleep Disorders. Accessed on 4 December 2021 at www.sleepassociation.org/about-sleep/sleep-statistics Angriman, M., Caravale, B., Novelli, L., Ferri, R., Bruni, O., et al. (2015). Sleep problems in children with neurodevelopmental disabilities. Neuropediatrics, 46, 199–210. Asztély, K., Kopp, S., Gillberg, C., Waern, M. & Bergman, S. (2019). Chronic pain and health-related quality of life in women with autism and/or ADHD: A prospective longitudinal study. Journal of Pain Research, 12, 2925–2932. Baker, E., Richdale, A., Short, M. & Gradisar, M. (2013). An investigation of sleep patterns in adolescents with high-functioning autism spectrum disorder compared with typically developing adolescents. Developmental Neurorehabiliation, 16(3), 155–165. DOI: 10.3109/17518423.2013.765518 Bartley, E. J. & Fillingim, R. B. (2013). Sex differences in pain: A brief review of clinical and experimental findings. British Journal of Anaesthesia, 111(1), 52–58. Blue, M. E. & Johnston, M. V. (1995). The ontogeny of glutamate receptors in rat barrel field cortex. Developmental Brain Research, 84(1), 11. Casanova, M. F. (2013a) Abdominal Pains and Migraine in Autism. Accessed on 7 December 2021 at https:// corticalchauvinism.com/2013/02/10/abdominal-pains-and-migraine-in-autism Casanova, M. F. (2013b) What Causes the Major Symptoms of Autism (Part 1)? Accessed on 7 December 2021 at http:// corticalchauvinism.wordpress.com/2013/01/29/what-causes-the-mayor-symptoms-of-autism-part-1 Casanova, M. F. (2014) The Body Plan in Autism: Stiffness and Anxiety. Accessed on 7 December 2021 at https:// corticalchauvinism.com/2014/06/02/the-body-plan-in-autism-stiffness-and-anxiety Casanova, M. F. (2015) Transitioning of Health Care Services for Autistic Individuals. Accessed on 7 December 2021 at https://corticalchauvinism.com/2015/12/07/transitioning-of-health-care-services-for-autistic-­ individuals Casanova, M. F. (2017) Internal Sensory Stress and Discomfort/Pain in Autism. Accessed on 7 December 2021 at https://corticalchauvinism.com/2017/02/20/internal-sensory-stress-and-discomfortpain-in-autism Casanova, M. F. & Casanova, E. L. (2019). The modular organization of the cerebral cortex: Evolutionary significance and possible links to neurodevelopmental conditions. Journal of Comparative Neurology, 527(10), 1720–1730.

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UNDERSTANDING AND TREATING SLEEP DISTURBANCES IN AUTISM Casanova, M. F., Buxhoeveden, D. P., Switala, A. E. & Roy, E. (2002). Minicolumnar pathology in autism. Neurology, 58(3), 428–432. Consens, F. B. & Chervin, R. D. (2008). Sleep disorders. In C. Goetz (ed.), Textbook of Clinical Neurology, 3rd edn. Philadelphia, PA: Elsevier Health Sciences. Devnani, P. A. & Hegde, A. U. (2015). Autism and sleep disorders. Journal of Pediatric Neuroscience, 10(4), 304–307. Gabriele, S., Sacco, R. & Persico, A. M. (2014). Blood serotonin levels in autism spectrum disorder: A systematic review and meta-analysis. European Neuropsychopharmacology, 24(6), 9191–9129. Goldman, S. E., Richdale, A. L., Clemons, T. & Malow, B. A. (2012). Parental sleep concerns in autism spectrum disorders: Variations from childhood to adolescence. Journal of Autism and Developmental Disorders, 42, 531–538. Gordon, C., State, R. C., Nelson, J. E., Hamburger, S. D., Rapoport, J. L., et al. (1993). A double-blind comparison of clomipramine, desipramine, and placebo in the treatment of autistic disorder. Archives of General Psychiatry, 50(6), 441–447. Gu, X., Zhou, T. J. & Anagnostou, E. (2018). Heightened brain response to pain anticipation in high-functioning adults with autism spectrum disorder. European Journal of Neuroscience, 47(6), 592–601. Haack, M., Sanchez, E. & Mullington, J. M. (2007). Elevated inflammatory markers in response to prolonged sleep restriction are associated with increased pain experience in healthy volunteers. Sleep, 30(9), 1145–1152. Hollander, E., Novotny, S., Allen, A., Aronowitz, B., Cartwright, C., et al. (2000). The relationship between repetitive behaviors and growth hormone response to sumatriptan challenge in adult autistic disorder. Neuropsychopharmacology, 22(2), 163–167. Hutsler, J. J. & Casanova, M. F. (2014). Cortical construction in autism spectrum disorder: Columns, connectivity and the subplate. Neuropathology and Applied Neurobiology, 42(2), 115–134. Janusonis, S., Gluncic, V. & Rakic, P. (2004). Early serotonergic projections to Cajal-Retzius cells: Relevance for cortical development. Journal of Neuroscience, 24(7), 1652–1659. Klintwall, L., Holm, A. & Eriksson, M. (2011). Sensory abnormalities in autism: A brief report. Research in Developmental Disabilities, 32, 795–800. Malow, B. A., Marzec, M. L., McGrew, S. G., Wang, L., Henderson, L. M., et al. (2006). Characterizing sleep in children with autism spectrum disorders: A multidimensional approach. Sleep, 29, 1563–1571. McDougle, C., Naylor, S. T., Cohen, D. J., Aghajanian, G. K., Heninger, G. R., et al. (1996). Effects of tryptophan depletion in drug-free adults with autistic disorder. Archives of General Psychiatry, 53(11), 993–1000. McDougle, C., Naylor, S. T., Cohen, D. J., Volkmar, F. R., Heninger, G. R., et al. (1998). A double-blind, placebo-controlled study of fluvoxamine in adults with autistic disorder. Archives of General Psychiatry, 53(11), 1001–1008. Mehlinger, R., Scheftner, W. & Poznanski, E. (1990). Fluoxetine and autism. Journal of the American Academy of Child and Adolescent Psychiatry, 29(6), 985. NCCIH. (2015) NIH Analysis Shows Americans Are in Pain. Accessed on 5 December 2021 at www.nccih.nih. gov/news/press-releases/nih-analysis-shows-americans-are-in-pain Persico, A. M., Mengual, E., Moessner, R., Hall, S. F., Revay, R. S., et al. (2001). Barrel pattern formation requires serotonin uptake by thalamocortical afferents, and not vesicular monoamine release. Journal of Neuroscience, 21(17), 6862–6873. Posar, A. & Visconti, P. (2001). Sleep problems in children with autism spectrum disorder. Pediatric Annals, 49(6), 278–282. DOI: https://doi.org/10.3928/19382359-20200511-01 Powrozek, T. A. & Zhou, F. C. (2005). Effects of prenatal alcohol exposure on the development of the vibrissal somatosensory cortical barrel network. Developmental Brain Research, 155(2), 135. Schain, R. J. & Freedman, D. X. (1961). Studies on 5-hydroxyindole metabolism in autistic and other mentally retarded children. The Journal of Pediatrics, 58, 315–320. Schreck, K. A., Mulick, J. A. & Smith, A. F. (2004). Sleep problems as possible predictors of intensified symptoms of autism. Research in Developmental Disabilities, 25, 57–66. Souders, M. C., Mason, T. B., Valladares, O., Bucan, M., Levy, S. E., et al. (2009). Sleep behaviors and sleep quality in children with autism spectrum disorders. Sleep, 32, 1566–1578. Souders, M. C., Zavodny, S. & Eriksen, W. (2017). Sleep in children with autism spectrum disorder. Current Psychiatry Reports, 19(6), 34.

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Sleep Disorders in Autism Steingard, R., Zimnitzky, B., DeMaso, D. R., Bauman, M. L. & Bucci, J. P. (1997). Sertraline treatment of transition-associated anxiety and agitation in children with autistic disorder. Journal of Child Adolescent Psychopharmacology, 7(1), 9–15. Stores, G. (1992). Sleep studies in children with a mental handicap. Journal of Child Psychology and Psychiatry, 33(8), 1303–1317. Vein Center of North Texas. (2021). History of RLS. Vein Center of North Texas. Accessed on 4 December 2021 at https://veincenternorthtexas.com/rls-history.html Walther, D. J. & Bader, M. A. (2003). Unique central tryptophan hydroxylase isoform. Biochemical Pharmacology, 66(9), 1673–1680. Whitaker-Azmitia, P. M. (2001). Serotonin and brain development: Role in human developmental diseases. Brain Research Bulletin, 56(5), 479–485. Xu, Y., Sari, Y. & Zhou, F. C. (2004). Selective serotonin reuptake inhibitor disrupts organization of thalamo­ cortical somatosensory barrels during development. Developmental Brain Research, 150(2), 151.

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CHAPTER 4

Diet, Nutrition, Sleep and those with Autism Spectrum Disorder Kelly McCracken Barnhill, MBA, CN, CCN, The Johnson Center for Child Health and Development, Texas

Sleep concerns in those with autism spectrum disorder (ASD) have not been well studied to date, though sleep has long been documented as an issue for many in this population. One 2019 study noted that over 80 percent of preschool-aged children with ASD had sleep difficulties (Carmassi et al., 2019). Strategies for nutritional support drawn from interventions trialed clinically and in research in other treatment populations can be individualized to address these concerns. This chapter aims to outline and discuss nutritional approaches to support better sleep and thus better health for those with ASD. As this publication makes clear, good-quality sleep and ample amounts of it are recommended for all of us. The National Sleep Foundation recommends 12–17 hours’ sleep for infants under 1 year, 11–14 hours’ sleep for toddlers 1–2 years old, 10–13 hours’ sleep for preschool-aged children, 9–11 hours’ sleep for children and pre-teens aged 6–13 years, and 8–10 hours’ sleep for adolescents aged 14–17 years.1 For most adults, those numbers are 7–9 hours’ sleep and 7–8 hours’ sleep for those over 65. A 2011 report issued by the American Academy of Pediatrics indicated that 25–50 percent of preschoolers and 40 percent of adolescents were not getting enough sleep (Bhargava, 2011). The Covid-19 pandemic has exacerbated the existing deficits in high-quality sleep across all age groups, and accentuated the need to employ multiple avenues 1

https://sleepfoundation.org/press-release/national-sleep-foundation-recommends-new-sleeptimes/page/0/1

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of care and intervention in improving both sleep quality and quantity (Bruni et al., 2021). The interrelationship between diet, nutrition and sleep has emerged as an area of research interest in the past decade. Original research primarily focused on diet, sleep and the impact on obesity risks in pediatric populations. That work has broadened to expand many other aspects of sleep status and nutrition as well. It is documented that children, adolescents and adults with ASD have an increased occurrence of sleep concerns over the general population (Baker & Richdale, 2015; Ballester et al., 2020; Bauman, 2010; Hodge et al., 2014; Richdale & Schreck, 2019; Souders et al., 2017). Dietary alterations and nutritional supplementation are solid clinical options with research support to address sleep in those with ASD. Professionally guided dietary change and nutritional supplementation with the support of a qualified clinician allow caretakers to make safe changes for children, adolescents and adults and positively impact sleep. This, in turn, can have a profound add-on effect, by improving medical data, behavior, and school/ therapy participation and performance. Appropriately applied diet plans do not detract from an individual’s health and well-being in any way, and can enhance health status significantly. This chapter specifically reviews the status of research in this arena and offers perspective on reasonable and recommended clinical interventions.

Food and Dietary Considerations Fundamental dietary recommendations for the population at large contribute to a healthy sleep pattern (USDA, 2015, 2020). Research supports this understanding that a healthy diet contributes to an ability to fall asleep faster and stay asleep longer, as well as improving the overall quality of sleep (St-Onge et al., 2016a). Recommendations encompass both food and nutrients to consume each day, as well as items to limit and/or avoid. Global targets for dietary consumption for the entire population are now referred to as Dietary Reference Intake (DRI) and were created to meet the nutrient requirements of almost all (97–98%) individuals in a life span group (Otten, Hellwig & Meyers, 2006). While clinical application clearly acknowledges variability in individual needs and requirements, DRI references help establish basic 68

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guidelines for intake recommendtions when considering dietary alterations to address inadequate sleep. The most widely researched dietary application in sleep intervention has been the Mediterranean Diet. Adherence to this dietary protocol involves a diet focused on whole foods such as fresh fruits and vegetables, complex grains, potatoes, beans, nuts and seeds. The Mediterranean Diet relies on olive oil as a primary fat source and utilizes dairy products, eggs, fish and poultry in low to moderate amounts. Red meats are discouraged or eliminated, and processed foods are not included in this approach. The Mediterranean Diet has been proven to support enhanced sleep in multiple studies across participant populations (Ferranti et al., 2016; Godos et al., 2019; Mamalaki et al., 2018; Muscogiuri et al., 2020; Rosi et al., 2020; Zuraikat et al., 2020). Additional research points to the impact of polyphenols found in fresh fruits and vegetables as supportive of appropriate sleep duration (Noorwali, Hardie & Cade, 2018), further reinforcing the focus on fresh produce in the diet.

Macronutrients Current research gives us some insight into eating behaviors and habits of those with ASD vs those without. One study evaluated dietary intake of children with and without ASD in a Mediterranean region (Valencia, Spain). Participants with ASD did not meet recommended dietary intake for vitamins B1, B2 and C, and calcium. In another pediatric cohort, all study participants consumed adequate quantities of all macronutrients. The majority of all participants consumed an inadequate amount of fat-soluble vitamins A, D and E, as well as folic acid and calcium. Children with ASD consumed lower levels of protein and calcium, and were deficient in a number of B vitamins, including B1, B2, B3, B6 and folate, compared to similarly aged children without ASD (Barnhill et al., 2018). In a more recent meta-analysis of similar data cohorts, researchers found that study participants did not meet recommended dietary intake for calcium and vitamin D, and participants with ASD consumed less of vitamins B1, B2 and B12, vitamin D, calcium, phosphorus and selenium than participants without ASD (Esteban-Figuerola et al., 2019). High-carbohydrate meals, particularly those with processed carbohydrates and sugars, can negatively impact sleep duration and quality (Afaghi, 69

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O’Connor & Chow, 2007). One publication reported that high-carbohydrate meals contributed to increased incidents of night-waking and decreased rapid eye movement (REM) sleep patterns (St-Onge et al., 2016a). Consuming highly processed carbohydrates and sugary foods can also induce daytime sleepiness, which contributes to a disordered sleep-wake cycle. Processed carbohydrate consumption triggers insulin production and release from the pancreas to address elevated blood sugar levels. Insulin regulates the metabolism of this sugar, and subsequently blood sugar levels drop dramatically, leading to exhaustion and daytime sleepiness. In both children and adults, this experience drives the cyclical consumption of processed foods (and in adults, caffeine can also be employed) to address dropping blood sugar levels. Additionally, on a related note, diets low in fiber have been shown to contribute to decreased restorative sleep in adults. Fiber slows the absorption of sugar in the gastrointestinal tract, and in doing so stabilizes blood sugar over time. Focusing on increasing fiber intake and meeting daily recommended intake is another strategy to maintain health and improve sleep status. This study also reported that more fiber intake predicted more time spent in deep sleep (St-Onge et al., 2016b). One of the biggest issues and concerns with the pediatric and adolescent population is the consumption of sugar-laden processed drinks such as sodas. A complicating factor given current trends in consumption is the inclusion of caffeine in preferred dietary products. Caffeine is a natural stimulant that is paired with sugar in many beverages. Sleep experts agree that across the population, it’s imperative to refrain from sugary drinks, processed carbohydrates and caffeine in the hours before bedtime. Caffeine is known to influence the ability to go to sleep, stay asleep and sleep restoratively (Clark & Landolt, 2017; Crispim et al., 2011). For adults, caffeine should not be consumed beyond the early afternoon to reduce the potential impact on sleep onset, duration and quality. Caffeine should not be a component of any child’s diet beyond the rare special occasion, and clearly this can be tricky given the preponderance of sodas and even naturally caffeinated beverages available now. Clearly the bidirectional relationship that can develop and be seen with increased processed carbohydrate intake and decreased fiber intake is circular and cyclical. When we are well-rested, we make better food choices and maintain healthier nutritional status. The reverse is also true: when we are 70

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not sleeping well, we tend to crave and indulge in more processed, sugary food options rather than real food. Recent research suggests that decreased sleep duration directly affects longer-term sleep patterns, hormone metabolism and circadian rhythms. This then contributes to weight changes and obesity risk, as well as the development of chronic health concerns such as type 2 diabetes and cardiovascular disease. Altered sleep status for an individual can begin as early as childhood and have repercussions throughout the life course (Frank et al., 2017). Further complicating this picture is the impact on hormones from our sleep habits. Ghrelin and leptin are hormones associated with hunger and satiety, respectively, which are impacted by altered sleep patterns. In a pattern of healthy sleep, ghrelin and leptin are modulated and stable. With shortened sleep duration and sleep deprivation, levels of ghrelin are significantly increased and those of leptin are decreased, which may influence overeating choices (Arora, Choudhury & Taheri, 2015; Taheri et al., 2004) and contribute to a pattern of insulin resistance (Lin et al., 2020). Healthy, restorative deep sleep also neutralizes the stress hormones adrenaline and cortisol, and conversely a sleep deficiency triggers the release of these stress hormones, increasing overall levels. The activation of this hypothalamic– pituitary–adrenal (HPA) axis also leads to an increase in inflammatory response and increased activity of the sympathetic nervous system (Hirotsu, Tufik & Andersen, 2015). This has been documented to increase the risk of muscle breakdown, heart disease and increased accumulation of belly fat (AHA, 2016; Stengel & Taché, 2012). Each of these concerning variables of modern Western diets is removed when employing the Mediterranean Diet approach. Given the impact of decreased sleep duration, quality and quantity on hormone metabolism, it is important to note that weight status has been a topic of investigation in the ASD community for years. There are concerns of overweight/obesity in those with ASD, which have been substantiated by many research studies (Healy, Aigner & Haegele, 2019; Kahathuduwa et al., 2019; Zheng et al., 2017). Under these circumstances, the relationship of sleep status and weight gain in this population particularly must be acknowledged. One study documented the importance of at least 10 hours’ sleep each night for children and adolescents to avoid weight gain (Ozturk et al., 2009). 71

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Others point to the direct impact of shortened sleep duration and quality of sleep on the development of overweight/obesity and subsequent concerns such as chronic disease (Arora et al., 2015; Garaulet et al., 2011; Iglowstein et al., 2003; Javaheri et al., 2011). High-fat diets have also been proven to impact sleep status in research studies—with some studies pointing to decreased sleep status, and others pointing to increased restorative sleep, depending upon the type of fat consumed. Increased saturated fat consumption is associated with diminished sleep duration (St-Onge et al., 2016a), while increased heart-healthy poly-unsaturated fat has been linked to increased quality and quantity of sleep (Martinez et al., 2017). As fats are somewhat more difficult for a healthy digestive system to process, it is best to refrain from eating higher fat meals at least 3 hours prior to bedtime to ensure a lack of interference with sleep. Higher protein content diets have also been shown to both increase and decrease sleep in several populations. Decreased overall protein intake and status has been associated with shortened sleep status (Grandner et al., 2013). Proteins, like fats, can be more difficult to digest and absorb than some carbohydrates, and in general protein intake within close proximity to bedtime is discouraged. However, increased lean protein intake consistently throughout the day has been documented to support better sleep in some populations (Zhou et al., 2016). Significant work has also been published in recent years showing the administration of easily digestible protein within the hours just prior to sleep to have no negative impact on sleep duration, quality and onset. The nutritional benefits of this single nutrient support approach assist with overnight muscle recovery and rejuvenation through availability of easily digested amino acids (Snijders et al., 2019). When considering a basic dietary approach to improving sleep quality for those with ASD, the Mediterranean Diet is a recommended approach (AHA, 2020; Mayo Clinic, 2021). The nuances of research in this area are complex, as research design cannot encompass the many bidirectional components involved, and single dietary change or patterns cannot easily be isolated and studied. In general, an approach that follows general guidelines for meeting overall dietary requirements for macro- and micronutrients while minimizing or eliminating processed “foods” is ideal, and addresses the multiple concerns associated with increased sugar and carbohydrate intake. 72

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Micronutrients An NHANES (National Health and Nutrition Examination Study) based study found that a lack of key vitamins and minerals, including fat-soluble vitamins A, D, E and K as well as vitamin C, calcium and magnesium, was associated with sleep issues (Ikonte et al., 2019). A comprehensive study evaluated the use of a broad-spectrum multivitamin and multimineral product (which could correct the deficits noted above) in a population of children with ASD. Among other data, caregivers reported significant improvements in core sleep components at the end of the 12-month study (Adams et al., 2018).

Vitamins A and D Research has pointed to lower levels of vitamin A in children with ASD, though little research has linked this deficiency with sleep problems. In a recently published study (Wen et al., 2021), researchers reported that children with ASD had lower serum vitamin A levels and a higher prevalence of sleep disturbances than children without ASD. Further, the incidence of vitamin A deficiency in participants with ASD and sleep disturbances was higher, and their symptoms more severe than those without sleep disturbances and ASD. Finally, the interaction between vitamin A deficiency and sleep disturbances was also associated with the severity of autism symptoms in study participants. Vitamin D deficiency has been correlated with poor sleep status in many populations (Gao et al., 2018; Ozkaya & Gungor, 2019). Intervention studies across multiple ages and diagnoses have also had positive results with vitamin D treatment (Majid et al., 2017). Low vitamin D levels have also been associated with poor sleep status in those with ASD. In a recently published study, vitamin D deficiency in children was associated with objectively measured decreased sleep duration and also poorer sleep efficiency (Al-Shawwa, Ehsan & Ingram, 2020). It is recommended that everyone should have their serum vitamin 25(OH)D level checked, and should take supplemental vitamin D in D3 (cholecalciferol) form to achieve optional levels if it is deficient.

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Iron Low iron stores have been reported in children with ASD (Dosman et al., 2007; Youssef et al., 2013). A recent meta-analysis of research evaluating those diagnosed with attention-deficit hyperactivity disorder (ADHD) concluded that those with ADHD present with lower serum ferritin levels and iron deficiency, which is relevant in that lower serum ferritin levels contribute to poor sleep (Tseng et al., 2018). Physicians working in pediatric sleep center settings recognize the importance of checking ferritin and other iron markers to evaluate the impact on sleep, and recommend supplemental iron to bring the serum ferritin level to > 50 ng/mL when it is lower than this threshold (Ingram & Al-Shawwa, 2019). In other work, researchers evaluating restless leg syndrome and ASD report significant response to iron supplementation in the treated population (23 positive responses of 25 treated study participants), which improved sleep status (Kanney et al., 2020). However, another recent intervention study in a similarly sized population (Reynolds, 2020) found no significant change in sleep status after 12 weeks of supplementation. A recent scoping review evaluating the relationship of iron deficiency to sleep quality and quantity concluded that ferritin and iron levels should be evaluated and potential supplementation should be considered for those presenting with sleep disorders and disturbances (Leung et al., 2020).

Magnesium Magnesium alone and also in combination with vitamin B6 has been studied in ameliorating symptoms associated with ASD. Results over the past 50 years are mixed with regard to sleep support and improvement, though primarily positive overall. A mouse model study reported that optimal magnesium levels, rather than levels above or below the clinically recommended range, have been found to be required for normal sleep regulation (Chollet et al., 2001). In reference to sleep in particular, a 2021 meta-analysis indicated more research would be needed to conclusively endorse magnesium support (Chan & Lo, 2021), but the more recent Coronary Artery Risk Development in Young Adults (CARDIA) study of over 5,000 young adults found a positive impact from magnesium intake on both sleep quality and duration (Zhang et al., 2021). 74

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Essential Fatty Acids Omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been shown to be protective against chronic sleep deprivation memory impairment (Alzoubi, Mayyas & Abu Zamzam, 2019). A smaller study with a pediatric population showed improvements in sleep with DHA supplementation (Montgomery et al., 2014).

The Complexities of Tryptophan, 5-Hydroxytryptophan (5HTP), and Melatonin The amino acid tryptophan is an essential amino acid required for protein synthesis, and it also functions in conversion to serotonin, melatonin, niacin and kynurenine (Friedman, 2018; Peuhkuri, Sihvola & Korpela, 2012). 5HTP is the intermediate metabolite in converting tryptophan into serotonin, which has been accepted as important in the relationships between dietary components and sleep. From a dietary perspective, building blocks for L-tryptophan can be found in bananas, plums, animal protein, grains, milk and seafood, but it can also be synthesized by the gastrointestinal tract microbiome (Gevi et al., 2016; Richard et al., 2009). A supplementation intervention study in an adult population found that evening dietary increases in tryptophan intake improved sleep in those with sleep disturbances and enhanced alertness in the morning, most likely as a result of improved sleep quality (Silber & Schmitt, 2010). Additional research indicates that tryptophan may be low in those with ASD (Kałużna-Czaplińska et al., 2017). Research indicates that individuals with ASD are known to have abnormal melatonin production. Melatonin is formed on the serotonin pathway from tryptophan and is responsible for the regulation of circadian rhythms. It is a neurohormone that is formed from serotonin and secreted by the pineal gland (Rossignol & Frye, 2011). Melatonin has now been used as a dietary supplement sleep aid for years in both adult and pediatric populations. A significant number of research studies have validated low levels of melatonin or urinary byproducts of melatonin production and synthesis specifically in children with ASD (Hayashi et al., 2021; Malow et al., 2012; Yuge et al., 2020). The sum of current research in this area points to decreased melatonin production, abnormal melatonin receptor sites and increased melatonin 75

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breakdown as potential factors in sleep delay and night waking for those with ASD (Anderson et al., 2008; Galli-Carminati, Deriaz & Bertschy, 2009; Giannotti et al., 2006). A recent study supports long-term use of melatonin in those with ASD with no adverse effects on sleep, growth, pubescence or body mass index reported. Additionally, families reported significant improvement in sleep disturbance, quality and quantity of sleep, and quality of life that was maintained for the 2-year duration of the study (Malow et al., 2021). While melatonin has been studied in those with ASD, clinical research on the use of tryptophan and 5HTP in this population is limited. Use has been studied in other pediatric and adult populations with good results. Use of a tryptophan supplement in conjunction with melatonin and vitamin B6 significantly improved sleep quality by reducing night waking in a study of children and adolescents, while a melatonin supplement alone showed no improvement (Bravaccio et al., 2020). From a clinical perspective, use of each component along this pathway to support improved sleep is a reasonable and appropriate approach to improving sleep duration and quality in those with ASD. Other nutritional components have been researched in amelioration of sleep concerns in those with ASD. Work evaluating the use of L-carnosine (Abraham et al., 2021) has consistently reported improvements in sleep duration and quality, though study sizes have been small and more research needs to be done. Clinical reports indicate gamma-aminobutyric acid (GABA), a non-proteinogenic amino acid that serves as an inhibitory neurotransmitter, can be highly supportive of sleep and reduced stress in those with ASD, and several research studies have been published regarding GABA support in the general population. A recent systematic review of the literature, however, indicates that very little research evidence for its use in enhancing sleep or stress is available (Hepsomali et al., 2020). Little evidence is also available for support of zinc use in sleep duration or quality improvement, though it is often clinically applied for this purpose and some positive studies exist (Ji & Liu, 2015; Saito et al., 2017).

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Conclusions and Clinical Recommendations Given the current status of literature evaluating the relationship between diet and sleep patterns in those with ASD, it is important to establish reasonable and appropriate recommendations for potential intervention to address sleep support for individuals in care. A solid baseline approach for dietetic counseling and nutritional support is the implementation of a Mediterranean Diet approach. This will embrace dietary intake based on a wealth of fresh fruits and vegetables and whole grains, reasonable protein intake and the elimination of processed foods. Focused counseling should include detailed guidance on fiber intake, water intake and elimination of all sugary beverages. For those patients who may require additional dietary intervention and elimination, the Mediterranean Diet provides the groundwork to enhance and individualize any dietary approach. Addressing eating behavior that can impact sleep with clients is also important. Establishing a meal routine to include heavier meals earlier in the day and a lighter meal in the evening can impact sleep. Avoiding meals within a few hours of bedtime is ideal, though for individual cases the addition of nutrient support prior to bedtime can be appropriate. Guidance on reasonable snacking is important, as one study reported those who snacked consistently between meals had decreased sleep duration and quality. Guidance on particular foods containing research-supported nutrients is encouraged. With regard to micronutrient intervention, we encourage the assessment of dietary intake for any client with a comprehensive 3-day food diary to evaluate current nutritional intake. Deficits noted here, particularly those that mirror the results found in multiple research studies outlined in this paper, can be addressed with a high-quality multivitamin/multimineral product, preferably one developed and researched to particularly address the needs of those on the autism spectrum. Implementation of a high-quality omega-3 essential fatty acid support protocol for overall nutritional support and health status could have a beneficial impact on sleep. Another reasonable clinical suggestion is to evaluate potential nutrition components that could affect sleep duration and quality. Assessment of serum vitamin 25(OH)D, ferritin and iron levels is a recommended step in evaluating nutritional variables to address. Treating with appropriate doses of the cholecalciferol form of vitamin D and a highly absorbable form of 77

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iron, such as ferrous gluconate or ferrous bisglycinate when needed, is recommended. Increasing magnesium support to the body is also a reasonable step to suggest. Adding magnesium citrate and glycinate forms to daily intake can assist in promoting sleep and relaxation. Another aspect of magnesium support to consider is the use of Epsom salt baths in the evening to enhance sleep onset and duration. The suggested routine as well as the magnesium absorption can contribute to better sleep hygiene. Finally, the targeted use of melatonin to support sleep onset and duration can be successful. When layering in other serotonin-related supplementation such as 5HTP and tryptophan, guidance should be provided by an experienced practitioner who can successfully assess and navigate the interaction of these supplements with diet, medication and nutritional supplementation components to maximize outcome and avoid any adverse response.

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CHAPTER 5

Sleep and Sensory Processing Virginia Spielmann, PhD, MSOT, STAR Institute for Sensory Processing Centennial, Colorado, Marco Leão, MS, OT, AcademiaPediatrica.com, Porto, Portugal, and Shelly J. Lane, PhD, OTR/L, FAOTA, Colorado State University

Preamble—Establishing Terms Sensory Integration and Processing is the term used to denote the neurobiophysiological foundations for sensing 1) the body and 2) the physical environment. It is a whole brain-body-nervous system process involving an amalgam of numerous subsystems each providing partial data toward the gestalt. Autism is a form of neurodivergence, characterized by differences compared to the neuromajority (individuals within the bell curve who do not meet criteria for a neurodevelopmental diagnosis). Although highly heterogenous, autistic differences are primarily evident in sensory integration and processing, and social and cognitive style (Pearson & Rose, 2021). Please note that in this chapter we use identity-first language (e.g., “autistic person” rather than “person with autism”) as requested by autistic communities and advocacy networks. Sleep health is vital for psychological and physical well-being. It plays a fundamental role in maintaining homeostasis, replenishing neural energy stores, stress recovery, mental health, and availability for relationships and learning (Galván, 2020; Krueger et al., 2016; Miletínová & Bušková, 2021; Tamaki et al., 2020). There is growing experimental evidence that sleep influences plasticity and connectivity and in some opinions neuroplasticity is a primary function of sleep (Krueger et al., 2016).

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Introduction Differences in sensory integration and processing have been shown to be as high as 90–95 percent in autistic populations (Robertson & Baron-Cohen, 2017; Tomchek & Dunn, 2007). This has been shown to impact sleep in children (Hollway, Aman & Butter, 2013; Mazurek & Petroski, 2015; Reynolds, Lane & Thacker, 2012), and to some extent in adults (Hohn et al., 2019); sleep is a commonly affected aspect of functioning in the autistic individual. Between 50–80 percent of children in the autistic population exhibit disordered sleep patterns (Reynolds & Malow, 2011) which can be chronic (Mazurek et al., 2019). In investigating sleep patterns and disorders in autistic children, Wiggs and Stores (2004) found that 67 percent of autistic children in their study had current sleep problems based on parent report, although all children had “compromised sleep quality” based on actigraphy (p.372), whereas about 25–50 percent of neuromajority children experience disordered sleep, principally related to difficulties settling down for the night and frequent awakening (Roussis et al., 2021). In this chapter we have drawn from our own systematic review on the relations between sleep and sensory integration/processing in autism. We have included findings from a range of study designs and methodologies, extending from explorations of neurobiological underpinnings to experimental designs. The chapter begins with an overview of sensory integration/processing and its relation to human development and psychological well-being. A brief review of the neurobiological mechanisms of sleep and wakefulness follows with connections to the sensory integration/processing systems and self-regulation. Sensory-informed approaches to research and health care are discussed and their place in an integrated biopsychosocial approach to sleep health is proposed.

Sensory Integration and Processing Thanks to sensory integration/processing we are able to sense where we are when we wake up in the morning, where our body is in relation to the covers we sleep under, who else is awake in the house and the room, and the state of our bladder and stomach. We can sense the brightness of the day as the light falls on our face and closed eyelids, smell breakfast activities downstairs, 84

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and lift our head and torso into an upright position, eventually placing our feet on the floor and rising to stand. Every event is a sensory event first, and our sensory systems give us information about the position and state of our own body within the busy and dynamic world around us. We are aware of the complete picture of our bodily self-awareness via the combination and interpretation of exteroceptive and interoceptive sensory data. Exteroceptive data include our distance senses (vision and sound), sense of bodily motion, and body position in relation to the environment and itself (i.e., I can tell my legs are crossed without looking under the table, I can predict how far I need to move my foot to touch the floor). Interoceptive data include our internal sense of well-being; this can be organic body function (gut motility, a racing heart, hunger) and somatic affective sensations (butterflies in my stomach, a sinking heart, etc.). These interoceptive elements are often referred to as visceral sensation. In sensory integration theory as conceptualized by Ayres (1979), seven dynamic sensory systems crosstalk, combine and overlap to provide the full picture of what is going on within and around an individual, thus enabling postural and motor development, use of sensory data for action generation, development of relationships and learning. See Table 5.1 for a summary of these systems. It is important to note that every sensory system has downstream connections with our emotion regulation system, emotional memories and cognition. Table 5.1 Outline of sensory systems and highlighted contributions to development System

Description

Significant contributions to development

Vestibular

Sense of head position in relation to gravity, and movement direction and speed.

Eye coordination and movement, sense of motion, head movement, coordination of head and body movement, postural control, spatial orientation, equilibrium, coordination of the two sides of the body and body position. cont.

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System

Description

Significant contributions to development

Proprioceptive

Sense of joint movement: pull or load/push, twist, etc. Speed and extent of muscle contraction or expansion, muscle tension, limb and musculoskeletal positioning.

Sense of inhabiting our body, ability to regulate the force with which we act, and our sense of position and movement through space and velocity of limb movement.

Tactile

Cutaneous/haptic-based perception of texture, shape, position, wetness, vibration, itch, temperature and pain.

Distinction between me and other (and therefore body schema), processing sensory consequences of motor output, understanding object properties, formation of attachment and interpersonal behaviors.

Visual

Retinal receptors detect edges, movement in the environment, gather data about the environment (shapes, dimensions, distance) and enable you to see your own body.

Personal movement/goal directed movement, sense of position within environment, awareness of external events, perceiving meaning, and attachment and interpersonal behaviors.

Auditory

Auditory receptor cells (hair cells) convert mechanical energy into electrical energy in the cochlea of the inner ear enabling detection of wave/ vibrations, and coding of pitch, amplitude, frequency, tone, rhythm, rate, volume, echo, etc.

Sense of self in space and time, self-motion, environmental awareness, interpersonal behaviors, linguistic and nonlinguistic communication.

Gustatory

Mouth- and throat-based sensations of flavor.

Attachment processes, ability to discern potentially harmful toxins and “gatekeep,” and dietary preferences.

Olfactory

Nostril-based odor detection and discrimination, works closely with taste.

Attachment processes, formation of emotional memories, and ability to sense strong emotions like fear and disgust.

Note: this table is not exhaustive and is designed to provide an overview of the importance of sensory integration/processing throughout human development and function. See Sensory Integration: Theory and Practice (Bundy & Lane, 2020) for a more detailed and in-depth discussion.

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These seven open interactive systems combine with interoceptive sensations (internal visceral data from a range of sensations) to provide the raw material for development of sense of self and our perception of the world around us, our sensory consciousness. Sensory integration is a whole brain-body process that involves both automatic/unconscious and conscious—at times effortful—processing. Maintaining a functional and ready posture and producing movement and action in response to perceived sensory events is part of sensory integration/processing. In an integrated and mature sensory system these actions are age appropriate and contingent on environmental (including interpersonal) and personal demands. This is known as the adaptive response. In concert with each other—and through processing the sensory-based feedback from our motor/behavioral outputs—our overlapping sensory systems continuously construct our conscious sense of reality through every waking moment. This is consistent with Guillery’s (2017) concept of the “interactive brain”; the idea that sensory inputs and motor outputs are not separate but are combined at every level of the nervous system. Every sensory system’s primary and most primitive responsibility is to keep you alive and safe; to that end sensory stimuli are among the fastest and most powerful triggers of the sympathetic nervous system. This includes, of course, fight/flight/freeze responses to real or perceived threats.

The Autonomic Nervous System and Stress Processes The autonomic nervous system (ANS) is a part of the nervous system that innervates automatic systems targeting three different types of tissues: smooth muscle, cardiac muscle and glands (Mason, 2017). The ANS has two main divisions: the sympathetic (SNS), responsible for our fight or flight; and the parasympathetic (PNS), responsible for rest and digest. These two systems generally work in harmony with each other to maintain homeostasis via body processes like heart rate, blood pressure, respiration rate and pupil dilation. The ANS responds to information about the body and the external environment and responds via modulation of sensory, metabolic and neuro­ endocrine functions by means of these two divisions (Christensen et al., 2020; Gibbons, 2019). In infancy humans tend to be parasympathetically 87

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dominated and in later years tend toward a more sympathetically dominated state (Oldehinkel et al., 2019). Although we typically think of the PNS and SNS as systems that work to support homeostatic balance, the SNS is important for its mediation of our stress responses. The adrenal gland is innervated solely by the SNS, and the adrenal medulla is responsible for releasing the stress hormone cortisol. Fight or flight, and extreme stress responses, the purpose of which is to keep the individual alive, are activated by the SNS. Fight or flight is a phrase coined to describe physiology, not behavior (Hopper, 2021). It refers to neurobiological survival reflexes triggered by the brain’s defense circuitry that pushes the body to action designed to mitigate danger and threat. The more an individual is chronically hypo- or hyper-aroused as a result of intolerable stress, the more their nervous system operates in a state of fight-or-flight readiness (Lillas & Turnbull, 2009). The cumulative burden of excessive chronic stress can impact the physiological stress response systems and cause long-term changes to the arousal and recovery systems. The cumulative effects of ongoing adaptation to chronic stress, and the toll this takes on the body, is referred to as allostatic load; allostatic overload is experienced in situations where the nervous system is no longer able to functionally adapt to stress or recover after a stressor is terminated (Guidi et al., 2021). Unsurprisingly the SNS and PNS have a profoundly influential role in the maintenance of circadian rhythm and sleep patterns; poor sleep and circadian disruption also contribute to the development of allostatic load/overload (Guidi et al., 2021).

Regulation and Sensory Integration/Processing Regulation begins at the nervous system/body level. A whole brain view of self-regulation refers to far more than self-control/self-governance and similar executive function-related skills. In early life the neocortex is not yet developed enough to contribute to self-regulation, therefore regulatory processes predominantly involve alterations in states of arousal (Olson & Sameroff, 2009). During these early years self-regulation primarily takes place in the brainstem and limbic regions (and within co-regulation via the “loaning” of the mature nervous system of the caregiver in the context of relational transactions). Habituating to novel and unpredictable sensations 88

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and experiences is a large part of the job of developing body-based regulatory capacity in the first years of life (Browne & Talmi, 2015). This early stage of regulatory development is sometimes referred to as homeostatic, physiological or arousal regulation. Foundational self-regulation involves registering one’s own body signals and sensory stimuli from the environment (including both people and objects); mastering signal communication to caregivers about dysregulation and discomfort; developing efficient stress recovery; internalizing soothing co-regulating inputs from others; deep sleep cycling; and moving into clearly demarcated optimal alert states for processing (DeGangi, 2017; Lillas & Turnbull, 2009). These foundational processes continue to support function throughout the lifespan and do not diminish with age. Rather, as the brain and body develop, additional sophisticated self-regulation processes come online. These higher-level processes of self-regulation are always reliant on a foundation of appropriate nervous system arousal according to the demands of the task and environment. Without this foundation, response inhibition, working memory, cognitive flexibility and more will be challenging to access. This continuum from physiological regulation through to effortful executive function incorporates many other dimensions of regulation. Some of these networks or subsystems include regulation of emotion, attention, cognitive, motor, prosocial and social (or social cognition) (Shanker, 2007). Often discussed as discrete, these facets of self-regulation are interconnected and mutually supportive or disruptive. Furthermore, the sophisticated neuro­ physiological-biopsychosocial “system” known as the human regulation system shares causal relationships with sensory modulation processes (Christensen et al., 2020; Sutton et al., 2013). Complex body-brain networks are continuously sorting and processing sensory/socio-sensory/sensoriaffective data and sending signals to the organs and brain that enable the body to shift/maintain state of arousal according to the demands of the environment. This continuous monitoring of potential stressors in the external and internal environments has a bidirectional relationship with arousal regulation. Both processes toggle between unconscious and conscious according to personal well-being (resources) and external demands (Baumeister, Tice & Vohs, 2018). Evidence and personal accounts suggest that the autistic experience of self-regulation requires more 89

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conscious attention than not, requiring more personal effort and cognitive resources than in the neuromajority population (Welch et al., 2020). In review, the neurophysiological-biopsychosocial systems involved in maintaining homeostatic equilibrium are incredibly important when considering human function. All human function is state dependent, and human regulation relies on robust sensory integration/processing of external and internal data. This includes our ability to self-regulate, co-regulate others and to accept co-regulatory overtures from those with whom we are in relationship. Sensory integration/processing and self-regulation are multi-­ faceted and interconnected processes that occur in tandem, at all levels of the nervous system. Sensory input can support or derail self-regulation, and regulatory state influences sensory integration/processing capacity. A dysregulated nervous system, for example, might exacerbate existing sensory sensitivities as the sympathetic nervous system moves closer and closer to a full fight or flight reaction in response to environmental events. The consideration of sleep quality and duration as an additional influential factor in wellness and function is of the utmost importance. Poor sleep diminishes regulatory capacity and can create cycles of high arousal wherein the individual is hyper-vigilant and hyper-reactive to sensory events and/or has less tolerance for challenging postural and motor activities. Conversely an individual with differences in posture and praxis (motor planning, coordination and execution) who is in a challenging environment with high levels of novelty and expectations of body/motor control may be pushed into dysregulation so frequently throughout their day that their arousal level disrupts development and maintenance of a functional circadian rhythm. In both cases, sleep is illusive. These cycles generate extensive repercussions throughout the day and week of the individual and their family. The cumulative effect of these challenges may be perceived as “behavioral” but is in fact deeply rooted in activation of limbic regions, chronic stress and corresponding allostatic load (Suvarna et al., 2020).

Neurobiological Mechanisms of Sleep While our focus in this chapter is on sleep, it is difficult to understand sleep without also considering what happens during wakefulness. As such, 90

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although the focus in this section will be on the neurobiology of sleep, we will also make note of neurobiologic aspects of wakefulness. Sleep is an altered state of consciousness, ranging from drowsiness (characterized by elevated sensory thresholds and some muscle twitching, such as you might experience when falling asleep or becoming drowsy in front of the TV), through deep sleep and into dreaming. Behaviorally, when we sleep, we typically assume a posture of comfort, which is generally laying down, commonly in a specific place such as the couch or the bed (Eban-Rothschild, Appelbaum & de Lecea, 2018). In contrast, wakefulness is a state of consciousness in which we can use our executive functions and interact with the people and things in the environment. During wakefulness we can and do take in sensation; it is a foundation for our interactions with the world. Importantly, wakefulness involves a continuum of arousal levels throughout the day (Bathory & Tomopoulos, 2017). We will experience variation in our degree of alertness throughout the day, for instance finding ourselves falling into drowsiness if the sensory environment supports this. However, during our waking hours we have the ability to return to wakeful arousal if desired or necessary. Broadly, sleep states include non-rapid eye movement sleep (NREM) and rapid eye movement sleep (REM). NREM is further divided into sleep stages 1–4. Stage 1 NREM is characterized by drowsiness and decreased responsiveness to sensation; the “falling asleep in front of the TV” phenomenon. In stage 2 sleep muscle activity is reduced, as are body temperature and heart rate, and sensory responsiveness is further diminished. Stage 2 NREM sleep is associated with a loss of conscious awareness of the environment. Stages 3 and 4 of NREM sleep are often grouped together and characterized by deep or “slow wave” sleep in which sensory responsiveness is minimal unless stimuli are highly meaningful (Eban-Rothschild et al., 2018; Scammell, Arrigoni & Lipton, 2017). Our REM sleep state is associated with dreaming and related rapid eye movements. During REM respiration becomes less regular, and both heart rate and blood pressure increase, resembling levels seen during periods of wakefulness. Interestingly, REM sleep is also characterized by a loss of muscle tone such that we are prevented from acting out our dreams. In contrast, wakefulness is characterized by a wide range of muscle activity, heart rate, respiratory rate and blood pressure, dependent on our arousal levels. 91

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Electroencephalogram (EEG) patterns distinguish sleep states and stages, along with the behavioral and physiological characteristics noted above. In stage 1 NREM sleep our EEG is characterized by slow brain waves known as theta waves; this stage is often considered a transition stage between wakefulness and sleep. In stage 2 NREM sleep our brain EEG shows sleep spindles, or rhythmic wave activity. In stages 3 and 4, or deep sleep, delta waves are seen. As we transition into REM sleep, our EEG also shifts such that brain waves resemble the pattern seen during wakefulness (Scammell et al., 2017). Waveforms during wakefulness are considered desynchronized; they are low voltage and high frequency. EEG waves during wakefulness vary depending on arousal level but may include alpha and beta during quiet times, and gamma and theta waves when we are more active (Eban-Rothschild et al., 2018). Sleep and wakefulness are surprisingly complex processes, involving multiple neurotransmitters and multiple brain regions. Increasing the difficulty in fully understanding the mechanisms controlling sleep is the fact that brain cells associated with sleep are often co-located with those mediating wakefulness. Much of the detail of sleep/wake neurobiology is beyond what can be addressed in this chapter. However, a general overview will be helpful. Wakefulness requires cortical activity and accompanying activity in multiple brain structures and involving multiple neurotransmitters. The hypothalamus, located just below the thalamus, is itself a complex structure associated with a range of functions that include maintaining physiologic homeostasis and autonomic regulation. The lateral hypothalamus plays a role in wakefulness in that neural fibers from this region project to other wake-producing systems (Murillo-Rodriguez et al., 2012). These fibers release the neurotransmitter hypocretin to activate their target neurons. Wake-producing neural systems then project to regions of the frontal cortex, using neurotransmitters such as acetylcholine, histamine, norepinephrine and serotonin to support arousal and wakefulness. Ascending fibers from the brainstem reticular formation project to several nuclei in the thalamus; from the thalamus there are widespread fibers projecting to and activating cortical neurons during wakefulness. Thalamic fibers to the cortex release the excitatory neurotransmitter glutamate, activating cortical neurons. Other fibers supporting our arousal and alertness come from brainstem nuclei such as the locus coeruleus (norepinephrine) and raphe nuclei (serotonin; 92

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Murillo-Rodriguez et al., 2012). Of note, sensory input triggers activity in many of these structures supporting wakefulness. Another region of the hypothalamus, termed the preoptic region, has been associated with sleep for many years, and is perhaps the best understood in its relation to sleep. We now understand that some preoptic neurons produce the neurotransmitter called gamma-aminobutyric acid, or GABA, an inhibitory neurotransmitter found extensively in the brain (Weber & Dan, 2016). Because sleep requires that arousal pathways be inhibited, activation of these GABA-producing cells is important. In fact, neurons from the preoptic region inhibit neurons that themselves activate the cortex, among other regions of the brain (Bathory & Tomopoulos, 2017); cells in the preoptic region of the hypothalamus produce GABA and project to wake-promoting arousal brain regions in the brainstem and hypothalamus, essentially turning them off in support of sleep. It has been suggested that these neurons might be sensitive to increased blood glucose (such as you might experience after eating a large meal) and overall energy status (Weber & Dan, 2016). Other close by brain regions also play a role in sleep, including regions of the lateral hypothalamus, the basal forebrain, the pons, a variety of brainstem nuclei and the midbrain. The thalamus, noted earlier, plays a role in that activity here is reduced, leading to less cortical activation from thalamic connections. Investigations are also beginning to tease apart neural control of NREM and REM sleep, but examining this is beyond the scope of this chapter. These very complex combinations of sleep and wake brain regions and neurotransmitters are regulated by two internal sleep drives: a sleep homeo­ static drive and a circadian drive (Wyatt, 2011). The sleep homeostatic drive is a function of the balance between sleep and arousal brain activity. Think of it this way: when you wake from a good night’s sleep, your brain is “fresh.” During sleep neural processes have removed metabolic byproducts and free radicals, and distributed nutrients such as glucose and amino acids, thereby reducing your homeostatic drive for sleep to near zero. As you go through the day, using your brain and neurons for any number of tasks, metabolic byproducts and free radicals build up while nutrients diminish with neural activity. Adenosine is one such byproduct; adenosine triphosphate (ATP) is released when neurotransmitters are released, and adenosine is one of the breakdown products of ATP, and one that is associated with the need for 93

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sleep (Bjorness & Greene, 2009; Lazarus et al., 2019). Interestingly caffeine is an adenosine antagonist, meaning it interferes with the action of adenosine and reduces sleepiness. Nonetheless, across the day substances such as adenosine build up in the basal forebrain, hippocampus and cerebral cortex, and the drive for sleep increases. Around the time for bed the homeostatic drive for sleep is high. This drive then is what promotes drowsiness or stage 1 NREM sleep onset, and it is responsible for about the first third to half of your nightly sleep. As sleep progresses through NREM stages the homeostatic drive is gradually diminished. Thus, in the roughly second half of the night we rely on the circadian drive for sleep maintenance. The circadian drive is linked to a specific nucleus in the hypothalamus, the suprachiasmatic nucleus (SCN). This structure is responsive to changes in environmental or ambient light, coordinating light/dark responsiveness, and thereby playing an important role in sleep-wake cycles (Eban-Rothschild et al., 2018). Details of the overall processes involved in entraining the SCN to light/dark cycles are another complexity we will not delve into here. However, it is worth noting that melatonin, a neurotransmitter produced by the pineal gland and released in response to darkness, acts on the SCN to synchronize both phase and amplitude of our circadian drive (Masters et al., 2014), supporting its use as an aid for sleep. Further, it is important to note that the SCN responds to both light and dark and thus is important in both sleep and wakefulness. In sleep, as noted earlier, the homeostatic drive is active initially, getting us to sleep and maintaining sleep for the first part of the night. During the second half of the night the circadian drive takes over to maintain sleep. In the morning the very low-level homeostatic drive brings us to wakefulness, in spite of some ongoing sleep promotion from the circadian drive. These drives work together best under conditions of good sleep habits: establishing a regular sleep-wake cycle, maintaining optimal length of these cycles and in the absence of substances that alter arousal levels. To recap, the circadian system provides a drive for wakefulness during the day that ceases about 2 hours before bed, allowing the homeostatic drive to help us fall asleep. This later drive dissipates partway through the night, and the circadian drive takes over to guide sleep for the rest of the night. In spite of some ongoing activity in the circadian sleep drive in the morning, the 94

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absence of a need for sleep based on the homeostatic drive moves us to wakefulness. This drive also allows us to be alert in the morning, and through at least part of the day. Later in the day the circadian drive comes into play again, opposing the building homeostatic drive, helping us stay awake until bedtime; the cycle begins again (Wyatt, 2011).

Sensory Integration/Processing and Sleep Older, but classic, literature indicates that there is a reciprocal influence between sleep and the processing of sensation (Velluti, 1997). In this seminal work Velluti indicates that sensation is used to settle into sleep, as in rocking a small child or infant, but that the reduction of sensory transmission also supports sleep. Other work suggests that the processing of sensation takes place during sleep, but that the processing is altered by the sleep state. In particular, early sensory processing such as takes place in the brainstem is not altered in sleep but later, more cognitive processing of sensation is both delayed and less intense (Wright & Conlon, 2009). More recent evidence exists indicating there is a relationship between sensory integration and processing differences and poor sleep across the age range and in both neuromajority and neurodivergent populations (Elliott et al., 2018; Engel-Yeger & Shochat, 2012; Milner et al., 2009; Rajaei et al., 2020; Reynolds et al., 2012; Shani-Adir et al., 2009; Sharfi & Rosenblum, 2015; Shochat, Tzischinsky & Engel-Yeger, 2009; Tauman et al., 2017; Thye et al., 2017; Wengel, Hanlon-Dearman & Fjeldsted, 2011). However, the specifics of findings in these studies leave one with the impression that these relationships continue to need refinement to enhance our understanding. Available research supports a relation between sensory processing differences and poor sleep (Milner et al., 2009; Shochat et al., 2009), but does not consistently establish cause and effect. Elliot and colleagues indicated that severity of insomnia predicted sensory sensitivity to visual and auditory input in a group of veterans with traumatic brain injury, suggesting that this relationship may stem from an overall increased ANS arousal level, potentially related to other factors such as post-traumatic stress disorder. Earlier work by Engel-Yeger and Shochat (2012) had indicated that tactile sensitivity and auditory avoiding in adults in the neuromajority predicted sleep quality. 95

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A similar prediction was identified by Sharfi & Rosenblum (2015) in adults with learning differences and those in the neuromajority, although their findings were more broadly related to sensitivity across sensory domains. Interestingly they also found that sleep quality was more strongly predicted by low registration to sensory input in the subgroup of participants with learning differences. These findings in adults suggest that the relationship between sensory reactivity and sleep quality and quantity is bidirectional and influenced by additional factors. However, due to the limited work in this area and differences in findings, this conclusion needs to be substantiated. In children, investigators have pointed to relationships between poor sleep and sensory processing differences, but research specifically examining the reciprocal relation between these constructs is missing. This literature points to a myriad of links between aspects of poor sleep and differences in sensory modulation, but does so inconsistently. Sensory sensitivities are one of the most consistent sensory modulation differences identified as related to poor sleep. Relations have been found between sensory sensitivities and overall sleep concerns as well as specific sleep features such as resistance to bedtime routines, sleep onset delay, sleep anxiety, parasomnias, sleep breathing difficulties, reduced sleep duration and daytime sleepiness (Rajaei et al., 2020; Reynolds et al., 2012; Shani-Adir et al., 2009; Shochat et al., 2009). These findings may be related to an underlying mechanism serving both sleep and sensory modulation, or related to other characteristics of sensory sensitivity such as high arousal and anxiety, particularly in neurodivergent children (Rajaei et al., 2020; Reynolds et al., 2012). Links between sensory avoiding and poor sleep are identified, but less consistently, which is surprising given that both sensory sensitivity and sensory avoiding are thought to reflect low sensory thresholds. Poor sensory registration appears to be somewhat more consistently identified in populations of children, both neurodivergent and neuromajority, to be associated with sleep concerns (Rajaei et al., 2020; Reynolds et al., 2012; Wengel et al., 2011), and may be due to difficulty on the part of the child in recognizing environmental cues about sleep. Finally, sensory seeking, which may or may not reflect a separate dimension of poor sensory modulation, shows a relation to daytime sleepiness and overall sleep concerns (Rajaei et al., 2020; Reynolds et al., 2012; Shochat et al., 2009).

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Sensory Integration/Processing and Sleep in Autism Preliminary findings in our recent systematic review offer broad support for the information in the previous section: there is at minimum a co-existent relation between multiple aspects of poor sleep and multiple aspects of differences in sensory modulation in autistic individuals. The majority of literature we identified reported on research conducted with children rather than with adults, defining a substantive gap in the research. When examined in autistic adults, Hohn et al. (2019) indicated that there was a positive association between insomnia and sensory hyper-reactivity such that sensory hyper-reactivity, along with social skills, predicted severity of insomnia. In autistic children there may be many factors to consider relative to poor sleep; among those are a variety of sensory processing concerns. Investigators have indicated that sensory hypo-reactivity and sensory seeking (often seen together), along with difficulties with auditory filtering, are related to poor sleep (Hollway et al., 2013; Neely et al., 2019). This may be an outgrowth of missing environmental cues about sleep, as was noted earlier (Maski et al., 2011). In addition, taste/smell sensitivity is related to resistance to bedtime routines and sleep anxiety (Hollway et al., 2013; Tzischinsky et al., 2018), and sensory hyper-reactivity has been consistently shown to share a relation with a variety of features of poor sleep (Cortese et al., 2020; Mazurek et al., 2019; Reynolds et al., 2012; Tzischinsky et al., 2018), particularly tactile sensitivity. Further, sensory hyper-reactivity in young children may be a predictor of sleep problems in older children (Manelis-Baram et al., 2021), providing support for a common underlying neural mechanism. Drawing from this and other literature, it appears that a variety of sleep concerns held by parents of autistic children are related to a variety of sensory processing differences. There are indications of a bidirectional relation in which sensory processing differences influence sleep and sleep-related behavior, and sleep quality and quantity influence sensory responsivity (Ben-Sasson et al., 2009). Matching the identified differences to our understanding of sleep mechanisms is challenging. It may be that sensory hypo-reactivity is more related to the circadian drive if in fact children with hypo-reactivity miss environmental cues. Sensory hyper-reactivity could be interfering with the sleep homeostatic drive, disrupting the process of settling for sleep. 97

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At present we do not have sufficient detail to determine the validity of either of these possibilities. What we do know is that inadequate sleep leads to difficult daytime behaviors and cognitive processing, and differences in sensory modulation may contribute to these issues. Much research is needed to fully understand these factors. Interestingly, melatonin has been shown to be related to both sensory processing and sleep in autistic individuals (Wu et al., 2020). In reviewing the literature, these investigators indicate that low melatonin levels may be a biomarker for autism because melatonin levels appear to also be linked to autistic features. Further, they suggest that sleep difficulties experienced by autistic individuals are linked to circadian drive disruption, and result in difficulties with social interaction and other related characteristics. Both sleep challenges and sensory processing differences have been linked to anxiety across many studies and this may be, in part, what draws them together in disrupting sleep. Wu et al. (2020) suggest that use of melatonin, known to support sleep in autistic individuals, may also lead to a reduction in anxiety and sensory processing concerns.

A Whole Brain–Body-Based Approach Oftentimes sleep is talked about from a behavioral perspective—take for example intervention approaches like sleep hygiene, sleep restriction, relaxation training, stimulus control therapy and cognitive behavioral therapy for insomnia. When we conceptualize sleep only in terms of behavior—rather than also in terms of the neurological, biological and physiological processes underlying the onset, duration and quality of sleep—we miss a large part of the picture. Furthermore, human development and function occur within interlinked bioecological milieus encompassing an array of contextualized social and cultural systems (Osher et al., 2020).

Bioecological Context The context of relationships as a driver of human development and constitutive factors for health and well-being throughout the lifespan is widely recognized (National Scientific Council on the Developing Child, 2004; 98

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Shonkoff & Phillips, 2000). The psychosocial domain is no less foundational or influential than others we have addressed when it comes to sleep (Kent et al., 2015; Kent de Grey et al., 2018). Through processes of co-regulation, social supports, helpfulness (joint problem solving) and so on, individuals are able to establish lifestyles that support sleep health and experience enhanced quality of life (which in turn supports sleep health and vice versa) (Kent et al., 2015). Conversely negative social experiences and relationships have been shown to negatively influence sleep (Ailshire & Burgard, 2012; Troxel et al., 2009).

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Figure 5.1 Representing the circular relations between sensory integration/ processing, regulation and relationships as foundational for sleep

Whether the relationship in question refers to parents or caregivers, romantic life partners or platonic co-habitation, the quality and nature of our socio­ affective situation influences our sense of self (and self-care), meaning making and sleep quality—and these dimensions can all be hypothesized to influence one another. Relational health (i.e., supportive relationships) can and should have a salutary effect on overall health (Cunningham & Barbee, 2000; Fogel, 1993), and relations are impossible to silo out from regulatory processes (Porges, 2011) and sensory integration (Mueller & Tronick, 2020). We depict our perspective on these crucial relationships in Figure 5.1. Table 5.2 maps

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our current conceptualization of the dynamic systems relations between the domains of sensory integration/processing, regulation and relationships as foundational supports for sleep health/quality.

Wakefulness

Table 5.2 Relations between the domains of sensory integration/processing, regulation and relationships as foundational supports for sleep health/quality Sensory integration/ processing

State/physiological/ arousal regulation

Socio-relational processes

Sensory registration, cataloguing, prioritization*, modulation, discrimination, multisensory synthesis, response planning and execution of motor actions (or behavior), postural responsiveness.

Stable state-organization.

Available for and learning via sociosensory exchanges.

Smoothly moves between: • active-alert • quiet-alert. Able to recover from dysregulation.

Circadian drive

Sleep

* Includes habituation to non-noxious familiar repeated sensations. Depressed arousal responses, registration, processing, muscle activation against gravity, movement.

Circadian drive codes to environmental cues obtained via sensory registration/ discrimination/ perception (spatial temporal orientation).

Stable state-organization. Smoothly moves between: • hypoalert/drowsy • active sleep (REM) • deep sleep (NREM).

Physical activity and pursuit/facilitation of the ‘just right’ state of arousal to engage in learning and daytime activities. Relaxing and soothing sensory/relational routines augment signals that bedtime is approaching and anchor arousal regulation.

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Attuned exchanges with communication partners, social problem solving, play, affection. Resolves cognitive and social cycles prior to expected sleep times.

Soothing. Supportive environmental accommodations. Identifying and resolving dysregulating/alerting factors (terminating unpredictable or continuous changes in environment). Safety, predictability and consistency. Entrainment supported by synchrony with eating, environment, daily movement and activity variation (begins in utero).

Sleep homeostatic drive

Sleep and Sensory Processing

Increased sensory (environmental or social) vigilance and activity levels (often sensory motor) over time influence variability in daily quota of global sleep need (“sleep pressure”). Attunement to bodily signals (often related to interoception).

Brain-based metabolic activity accumulates driving substrate of sleep need, initiates somnolence.

Facilitating a balanced daily/weekly schedule, ensuring occupational balance between work/ play/relaxation.

Motivational processes impact readiness for sleep and this may include safety, hunger, locomotor activity, unfinished social cycles (interrupted storytelling, unfulfilled monotropism, continuous expectations of masking).

Minimizing or dosing and pacing overstimulating environments. Communication partners/caregivers and own attunement to interoceptive signals support sleep readiness.

Interventions for Sleep Concerns and their Effectiveness Much of the literature on sleep and sensory processing in autistic individuals is focused on characterizing the relationship between these two factors, as described previously. We have much more limited information about interventions to ameliorate poor sleep and their effectiveness in doing so. In our recent review we searched the literature for articles specifically addressing aspects of sensory processing and sleep challenges in autistic individuals across the life span. We included only peer reviewed articles but did not impose a date restriction. Perhaps due to the restriction to peer review, we identified a limited number of intervention studies. All were conducted with children under 16 years old. In examining this literature, the studies we found did not use Ayres Sensory Integration® but rather were sensory based in nature. As noted by Bundy and Lane (2020), sensory integration based on Ayres’ theory must include purposeful use of sensation, as well as active participation by the child in meaningful activities designed to promote sensory modulation and/or discrimination, postural control and/or praxis, and importantly self-regulation. In examining the studies identified in our review we developed a simple model we found useful in categorizing these sensory-based approaches based on the role sensation plays (Figure 5.2). Not explicitly reflected in this model is consideration of the setting. We propose four categories relative

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to the incorporation of sensation in intervention: 1) sensory informed: use of sensation in treatment and study design is informed by and grounded in principles of sensory integration theory as conceptualized by Ayres (this necessitates active client-led engagement in meaningful activities); 2) sensory aware: use of sensation in treatment and study design, applies sensory strategies and intentionally incorporates the sensory domain, often one sensory system/modality at a time, includes client-led or prescribed activities; 3) incidental sensory: use of sensation in treatment and study design, incorporates intense sensory inputs, generally passively applied within prescribed activities, or addresses differences in sensory integration without acknowledging this domain; and 4) disregards sensory: no consideration of sensation in treatment or study design and does not mention or consider sensory integration/processing. All studies we included in our review fell, at best, into category 3, incidental use of sensation. Incidental sensory

Sensory aware

Disregards sensory

Sensory informed

Figure 5.2 A continuum of sensory-based strategies supporting sleep quality

Sensory integration theory—as developed by Ayres (1972)—is a theory of human function that explains how differences in sensory integration/processing contribute to (or cause) differences in state regulation, movement, processing information, learning and relating. Ayres’ work emerged from her observations that children who were being categorized as poor learners or badly behaved were in fact processing sensation differently to their peers. These differences resulted in a fundamentally different lived experience of the world and manifested as perceived behaviors. Ayres’ work was a

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synthesis of her backgrounds in neuroscience, educational psychology and occupational therapy (Bundy & Lane, 2020). Sensory integration therapy is an evidence-based support of functional family goals including pre-academic/ academic, adaptive/self-help, challenging behavior, cognitive, motor and social development (Schoen, Miller, et al., 2019; Steinbrenner et al., 2020). As noted, none of the studies we included in our review could be categorized as sensory informed. The study closest to this end of the continuum was that of Lawson and Little (2017), examining a sensory-enriched swimming intervention. All studies focused narrowly on sensory modulation differences. Conspicuously absent was any consideration of the sensory-based motor functions and sensory discrimination that might also contribute to sleep challenges. In fact, there is some thought that poor praxis might interfere with overall pre-sleep routines such as bathing, getting into pajamas and brushing teeth, and thereby interfere with aspects of sleep (Mazurek & Petroski, 2015). The studies we identified used widely diverse forms of interventions, with equally diverse intensity and timing of intervention delivery. For instance, some investigators employed applied sensations such as weighted blankets (Gee et al., 2020), specialized mattresses delivering sound, vibration or both (Frazier et al., 2017), and Qigong massage (Silva et al., 2007), while others actively engaged participants in tasks such as swimming and yoga (Lawson & Little, 2017; Narasingharao, Pradhan & Navaneetham, 2017). Frazier’s specialized mattress and Gee’s weighted blankets were used on a nightly basis and provided sensory input continuously through the night. In contrast, yoga and Qigong were provided daily but clearly outside of regular bedtime activities. The swimming intervention took place once weekly in a 30-minute session. Duration of interventions varied, with interventions implemented across a 2-week period (Frazier et al., 2017; Narasingharao et al., 2017), 1 month (Gee et al., 2020), 2 months (Lawson & Little, 2017) and 5 months (Silva et al., 2007). An important consideration as we define these relations is that sensory modulation concerns are defined by the assessment tool used. These studies used parent report tools such as the Sensory Profile (Dunn, 1999; used by Lawson & Little, 2017; Silva et al., 2007), the Short Sensory Profile (Dunn, 1999; used by Frazier et al., 2017), and the Sensory Processing Measure (Parham et al., 2007; used by Gee et al., 2020) to obtain information on the 103

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child’s sensory processing/integration strengths and challenges. Descriptions of sensory modulation and sensory modulation concerns reflect the scoring system within each tool. To obtain a thorough perspective, sensory-informed research is best supported through multiple means of data gathering including: observations of the client during meaningful activities and movement; structured/formal clinical observations that reflect sensory integration capacity (i.e., soft neurological signs); and standardized evaluations of sensory integrative capacity (such as the Sensory Integration and Praxis Tests; SIPT). Tests of participation/performance skills can also be used to clarify findings, and clinicians with advanced post-degree training in sensory integration may be able to use these instead of evaluations directly assessing sensory integration functions. No study assessed sensory integration/processing through direct observation of the child’s performance and engagement or tools such as the SIPT. A myriad of sleep difficulties were targeted as outcomes in the studies we identified. Sleep-related challenges include such things as bedtime resistance, sleep onset delay, sleep duration, sleep anxiety, night wakening, parasomnias, sleep-disordered breathing and daytime sleepiness. In examining these challenges investigators used a variety of tools, and often used more than a single source of information. Sleep assessment included sleep questionnaires like the Children’s Sleep Habit Questionnaire (CSHQ; Owens, Spirito & McGuinn, 2000) in Gee et al. (2020) and Lawson & Little (2017), and the Family Inventory of Sleep Habits (FISH; Malow et al., 2009) in Frazier et al. (2017). Sleep was also assessed by study-specific questionnaires (Narasingharao et al., 2017; Silva et al., 2007), sleep diaries reported by parents (Frazier et al., 2017; Gee et al., 2020) and actigraphy (Frazier et al., 2017). As was expected, outcomes were focused on sleep; only Silva et al. also looked for changes in sensory characteristics. Results suggested changes in overall sleep quality (Frazier et al., 2017; Lawson & Little, 2017; Silva et al., 2007), daytime sleepiness (Narasingharao et al., 2017), sleep duration (Frazier et al., 2017; Gee et al., 2020; Narasingharao et al., 2017), and ease of falling asleep and sleep efficiency (Frazier et al., 2017) with the programs described. While none of the studies presented a discussion about the specific relationship between sensory processing/integration and sleep, we can draw some

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tentative conclusions. Together these studies indicate a potential role for sensory processing/integration in ameliorating sleep challenges. We recognize that it is rarely feasible, in research or clinical practice, to include data gathering activities from every modality represented in Table 5.1. However, we hope to encourage multidimensional research design that extends beyond sensory over-responsivity in single sensory systems and looks at discrimination, posture and motor coordination. There is also a need to expand our understanding of sensory hypo-responsivity and intrapersonal variations in sensory modulation. Sensory-informed research design should extend beyond exclusive use of questionnaire-based data collection and especially needs to diversify beyond second-person report measures. Realistically, especially given the rich discussions on autistic-to-autistic reciprocity and the double empathy problem (see the work of Dr. Milton), second-person observations may or may not be a reality for the first person. A 2019 review of recently available and in-development assessment tools is available at www.aota.org/Publications-News/SISQuarterly/children-youth-practiceconnections/SIPSIS-11-19.aspx Clearly, more research is needed to support an understanding of the use of sensory processing/integration tools in improving sleep for autistic individuals. The limited information available is focused on children; it is unclear how this applies to autistic adults. Additional investigation into sensory processing/integration supports for sleep can address such things as intervention intensity (daily vs weekly) and timing (nightly during sleep vs day outside of sleep activities), differences between active vs passive sensory input, and the role the parent-child relationship might play in intervention effectiveness for children. In addition, the influence that parent-based strategies might have on families’ empowerment should be considered.

Clinical Implications Dr. Jean Ayres (1972, p.11) first defined sensory integration as “the neurological process that organizes sensation from one’s own body and the environment and makes it possible to use the body effectively within the environment.” Sensory integration/processing does not happen in a vacuum. It is a cornerstone neurophysiological process that makes it possible 105

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for individuals to participate, engage actively and experience success in their daily occupations. Sensory integration/processing and function are indissociable because we need to make sense of all the information from our bodies and the environment to participate in daily occupations and relationships. Sleep is a vital occupation, related to and critical for many body and brain functions. It is therefore no surprise that adequate sleep serves as a foundation for optimal occupational performance, enhanced participation and engagement in daily life (American Occupational Therapy Association (AOTA), 2017, p.2). Poor sleep has been linked to decreased productivity at work (AOTA, 2017), motor vehicle crashes and industrial accidents (CDC, 2015). Insufficient sleep can also be related to reduced performance and behavioral problems in the school setting (Paavonen et al., 2010). Additionally, sleep issues can also influence individual capacities like problem-solving, reasoning, executive function, coordination and social-emotional abilities, affecting performance in all areas of occupation (American Sleep Association (ASA), n.d.; Spruyt, 2019). Lack of sleep impacts self-regulation and alertness, and poor sleepers experience daytime sleepiness and are frequently more tired than people who sleep well (ASA, n.d.). This inefficiency contributes to higher irritability, inattention, hyperactivity and physical aggression (Hollway et al., 2013; Mazurek & Sohl, 2016). In the autistic population poor sleep has been shown to be related to anxiety and difficulty with social interaction (Uren et al., 2019). Sleep disturbances are frequently a family systems issue. Not only does disrupted sleep affect the person who experiences it, it also influences the sleep routines of caregivers and family. This is especially true during childhood but certainly not exclusively limited to pediatric clients. Literature shows that poor sleep in children can contribute to insufficient sleep, elevated stress and decreased quality of life for family members (Becker, Langberg & Byars, 2015; CDC, 2015; Delahaye et al., 2014). Critically, as outlined by Krizan and Hisler (2016, p.195), “some efforts to compensate for sleep loss involve very conscious self-regulation.” For example, ingesting sweet food, cola or coffee is often a deliberate effort to combat sleepiness. Other strategies involve increasing motor activity or sensory stimulation—think of the driver who turns the music up, winds the window down and dances in their seat to move out of a state of low arousal. Strategies 106

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like this reflect deliberate attempts to up-regulate low arousal states in the name of other priorities. How then might this relate to “repetitive behaviors”? When there are existing differences in sensory integration/processing it is likely that the self-regulatory strategies employed by the individual will relate to these differences. For example, increased hand flapping or pacing (often termed as stimming) may, in fact, be a strategy employed to compensate for inadequate sleep/low arousal. Extinguishing this behavior then becomes detrimental and a further drain on the resources of the individual, likely diminishing functional capacity even further. At present we can only hypothesize about this relation; more research is needed. Contributors to sleep dysfunction can be multifactorial, and as we have discussed in this chapter, differences in sensory integration/processing can be one of those factors. Our work has shown that all aspects of sensory modulation differences in autistic children can have a relationship with different features of poor sleep. Therefore, when assessing and addressing sleep, practitioners need to consider sensory integration/processing. Occupational therapy using a sensory integration approach has been shown to successfully and significantly improve participation outcomes in autistic children (Pfeiffer et al., 2011; Schaaf & Miller, 2005; Schoen, Lane, et al., 2019). A sensory-­ informed approach, especially one supported by occupational therapists with advanced training in Sensory Integration Theory and Practice, benefits the whole interdisciplinary team and is likely to improve outcomes significantly. Therapeutic interventions designed to improve the quality of life of the autistic individual benefit from integrating these foundational considerations into any support plan.

Case Vignette: Gus Gus is 13 years old and showing decreased resilience at school and at home. Upon interview by the assessing clinician, it becomes evident that, among other concerns, Gus has difficulty both falling and staying asleep. Participation questionnaires demonstrate hyper-reactivity to tactile input. In the support/intervention phase and in interdisciplinary collaboration with an occupational therapist trained in sensory integration treatment, a

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threefold approach emerges supporting Gus’ body, changing the environment and empowering his closest relationships. The clinical team designs therapeutic activities that promote modulation to tactile input, activities rich in proprioceptive and deep touch sensations to help the brain modulate tactile sensations. Environmental adaptations are also recommended based on assessment results. In this case, Gus was encouraged to trial heavy blankets in bed to increase deep touch. Gus also began taking his showers in the morning and brushing teeth right after dinner (and not immediately before bed) to minimize the stress those tactile activities cause his nervous system. He began sleeping inside a mosquito net and removed all soft toys and extra cushions from his bed. Gus’ parents and older siblings are an integral part of the support process, and as they all learn about supporting his state regulation through minimizing disruptive tactile experiences, they also begin to incorporate other stress reduction strategies into his evenings.

Therapeutic Process Data Gathering

A combination of assessment tools that tap into sensory integration/processing, sleep (including sleep readiness routines) and the environment will support a comprehensive evaluation pathway. As noted earlier, data are most thorough when collected from both clients (where possible and appropriate) and caregivers, and when they include measures of quality of life, sleep quality and quantity, sensory integration/processing, home environment and social-emotional/relationship quality. Self-report measures adapted for autistic populations are increasingly available and many are beginning to incorporate the use of imagery and words that are specifically designed to resonate with the autistic experience (these are often designed by autistic researchers). Interviews with the client and family can establish functional goals, strengths and challenges that the client and their family hope to address. The home environment can be evaluated as part of interviews and/or home visits or virtual consults. Simple technological tools like smartwatches, Fitbit

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bands or other sleep trackers can provide additional data that reflect client performance. Including this type of information allows evaluators to establish the “big picture” based on multiple sources of information.

Data Interpretation Combining data about a client’s sensory integration/processing profile and their home environment can serve as a robust sensory-informed “triage” of causal factors in sleep disturbances. Some speculative examples reflecting different profiles of sensory processing differences and sleep challenges, environmental or ecological considerations, and therapeutic recommendations to support sleep health can be found in Table 5.3. Table 5.3 Examples of sensory-informed therapeutic recommendations to support sleep health Sensory difference, sleep concern profile

Ecological considerations

Therapeutic recommendations

Over-responsive to tactile, auditory and visual stimuli likely leading to difficulty settling, delayed sleep onset, frequent waking.

Apartment block in busy neighborhood; shares room with siblings; mobiles hanging from ceiling; lots of toys available in environment.

Collaborate with caregivers about sensory over-responsivity and regulation.

Already engaged with a sensory integration trained OT.

Remove moving décor from room (i.e., hanging mobiles etc.). If possible, store toys in alternative room or out of sight. Provide “low arousal” sleep space, for example moving child to the top bunk and installing a sleep tent. Using a white noise machine or app on mobile device. Trial different sleep clothes and covers for best comfort and minimizing tactile inputs. cont.

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Sensory difference, sleep concern profile

Ecological considerations

Therapeutic recommendations

Sensory-based postural disorder resulting in frequent waking due to tossing and turning. Child wakes up irritable.

Sleeps alone in large bed and often changes positions, sometimes falls out of bed at night.

Consider lycra bed sheet to provide sense of support in bed—may decrease tossing and turning and odd sleep positions.

Bedwetting a frequent occurrence.

Trial body pillow for individual to use as sleep aid and posture aid.

No toys or extra pillows in bed.

Raised bed head may provide sense of position in space; smaller width bed may also help individual feel contained.

Large waterproof sheet on mattress that slips and provides no postural containment.

Trial different styles of bed rails if possible. Assess for sleep apnea (physiological factor related to low tone/hypotonia). Refer to sensory integration trained occupational or physical therapist for work on posture with view to improving breath capacity and bladder control.

Dyspraxia resulting in difficulties with bedtime routines and fatigue. Child often gets to bed feeling frustrated and angry. Often does not fall asleep until after 1 am and wakes around 5 am.

Frequent battles with caregivers that begin before dinner time and extend through to being “put to bed.” Difficulty with transitions manifest as difficulty getting settled in bed, getting out of bed frequently asking for water, expressing anxiety, etc.

Engage with sensory integration trained occupational or physical therapist. Implement cognitive strategies to support success in routines at home and sense of control of bedtime routine. Prior to dinner engage in an activity that is achievable and facilitates a sense of mastery for the individual. Collaborate with caregivers around implications of dyspraxia and sense of time and space. Decrease demand in evenings and provide achievable self-care routines that enable success for whole family system. Use supports (including rich environmental cues) that increase orientation to time for sleep and time for waking.

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In 2015, Schaff introduced the Data Driven Decision Making (DDDM) model to help occupational therapy researchers and clinicians systematically design intervention processes based on the data generated from assessment. An essential concept in Schaff’s work is the reference to proximal and distal factors (Schaaf, 2015). Proximal factors are specific sensory-motor functions, such as poor proprioception or tactile hyper-reactivity, that can affect participation. Distal factors are related to the individual’s specific participation challenges, such as the inability to prepare a good bedtime routine or the difficulty of staying asleep during the night. Distal factors align closely to occupational goals, like sleep in this case. Connecting causal factors in relation to sensory integration/processing differences and other ecological factors and linking them to meaningful outcomes related to quality of life is paramount.

Individualizing Intervention Differences in sensory integration/processing can present similarly in clients despite having very different root causes; this is reflected in Table 5.3. Thus, a full standardized assessment of sensory integration is the only way to establish a confident hypothesis about a client’s individual profile. For example, a child with difficulty discriminating sensory data from the vestibular system may appear distressed while moving in cars, elevators and escalators. This could easily be interpreted as sensory hyper-responsivity but may instead be related to the child’s sense of confusion in interpreting the movement, as opposed to a sense of overwhelm. Therapeutic supports are wholly different to desensitization, and in no way involve behavioral conditioning goals. Rather, this approach aims to minimize intolerable stress, decrease arousal, and increase comfort and sense of safety in the world. This way, clinicians can provide supports at the sensory level that will enable clients to better access cognitive supports that may be available and appropriate. We do not use sensory interventions for the sake of solely improving sensory-motor functions. Sensory interventions purposefully address the impact of individual differences in sensory integration/processing on psychological well-being and daily life occupations. When comprehensively and properly addressed, sensory-informed therapies 111

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enable optimization of participation and engagement in occupations across the lifespan, including sleep, and form a critical component of an integrated biopsychosocial approach for improving sleep, as illustrated in Figure 5.3. In this chapter we have focused on sensory integration/processing interventions and also considered environmental accommodations, and touched briefly on addressing physiological needs (consideration of arousal and stress levels) and attuned interpersonal supports. Physiological needs

Sensory integration evaluation and therapy

Environmental accommodations

Sleep health

Attuned interpersonal supports

Figure 5.3 A biopsychosocial view of sleep health

Conclusion Sensory integration and processing difficulties are a significant factor in the lived experience of autistic individuals. Research shows that these difficulties influence sleep in a meaningful manner. Children on the autism spectrum often experience variables that could potentially “impact usual signals of entrainment, including hyper- and hypo-sensitivities to visual and auditory stimuli (Talay-Ongan & Wood, 2000), decreased attention to social cues (Dawson et al., 1998), and possible misalignment between circadian phase and light–dark cycles” (Glickman, 2010, p.763). In considering the neural links between regulation and wakefulness we can hypothesize that what we want is for individuals to be able to “shut off the cortex.” We can support this through deliberate strategies designed to decrease input that activates the reticular formation, the thalamus and ultimately the cortex. We do this through providing support and relational safety, a low arousal approach to the environment, diminishing excess stressors and supporting recovery from the day. 112

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Paying attention to sleep is as fundamental as proactively addressing sensory integration/processing differences and physiological regulation, yet often these cornerstones of human function are neglected. The amount of activity an individual can attend to or engage in at any given moment is limited by a maximal physiological processing capacity. “Sleep plays an indispensable role in people’s cognitive and emotional functioning, … disruption of both sleep quantity and quality undermines self-regulatory outcomes from virtually all domains of human behavior” (Krizan & Hisler, 2016, p.190). In order to support individuals to engage their higher-level reasoning and reflective capacity, the fundamental processes of sensory integration/processing, physiological regulation and sleep must be addressed. Naturally, not all sleep disruption in autism can be linked to sensory integrative differences, therefore sensory integration therapy and sensory-­ informed environmental accommodations may not be implicated in every situation. However, a sensory-informed approach allows the practitioner, regardless of discipline, to carefully assess this domain of function and rule it out or in accordingly. A sensory-informed approach benefits both the design of sleep supports and sleep research in autism. It facilitates a whole brainbody approach and, coupled with proactive regulation supports, ensures that individuals are available for other types of support that may require neocortex availability.

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CHAPTER 6

Behavioral Interventions for Sleep Problems Lauren J. Moskowitz, PhD, St. John’s University, New York, and V. Mark Durand, PhD, University of South Florida St. Petersburg

This chapter reviews research on interventions for common sleep problems displayed by individuals with autism spectrum disorder (ASD), including disruptive and non-disruptive problems at bedtime, disruptive and non-disruptive night waking and sleeping at the wrong times (circadian rhythm problems), as well as the parasomnias (sleepwalking, sleep talking, sleep terrors and nightmares). Several systematic reviews (e.g., Kirkpatrick, Louw & Leader, 2019) and a meta-analysis (Carnett et al., 2020) have shown that behavioral interventions, including parent training, sleep hygiene (i.e., establishing good sleep habits), extinction (i.e., removing reinforcement for sleep-disrupting behavior), graduated extinction, bedtime fading and positive reinforcement for sleep-­promoting behaviors can improve sleep problems in youth with ASD (Hunter et al., 2020). Moreover, a systematic review of the collateral effects of behavioral sleep interventions in children and adolescents with ASD found that in all ten treatment studies, at least some aspect of sleep behavior for youth with ASD improved, with eight of the ten studies also reporting collateral improvement in one (or more) aspect of daytime functioning (e.g., stereotypic behaviors, internalizing and externalizing symptoms, and quality of life) (Hunter et al., 2020). We will now describe the most common and evidence-based behavioral interventions used to treat sleep problems in youth with ASD.

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Bedtime Disturbances and Night Waking Different intervention approaches have some empirical support for improving bedtime disturbances—including bedtime resistance and tantrums—as well as night waking. In fact, the first documented use of a behavioral intervention for an individual with ASD was standard extinction for bedtime tantrums (Wolf, Risley & Mees, 1963).

Sleep Hygiene The first line of intervention for problems surrounding sleep is to assess and, when warranted, change the person’s sleep hygiene (Vriend et al., 2011). Sleep hygiene refers to an assortment of behaviors and activities conducive to falling asleep at night; when hygiene is poor, it can also influence night waking or generally interrupt sleep patterns. The time we go to sleep and wake up, the foods we eat or drink, when we exercise, noise and light, and the activities we do in bed and during the half hour before bedtime can all impact our sleep. Just as good physical hygiene helps people to be healthier physically, good sleep hygiene—or good sleep habits—can help people to sleep better (see “The Good Sleep Habits Checklist”) (Durand, 2014).

The Good Sleep Habits Checklist … Establish a set bedtime routine. … Develop a regular bedtime and a regular time to awaken. … Eliminate 6 hours before bedtime all foods and drinks that contain caffeine. … Limit any use of alcohol. … Limit any use of tobacco. … Try drinking milk before bedtime. … Eat a balanced diet, limiting fat. … Do not exercise or participate in vigorous activities in the hours before bedtime.

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… Do include a weekly program of exercise during the day. … Restrict activities in bed to those that help induce sleep. … Reduce noise in the bedroom. … Reduce light in the bedroom. … Avoid extreme temperature changes in the bedroom (i.e., too hot or too cold). Source: Adapted from Durand (2014)

Perhaps the most important good sleep habit is to set a consistent and predictable bedtime routine that lasts for 20–30 minutes. A bedtime routine refers to a relaxing sequence of activities that the person does at about the same time and in the same order every night. These routines seem to have a calming effect and help most people associate this time with sleep. An example is: 1) take a bath; 2) change into pajamas; 3) brush hair and teeth; 4) read book; 5) turn out light; and 6) go to sleep (Christodulu & Durand, 2004). This type of routine is important for any person, but even more important for those with ASD. However, children with ASD can latch onto routines so strongly that they become rituals, and any variation in these rituals can lead to a tantrum. So, for some children with ASD, it might be helpful to build in some variation, such as changing the order of activities each night. In the hour before bedtime, it is best to avoid high-energy or arousing activities, including physically arousing activities (e.g., exercising) and cognitively arousing activities (e.g., watching television, playing video games, engaging with smartphones or tablets). Although regular exercise early in the day (4–6 hours before bedtime) can help people sleep better, exercising or engaging in vigorous activity too close to bedtime can make it difficult for many people to fall asleep. It is also recommended to avoid activities that could cause conflict (e.g., picking out clothes for school) during the bedtime routine. Finally, it is important to avoid extending the time for the bedtime routine (e.g., “Just one more story? Pleeeease!”). See “Guidelines for Bedtime Routine” for a summary of guidelines.

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Guidelines for Bedtime Routine 1. Make the last 30 minutes before bedtime a regular routine. 2. Include activities such as dressing for sleep, washing and reading. 3. Keep the order and timing of the activities about the same each night. 4. Do not include activities that could cause conflict for your child (e.g., picking out clothes for school, organizing papers). 5. Avoid television watching during this time, which can interfere with sleep. 6. Avoid extending the time for the bedtime routine (e.g., “Just one more story? Pleeease!!”) Source: Adapted from Christodulu & Durand (2004)

Although positive routines are almost always part of multi-component sleep interventions (e.g., Christodulu & Durand, 2004), they are usually not examined on their own. However, Delemere and Dounavi (2018) found that, when examining positive routines in isolation, it resulted in decreased sleep onset latency and increased total sleep duration for two out of three children with ASD. Along with a regular bedtime routine, it is important to have a set bedtime and wake time, which entails going to bed at the same time every night and waking up at the same time every morning (not deviating more than 30 minutes from those set times). Using a sleep log, we determine the number of hours of sleep the child generally seems to need to be well-rested (e.g., 10 hours), and then count backwards from the desired wake time (e.g., 7 am) in order to arrive at the optimal bedtime (e.g., 9 pm) (Durand, 2014). Many people associate their bed or bedroom with activities that interfere with sleep, such as doing work in bed (for adults) or roughhousing in bed with a parent or sibling (for children). For some people this may not be a problem but, for other people, these negative sleep associations (e.g., bed = play wrestling with Mom) can make it difficult for the person to fall asleep in their bed/bedroom. Therefore, we recommend that parents try to restrict their

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child’s activities in the bed to only sleeping (known as “stimulus control”), so that the bed triggers behaviors that help sleep rather than interfere with it. In other words, we want to change the previously learned association (such as “bed = wrestling”) to a new association (i.e., “bed = sleep”). Related to this, if individuals are lying awake in bed for too long (i.e., more than 20 minutes) without sleeping, it is recommended to get out of bed and sit in a chair and then, once they are sleepy, return to bed. This is because we want people to connect the bed with sleeping rather than lying awake. Another recommendation for good sleep hygiene is to avoid certain substances and noise/light. Although caffeine, alcohol and tobacco affect each person differently, they are all substances that can interfere with sleep. Given that caffeine is a stimulant that stays in our system for up to 6 hours, it is best to avoid foods and drinks that contain caffeine (e.g., coffee, tea, soda, chocolate, cold/allergy medications) in the 6 hours prior to bedtime. Similarly, the nicotine in tobacco is a stimulant that can overstimulate the brain and interfere with sleep, and should be avoided before bedtime. Although alcohol can relax individuals at bedtime, it can also disrupt their sleep, and therefore should also be avoided. It is also important to eliminate other things that could be interfering with the person’s sleep, such as loud conversations outside the bedroom door, a TV playing too loudly in the next room or a too-bright hallway light, for example. The bedroom should be quiet and dark while attempting to fall asleep. Some individuals with ASD might even need absolute darkness; even a pin light from a computer monitor’s power indicator could disturb some individuals.

Function-Based Behavioral Interventions When a child is resisting going to bed and/or having difficulty falling asleep and keeps getting out of bed, it is important to conduct a functional behavior assessment (FBA) of the bedtime problem to identify the antecedents that appear to trigger the problem behavior (e.g., external antecedents such as noise/light or internal antecedents such as worrying about going to school the next day), as well as the consequences that maintain the behavior (e.g., child gets to escape or avoid sleeping in his own bed, sleeps in parents’ bed, gets attention from parents). Once those are identified, it is important to 123

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eliminate or at least minimize the antecedents that trigger bedtime problems as well as alter the consequences so that the child is no longer reinforced for these problem bedtime behaviors but is instead reinforced for positive bedtime behaviors. In other words, it is important to teach parents to reinforce or reward the child’s appropriate bedtime behaviors while ignoring or not reinforcing inappropriate ones. A case analysis of 41 youth with ASD revealed that multi-component, parent-delivered, function-based interventions may improve sleep problems in children and adolescents with ASD (McLay et al., 2021). With regard to antecedents, it is important for parents to observe and record the various triggers of sleep problems so that they can notice patterns and thus anticipate and prevent the problems before they start. For example, if a child frequently gets out of bed because she says the hall light is too bright or because she wants a glass of water, it is best to make sure that the hall light is turned off or dimmed and that the child has a glass of water next to her bed before she goes to bed. These are antecedent-based modifications for sleep problems in children with ASD—others include changing the location of sleep onset, visual supports, sleep hygiene modifications (e.g., consistent bedtime routine, sleep-promoting environment), scheduling pre-bedtime access to reinforcers that previously interfered with sleep and faded bedtime (i.e., delaying bedtime to within 15 minutes of the average time of sleep onset during baseline) (McLay et al., 2021). Consequence-based modifications involve using reinforcement (social, tangible or token systems of reinforcement) for sleep-promoting behaviors as well as placing sleep-interfering behaviors on “extinction” (McLay et al., 2021).

Extinction With regard to consequences, one of the main interventions for bedtime problems (and challenging behaviors in general) is to make sure that the problem behavior is no longer being reinforced, a process known as “extinction.” Extinction is a procedure in which reinforcement of a previously reinforced behavior is discontinued (Cooper, Heron & Heward, 2019). For example, if the child’s bedtime problems are being reinforced by his parents’ attention (e.g., for refusing to get into bed, getting out of bed, calling out, 124

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crying and/or yelling from bed), then extinction involves the parents no longer providing attention for those behaviors. As another example, if a child’s bedtime problems are being reinforced by access to their electronic devices, then extinction would involve no longer allowing access to the electronic device. To return to the first example, when the child’s sleep-related problem behavior results in extra attention, it is important for parents not to reinforce the problems by ignoring the child’s protests about going to bed as much as possible, not coming back into the child’s bedroom when the child cries or yells or calls out, and/or taking the child back to their bed each and every time they come out, without saying anything. For example, if the child is yelling or crying or protesting that they do not want to go to bed, parents should calmly state that it is bedtime without engaging in an argument or debate. Moreover, it is important to not reinforce or “give into” the crying or yelling or whining by allowing children to stay up an extra half hour later (for example), since they may learn they will be reinforced or rewarded for protesting or resisting going to bed. In general, if parents decide that they want to implement extinction, they must be consistent in doing so every night and not “give in” on some nights, since intermittently reinforcing the bedtime problem behavior on some nights makes the behavior more difficult to extinguish overall. For example, even if the parents have ignored the child’s bedtime problem behavior for three nights in a row, if they respond by going into the child’s room or talking to the child on the fourth night (for example), this will likely cause the child to “up the ante” in an attempt to get reinforced again on the fifth night and possibly the sixth or seventh night and so on, thus leading to an increase in the problematic behavior on subsequent nights. To illustrate, Weiskop and colleagues (2001, 2005) used standard extinction to treat bedtime disturbances in children with ASD and Fragile X syndrome; parents were taught to explain the rules to their child and, when the child is in bed, leave the room and ignore all crying or calling out. If the child comes out of their room, the parents were taught to take the child back to bed immediately without making eye contact, cuddling, talking to or yelling at the child. Parents were informed that they may need to do this many times. They were also informed about the possibility of an “extinction burst,” meaning that the child would temporarily escalate his/her problem behavior as an attempt to get reinforced. 125

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Graduated Extinction Given that it can be challenging for some parents to implement standard extinction (e.g., it can be very distressing to hear their child cry even for 10 minutes and not respond at all), which involves totally eliminating reinforcement all at once, parents often choose to use “graduated extinction,” also known as “gradual extinction,” which involves gradually fading out reinforcement rather than eliminating it all at once. The goal (for both standard and graduated extinction) is for the child to ultimately fall asleep independently, on their own in their own bedroom. The most common way to implement graduated extinction is for the parent to spend increasingly longer amounts of time ignoring the child’s crying, yelling, protesting or other problematic bedtime behaviors (Durand, 2014). This approach involves ignoring the child’s cries/protests but also checking in on the child periodically. The first step is for parents to decide how long they are able to wait before going back into the child’s bedroom and checking on their child, such as 3 minutes (Durand, 2014). Next, on the first night of the intervention plan (which should ideally be a night on which parents can afford to get less sleep, such as a Friday night), parents should put the child to bed, leave the bedroom, wait a full 3 minutes before re-entering the bedroom, tell the child to go to bed (without picking up the child, engaging in conversation, giving him food/drink, etc.) and leave again (Durand, 2014). Parents should then wait another 3 minutes and go back into the room if the child is still crying. This pattern should continue, every 3 minutes, until the child is asleep (Durand, 2014). On each subsequent night, the parents should extend the time between check-ins by 2 or 3 minutes (e.g., on the second night, briefly re-enter the room every 5 minutes; on the third night, briefly enter the room every 8 minutes). It is important to recognize that some parents may find that even 3 minutes is too long to let their child cry before checking on them; for some parents, they may need to start with only 30 seconds between check-ins and increase each night by 15 seconds, for example (Durand, 2014). Standard extinction, graduated extinction and parent education/prevention all meet criteria for “well-established” interventions for bedtime disturbance and frequent night-waking (Kuhn & Elliott, 2003) in neurotypical children without ASD, although there are fewer studies using graduated 126

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extinction for youth with ASD. Durand, Gernert-Dott and Mapstone (1996) used graduated extinction to treat bedtime disturbances and night-waking in children with developmental disabilities, two of whom had ASD. Prior to intervention, both children with ASD exhibited tantrum behavior (e.g., crying, screaming) when their parents attempted to put them to bed, lasting anywhere from 1 to 4 hours for the 12-year-old and 15 minutes to 3 hours for the 2-year-old. Their problematic bedtime behaviors served the function of gaining attention from parents, with the 12-year-old’s parents responding by telling him to lie down and eventually getting into bed with him, and the 2-year-old’s parents responding by bringing her into bed with them or by letting her sleep on the mother’s lap while she watched television. The intervention, which involved creating a consistent bedtime routine and used graduated extinction, resulted in reducing the bedtime disturbances for both children with ASD (Durand et al., 1996). It is worth noting that, although checking in on the child periodically may make parents feel better than ignoring the child’s cries completely, graduated extinction may actually result in more crying than standard extinction (France & Blampied, 2005), because the parent’s re-appearances may be enough to intermittently reinforce the crying. There is some evidence that extinction with parental presence (in which the parent remains in the bedroom with the child but pretends to sleep and does not interact with the child) results in less crying than both standard and graduated extinction (France & Blampied, 2005), although there is limited research on this approach for youth with ASD.

Stimulus Fading Another way to implement a more gradual approach is by fading parental presence or “gradual distancing” (i.e., for parents to fade out reinforcement (their presence) by distance). This is also known as “stimulus fading,” in which the parent gradually and progressively increases their distance from the child’s bed. This initially involves having the parent stay in the child’s bedroom with them but keeping all contact to a minimum. On the first night of the intervention plan, one of the parents can sit in a chair (or lie down next to the crib or bed) without touching or talking to the child, and then 127

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gradually move farther and farther away from the crib or bed each night until the parent is no longer in the child’s bedroom. For some parents we have used an even more gradual approach, such as the parent lying down in the child’s bed with them to fall asleep the first night, sitting up in the child’s bed the second night, sitting in a chair next to their bed the third night, moving the chair 1 meter farther the fourth night, moving the chair 2 meters farther the fifth night, moving the chair 3 meters farther the sixth night, and so on, until the parent is sitting in a chair outside of the child’s bedroom. To provide an example from the research literature, Howlin (1984) used gradual distancing with a 5-year-old boy with ASD whose mother often sat with him for at least an hour until he fell asleep; prior to intervention, if he woke up at night, he was taken into his parents’ bed or his mother slept all night in his bed. Over 2 months, intervention involved the mother sleeping on an inflatable mattress and gradually moving that mattress from the boy’s bedroom, to the hallway, and finally to the mother’s room, eventually eliminating co-sleeping (Howlin, 1984).

Bedtime Fading Although graduated extinction can be effective for many children with problem bedtime behaviors, and it is easier for most parents to implement than standard extinction, there are still many parents who have difficulty tolerating any amount of crying or yelling or distress from their child, even for 30 seconds or a minute, without responding. Some of these parents eventually come to realize that they are teaching their child how to self-soothe and get themselves to sleep, which will be helpful to the child, but other parents worry that they are cruel for not responding to their child, and/or that their child will feel unloved. Some other parents believe that the bedtime tantrums may be too disruptive or dangerous to ignore. For all of these families, an alternative approach to ameliorating bedtime resistance is “bedtime fading,” which involves keeping the child up so late at night that they fall asleep on their own (Durand, 2014; Durand & Christodulu, 2004), without any fuss or fighting. The rationale for this approach is the same as the rationale for associating the bed with sleep (mentioned

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previously); if the child stays up late and—as a result—falls asleep right away, they will come to associate their bed with sleep rather than with staying awake. In short, the bed, the bedroom and the bedtime routine should all signal sleep (Durand, 2014). To illustrate, if the child’s bedtime is typically 8:30 pm but they fight going to bed at that time, then the parents should choose a bedtime when the child is likely to fall asleep easily (within about 15 minutes), such as 11:30 pm (for example), and then add 30 minutes (i.e., new bedtime = 12:00 am). If the child falls asleep easily (with little or no resistance) at the new bedtime of 12:00 am for two consecutive nights then, on the third night, the parents can move bedtime back 15 minutes (e.g., from 12:00 am to 11:45 pm). The parents should continue fading the bedtime back in small increments until they reach the desired bedtime (e.g., fourth night 11:30pm, fifth night 11:15 pm and so on). For bedtime fading to be successful, the child should be kept awake until the new bedtime even if he/she seems to want to fall asleep (Durand, 2014). Additionally, if the child does not fall asleep within about 15 minutes after being put to bed, the parents should have the child leave the bedroom and extend the bedtime for 1 more hour (Durand, 2014). The advantage of bedtime fading over extinction or graduated extinction is that, when the child is kept up very late and falls asleep quickly and easily, parents can usually avoid having to endure the child’s crying or tantrums or other disruptive behaviors (i.e., there is little or no “extinction burst”). However, the disadvantage of bedtime fading is that this can be a very slow process and some parents do not want to have to stay up very late for the first few nights or week or two (see Table 6.1 comparing graduated extinction to bedtime fading). Although many studies have used bedtime fading as part of multi-component sleep packages for youth with ASD (e.g., Christodulu & Durand, 2004; Piazza & Fisher, 1991), only two studies have examined bedtime fading in isolation for children with ASD (Delemere & Dounavi, 2018; DeLeon, Fisher & Marhefka, 2004). Specifically, Delemere and Dounavi (2018) found that bedtime fading increased total sleep duration and decreased sleep onset latency (the amount of time between putting the child to bed and when the child falls asleep) for all three children with ASD (ages 2.5–6.2 years).

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Table 6.1 Comparing graduated extinction to bedtime fading Graduated extinction

Faded bedtime

Pluses

Minuses

Pluses

Minuses

• Can be used at the regular bedtime rather than having to wait until late at night. • Can check on the child for reassurance. • Usually works within the first week.

• Requires listening to child’s cries, which can be difficult for many families. • Can result in an increase in behavior problems (known as an “extinction burst”). • Some behaviors, such as self-injurious behaviors, cannot be ignored.

• Often can be “errorless,” with no increase in behavior problems. • Often prevents long bouts of crying or tantrums.

• Requires that someone remain up late at night. • Can take several weeks before the desired bedtime is reached.

Source: Adapted from Durand (2014)

Positive Reinforcement As previously noted, when it is time to go to bed, children—both with and without ASD—often engage their parents in interactions that serve two functions or purposes: to avoid/delay going to bed and to get attention. Therefore, in addition to eliminating attention for problem bedtime behaviors (i.e., extinction), it is important to teach parents to provide attention and other forms of reinforcement for engaging in a positive bedtime routine, staying in bed and other sleep-facilitating behaviors. Although positive reinforcement has not been examined on its own (in the absence of standard extinction, graduated extinction, bedtime fading, positive bedtime routine, etc.) in the treatment of bedtime problems in youth with ASD, it is often used as one of the interventions in function-based multi-component intervention packages. For example, a pilot study by van Deurs et al. (2019) implemented individualized, FBA-based, multi-component interventions for three children/adolescents with ASD (ages 9–14 130

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years). Individualized components for the children included: 1) social stories to illustrate sleep routines, sleep-promoting behaviors and how participants would be reinforced; 2) sleep checklists (a visual schedule depicting the bedtime routine); 3) visualization strategies to redirect sleep-interfering thoughts; and 4) Gro-clocks (to provide a discriminative stimulus for sleep/ wake times). Individualized components for the parents included: 1) bedtime fading and sleep restriction; 2) appropriate sleep dependencies (the parents provide the child with sleep-promoting stimuli such as a soft toy); 3) clear discriminative stimuli for bed preparation and sleep onset (e.g., consistent statements about bedtime and sleep); 4) scheduled access to reinforcers; 5) graduated extinction; and 6) positive reinforcement for successive approximation toward desired sleep behavior (van Deurs et al., 2019). The authors found that the individualized multi-component intervention package was effective in eliminating sleep disturbance for all three participants with ASD, and that improvements were maintained during an 18- to 24-month follow-up. The second major complaint by parents is frequent and/or disruptive night waking. Sometimes this results in the child sleeping in the parent’s bed for the rest of the night. Interventions for night waking mirror those for bedtime problems. One additional intervention for night waking is called scheduled awakenings (Vriend et al., 2011). Scheduled awakenings involve rousing the child from sleep approximately 30 minutes before an expected night waking episode (Durand, 2014). There are limited data on this intervention for night waking in children with ASD (Vriend et al., 2011), although—as we mention later—there is one study using this intervention for sleep terrors (Durand, 2002).

Breathing and Limb Movement-Related Sleep Disorders Although there is scant research on sleep-related breathing disorders (e.g., apnea) or on sleep-related movement disorders (e.g., restless leg syndrome) in ASD, they do appear to occur in this population at levels comparable to those without ASD (Williams, Sears & Allard, 2004). It is important to check for these types of sleep problems because they can reveal why someone might have a difficult time being awakened in the morning after what appears to 131

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be a good amount of sleep (Malow et al., 2006). Interrupted breathing or excessive limb movement during sleep can cause a person to awaken briefly without awareness numerous times throughout the night (partial wakings), and this disturbed sleep can cause waking in the morning to be difficult. A medical evaluation of nighttime breathing and limb movement problems is essential in order to improve sleep and avoid potentially dangerous outcomes, especially resulting from interrupted breathing.

Parasomnias Disturbances in arousal and sleep stage transition that intrude into the sleep process are referred to as parasomnias. These include nightmares, sleep terrors, sleep talking (formally called “somniloquy”) and sleepwalking (formally called “somnambulism”) (Durand, 2006; Durand & Christodulu, 2003). Although they may present themselves in a similar manner (e.g., child crying out after a period of sleep), nightmares need to be distinguished from sleep terrors because intervention differs for these two nighttime disturbances. Nightmares are disturbing dreams that awaken the sleeper. Because nightmares occur during rapid eye movement (REM) sleep, the person is essentially paralyzed, making it difficult to walk around or talk. Crying or screaming occurs when the person awakens from the bad dream. In contrast, sleep terrors occur while the child is still asleep and usually begin with a piercing scream. The child is extremely upset, often sweating, and frequently has a rapid heartbeat. On the surface, sleep terrors appear to resemble nightmares because the child cries and appears frightened. However, sleep terrors occur during non-REM (NREM) sleep and therefore are not caused by frightening dreams (Durand, 2006). During sleep terrors, children are asleep and cannot be easily awakened and comforted, as they can during a nightmare. Children typically do not remember sleep terror events the next morning despite their often dramatic effect on the observer. Nightmares occur during REM (or dream) sleep while the other parasomnias are primarily observed during deeper stages of NREM sleep. There is conflicting evidence for the prevalence of parasomnias among children with ASD, although most studies in this area suggest that they may also be more frequent in this population (Liu et al., 2006; Schreck & 132

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Mulick, 2000; Williams et al., 2004). There is some evidence that this increased prevalence of parasomnias declines in adolescence (Goldman et al., 2012).

Sleep Terrors To date, there is only one study on an attempt to treat sleep terrors in children with ASD (Durand, 2002). In this study, among children with ASD who had chronic sleep terrors (two to five episodes per week), the effectiveness of one behavioral intervention (scheduled awakenings) was evaluated. Logs parents completed for several weeks noted the time the sleep terrors occurred. Results through a 12-month follow-up using a multiple baseline across three children indicated that this intervention quickly and durably reduced the frequency of their nighttime difficulties. Unfortunately, sometimes parents find this treatment disruptive to their own sleep—having to get out of bed late at night or early in the morning to awaken their child. However, a remote device may be able to make this easier. The Lully Sleep Guardian 2 is a small bluetooth-enabled electronic tool that slides under the child’s mattress (www.lullysleep.com). It works by rousing a child with gentle vibrations just before a night terror occurs, preventing them from entering the deleterious stage of sleep. More research on this device is needed.

Nightmares There does not appear to be any empirical evidence for treating nightmares in persons with ASD (Durand & Christodulu, 2003). The research with persons without ASD suggests that several cognitive-behavioral interventions may help reduce the frequency and intensity of nightmares (Augedal et al., 2013).

Summary A review of sleep-based interventions for children with ASD finds that behavioral interventions, parent education/education program interventions and melatonin appear to be the most effective at ameliorating multiple domains of sleep problems (Cuomo et al., 2017) (see Chapter 1 in this book by Hirota, Nakaishi, Whitley and Hendren for more information about melatonin as 133

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a treatment for bedtime problems in ASD). Specifically, behavioral interventions have a very strong effect on morning waking, co-sleeping and self-settling (Cuomo et al., 2017). However, the majority of the behavior interventions were not tested individually; rather, studies commonly used a combination of principles and procedures, including extinction (standard and graduated), sleep hygiene, positive reinforcement, sleep restriction, stimulus fading, scheduled awakening and faded bedtime (Cuomo et al., 2017). That said, this is reflective of the way treatment is implemented in the real world, in which several different interventions are often used together to address sleep problems.

References Augedal, A. W., Hansen, K. S., Kronhaug, C. R., Harvey, A. G. & Pallesen, S. (2013). Randomized controlled trials of psychological and pharmacological treatments for nightmares: A meta-analysis. Sleep Medicine Reviews, 17(2), 143–152. Carnett, A., Hansen, S., McLay, L., Neely, L. & Lang, R. (2020). Quantitative-analysis of behavioral interventions to treat sleep problems in children with autism. Developmental Neurorehabilitation, 23(5), 271–284. Christodulu, K. V. & Durand, V. M. (2004). Reducing bedtime disturbance and night waking using positive bedtime routines and sleep restriction. Focus on Autism and Other Developmental Disabilities, 19, 130–139. Cooper, J. O., Heron, T. E. & Heward, W. L. (2019). Applied Behavior Analysis, 3rd edn. New York: Pearson. Cuomo, B. M., Vaz, S., Lee, E., Thompson, C., Rogerson, J. M. & Falkmer, T. (2017). Effectiveness of sleepbased interventions for children with autism spectrum disorder: A meta-synthesis. Pharmacotherapy, 37(5), 555–578. Delemere, E. & Dounavi, K. (2018). Parent-implemented bedtime fading and positive routines for children with autism spectrum disorders. Journal of Autism & Developmental Disorders, 48, 1002–1019. DeLeon, I. G., Fisher, W. W. & Marhefka, J. M. (2004). Decreasing self-injurious behavior associated with awakening in a child with autism and developmental delays. Behavioral Interventions, 19(2), 111–119. Durand, V. M. (2002). Treating sleep terrors in children with autism. Journal of Positive Behavioral Interventions, 4, 66–72. Durand, V. M. (2006). Sleep terrors. In J. E. Fisher & W. T. O’Donohue (eds.), Practitioner’s Guide to Evidenced Based Psychotherapy. New York: Springer. Durand, V. M. (2014). Sleep Better! A Guide to Improving Sleep for Children with Special Needs, revised edn. Baltimore, MD: Paul H. Brookes. Durand, V. M. & Christodulu, K. V. (2003). Nightmares. In T. H. Ollendick & C. S. Schroeder (eds.), Encyclopedia of Pediatric and Child Psychology. New York: Kluwer Academic/Plenum Publishers. Durand, V. M. & Christodulu, K. V. (2004). A description of a sleep restriction program to reduce bedtime disturbances and night waking. Journal of Positive Behavioral Interventions, 6, 83–91. Durand, V. M., Gernert-Dott, P. & Mapstone, E. (1996). Treatment of sleep disorders in children with developmental disabilities. Journal of the Association for Persons with Severe Handicaps, 21, 114–122. France, K. G. & Blampied, N. M. (2005). Modifications of systematic ignoring in the management of infant sleep disturbance: Efficacy and infant distress. Child & Family Behavior Therapy, 27(1), 1–16. Goldman, S. E., Richdale, A. L., Clemons, T. & Malow, B. A. (2012). Parental sleep concerns in autism spectrum disorders: Variations from childhood to adolescence. Journal of Autism & Developmental Disorders, 42, 531–538. DOI 10.1007/s10803-011-1270-5 Howlin, P. (1984). A brief report on the elimination of long term sleeping problems in a 6-year-old autistic boy. Behavioural and Cognitive Psychotherapy, 12(3), 257–260.

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Behavioral Interventions for Sleep Problems Hunter, J. E., McLay, L. K., France, K. G. & Blampied, N. M. (2020). Systematic review of the collateral effects of behavioral sleep interventions in children and adolescents with autism spectrum disorder. Research in Autism Spectrum Disorders, 79, 101677. Kirkpatrick, B., Louw, J. S. & Leader, G. (2019). Efficacy of parent training incorporated in behavioral sleep interventions for children with autism spectrum disorder and/or intellectual disabilities: A systematic review. Sleep Medicine, 53, 141–152. Kuhn, B. R. & Elliott, A. J. (2003). Treatment efficacy in behavioral pediatric sleep medicine. Journal of Psychosomatic Research, 54(6), 587–597. Liu, X., Hubbard, J. A., Fabes, R. A. & Adam, J. B. (2006). Sleep disturbances and correlates of children with autism spectrum disorders. Child Psychiatry & Human Development, 37(2), 179–191. Malow, B. A., McGrew, S. G., Harvey, M., Henderson, L. M. & Stone, W. L. (2006). Impact of treating sleep apnea in a child with autism spectrum disorder. Pediatric Neurology, 34(4), 325–328. McLay, L., France, K., Blampied, N., van Deurs, J., Hunter, J., et al. (2021). Function-based behavioral interventions for sleep problems in children and adolescents with autism: Summary of 41 clinical cases. Journal of Autism and Developmental Disorders, 51, 418–432. Piazza, C. C. & Fisher, W. W. (1991). Bedtime fading in the treatment of pediatric insomnia. Journal of Behavior Therapy & Experimental Psychiatry, 22(1), 53–56. Schreck, K. A. & Mulick, J. A. (2000). Parental report of sleep problems in children with autism. Journal of Autism and Developmental Disorders, 30(2), 127–135. van Deurs, J. R., McLay, L. K., France, K. G., Blampied, N. M., Lang, R. B. & Hunter, J. E. (2019). Behavioral sleep intervention for adolescents with autism spectrum disorder: A pilot study. Advances in Neuro­ developmental Disorders, 3, 397–410. Vriend, J. L., Corkum, P. V., Moon, E. C. & Smith, I. M. (2011). Behavioral interventions for sleep problems in children with autism spectrum disorders: Current findings and future directions. Journal of Pediatric Psychology, 36(9), 1017–1029. DOI: 10.1093/jpepsy/jsr044 Weiskop, S., Matthews, J. & Richdale, A. (2001). Treatment of sleep problems in a 5-year-old boy with autism using behavioural principles. Autism, 5(2), 209–221. Weiskop, S., Richdale, A. & Matthews, J. (2005). Behavioural treatment to reduce sleep problems in children with autism or Fragile X syndrome. Developmental Medicine & Child Neurology, 47(2), 94–104. DOI: 10.1111/j.1469-8749.2005.tb01097.x Williams, P. G., Sears, L. L. & Allard, A. (2004). Sleep problems in children with autism. Journal of Sleep Research, 13(3), 265–268. DOI: 10.1111/j.1365-2869.2004.00405.x Wolf, M., Risley, T. & Mees, H. (1963). Application of operant conditioning procedures to the behaviour problems of an autistic child. Behaviour Research and Therapy, 1(2), 305–312.

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Conclusion Stephen M. Edelson, PhD, Autism Research Institute, San Diego

Sleep problems are a serious challenge for many with autism spectrum disorder (ASD), often disrupting the lives of their caregivers as well. As this book shows, there are many possible contributors to these problems, and identifying them can often lead to successful treatment plans that dramatically improve the quality of life of people with ASD and their families. Unfortunately, there is less research into the causes and treatment of sleep problems in autism than there is into other biologically related issues such as genetics, neurology and gastrointestinal distress. It is important for researchers and clinicians to recognize the serious effects of sleep problems, because the more we understand how sleep deprivation truly impacts individuals with ASD, the more likely funding agencies will be to sponsor additional research. Clearly, sleep problems can play a significant role in exacerbating some symptoms of autism, and future research can help to elucidate this association. Another potentially important area of research, given the heterogenous nature of autism, involves the effects of genetic influences on sleep disturbances. For instance, a recent article documented sleep problems in those with 16p11.2 copy number variants (i.e., deletion and duplication phenotypes) as compared to community controls (Damara et al., 2021). While researchers should continue to explore these and other related topics, clinicians can make use of existing knowledge to help their patients or clients who are struggling with these issues. As this book shows, sleep problems can have multiple causes and may require multiple treatments. Currently, clinicians tend to prescribe treatments based on their professional training. A sensory therapist will most likely administer a sensory-related

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intervention; a behavioral therapist will probably employ “sleep hygiene” strategies; and a psychiatrist may prescribe a medication. Given the multifactorial roots of sleep problems, clinicians are more likely to achieve optimal results if they conduct an extensive examination of each individual, including assessments to identify biological, sensory and environmental triggers. Sometimes, of course, the type of sleep disturbance may point to the most likely contributors and indicate the most appropriate treatments. For instance, playing computer games prior to bedtime is likely to lead to difficulty falling asleep, rather than waking up in the middle of the night or in the early morning hours. But often the identification of contributing factors will require a detailed analysis and multiple approaches to treatment. This book is the third in a series on understanding and treating autism from a multi-disciplinary perspective. The first two books are Understanding and Treating Anxiety in Autism and Understanding and Treating Self-Injurious Behavior in Autism. The three books complement one another, because anxiety, sleep issues and self-injurious behavior often involve common factors. Other extensive multidisciplinary reviews are also needed in the autism literature; important topics that need to be addressed include aggression, eating problems, severe tantrums and toileting issues, in addition to depression, obsessions/compulsions and suicidal ideation. We hope this extensive analysis of sleep disturbances, based on a multitude of perspectives, will encourage funding agencies to support additional research into this important topic. In addition, we hope it will encourage clinicians to take sleep issues seriously and to seek effective solutions, as these issues impact nearly all aspects of life for individuals with ASD and their families.

References Damara, D., De Boeck, P., Lecavalier, L., Neuhaus, E. & Beauchaine, T. P. (2021). Characterizing sleep problems in 16p11.2 deletion and duplication. Journal of Autism and Developmental Disorders. DOI: 10.1007/ s10803-021-05311-2

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S U B J E CT I N D E X

5-Hydroxytryptophan (5HTP) 75–6 alpha agonists 25 Angelman syndrome 44, 45 antidepressants 26–7 antihistamines 27–8 antipsychotics 29 anxiety 47 assessments behavioral assessments 18 causes of sleep problems 17–18 environmental assessments 18 genetic assessments 18 medical assessments 19 psychiatric assessments 19–20 sensory assessments 19 and sensory integration and processing 103–4, 108–11 attention-deficit hyperactivity disorder (ADHD) 19–20 autism causes of sleep problems 17–18, 54 description of 37, 83 diagnosis of 52 and pain 59–60 related conditions 44–5 and REM sleep 55–6 and sensory integration and processing 84, 97–8 and serotonin 56–8 sleep problem prevalence 15, 37, 54–5, 67, 84 autonomic nervous system (ANS) 87–8 Ayres Sensory Integration® 101, 102

bedtime and waking time 122–3 bedtime fading 128–30 bedtime routines 121–2 behavioral assessments 18 behavioral interventions bedtime and waking time 122–3 bedtime fading 128–30 bedtime routines 121–2 body and limb movements 131–2 breathing difficulties 131–2 extinction procedure 124–7 nightmares 133 parasomnias 132–3 positive reinforcement 130–1 research in 119 scheduled awakenings 131 sleep hygiene changes 120–3 sleep terrors 132, 133 stimulus fading 127–8 trigger identification 123–4 benzodiazepines (BZDs) 30 body and limb movements 41–2, 131–2 breathing difficulties 40–1, 131–2 bruxism 46 case vignettes medication 22–3, 31–2 sensory integration and processing 108–9 causes of sleep problems 17–18, 53, 54 clinicians role in polysomnography 47–8 clonidine 25 comorbidities 46–7, 53–4 complementary therapies 32 Covid-19 pandemic 67–8

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Data Driven Decision Making (DDDM) model 111 data gathering 108–11 Democritus 53 diet see nutrition Dietary Reference Intake (DRI) 68–9 effects of sleep problems 37–8, 54, 55–6, 105–7 environmental assessments 18 epilepsy 45 esophagitis 46 extinction procedure 124–7 fatty acids 75 food see nutrition gabapentin 30 gamma-aminobutyric acid (GABA) 16–17, 76 genetic assessments 18 GERD 46 guanfacine 26 hyper-arousability 45 hypo-arousability 45 Infantile Autism: The Syndrome and its Implications for a Neural Theory of Behavior (Rimland) 10 integrative therapies 30 iron 74 Landau-Kleffner syndrome 44 macronutrients 69–72 magnesium 74 medical assessments 19

UNDERSTANDING AND TREATING SLEEP DISTURBANCES IN AUTISM medications 61–2 alpha agonists 25 antidepressants 26–7 antihistamines 27–8 antipsychotics 29 benzodiazepines 30 case vignettes 22–3, 31–2 clonidine 25 complementary therapies 32 considerations for using 20–1 gabapentin 30 guanfacine 26 integrative therapies 30 melatonin formulations 23–5, 62 starting 21–2 Mediterranean Diet 69, 72, 77 melatonin as formulation 23–5, 62 and nutrition 75–6 role in sleep physiology 17 micronutrients 73–4 nightmares 133 non-rapid eye movement sleep (NREM) 91–2 non-REM parasomnias 42 nutrition 5-Hydroxytryptophan (5HTP) 75–6 considerations for 68–9 fatty acids 75 iron 74 macronutrients 69–72 magnesium 74 melatonin 75–6 micronutrients 73–4 research on link to sleep 68 as treatment 77–8 tryptophan 75–6 vitamin A 73 vitamin D 73 pain 59–60 Parkinson’s disease 43 parasomnias 132–3

paroxysmal non-epileptiform activity 45 physiology of sleep gamma-aminobutyric acid (GABA) 16–17 melatonin 17 role of 16 serotonin 17, 58–9 polysomnography body and limb movements 41–2 breathing difficulties 40–1 bruxism 46 clinician role in 47–8 comorbidities 46–7 description of 38 epilepsy 45 esophagitis 46 GERD 46 hyper-arousability 45 hypo-arousability 45 limitations of 38–40 non-REM parasomnias 42 paroxysmal nonepileptiform activity 45 REM-related parasomnias 42–3 sleep-related EEG abnormalities 43–5 teeth-grinding/clenching 46 uses of 38–40 positive reinforcement 130–1 prevalence of sleep problems 15, 37, 53, 54–5, 67, 84 psychiatric assessments 19–20 reduplicaton syndrome 44–5 regulation of sensory integration and processing 88–90, 98–101 REM-related parasomnias 42–3 REM sleep 55–6, 91 scheduled awakenings 131 sensory assessments 19 sensory integration and processing assessments in 103–4, 108–11

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and autonomic nervous system (ANS) 87–8 case vignettes 108–9 clinical implications 105–7 data gathering 108–11 description of 83–5 functions of 84–7 individualizing interventions 111–12 interventions for sleep problems 101–5 regulation of 88–90, 98–101 and relationships 98–101 and sensory systems 85–7 and sleep 95–8 serotonin and autism 56–8 role in sleep physiology 17, 58–9 sleep patterns 91–2, 93–5 sleep problems and ADHD 19–20 causes of 17–18, 53, 54 and comorbidities 53–4 and Covid-19 pandemic 67–8 effects of 37–8, 54, 55–6, 105–7 medication for 15–16, 61–2 and pain 59–60 and polysomnography 40–7 prevalence of 15, 37, 53, 54–5, 67, 84 and sensory integration and processing 95–8, 101–5 treatments for 61–2 sleep-related EEG abnormalities 43–5 sleep terrors 132, 133 stimulus fading 127–8 teeth-grinding/clenching 46 vitamin A 73 vitamin D 73 wakefulness 90–5 Willis, Thomas 53

AUTHOR INDEX

Abel, E. A. 55 Abraham, D. A. 76 Abu Zamzam, H. I. 75 Adams, J. B. 73 Adham, N. 59 Afaghi, A. 69 Ahearn, W. H. 19 Aigner, C. J. 71 Ailshire, J. A. 99 Al-Shawwa, B. 73, 74 Allard, A. 38, 131 Allen, J. E. 27 Alzoubi, K. 75 Aman, M. G. 26, 28, 30, 84 American Academy of Pediatrics 67 American Heart Association (AHA) 71, 72 American Occupational Therapy Association 106 American Psychiatric Association 37 American Sleep Association 53, 106 Anagnostou, E. 60 Andersen, M. 71 Anderson, I. M. 72 Angriman, M. 54 Appelbaum, L. 91 Arkilo, D. 44 Armstrong, K. L. 18 Arnulf, I. 18 Arora, T. 71, 72 Arrigoni, E. 91 Asztély, K. 60 Augedal, A. W. 133 Autism Research Institute (ARI) 10 Ayres, A. J. 85, 102, 105 Bader, M. A. 57 Baker, E. 54, 68 Ballester, P. 16, 17, 32, 68

Baranek, G. T. 19 Barbee, A. P. 99 Barnhill, K. 69 Baron-Cohen, S. 84 Bartley, E. J. 60 Bathory, E. 91, 93 Bauman, M. L. 68 Baumeister, R. F. 89 Becker, S. P. 106 Ben-Sasson, A. 97 Bertschy, G. 76 Besedovsky, L. 9 Bhargava, S. 67 Bjorness, T. 94 Blampied, N. M. 127 Blaszczyk, B. 30 Blue, M. E. 58 Bravaccio, C. 76 Broekman, B. F. P. 9 Broomall, E. 18 Browne, J. 89 Bruni, O. 17, 21, 24, 27, 28, 68 Buie, T. 46, 48 Bundy, A. C. 86, 101, 103 Burgard, S. 99 Bušková, J. 83 Butter, E. 84 Byars, K. 106 Cade, J. 69 Carmassi, C. 9, 67 Carnett, A. 119 Casanova, E. L. 58 Casanova, M. F. 58, 59, 61, 63 Centers for Disease Control and Prevention (CDC) 106 Chan, V. 74 Chervin, R. D. 42, 45, 53 Chollet, D. 74 Choudhury, A. R. 71 Chow, C. M. 70 Christensen, J. S. 87, 89

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Christodulu, K. V. 121, 122, 129, 132, 133 Clark, I. 70 Cohen, E. M. 32 Conlon, E. G. 95 Consens, F. B. 53 Cooper, J. O. 124 Cortese, S. 20, 97 Cortesi, F. 16 Couturier, J. L. 15, 37 Crispim, C. A. 70 Cunningham, M. R. 99 Cuomo, B. M. 24, 133, 134 Czapinski, P. 30 Dadds, M. R. 19 Damara, D. 137 Dan, Y. 93 Dawson, G. 112 de Lecea, L. 91 DeBassio, W. 22 DeGangi, G. 89 Delahaye, J. 106 Delemere, E. 129 DeLeon, I. G. 129 Deriaz, N. 76 Devnani, P. A. 61 Dosman, C. F. 74 Dounavi, K. 129 Dunn, W. 84, 103 Durand, V. M. 120, 121, 122, 126, 127, 129, 130, 131, 132, 133 Eban-Rothschild, A. 91, 92, 94 Edelson, S. M. 9 Ehsan, Z. 73 Ekambaram, V. 21 El-Ad, B. 42, 45 Elliott, J. E. 95 Elrod, M. G. 9 Engel-Yeger, B. 95 Eriksen, W. 54 Eriksson, M. 59 Esteban-Figuerola, P. 69

UNDERSTANDING AND TREATING SLEEP DISTURBANCES IN AUTISM Ferranti, R. 69 Fiks, A. G. 25, 26 Fillingim, R. B. 60 Fisher, W. W. 129 Fjeldsted, B. 95 Fogel, A. 99 France, K. G. 127 Frank, S. 71 Frazier, T. W. 103, 104 Freedman, D. X. 57 Friedman, M. 75 Frye, R. E. 24, 75 Gabay, M. 30 Gabriele, S. 57 Gabriels, R. L. 45 Galli-Carminati, G. 76 Galván, A. 83 Gao, Q. 73 Garaulet, M. 72 Gee, B. M. 103, 104 Gernert-Dott, P. 127 Gevi, F. 75 Giannotti, F. 76 Gibbons, C. H. 87 Glickman, G. 112 Gluncic, V. 58 Godos, J. 69 Goldman, S. E. 15, 55, 132 Goldstein, A. 9 Golubchik, P. 29 Gopal, S. 25 Gordon, C. 59 Grandner, M. A. 72 Green, J. 32 Greene, R. 94 Grigg-Damberger, M. 24 Gu, X. 60 Guidi, J. 88 Gungor, O. 73 Gururaj, V. J. 27 Haack, M. 9, 60 Haegele, J. A. 71 Hanlon-Dearman, A. C. 95 Hardie, L. 69 Hayashi, M. 75 Healy, S. 71 Hegde, A. U. 61 Hellwig, J. P. 68 Hepsomali, P. 76 Hering, E. 38 Heron, T. E. 124 Heward, W. L. 124 Hirotsu, C. 71

Hisler, G. 106, 113 Hodge, D. 68 Hohn, V. D. 84, 97 Hollander, E. 58 Hollway, J. A. 26, 28, 30, 84, 97, 106 Holm, A. 59 Honomichl, R. D. 38 Hood, B. S. 9 Hopper, J. 87 Howlin, P. 128 Hunter, J. E. 119 Hutsler, J. J. 58 Hvolby, A. 20 Iglowstein, I. 72 Ikonte, C. J. 73 Ingram, D. G. 73, 74 Ingrassia, A. 25 Jamadarkhana, S. 25 Janusonis, S. 58 Javaheri, S. 72 Ji, X. 76 Johnson, J. B. 9 Johnston, G. A. R. 30 Johnston, M. V. 58 Kahathuduwa, C. N. 71 Kałużna-Czaplińska, J. 75 Kanney, M. L. 74 Kent, R. 47, 99 Kent de Grey, R. 99 Khan, R. 32 Kirkpatrick, B. 119 Klintwall, L. 59 Klukowski, M. 46 Konofal, E. 20 Korpela, R. 75 Kotagal, S. 18 Kothare, S. V. 22 Krakowiak, P. 15 Kratochvil, C. J. 23, 26, 27 Krizan, Z. 106, 113 Krueger, J. M. 83 Landolt, H. 70 Lane, S. J. 84, 86, 101, 103, 107 Langberg, J. M. 106 Lange, T. 9 Lawson, L. 103, 104 Lazarus, M. 94 Leader, G. 119 Lecendreux, M. 20

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Leung, W. 74 Lillas, C. 87, 89 Lin, J. 71 Lipton, J. O. 91 Little, L. 103, 104 Liu, J. 76, 132 Lo, K. 74 Louw, J. S. 119 MacDuffie, K. E. 9 Majid, M. S. 73 Malow, B. A. 9, 16, 17, 20, 22, 30, 43, 47, 55, 75, 76, 84, 104, 132 Mamalaki, E. 69 Mancuso, C. E. 30 Mandell, D. S. 26 Manelis-Baram, L. 97 Mapstone, E. 127 Maras, A. 24 Marhefka, J. M. 129 Marrosu, F. 30 Martinez, S. 72 Marzec, M. L. 39 Maski, K. P. 97 Mason, P. 87 Masters, A. 94 Maxwell-Horn, A. C. 17 Mayes, S. D. 20 Mayo Clinic 72 Mayyas, F. 75 Mazurek, M. O. 18, 19, 20, 84, 97, 103, 106 McCall C. 27 McCall, W. V. 27 McDougle, C. 59 McGrew, S. G. 47 McGuinn, M. 104 McLay, L. 124 Mees, H. 120 Mehlinger, R. 59 Merikanto, I. 9 Meyers, L. D. 68 Mignot, E. 18 Miletínová, E. 83 Miller, L. J. 103, 107 Milner, C. E. 95 Mindell, J. A. 27 Ming, X. 25 Montgomery, P. 75 Monti, J. M. 17 Moskowitz, L. J. 9 Mrakotsky, C. 27 Mueller, I. 99 Mulick, J. A. 55, 132

Author Index Mullington, J. M. 60 Murata, E. 41 Murillo-Rodriguez, E. 92, 93 Muscogiuri, G. 69 Muthu, M. S. 46 Naito, S. 41 Narasingharao, K. 103, 104 National Scientific Council on the Developing Child 98 Navaneetham, J. 103 NCCIH 60 Neely, K. A. 96 Nir, I. 17 Noorwali, E. 69 O’Connor, H. 69 Oldehinkel, M. 87 Olson, S. L. 88 Osher, D. 98 Otten, J. J. 68 Owens, J. A. 23, 26, 27, 104 Ozkaya, A. 73 Ozturk, A. 71 Paavonen, E. J. 106 Paprocka, J. 25 Parham, L. D. 103 Parmeggiani, A. 28 Pawlowski, M. 20 Pearson, A. 83 Pelayo, R. 25 Persico, A. M. 57, 58 Petit, D. 42 Petroski, G. F. 19, 20, 84, 103 Peuhkuri, K. 75 Pfeiffer, B. A. 107 Phillips, D. 99 Piazza, C. C. 129 Pillar, G. 40 Politte, L. C. 26 Pollack, S. F. 45 Porges, S. W. 99 Posar, A. 28, 54, 55 Posey, D. J. 27 Potter, G. D. M. 9 Powrozek, T. 58 Poznanski, E. 59 Pradhan, B. 103 Prathibha, K. M. 46 Quinn, R. A. 19

Rajaei, S. 95, 96 Rakic, P. 58 Ralls, F. 24 Rana, M. 22, 25 Relia, S. 21 Reynolds, A. M. 15, 74, 84 Reynolds, S. 84, 95, 96, 97 Richard, D. M. 75 Richdale, A. I. 16, 37, 38, 68 Rico, T. J. 18 Rimland, B. 10 Risley, T. 120 Robertson, C. E. 84 Robinson, A. A. 30, 42 Rose, K. 83 Rosen, C. L. 27 Rosenblum, S. 95, 96 Rosi, A. 69 Rossi, P. G. 28 Rossignol, D. A. 24, 75 Roussis, S. 84 Rugino, T. A. 26 Russo, R. M. 27 Rzepka-Migut, B. 25 Sacco, R. 57 St-Onge, M. P. 68, 70, 72 Saito, H. 76 Sameroff, A. J. 88 Sanchez, E. 60 Sari, Y. 58 Sassower, K. C. 44, 45 Sateia, M. J. 29 Scammel, T. E. 91, 92 Schaaf, R. C. 107, 111 Schain, R. J. 57 Scheftner, W. 58 Schmitt, J. 75 Schneider, N. 9 Schoen, S. A. 103, 107 Schreck, K. 16, 55, 68, 132 Sears, L. L. 38, 131 Sever, J. 29 Shah, Y. D. 27 Shani-Adir, A. 95, 96 Shanker, S. G. 89 Shao, Y. 17 Sharfi, K. 95, 96 Shellhaas, R. A. 9 Shinjyo, N. 32 Shochat, T. 95, 96 Shonkoff, J. P. 99 Shubin, R. A. 30, 42 Siegel, M. S. 18 Sihvola, N. 75

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Silber, B. 75 Silva, L. M. T. 103 Simonoff, E. 47 Simons, F. E. R. 28 Smith, A. F. 55 Smith, W. E. 18 Snijders, T. 72 Souders, M. C. 54, 55, 68 Spirito, A. 104 Spruyt, K. 106 Starkstein, S. 43 Steiger, A. 20 Steinbrenner, J. R. 103 Steingard, R. 59 Stengel, A. 71 Stores, G. 38, 54, 84 Sullivan, E. C. 9 Sutton, D. 89 Suvarna, B. 90 Taché, Y. 71 Taheri, S. 71 Talay-Ongan, A. 112 Talmi, A. 89 Tamaki, M. 83 Tanzi, M. 30 Tassniyom, K. 29 Tauman, R. 95 Thacker, L. 84 Tham, E. K. H. 9 Thirumalai, S. S. 30, 42 Thompson, W. 29 Thye, M. D. 95 Tice, D. M. 89 Tomchek, S. D. 84 Tomkies, A. 40 Tomopoulos, S. 91, 93 Tordjman, S. 17 Tronick, E. Z. 99 Troxel, W. M. 99 Tseng, P. T. 74 Tufik, S. 71 Turk, J. 25 Turnbull, J. 87, 89 Tzischinsky, O. 9, 95, 97 United States Departments of Agriculture (USDA) 68 Uren, J. 106 van Deurs, J. R. 130 Varju, P. 16 Veatch, O. J. 17 Vein Center of North Texas 53

UNDERSTANDING AND TREATING SLEEP DISTURBANCES IN AUTISM Velluti, R. 95 Verhoeff, M. E. 9 Visconti, P. 54, 55 Vohs, K. D. 89 Vriend, J. L. 120, 131 Waddell, G. 32 Walker, M. P. 9 Walther, D. J. 57 Wang, M. 25, 28 Wasilewska, J. 46 Weber, F. 93 Weiskop, S. 124

Weizman, A. 29 Welch, C. 90 Wen, J. 73 Wengel, T. 95 Whitaker-Azmitia, P. M. 56 Wiggs, L. 38, 84 Williams, P. G. 38, 131, 132 Wintler, T. 9 Wolf, M. 120 Wood, K. 112 Wright, C. M. 95 Wu, Z. 98 Wyatt, J. K. 93, 95

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Xu, Y. 58 Yalamanchali, S. 40 Youssef, J. 19, 74 Yuen, K. 25 Yuge, K. 75 Zavodny, S. 54 Zhang, Y. 74 Zheng, Z. 71 Zhou, J. 72 Zhou, T. J. 58, 60 Zuraikat, F. M. 69