ENDOCRINOLOGY RESEARCH AND CLINICAL DEVELOPMENTS

MELATONIN, SLEEP AND INSOMNIA

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ENDOCRINOLOGY RESEARCH AND CLINICAL

DEVELOPMENTS

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Melatonin, Sleep and Insomnia Yolanda E. Soriento (Editor)

2010. ISBN: 978-1-60741-859-7

ENDOCRINOLOGY RESEARCH AND CLINICAL DEVELOPMENTS

MELATONIN, SLEEP AND INSOMNIA

YOLANDA E. SORIENTO EDITOR

Nova Biomedical Books New York

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Melatonin, sleep and insomnia / editor, Yolanda E. Soriento.

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ISBN 978-1-61122-834-2 (eBook)

Published by Nova Science Publishers, Inc. New York

Contents

Preface vii

Chapter I Conditioned Arousal in Insomnia Patients: Physiological, Cognitive, CorticalAn and/or Question? 1 Aisha Cortoos, Elke De Valck and Raymond Cluydts

Chapter II Neuropathology of Insomnia in the Adult: Still an Enigma! 35 Jean-Jacques Hauw and Chantal Hausser-Hauw

Chapter III Non-Pharmacological Alternatives for the Treatment of Insomnia Instrumental EEG Conditioning, a New Alternative? 69 Kerstin Hoedlmoser, Thien Thanh Dang-Vu, Martin Desseilles

and Manuel Schabus

Chapter IV A Novel Disease Condition Presenting with Insomnia and Hypersomnia Asynchronization 103 Jun Kohyama

Chapter V Aggression in Older Adult Populations 135 Sarah E. Parsons, Luis F. Ramirez, Philipp Dines, Scott Magnuson

and Martha Sajatovic

Chapter VI The Impact of Cultural Changes on the Relationship between Senior Sleep Disturbance and Body Mass Index among Older Adults in Two Asian Societies 161 Bingh Tang and Lyn Tiu

Chapter VII A Novel Model Using Generalized Regression Neural Network (GRNN) for Estimating Sleep Apnea Index in the Elderly Suffering from Sleep Disturbance 191 Bingh Tang and Weizhong Yan

Chapter VIII Hormones and Insomnia 205 Axel Steiger and Mayumi Kimura

Contents vi

Chapter IX Insomnia Among Suicidal Adolescents and Young Adults: A Modifiable Risk Factor of Suicidal Behaviour and A Warning Sign of Suicide? 227 Latha Nrugham and Vandana Varma Prakash

Chapter X Melatonin and Nocturia 249 Kimio Sugaya, Saori Nishijima, Katsumi Kadekawa

and Minoru Miyazato

Chapter XI Melatonin and Other Sleep-Promoting Melatoninergic Drugs Under the Aspects of Binding Properties and Metabolism 273 Rdiger Hardeland

Chapter XII Melatonin for Medical Treatment of Childhood Insomnias 291 Jan Froelich and Gerd Lehmkuhl

Chapter XIII Melatonin: Its Significance with Special Reference to Sedation and Anesthesia 303 Argyro Fassoulaki, Anteia Paraskeva and Sophia Markantonis

Chapter XIV Sleep Disturbance in Obsessive-Compulsive Disorder 315 Enrico Pessina, Sylvia Rigardetto, Umberto Albert, Filippo Bogetto

and Giuseppe Maina

Chapter XV Effects of Sunbathing on Insomnia, Behavioural Disturbance and Serum Melatonin Level 329 Keiko Ikemoto

Chapter XVI Neuroimaging Insights into Insomnia 337 Martin Desseille, Thien Thanh Dang-Vu, Manuel Schabus,

Kerstin Hoedlmoser, Camille Piguet, Maxime Bonjean,

Sophie Schwartz and Pierre Maquet

Chapter XVII Neuroimaging Insights into the Dreaming Brain 357 Martin Desseilles, Thien Thanh Dang-Vu, Manuel Schabus,

Virginie Sterpenich, Laura Mascetti, Ariane Foret,

Luca Matarazzo, Pierre Maquet and Sophie Schwartz

Index 375

Preface Melatonin is a naturally occurring hormone that is released into the body when the eyes

register that it's getting dark. When the eyes send the message to the brain that darkness is falling, a gland in the brain (the pineal gland) releases melatonin, which then signals the body to "wind down" and prepare for sleep. Melatonin regulates our waking and sleeping cycles in addition to performing other jobs. Consequently, insomnia is a symptom of a sleeping disorder characterized by persistent difficulty falling asleep or staying asleep despite the opportunity. Insomnia is a symptom, not a stand-alone diagnosis or a disease. By definition, insomnia is "difficulty initiating or maintaining sleep, or both" and it may be due to inadequate quality or quantity of sleep. It is typically followed by functional impairment while awake. This new and important book gathers the latest research from around the world in the study of melatonin and insomnia with a focus on such topics as: the neuropathology of insomnia in adults, hormones and insomnia, insomnia among suicidal adolescents, melatonin and nocturia, melatonin and its significance with anesthesia and sedation, and others.

Chapter I - Insomnia has become fully recognized as one of the most prevalent sleep disorders in society with a profound impact on multiple aspects of daytime functioning and quality of life. Major advances in the non-pharmacological approach to insomnia include the work of Morin and colleagues on the behavioral and cognitive treatment of insomnia and the introduction of the behavioral model published by Spielman and Glovinsky (1991). Other researchers quickly followed resulting in an increasing amount of studies validating this perspective with its separate components. In the last 15 years, the nature of the conditioned arousal as one of the components in this model has been a major topic of interest. In this context, the neurocognitive model, published by Perlis and colleagues in 1997, argues for the extension of the arousal concept with a third component: cortical arousal. The latter is reflected by high frequency EEG activity during sleep, which is thought to mirror the lack of cognitive deactivation, resulting in a disruption of the normal sleep onset and maintenance processes. Some studies have shown the presence of high frequency EEG activity during the sleep onset period, NREM and REM sleep. Furthermore, beta and gamma EEG activity seem to be related to the subjective misperception of sleep, so often seen in insomnia patients. However, other studies revealed no significant differences in the sleep EEG between insomnia patients and controls. In addition to the theoretical overview, this chapter includes a

Yolanda E. Soriento viii

study exploring the different arousal components in a group of selected insomnia patients with objective findings.

Seventeen insomnia patients diagnosed according to DSM-IV criteria and 12 healthy controls were included in our study. Next to a general assessment of hyperarousal through the use of cortisol assay and questionnaires, a wake EEG and polysomnography were performed to evaluate the presence of cortical hyperarousal both during wakefulness and sleep.

In comparison to a control group, insomnia patients experienced more cognitive and emotional arousal, but no increase in physiological arousal, both subjectively as well as objectively. Indications of cortical arousal were only present during the sleep onset period, reflected by a stable alpha EEG level and slower increase of delta power, related to longer sleep onset latencies. Furthermore, the cortical arousal variables were correlated significantly with objective sleep disruption, not with sleep perception. Together with previous studies, these results point to a large variability in insomnia patients as to the expression of hyperarousal and its different components.

Chapter II Insomnia Insomniais a very frequent symptom, usually due to non organic brain diseases. In some organic brain disorders, however, sleep impairment occurs through a series of mechanisms: structures responsible for need for sleep are lesionned ; the biological clock doesnt give the start for sleep; sleep networks responsible for inhibition of waking structures are not efficient; mechanisms carrying on sleep or responsible for waking stages are damaged.

In each case, examples of those brain disorders leading to insomnia (tumors, strokes, traumas, neurodegenerative disorders) are reviewed, focusing on the neuropathological description of structures involved in sleep network. When possible, clinicopathological correlates are suggested.

Chapter III - There is already profound knowledge about the evidence that cognitive behavioral therapy (CBT) is effective for the treatment of insomnia (Benca, 2005; Morin et al., 1999; Morin, 2004; Morin et al., 2006). However, the characterization of non-pharmacological treatment effects like CBT on specific sleep parameters (e.g., sleep spindles, sleep architecture, electroencephalographic (EEG) power densities during sleep after CBT) are scarce (Cervena et al., 2004). In our approach we investigated if instrumental conditioning of 12-15Hz EEG oscillations would enhance sleep quality as well as declarative memory performance in healthy subjects. Additionally preliminary data indicating instrumental conditioning of 12-15Hz EEG oscillations as a promising treatment of insomnia will be presented. EEG recordings over the sensorimotor cortex show a very distinctive oscillatory pattern in a frequency range between 12-15Hz termed sensorimotor rhythm (SMR). SMR appears to be dominant during quiet but alert wakefulness, desynchronizes by the execution of movements and synchronizes by the inhibition of motor behavior. This frequency range is also known to be high during light non-rapid eye movement (NREM) sleep, and represents the sleep spindle peak frequency. In the early 70ies Sterman, Howe, and MacDonald (1970) could demonstrate in cats that instrumental conditioning of SMR during wakefulness can influence subsequent sleep. Hauri (1981) was then the first to apply effectively a combination of biofeedback and neurofeedback to humans suffering from psychophysiologic insomnia. Results revealed that the patients benefited from the instrumental conditioning protocols. As research surprisingly stopped at that point, we

Preface ix

intended to clarify the effects of instrumental SMR conditioning (ISC) on sleep quality as well as on declarative memory performance with todays technologies and by using a well controlled design which included a control group receiving the same amount of attention and training. Our results confirmed that within 10 sessions of ISC it is possible to increase 12-15Hz activity significantly. Interestingly, the increased SMR activity (i) was also expressed during subsequent sleep by eliciting positive changes in various sleep parameters like sleep spindle number or sleep onset latency and (ii) was associated with the enhancement of declarative learning. In addition to these fascinating results, preliminary data from our laboratory point to the possibility that people suffering from primary insomnia could likewise benefit from this conditioning protocol as indicated by improved measures of subjective and objective sleep quality.

Chapter IV - More than half of the preschoolers/students in Japan have recently complained of daytime sleepiness, while approximately one quarter of junior and senior high school students reportedly suffer from insomnia. These children might suffer from behavioral-induced insufficient sleep syndrome due to inadequate sleep hygiene, and conventional therapeutic approaches often fail. The present study addressed whether asynchronization, a novel clinical notion, could be responsible for the pathophysiology of these sleep disturbances and could provide a better understanding for successful interventions. This clinical concept was designed with special reference to the basic concept of singularity. The essence of asynchronization comprises disturbances in various aspects (e.g., cycle, amplitude, phase, and interrelationship) of biological rhythms that normally exhibit circadian oscillation. These disturbances presumably involve decreased activity of melatonergic and serotonergic systems. The major triggers for asynchronization are hypothesized to be a combination of light exposure during the night, which decreases melatonin secretion, as well as lack of light exposure in the morning, which decreases activity in the serotonergic system. Prevention of asynchronization must include acquisition of morning light and avoidance of nocturnal light. Possible potential therapeutic approaches for asynchronization involve conventional and alternative therapies. We should know more about the property of the biological clock.

Chapter V - In 2005, a report from the United Nations Populations Division noted that the number of individuals aged 60 years and older is expected to nearly triple, increasing from 672 million in 2005 to almost 1.9 billion by 2050. Currently the elderly population in developed countries has surpassed the number of individuals under the age of 14 years, and by the year 2050 it is anticipated that there will be two elderly persons for every child. Population aging is thus anticipated to precipitate a situation in the United States where health care needs for older-adult populations may exceed care access and availability. This may be particularly pressing in the case of mental health conditions accompanied by behavior that put individuals at physical risk.

It has been reported that 27% of all workplace violence occurs in nursing homes. Aggressive behavior by older individuals with mental disorders incurs substantial humanitarian and financial burden on patients, families and society at large. This review will address aggression in elderly populations with general medical conditions that include delirium, toxic states and drug-drug interactions as well as in populations with dementing illness, mood and anxiety disorders and psychotic disorders. A pragmatic approach

Yolanda E. Soriento x

optimizing safety and quality of life for individuals, families and caregivers is stressed. Lastly, recommendations for future research in late-life aggressive behavior are provided.

Chapter VI Population aging has materialized as an innovative demographic inclination with imperative insinuation for government programs, public health and education, and family restructuring. Among such changes, insomnia, snoring and sleep apnea, in conjunction with sleep hygiene have been usually ignored. Changes in sleep are part of the ageing process. Nocturnal total sleep time can become more fragmented with age, with an increase in awaking early in the morning and nighttime awakenings.

Body mass Index (BMI) and body weight have important health and educational implications across the lifespan. Most recent attention has been focused on the issue of obesity, an epidemic that occurs in most parts of the world. Yet the older Filipinos have prevalence of underweight, approximately thirty per cent of the population, while that of overweight close to ten percent. By comparison, in Taiwan, the prevalence of underweight is less than ten percent, while approximately thirty percent of Taiwanese elderly are overweight.

The main purpose of this chapter is to signify the economic and cultural impacts on healthy weight and BMI maintenance in potentially decreasing the prevalence of sleep disturbance and improving quality of the elderly life in two Asian societies.

With advancing age, age-related changes have been described for sleepwakefulness and additional behavioral cycles. Trends in the relationship between elderly sleep disturbance and BMI in the observed two societies merit our serious attention. Further study is necessary to investigate whether the differences between two societies are caused the limitation of hospital-based study or by differences in ethnicity.

Chapter VII Objective: The main objective of this chatper is to present a novel model for classifying senior patients into different apnea/hypopnea index (AHI) categories based on their clinical variables.

Methods and materials: The proposed model is a generalized regression neural network (GRNN). Three important variables were first selected from the original 30 clinical variables. The GRNN was trained using 75 patients that were randomly selected from the 117 patients. The remaining 42 patients were used for testing GRNN model. The design parameter of the network, i.e., the spread of the radial basis function, was empirically optimized. To alleviate the model complexity, the original AHI values were dichotomized into two different groups, i.e., AHI>13 and AHI

Preface xi

hormones. A bidirectional interaction exists between these two components of sleep. During disturbed sleep, changes of sleep EEG and of hormone secretion occur. For example during an episode of depression and during normal ageing, slow wave sleep and growth hormone (GH) secretion decrease whereas wakefulness increases and the activity of the hypothalamo-pituitary-adrenocortical (HPA) system is changed. During depression and during primary insomnia, elevated HPA activity is mirrored by increased cortisol levels. There is much evidence from preclinical and clinical studies that various neuropeptides and steroids participate in sleep regulation, and that changes in their activity contribute to disturbed sleep. The reciprocal interaction of the peptides growth hormone-releasing hormone (GHRH) and corticotropin-releasing hormone (CRH) plays a keyrole in sleep regulation. In young normal male subjects, GHRH promotes slow wave sleep and GH secretion, whereas CRH exerts opposite effects. Changes in the GHRH/CRH ratio in favour of CRH are thought to result in disturbed sleep, particularly in insomnia-related depression (CRH overactivity) and in normal ageing (reduced GHRH activity). Treatment with a CRH-1 receptor antagonist was shown to improve sleep in patients with depression. The menopause is a major turnpoint of sleep quality in women. In postmenopausal women the levels of circulating estrogens and progesterone are low. Replacement therapy with these steroids improved sleep in postmenopausal women.

Chapter IX This chapter examines existing research literature on sleep difficulties, primarily insomnia and the various dimensions of suicidality among adolescents and young adults as compared to adults. Studies have been grouped into epidemiological studies, clinical studies and reviews. Findings on gender have been given special importance. The literature overview has been complemented by case vignettes from a major corporate hospital in New Delhi (India). The chapter concludes by stating that a relationship appears to exist between insomnia and suicidality, especially with completed suicide, regardless of age. However, far too little is known about the relationship for clinicians to be able to use it as research evidence, as almost all the findings on suicidal behaviour came from cross-sectional studies, whether epidemiological or clinical. Therefore, the conclusion calls for research studies with a prospective design.

Chapter X - Nocturnal frequency of urination (nocturia) is common in the elderly, and it is one of the most troublesome urologic symptoms. Urinary frequency interferes with daily activities, while nocturia may also result in sleep disturbance that can cause daytime fatigue as well as worsening the quality of life (QOL). Multiple factors may contribute to the occurrence of nocturia, including pathological conditions such as cardiovascular disease, diabetes mellitus, lower urinary tract obstruction, anxiety disorders or primary sleep disorders, and various other behavioral and environmental factors. Recently published guidelines have attributed the occurrence of nocturia to nocturnal polyuria and/or diminished nocturnal bladder capacity. However, since these factors may express the states of nocturia rather than the causes, it remains difficult to develop effective treatments for nocturia if the underlying etiology is not determined.

Accordingly, in order to investigate which factors are strongly related to occurrence of nocturia, we performed a suite of examinations in elderly persons who had nocturia without any other diseases (elderly nocturia group) and two (young adult and elderly) control groups. As the results, sleep disturbance (a decrease of the nighttime plasma melatonin level),

Yolanda E. Soriento xii

hypertension (an increase of nighttime plasma catecholamine levels), and excessive fluid intake (an increase of total urine volume) were major factors contributing to nocturia in the elderly.

On the other hand, some elderly persons do not consider nocturnal urination to be bothersome even if they have a number of episodes. So, as a next step, the factors related to nocturnal urination that was not considered bothersome by comparing biochemistry tests were investigated between subjects who felt nocturnal urination ( twice per night) as bothersome and those who did not. As the results, the plasma melatonin level was lower in the bothersome group than in the non-bothersome group. Therefore, nocturnal urination might be not considered bothersome when subjects maintain sufficient levels of melatonin.

As the third step, the effects of melatonin and the hypnotic, rilmazafone, on nocturia were compared in the elderly patients. After 4 weeks treatment, the number of nocturnal urinations was decreased and the QOL score was improved in both groups. Melatonin and rilmazafone were equally effective for nocturia in the elderly, and the plasma melatonin level was increased in the melatonin-treated group.

Therefore, the decrease of the plasma melatonin level may be one of the most important causes of nocturia, and sleep disturbance should be considered when choosing a therapy for nocturia.

Chapter XI - In humans and other diurnally active mammals, melatonin acts as a sleep-promoting agent, but, for practical purposes, its short half-life in the circulation has been a major obstacle. Two different approaches have intended to overcome this problem, the development of slow-release pills and of other melatoninergic agonists, such as ramelteon and agomelatine, representing two non-indolic analogs of melatonin. With regard to sleep, melatonin and these analogs are acting in the same way, via the membrane-bound, high-affinity melatonin receptors MT1 and MT2 in the suprachiasmatic nucleus, which controls the hypothalamic sleep switch. Ramelteon displays a considerably higher receptor affinity, in conjunction with a much longer lifetime in the circulation, plus a contribution of one of its metabolites, M-II, to the melatoninergic actions. The affinities of agomelatine are close to those of melatonin, but the half-life of the analog is longer. In addition, agomelatine was shown to inhibit the serotonin receptor subtype 5-HT2C, an effect associated with additional antidepressive actions. In spite of the similarities with regard to sleep, several profound differences between the three compounds may be of importance. The use of slow-release melatonin should exert a much broader spectrum of effects, since this indoleamine acts, in addition to MT1 and MT2, via other binding sites, too, such as subtypes of the nuclear receptors ROR and RZR, quinone reductase 2, calmodulin, calreticulin and mitochondrial binding proteins. The actions of ramelteon and agomelatonine seem to be much more specific for the membrane receptors, although binding to the last-mentioned proteins has not yet been tested. Another profound difference concerns the metabolism of the agonists. The non-indolic compounds are hydroxylated, dealkylated or further oxidized in positions not homologous to those of the natural indoleamine. The entire kynuric pathway of melatonin metabolism is absent in ramelteon and agomelatine. Since biological effects have been ascribed to the melatonin-derived kynuramines AFMK (N1-acetyl-N2-formyl-5-methoxykynuramine) and AMK (N1-acetyl-5-methoxykynuramine), this sector of melatonins actions is missing. To date it is difficult to judge whether the full spectrum of melatonins effects represents an

Preface xiii

advantage of the parental compound, when only sleep promotion is intended, or whether the higher selectivity of the analogs for membrane receptors will turn out to be a favorable property. However, the poorly understood actions of metabolites from ramelteon and agomelatine, including disproof or proof of toxicity, may be relevant for a future decision on the most suitable compound.

Chapter XII - Sleep disorders in childhood and adolescence are regarded as a common manifestation of symptoms of a disorder, mostly transitory in nature and in many cases caused by unsatisfactory sleep hygiene or maladjusted parent-child interaction during the falling asleep and sleeping through the night process. Furthermore, sleep disorders could exhibit comorbid symptoms with manifestations of psychiatric and neurological diseases [16, 17]. In these cases, they are often chronic and partially also serious in nature. In most cases, during consultation behaviorial therapeutic measues are indicated and are also sufficient. With manifestations of chronic disorders, medicinal measures play an important role [45]. Thus far, the use of an antihistamine, benzodiazepine or a neuroleptic can only be used with reservation or at least in the short term due to long-term side effects, the potential for dependency and substantial negative impacts on daytime alertness and memory functions [45]. With melatonin as an endogenous sleep-inducing hormone, for the first time a pharmacological treatment method essentially free of side effects could be offered for children. This paper summarizes the current, however still relatively narrow-based findings. The literature search is based on Medline-Search, in which substantial papers have been stored since 1985. Due to the still very provisional study status however, this could not consider exclusively randomized studies.

Chapter XIII - Melatonin has been used to relief preoperative anxiety and stress. Several investigators reported that melatonin produces preoperatively anxiolysis and sedation. Patients undergoing laparoscopic cholecystectomy and pretreated with melatonin or midazolam exhibited less anxiety and increased sedation preoperatively compared with the controls. Similarly, patients undergoing gynecological laparoscopic surgery and premedicated with 5 mg of melatonin or with 15 mg of midazolam, or placebo were sedated in contrast to the control group. Psychomotor impairment after premedication was observed only in patients treated with midazolam.

However, these effects are not reproducible by other studies. In elderly patients undergoing elective surgery 5 mg of melatonin or placebo given by mouth decreased anxiety scores to a similar degree. Melatonin premedication did not enhance the induction of anesthesia with sevoflurane as assessed by the bispectral index (BIS) monitor. Regarding the effect of sedative interventions and anesthesia on the endogenous melatonin release, acupuncture and acupressure may or may not affect melatonin levels. Also the inhalation anesthetic sevoflurane has been reported to decrease or to have no effect on endogenous melatonin.

The different results may be attributed to the great variability associated with the measurements in melatonin levels, the different anesthetic techniques and co-administration of other agents, different populations in the relevant studies and other undetermined factors. Nevertheless, the interaction of sedative and anesthetic techniques with melatonin and vice versa is challenging and provocative in understanding the underlying mechanisms of sedation and anesthesia.

Yolanda E. Soriento xiv

Chapter XIV - Introduction: Obsessive-Compulsive Disorder (OCD) is a common, chronic disorder which results in marked distress and impairment of social and occupational functioning. Sleep disturbance often accompanies mental disorders, but there have been few studies of sleep disturbance in OCD. These have produced contradictory findings, with some reporting sleep disruption, and others a normal sleep pattern.

The aim of the present study is to examine sleep patterns in OCD, to establish the frequency of the different types of insomnia (early, middle and late insomnia) in a sample of patients with OCD. The study also intends to determine whether the presence of a comorbid mood disorder influence frequency and type of insomnia.

Methods: all patients with a primary diagnosis of OCD (according to DSM-IV criteria) consecutively referred to the Mood and Anxiety Disorder Unit, Department of Neuroscience, University of Turin, from January 2003 to June 2008, were recruited. Frequency and severity of the different types of insomnia were evaluated on the basis of the Hamilton Depression Rating Scale (HDRS) specific items score (item 4-5-6). A statistical comparison between OCD patients with and without insomnia was performed to examine whether there was any difference in clinical features.

Then a statistical comparison between patients with and without depressive comorbidity was performed to examine whether there was any difference in prevalence and type of insomnia.

Results: The sample included 315 OCD patients. More than a half of the sample suffered from any type of insomnia. The most frequent type of insomnia was early insomnia (about 44,8%). We didnt find a positive correlation between the severity measured with total Y-BOCS score or obsessions and compulsions sub-score clinical and socio-demographic features and insomnia. The presence of any comorbid depressive disorder increased the frequency of insomnia.

Chapter XV - It has been suggested that sunbathing may increase the amplitude of the sleep-wake rhythm and nocturnal serum melatonin secretion, and have effects on insomnia as well. A case report of a patients with epilepsy, cerebral palsy, and severe mental and intellectual disabilities (SMID) with severe behavioral disturbance is presented, in which the sleep-wake-cycle (SWC) was markedly improved by a sunbathing for seven months. The schedule included a sunbathing for 30 minutes in the morning, and a walk with a sunbathing for 1030 minutes in the afternoon. Reduction of frequency of excitement and pyrexia was also observed, and the latter effect persisted for more than six months after the completion of this schedule. In the present case, being similar to the effects of light therapy for insomnia in elderly persons, low level of nocturnal melatonin level exhibited a tendency toward normalization. These findings show that a sunbathing is an effective and simple method for the treatment of insomnia and behavioral disturbance associated with severe mental retardation. The effects of light therapy and / or a sunbathing on insomnia and serum melatonin level, particularly in individuals with brain damages, are reviewed based on the literatures.

Chapter XVI Insomnia is a frequent symptom or syndrome defined by complaints of trouble in initiating or maintaining sleep or of nonrestorative sleep. This causes significant impairments in several areas of daytime functioning including mood, motivation, attention and vigilance.

Preface xv

Significant advances in our neurobiological knowledge of insomnia have been brought by electrophysiological data (e.g. electroencephalography (EEG) and by functional neuroimaging data (e.g. single photon emission computed tomography (SPECT), positron emission tomography (PET) acquired during wakefulness, transition from waking to non rapid-eye-movement (NREM) sleep and REM sleep itself.

Indeed it has been shown that idiopathic insomnia is characterized by a specific pattern of regional brain activity: (i) during the transition from waking to NREM sleep: failure to decrease brain activity in the ascending reticular activating system, medial prefrontal cortex, limbic/paralimbic areas (including insular cortex, amygdala, hippocampus, anterior cingulate), thalamus and hypothalamus, (ii) during NREM sleep: deactivation of the parietal and occipital cortices, and basal ganglia, and (iii) during wakefulness: deactivation in brainstem reticular formation, thalamus, hypothalamus, prefrontal, left superior temporal, parietal and occipital cortices.

This specific distribution of brain activity might relate to (i) specific impairments in daytime functioning (e.g. hypoactivity in prefrontal cortex during wakefulness is consistent with reduced attentional abilities), (ii) hyperarousal hypothesis as a common pathway in the pathophysiology of insomnia (e.g. overall cortical hyperarousal characterized by an increase in EEG beta/gamma activity (14-35 / 35-45 Hz) at sleep onset and during NREM sleep) and (iii) the potentially overlapping pathophysiology with major depressive disorder as this illness has shown similarly altered cortical patterns (e.g. both illnesses have impairments in limbic/paralimbic areas as well as in basal ganglia).

The goal of this chapter is to show that combining recent neurophysiological and neuroimaging data on human sleep offers new insights into the pathophysiological mechanisms of insomnia and potentially opens new therapeutic perspectives.

Chapter XVII - Dreams are sensory, cognitive, and emotional experiences that occur spontaneously during sleep. Dream reports tend to be more frequent, vivid, and longer during rapid eye movement (REM) sleep than during non-REM sleep. This is why our current neurobiological knowledge about dreaming primarily derives from functional neuroimaging data acquired during REM sleep (e.g. electroencephalography, positron emission tomography, and functional magnetic resonance imaging). Recent neuroimaging results showed that REM sleep is characterized by a specific pattern of regional brain activity: (i) activation of the thalamus, pons, temporo-occipital and limbic/paralimbic areas (encompassing amygdala, hippocampal formation and anterior cingulate cortex), and (ii) deactivation of the dorsolateral prefrontal and inferior parietal cortices. This heterogenous distribution of brain activity might relate to some characteristic dream features (e.g. amygdala activation is consistent with frequent threat-related emotions in dream reports). Reciprocally, specific dream features suggest the activation of specific brain regions during sleep. Based on these observations, we previously proposed that a neuropsychological or cognitive neuroscience approach to dreaming can usefully contribute to the interpretation of neuroimaging maps of sleep. The goal of this chapter is to show that connecting recent neurophysiological and neuroimaging data on human sleep and the content of dreams offers new insights into the brain correlates of dreaming and possibly into dream functions.

In: Melatonin, Sleep and Insomnia ISBN: 978-1-60741-859-7 Editor: Yolanda E. Soriento 2010 Nova Science Publishers, Inc.

Chapter I

Conditioned Arousal in Insomnia

Patients: Physiological, Cognitive,

CorticalAn and/or Question?

Aisha Cortoos, Elke De Valck and Raymond Cluydts Unit of Biological Psychology, Vrije Universiteit Brussel, Belgium

Abstract

Insomnia has become fully recognized as one of the most prevalent sleep disorders in society with a profound impact on multiple aspects of daytime functioning and quality of life. Major advances in the non-pharmacological approach to insomnia include the work of Morin and colleagues on the behavioral and cognitive treatment of insomnia and the introduction of the behavioral model published by Spielman and Glovinsky (1991). Other researchers quickly followed resulting in an increasing amount of studies validating this perspective with its separate components. In the last 15 years, the nature of the conditioned arousal as one of the components in this model has been a major topic of interest. In this context, the neurocognitive model, published by Perlis and colleagues in 1997, argues for the extension of the arousal concept with a third component: cortical arousal. The latter is reflected by high frequency EEG activity during sleep, which is thought to mirror the lack of cognitive deactivation, resulting in a disruption of the normal sleep onset and maintenance processes. Some studies have shown the presence of high frequency EEG activity during the sleep onset period, NREM and REM sleep. Furthermore, beta and gamma EEG activity seem to be related to the subjective misperception of sleep, so often seen in insomnia patients. However, other studies revealed no significant differences in the sleep EEG between insomnia patients and controls. In addition to the theoretical overview, this chapter includes a study exploring the different arousal components in a group of selected insomnia patients with objective findings.

17 insomnia patients diagnosed according to DSM-IV criteria and 12 healthy controls were included in our study. Next to a general assessment of hyperarousal through the use of cortisol assay and questionnaires, a wake EEG and polysomnography

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were performed to evaluate the presence of cortical hyperarousal both during wakefulness and sleep.

In comparison to a control group, insomnia patients experienced more cognitive and emotional arousal, but no increase in physiological arousal, both subjectively as well as objectively. Indications of cortical arousal were only present during the sleep onset period, reflected by a stable alpha EEG level and slower increase of delta power, related to longer sleep onset latencies. Furthermore, the cortical arousal variables were correlated significantly with objective sleep disruption, not with sleep perception. Together with previous studies, these results point to a large variability in insomnia patients as to the expression of hyperarousal and its different components.

Introduction Sleep is a behavior we engage in approximately one third of our lives. Falling asleep and

staying asleep is a natural phenomenon for most people. However, approximately 10 to 20% of the population report difficulties initiating or maintaining sleep, accompanied by impairment of one or more aspects of daytime functioning [1]. When facing the fact that sleep initiation is delayed or has to be repeated several times during the night, the process of falling asleep loses its obvious characteristics and becomes a conscious and often frustrating task. Most people encounter this kind of situation at least once in their lives. Often a stressful or disruptive event causes the temporary sleep difficulties, which in turn will disappear when the stressor fades away. However, some people are more sensitive to a disruption of their sleep-wake rhythm and will continue having sleep problems even when the initial cause has disappeared. Often reported characteristics of sleep initiation or reinitiating problems are the presence of racing thoughts, rumination and a state of alertness at a time and place when relaxation is necessary [2, 3]. In reaction to the resulting sleep difficulties, behavioral coping strategies are developed, aiming at an increase of sleep time. When this process is repeated for a period of time, it becomes connected or linked to the specific environment within which it occurs; a phenomenon called conditioned arousal.

The development of this subtype of insomnia is well described and widely known as the behavioral model [4]. Sleep is considered a complex behavior, partially dependant on daytime stimuli. The focus lies on the conditioned arousal, manifesting itself on different levels, such as anxiety, muscle tension, destructive and/or obsessive cognitions about sleep, and the consequences of sleep shortage. Within this model, the so-called 3 Ps (predisposing, precipitating and perpetuating factors) describe the 3 most important factors playing a key role in the development of insomnia [5]. First of all, it is suggested that insomnia patients are characterized by predisposing factors, making them more sensitive to sleep disruptive phenomena. These trait or predisposing factors can be related to personality traits, biological and/or psychological factors. At this point, however, a significant sleep disruption should not be present. It is only with the occurrence of a precipitating factor, mostly a stressful life event, that an interference of normal sleep processes takes place. As a reaction to the delayed and/or fragmented sleep period certain behavioral strategies, such as an extended time in bed, are employed as a way of catching up on sleep. These strategies or perpetuating factors,

however, reinforce the relationship between wakefulness and the bedroom, which in turn will

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result in conditioned arousal, and finally in a more severe sleeping problem. At this point a negative vicious cycle is installed, maintaining the sleep disruption and its facilitating processes. Within this model it is assumed that the sleep disturbances in chronic insomnia are maintained because of these perpetuating factors, which in turn form the focus of attention for treatment interventions.

The Concept of Arousal: Validation

of the Behavioral Model Arousal mechanisms are essential for surviving and have an adaptive function enabling

our most basic behaviors, such as movement, sleep, rest, wakefulness, and danger orientation. As such, arousal is part of our daily life and makes it possible to perform certain physical and/or mental tasks. However, the perception of arousal may vary according to the possible presence of emotions related to the situation [6]. Performing sports after work will often not be recognized as a situation of arousal, although all characteristics of physical arousal are present, such as muscle activation, increased heart rate and ventilation. However, when confronted with a possible dangerous situation, we are more aware of the changes inducing a state of arousal. Together with the physical preparation, our cognitive system reacts as well, by scanning the environment for dangerous cues, and as such selective attentional processes are activated. Chronic insomnia patients tend to perceive sleep-related situations, such as the bedroom and bedtime, as stressors, as such inducing an arousal response, as proposed by the behavioral model. This theoretical perspective has given rise to a growing amount of research concentrating on the assessment of different arousal components in insomnia patients. One of the major difficulties in these studies, however, is the differentiation of the different arousal components involved, because of possible similarities in the underlying etiologies [7].

Physiological Arousal

The process of falling asleep is accompanied by a series of events indicating a

deactivation of several bodily systems, as such reflecting a state of physiological de-arousal [8]. During sleep onset, a decrease in muscle activation of the upper airway dilator muscles and respiratory pump muscles result in a fall in ventilation [9], which is also accompanied by a gradual decrease in heart rate [10]. Although EMG changes during sleep onset are not often studied in detail, findings regarding other related topics of sleep onset, such as passive behavioural sleep devices or changes in respiratory activity, suggest a decrease in overall EMG activity during sleep onset. In light of these findings, it is obvious that an interference of physiological deactivation can result in an impairment of sleep onset processes, a phenomenon called physiological arousal. This can be often observed in insomnia patients.

One of the first studies assessing aspects of physiological arousal [11] showed that insomnia patients were characterized by elevated rectal temperature, skin resistance, and phasic vasoconstrictions. Hyperarousal was present half an hour before bedtime, as well as during sleep. This study was the starting point for many other researchers evaluating the

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possible link between physiological arousal and sleep disturbances. Freedman and Sattler [12] and Freedman [13], for example, revealed that insomnia patients dominantly suffering from sleep onset problems, featured increased facial muscle activity during the sleep onset period, as well as increased beta and decreased alpha EEG activity during wakefulness, phase 1 and REM sleep. Other studies reported increased heart rate in insomnia patients during the night [14, 15], as well as in the morning when confronted with a stressful event [14]. Moreover, there appears to be a correlation between specific alterations in body temperature, related to impairments of the circadian rhythm, and different types of insomnia [16]. Sleep onset insomnia might partially be associated with a delay in temperature rhythm. As such, they try to fall asleep during their wake maintenance zone [17] resulting in increased sleep latencies. Early morning awakening insomniacs, on the other hand, appear to be characterized by a phase advanced temperature rhythm, causing an early circadian wake up time. Sleep maintenance insomnia apparently is not associated with a temperature rhythm impairment, but with overall nocturnal elevated body temperature [18]. Finally, it is suggested that insomnia patients suffering from a combination of sleep-onset and maintenance problems are associated with a 24-hour elevated core body temperature [16]. The mediating role of the hypothalamic-pituitary-adrenal (HPA) axis has been another main focus in arousal studies in insomnia patients. Some studies have shown that insomnia patients have increased levels of evening cortisol, which are also correlated with the amount of awakenings during the night [19-21]. Backhaus et al. [22], on the other hand, only found decreased cortisol levels in the morning, negatively correlated with the reported subjective sleep quality. Although these studies report different results, they all mention some impairment of hormones related to the HPA axis. Therefore, it can be proposed that the hypothalamic-pituitary-adrenal (HPA) axis is overactivated, mostly due to stress and anxiety, keeping the cortisol levels high en thus interfering with normal sleep onset and maintenance processes [23, 24]. Despite these impressive results, other studies failed to find significant differences in the mentioned parameters of physiological arousal. Riemann and colleagues [25] for example, did not found elevated levels of evening cortisol, but only decreased levels of melatonin. No increased heart rate was found in the study by Monroe (1967). Varkevisser and colleagues [26] performed a 24-hour sleep deprivation protocol in insomnia patients and evaluated several indicators of physiological arousal (cardiovascular parameters, cortisol, and body temperature) but found no significant differences in comparison to healthy controls. These mixed results suggest a vast heterogeneity in regard to the presence and expression of physiological arousal in insomnia patients.

Cognitive Arousal

As discussed above, falling asleep is accompanied by relaxation and deactivation of

several bodily functions, which can be impaired at several levels in insomnia patients. However, a reduction in physiological processes is not the only requirement for a rapid sleep onset. The mind is a powerful and sometimes uncontrollable entity, processing all incoming information from external and internal stimuli during the day, which can also interfere with sleep onset. Increased presleep cognitive activity has been consistently associated with the

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maintenance of insomnia. Studies have repeatedly shown that insomnia patients experience intrusive thoughts, which are mostly negatively toned, as well as excessive worry, typically about sleep, the lack of sleep and its consequences on daytime functioning [27-29]. Studies evaluating self-reported attributions showed that insomnia patients report more presleep cognitive activity during the sleep onset period in comparison to healthy sleepers, and experience more sleep disturbances from presleep cognitive activity [30]. Furthermore, cognitive arousal appears to be more dominantly present as opposed to physiological arousal [3]. Besides the plain existence or presence of disruptive cognitive activity, it is also very interesting to evaluate its specific content in patients suffering from insomnia, especially in light of therapeutic interventions. Regarding the nature of cognitive activity, it has been reported that problem solving, worries and concerns, and listening to noises are a major focus of attention when trying to fall asleep [30]. Furthermore, thoughts about sleep shortage and re-evaluating the day are often reported. Another characteristic of insomniacs in comparison to healthy sleepers is the perceived control over presleep thoughts and worries. Whereas normal sleepers report that their presleep cognitive activity is intentionally, insomniacs describe this as being uncontrollable. Wicklow and Espie [31] conducted a study were they evaluated the content of intrusive thoughts and their relationship with actigraphic measured sleep and self report. Through the use of Principal Component Analysis, they were able to derive three major factors of intrusive thoughts. The first factor was referred to as active

problem solving, which correlated with objective sleep latency and was relatively unaffected by emotional tone. The second factor was present state monitoring, reflecting self-awareness and self-monitoring. No connection was found with the objective sleep latency, but an inverse correlation was present with emotional tone. Environmental reactivity was the third factor, but no relations were found with any sleep parameter. Regarding the subjective sleep report, none of the factors apparently correlated with perception of sleep. The role of cognition in insomnia has been elegantly described by Harvey [32] in her paper the cognitive model of insomnia. It is suggested that insomnia patients are overly worried

about their sleep and the possible consequences of sleep shortage on daytime functioning, which results in excessively negatively toned cognitive activity. This in turn leads to an

arousal response and emotional distress, triggering selective attention towards all kinds of stimuli that are perceived as threads for a good night sleep. The combination of arousal and distress, as well as specific selective attentional processes cause a distortion in the perception of the sleep complaints and impairments in daytime functioning. This in turn fuels again the negatively toned cognitive activity, and is the starting point for a negative vicious cycle. In line with the behavioral perspective described earlier, this negative cognitive activity gives rise to certain beliefs about sleep and their sleep problem, as well as safety behaviors, comparable with the perpetuating factors of the behavioral model. Other researchers have also demonstrated the presence of a sleep related attentional bias. Taylor et al. [33] compared two groups of cancer patients with insomnia, the first group at 0-3 months and the second at 12-18 months after cancer diagnosis. All patients had been good sleepers before the diagnosis. Results from the Stroop paradigm showed that both groups presented an attentional bias for cancer words, but only the persistent insomnia patients who still experienced sleep disturbances a year after their diagnosis, demonstrated attention bias for sleep-related words. In a recent study, Spiegelhalder and colleagues [34] for example,

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compared insomnia patients, sleep experts and healthy controls using an emotional Stroop task. They found significant higher attentional bias scores in the insomnia group in comparison to the sleep expert group, suggesting that the attentional bias for sleep-related words is due to specific emotional, cognitive or procedural processing rather than differences in habitual exposure to these concepts.

In summary, these results suggest that insomnia patients are characterized by some form of cognitive arousal, mainly consisting of thoughts concerning problem solving and monitoring. As is shown by Harveys cognitive model of insomnia, specific selective attentional processes play an important role in the maintenance of insomnia, which in turn has been repeatedly shown by studies who found an attentional bias in insomnia patients for sleep related words or cues. Espie and colleagues [35] reviewed literature about attentional bias in insomnia patients and introduced an important sleep inhibitory process, namely the attention-intention-effort pathway. They point out that the automaticity of the sleep system in insomnia patients is inhibited by three factors: first, the selective attention to sleep; secondly, the explicit intention to sleep; and finally, a dysregulation by both direct and indirect sleep effort. As such, when considering therapeutic intervention, the cognitive processes and attentional bias should be an important focus of attention.

Clinical Applications: Cognitive and Behavioral Interventions for Insomnia

The growing literature regarding physiological and cognitive arousal in insomnia patients

resulted in studies evaluating different interventions aiming at a reduction of these arousal components. Since the 1970s the impact of different relaxation techniques on physiological arousal and sleep quality were examined. Borkovec and Fowles [36] for example, evaluated three different relaxation trainings as well as a waiting list no-treatment control group. They used progressive relaxation, hypnotic relaxation and self-relaxation as a way to influence physiological arousal in insomnia patients. They hypothesized that only the progressive and hypnotic relaxation groups would demonstrate significant improvement after training. However, results showed an equal improvement in sleep onset latency, number of awakenings and waking up refreshed in all three training groups. Surprisingly, the reduction in physiological arousal reflected by skin conductance, heart rate and respiration was not related to treatment outcome. The authors suggested that the general instruction in all groups to relax and focus on pleasant internal feelings might be the mediating factor responsible for the general improvement in all groups. As such they hypothesized that attention focusing may be enough as treatment intervention for moderate insomnia patients. A similar study was performed by Nicassio and Bootzin [37] using progressive relaxation and autogenic training as active treatment groups, and a self-relaxation and waiting list group as control groups. In contradiction with Borkovec and Fowles [36] they only found significant improvement after progressive relaxation and autogenic training, suggesting that the mere instruction to relax at a scheduled time is not enough to result in significant improvements in sleep. As their sample of insomnia patients had more severe sleep problems, it was also suggested that the self-relaxation instruction may lose its value with increasing severity of the sleep complaints.

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In addition to this line of research, much attention has been paid to other behavioral interventions, mostly based on operant or instrumental conditioning. The use of stimulus control [38], for example, was one of the first interventions successfully applied in insomnia patients, which is based on the fact that spending to much time in bed is an important perpetuating factor playing a key role in the maintenance of the sleep complaints [4]. It has been shown that avoiding wakefulness in bed during the night as well as daytime napping results in a significant improvement of total sleep time, wake after sleep onset, sleep efficiency and sleep onset. The main objective of this intervention technique is to reassociate the sleep environment with relaxation and fast sleep onset, resulting in a new conditioned response as opposed to the arousal response leading to the reported sleep complaints. The American Academy of Sleep Medicine has recommended stimulus control instructions as a standard treatment for primary insomnia [39].

A second behavioral intervention that has received much attention is the use of sleep restriction therapy [40] were the time in bed is restricted to the reported total sleep time, as such that a mild sleep deprivation results in fast sleep onset latencies and increased sleep efficiency. In addition to these two major behavioral interventions, sleep hygiene instructions [29, 41] are recommended to ensure that poor sleep habits do not interfere with the beneficial effects of other interventions.

Finally, in the 1990s cognitive therapy was introduced in order to directly intervene on the level of dysfunctional beliefs and attitudes about sleep [29]. These different components were then integrated into a multi-component treatment for insomnia, widely known as Cognitive Behavioral Therapy for Insomnia (CBT-I) [42]. The use of these different components in one integrated training program results in better outcome in comparison to single component treatment, and the addition of cognitive restructuring to the behavioral components causes slightly greater benefits than behavioral treatment alone [43]. Furthermore, it has been shown that CBT-I does induce a greater decrease in maladaptive beliefs and attitudes about sleep in comparison to relaxation therapy and placebo [44]. This effect is maintained at follow-up 6 months after completing the training program. Morin and colleagues [45] performed a similar study comparing a CBT-I group, pharmacotherapy, combined therapy of CBT-I and pharmaco and a placebo medication group. Again they showed that CBT-I or the combination of CBT-I with medication resulted in greater improvements of beliefs and attitudes about sleep. Furthermore, both studies showed that a decrease in maladaptive beliefs and attitudes were correlated with objective and subjective sleep improvement.

Although CBT-I is regarded the gold standard for psychological management of insomnia, there are limitations, suggesting that a further exploration of additional interventions or treatments is still required [46]. First of all, the majority of insomnia patients following CBT-I show an average improvement that does not bring them into the good sleeper range, which means that they still show some impairment after treatment [46-48]. Secondly, the effect sizes after CBT-I training are markedly lower in insomnia patients in comparison to the effect sizes resulting from CBT in other psychophysiological disorders [46]. Thirdly, although the combination of CBT-I with pharmacotherapy might result in better improvements on the short term, Hauri [49] also showed that the progress obtained after a combined therapy are not maintained over a follow-up period of 10 months in

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comparison to the use of CBT-I alone. Fourthly, the different components of CBT-I, such as sleep restriction and stimulus control, require a certain amount of dedication and the will to make some changes in habitual life style to produce the desired effects, which is not always obvious [48]. Finally, it has to be noted that about 19% to 26% of patients do not respond to CBT-I [46, 48]. These observations suggest that a focus on physiological and/or cognitive/behavioral components of arousal might not be enough for a substantial group of insomnia patients, and other factors may be in play causing sleep disruption.

The Neurocognitive Model: Introduction

of a New Arousal Component As a theoretical perspective on insomnia the behavioral model has been dominantly used

since the 1980s, and it has given rise to new and efficient therapeutic interventions. However, some characteristics or paradoxes observed in insomnia patients can not be fully explained by this model [50]. A first paradox refers to the phenomenon perceiving sleep as wakefulness. There appears to be a misperception of sleep resulting in a discrepancy between polysomnographically measured sleep and the subjective report through sleep logs [51-54]. Secondly, insomnia patients tend to overestimate the time needed to fall asleep and underestimate their total sleep time [11, 52, 55]. Thirdly, when using hypnotic medication there appears to be a discrepancy between the benefits reported by the patients and the objective gains [53, 56]. Furthermore, it has been shown that the administration of benzodiazepines does not normalize sleep; in fact it decreases SWS, while insomnia patients tend to report great benefits of them. In 1997, Perlis and colleagues introduced the neurocognitive perspective, an extension of the previous discussed behavioral model, which focuses on a third arousal component, namely cortical arousal [50]. They hypothesize that the presence of high frequency EEG activity during sleep reflects a state of hyperarousal, interfering with the normal sleep onset and maintenance processes. The presence of cortical arousal makes it possible to explain some of the mentioned paradoxes as cognitive alterations may result from high frequency EEG activity. It is suggested by the authors that cortical arousal results in heightened sensory and information processing. These cognitive alterations in turn are able to clarify certain characteristics of insomnia, such as the complaint of not falling asleep, the perceived misperception between wakefulness and sleep and the overestimation of wakefulness. The past decade research concerning cortical arousal in insomnia patients has received much attention and suggests that this sleeping disorder is characterized by the presence of high frequency EEG activity during sleep onset and sleep. Nevertheless, results are still inconsistent, probably due to different methodologies and inclusion criteria. On the other hand, literature shows that the presence of physiological and/or cognitive arousal is not a uniform phenomenon as well. Indeed, the insomnia population appears to be quite heterogeneous, which might also be the case for cortical arousal.

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Cortical Arousal

As discussed in the previous sections, the concept of arousal in insomnia patients has

traditionally been explained in terms of physiological and/or psychological processes. However, arousal can also be seen as a brain process reflected by changes in specific EEG frequency rhythms, referred to as cortical arousal. A state of arousal or high vigilance means that the brain is open to signals from the outside world, ready to process and react on these stimuli [57]. One of the most important structures in the brain involved in the control of information flow to the cerebral cortex is the thalamus. During sleep, synaptic inhibition occurs, blocking the incoming signals of being processed by the thalamus, as such the brain closes of from irrelevant external cues. The specific functions of the thalamus can be related to the EEG frequencies produced by this structure and measured on the scalp. The process of falling is asleep is normally characterized by a decrease of high frequency and an increase of slow frequency EEG activity [58, 59], reflecting the inhibition of incoming stimuli by the thalamus resulting in a slowing down of general brain EEG activity. Several studies have shown a different EEG pattern in insomnia patients during sleep onset and sleep, suggesting higher arousal levels in comparison to healthy sleepers. Freedman [13] was the first to investigate possible differences in EEG frequencies between insomnia patients and healthy controls. He examined the first minute of every sleep stage and found increased beta and decreased alpha EEG activity during wakefulness, stage 1 and REM sleep. Since possible EMG interferences were not taken into account, and patients were not screened for psychiatric disorders, these results should be interpreted with caution. Two other studies evaluated the specific EEG changes during sleep onset in insomnia patients [60, 61] and found decreased delta and alpha EEG power, as well as increased beta EEG power in comparison to healthy controls and even psychiatric insomniacs [60]. These results suggest an impairment of normal sleep onset processes, possible related to heightened cortical arousal. Moreover, the authors posit that the presence of beta EEG activity during sleep onset might also be related to the tendency in insomnia patients of overestimating sleep onset latency [60]. Finally, Staner et al. [62] assessed the sleep onset period and first NREM cycle in 21 controls, primary insomniacs and depressives. In contrast to the other studies, they found that insomnia patients were characterised by lower beta1 (13-21.5 Hz) EEG activity at the beginning of sleep onset, resulting in a relatively stable evolution during the sleep onset period. However, in line with the research of Lamarche and Ogilvie [60] they found decreased levels of alpha power. Both EEG frequencies however, are supposed to show a progressive decline during sleep onset. As such these results are interpreted as reflecting an impairment of the wakefulness propensity or a state of hyperarousal, interfering with normal sleep onset processes.

Besides the EEG differences during the sleep onset period, there have also been some studies evaluating sleep EEG profiles during NREM and REM sleep. Merica, Blois and Gaillard [63] examined the first 4 NREM/REM cycles and found significant EEG difference in NREM, as well as in REM sleep. Decreased delta and theta and increased beta EEG activity were present in both NREM and REM stages. For alpha power a different pattern was found: this EEG rhythm was reduced during NREM and elevated during REM sleep. It is suggested that these results indicate on the one hand presence of cortical arousal reflected by

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heightened levels of beta activity during sleep, and on the other hand a slow wave sleep deficiency reflected by the lack of slow frequencies during NREM sleep, more specifically delta power. They proposed a neurophysiological interpretation combining two related theories, namely the neuronal group theory of sleep function [64] and the Neuronal Transition Probability (NTP) model [65] to clarify and combine both results. First of all, the neuronal group theory posits that alertness and sleepiness are two concepts of a continuum, in which the varying degree of these two states are dependent on the amount of sleep intensity. The perception of sleep, in turn, is dependant on the amount of neuronal groups being in a sleep (or disjunctive) state. As such, a lesser number of neuronal groups entering the disjunctive state might be a characteristic of insomnia patients, resulting in a part of the brain that remains alert or awake, reflected by higher levels of beta EEG activity. Secondly, the Neuronal Transition Probability model [65] makes use of the work of Steriade et al. [57] who showed that the hyperpolarisation of thalamocortical neurons produce delta oscillatory modes, resulting in SWA and deep sleep, and subsequent depolarization creating a disappearance of the delta oscillations leading to a transition to light sleep. This process is accompanied by oscillation changes of the neurons, following a sequence: beta sigma delta sigma beta [65]. In light of this model, their observation of a broader sigma peak and delayed delta peak in insomnia patients would suggest that the thalamocortical neurons become hyperpolarized at a slower rate, resulting in a slower transition from the sigma to the delta oscillatory mode [63].

Two more studies performed by Perlis and colleagues [66, 67] found increased beta1 (14-20 Hz), beta2 (20-35 Hz) and gamma (35-45 Hz) EEG power during NREM sleep, as well as heightened levels of beta2 activity during REM sleep in insomnia patients compared to psychiatric insomniacs and good sleepers. Furthermore, the increased beta activity was correlated with the tendency to underestimate total sleep time. By analyzing the temporal and stagewise distribution of high frequency activity, they found an inverse relationship between delta and beta EEG activity in healthy controls, which disappeared in insomnia patients during the second part of the night. All these studies, however, did not take into account the amount of discrepancy between objective and subjective sleep complaints and thus possible subtypes of primary insomnia. Krystal et al. [68] evaluated NREM sleep EEG spectral analysis between subjective and objective insomnia patients and healthy controls. Results showed distinctive different EEG patterns between both insomnia groups. Diminished delta and greater alpha, sigma and beta EEG relative spectral power during NREM sleep were observed and more prominent in the subjective insomnia patients. These EEG differences were also correlated with the subjective sleep complaints of the subjective group, but not with the objective insomniacs. A correlation was found between the lower relative delta power during NREM sleep and the discrepancy between subjective and objective sleep measures. This result seemingly contrasts the finding of Perlis et al. [67] who found a positive correlation between the presence of beta power and the underestimation of TST. However, the authors suggest that since delta and beta EEG power appear to be negatively correlated, both findings might be related. Finally, a very recent study by Buysse and co-workers [69] performed an interesting study on EEG profiles during NREM sleep, examining the possible effects of gender on sleep EEG. Surprisingly, they did found a significant impact of gender on the sleep EEG profiles, namely women were characterised by elevated high

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frequency EEG activity, as well as increased low frequency EEG activity. These differences were not found in men suffering from insomnia compared to healthy men. These results raise the question whether the earlier findings on heightened beta EEG activity might be related to gender as opposed to the sleep complaints, especially since insomnia complaints are more prevalent in woman? Moreover, they found no relationship between high frequency EEG activity and clinical characteristics of insomnia in both men and woman.

Overall, it is obvious that although certain studies report evidence for cortical arousal during sleep in insomnia patients, the results are still inconclusive. There have been reports of increased beta EEG activity in primary insomniacs [63, 66, 67, 70] or only in subjective insomniacs [68] or only in women suffering from insomnia [69] or even no differences during NREM [13]. The same picture is found for the sleep onset period. Further research is necessary to clarify these mixed results on cortical arousal during sleep in insomnia patients.

The Concept of Arousal: Interrelationships between the 3 Components

By reviewing the literature on the presence of arousal in insomnia patients, it is clear that

there exists a certain amount of variability. Hyperarousal, if present, can manifest itself in different ways, such as elevated heart rate, EMG, cortisol levels, cognitive activity, high frequency EEG activity, but as to why it expresses itself in different manners has not been explained yet. The neurocognitive model [50] posits that conditioned arousal can present itself in three different modalities, being physiological, cognitive and/or cortical. However, few studies have evaluated the expression of hyperarousal in these three systems at the same time. Furthermore, one can ask to what extend these three components are (in)dependent of each other and what are their interrelationships? An important question not yet received much attention.

In a recent review by Perlis and colleagues [71] the same question has been put forward. In line of the neurocognitive perspective, they posit that the three arousal components are relatively distinct and rather independent from one another, as such that heightened arousal in one component does not necessarily lead to an increase in the other components. One of the arguments put forward to ground this hypothesis, is the disconnection between the peripheral nervous system and the brain during REM sleep; muscle activity is practically shut down at the same time that the brain shows signs of arousal in the EEG. On the other hand, it has been shown that the sympathetic activation during wakefulness reflected by heart rate, decreases entering NREM sleep, and rises again towards mean awake levels during REM sleep [72]. Interestingly, here we see an example were two parameters reflecting physiological (de)arousal suggesting different states of arousal. A second consequence of viewing arousal as a three-construct system with limited interrelations, is the lack of knowledge to know which component might be elevated reflected by which parameter and under which conditions? This might also explain the mixed results concerning the different arousal components in insomnia. To clarify this rather complex question can be seen as a challenge.

A few studies have tried to clarify the interrelationship between different arousal components. One of the main objections against the presence of high frequency EEG activity in insomnia patients is the possible influence of increased EMG levels on the EEG spectrum.

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Indeed, it has been suggested that the raise of beta EEG activity under stress or arousal conditions, might be related to the raise in muscle tension, as such not exclusively reflecting a change in brain activity [73], but rather a expression of physiological arousal. Bonnet and Arand [74] targeted this question by evaluating the effect of different states of physiological arousal and increased EMG upon spectral EEG measures in healthy sleepers. The different conditions used were sitting, standing, walking, a mathematical task, gritting teeth and clenching fists. Indeed, it was shown that the production of physiological arousal resulted in an increase in high frequency EEG activity. Heightened levels of EMG produced EEG changes above 24 Hz, which includes the beta EEG band often referred to in insomnia studies. At the same level, an increase in heart rate was observed during arousal condition, which in turn was related to changes in the EEG spectrum. As such, it is hypothesized that increased high frequency EEG activity may not be a sign of cortical arousal, but might just be a reflection of physiological arousal such as heart rate or tension. A second study by De Valck et al. [75] evaluated the effect of experimentally induced cognitive arousal on the subsequent physiological and cortical arousal components in healthy sleepers. The unannounced visit of a camera crew filming a documentary on sleep and related issues was used as a trigger for cognitive arousal. Cognitive, physiological and cortical arousal were assessed using respectively the POMS tension subscale, heart rate (HR) and HRV, and beta EEG activity during the first and last 5 minutes of an MSLT. All subjects were exposed to an arousal and neutral condition during a 2-day partial sleep deprivation protocol. The arousal condition resulted in significant increases in cognitive subjective arousal and physiological arousal reflected by higher scores on the POMS and an increase in heart rate, which in turn gave rise to increased sleep latency during the MSLT. In regard to the impact on cortical arousal, a trend was found for increased beta2 (20-35 Hz) EEG activity during the first and last 5 minutes of the MSLT. None of these changes were observed during the neutral condition. Surprisingly, none of the arousal parameters correlated with objective sleep latency. These findings suggest a partial interrelationship between the three arousal components, with a more pronounced connection between cognitive and physiological arousal, as opposed to cortical arousal. Furthermore, since the increase in physiological arousal did not result in a similar magnitude of increased cortical arousal, this might suggest that heightened levels of beta EEG activity are not solely the result of increased physiological arousal. Methodological difference between the former and latter study are related to the experimentally provoked arousal component used. Bonnet and Arand induced physiological arousal and evaluated its impact on cortical arousal, whereas De Valck and colleagues used cognitive arousal as a starting point.

Thirdly, Tang and Harvey [76] performed two napping experiments in order to clarify the different effects of physiological versus cognitive and emotional arousal, and their impact on perception of sleep. The first experiment aimed at evaluating the specific influence of presleep cognitive arousal on the distortion of sleep perception, reflected by the SOL and TST discrepancy, during an afternoon nap. Secondly, the cognitive arousal group was divided in two subgroups, the first being the anxious cognitive arousal and the second the neutral cognitive arousal group. It was hypothesized that both anxious and neutral cognitive arousal would lead to a prolonged sleep latency and an increase in the discrepancy between self reported sleep and actigraphy-defined sleep in comparison to a no manipulation group.

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Indeed, analysis showed an increase in self reported cognitive arousal in both groups, but only the anxiety group reported a significant increase in anxiety during the sleep onset period. Regarding the objective sleep parameters, only the cognitive anxious arousal group showed a significant increase in sleep onset latency, as opposed to the neutral cognitive arousal group. However, both arousal groups did show an overestimation in reported sleep onset latency compared to the no manipulation group, supporting the hypothesis that the amount of presleep cognitive arousal is related to the discrepancy in sleep perception. A second experiment compared the relative effects of an anxious cognitive arousal group with a physiological arousal group, induced by caffeine intake, in relation to the objective measures of sleep quality by means of actigraphy, as well as distortion of sleep perception. Results showed that both arousal groups resulted in a distorted perception of sleep. In regard to the objective sleep parameters, only the anxious cognitive arousal group showed increased sleep latencies.

Summarizing, these studies have resulted in some preliminary insights into the different arousal components and their specific influences on sleep parameters, perception and other arousal dimensions. Inducing physiological arousal by means of physical activity and additional raises in EMG level, results in parallel increases in beta EEG activity, probably due to the specific effects of EMG on the EEG spectrum. On the other hand, when using a protocol that induces cognitive arousal, a similar increase in physiological arousal is produced, but not in cortical arousal, suggesting that this methodology might avoid to some extent the confounding effect of muscle tension on the EEG. Furthermore, when using an experimentally induced cognitive arousal protocol, attention must be paid to the possible occurrence of emotions, such as anxiety. As Tang and Harvey [76] showed, combined occurrence of emotion and cognitive arousal, will have a greater impact on objective sleep variables.

Conditioned Arousal or a Predisposing Factor? Based on the many studies regarding this topic during the last decade, hyperarousal is

recognized as an important characteristic in primary insomnia today. However, the specific nature of this arousal remains unclear: is it a conditioned response or a predisposing factor? Furthermore, the two are not mutually exclusive. More specifically, the basic level of arousal that predisposes people to develop insomnia may be another key factor [7].

According to the neurocognitive perspective [50], arousal in insomnia patients is a conditioned response as a results of the presence of predisposing factors in combination with a precipitating event and perpetuating factors. As such, arousal responses should only occur in situations that have become associated with threatening sleep-related environments or contexts or as a result of such responses. Most studies on arousal assessed its presence in sleep-related contexts or environments, such as the bedroom, the sleep onset period, during the entire night or in the morning. Indeed, indications for hyperarousal such as increased muscle activity, beta EEG activity, cortisol levels, temperature or HR during the sleep onset period or during sleep could be interpreted as being a conditioned arousal in response to the sleep environment. However, if considered a conditioned response, these increases in arousal should not be present in situations not related to sleep. As mentioned before, there exists a

Aisha Cortoos, Elke De Valck and Raymond Cluydts 14

certain amount of variability and not all studies found the same increased arousal in insomnia patients, suggesting that the arousal response may vary between subjects. Another explanation is that the conditioned response is triggered in different situations, being bedtime or during awakenings or in the morning after a bad night sleep, which might clarify to some extend the mixed results mentioned before. A way of examining this is to evaluate specific measurements of arousal during a longer period, such as 24 hour protocol. Indeed, Bonnet and Arand [77] performed a study targeting these limitations of previous studies by arguing that the mixed results concerning hyperarousal in insomnia might be related to the fact that the involved physiological systems differ between insomnia patients and that the measurements were limited in time to a specific moment. As such, a more general measure of physiological arousal, for example metabolic rate reflected by whole body oxygen use, would give more consistent and accurate results. Insomnia patients showed increased metabolic rate during the day and the night, suggesting a general 24-hour hyperarousal disorder, which in turn is responsible for the reported sleep impairments. This surprising result lead to the suggestion that the presence of such a general hyperarousal could also be considered as a predisposing factor, making a person more prone to emotional and/or cognitive arousal and the resulting sleep impairments, and not as a conditioned arousal response. This conclusion can be considered a very important and topical subject. The presence of a predisposing arousal factor is not present in all insomnia patients however, as was shown by the study of Varkevisser et al. [26] who found no significant difference in 24-hour cardiovascular parameters, free cortisol, and body temperature. It was suggested that their insomnia sample was not characterised by a general hyperarousal disorder on the level of physiological arousal. These results imply the possible presence of two distinct categories of insomnia patients, namely a group characterised by a predisposing arousal disorder, and a second group distinguished by specific conditioned arousal responses related to sleep and sleep difficulties.

Recent research on the possible influence of specific genes on sleep propensity and waking performance has given preliminary evidence for a predisposing factor with an impact on the sleep and wake EEG in healthy sleepers [78]. The presence of PER34/4 or PER35/5 in healthy sleepers results in different SWS, SWA and waking performance. It has been shown that people with PER35/5 are characterised by a greater sleep propensity during NREM sleep, reflected by faster sleep onset and higher SWA during NREM sleep, in comparison to subjects characterized by PER34/4. The differential effects of both genes was even more apparent after sleep deprivation, since the presence of PER34/4 resulted in less inhibition of REM sleep during recovery, no increase in theta EEG power and less decrements in waking performance during sustained wakefulness. Future research evaluating PER3 VNTR polymorphism in insomnia patients might clarify some of the unanswered questions regarding arousal and predisposing factors.

Arousability and Habituation A final relevant question regarding arousal and its role in t