Melatonin, Sleep and Insomnia (Endocrinology Research and Clinical Developments)

ENDOCRINOLOGY RESEARCH AND CLINICAL DEVELOPMENTS

MELATONIN, SLEEP AND INSOMNIA No part of this digital document may be reproduced, stored in a retrieval system or transmitted in any form or by any means. The publisher has taken reasonable care in the preparation of this digital document, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained herein. This digital document is sold with the clear understanding that the publisher is not engaged in rendering legal, medical or any other professional services.

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ENDOCRINOLOGY RESEARCH AND CLINICAL DEVELOPMENTS

MELATONIN, SLEEP AND INSOMNIA

YOLANDA E. SORIENTO EDITOR

Nova Biomedical Books New York

Copyright © 2010 by Nova Science Publishers, Inc. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers‘ use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works. Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. Library of Congress Cataloging-in-Publication Data Melatonin, sleep and insomnia / editor, Yolanda E. Soriento. p. ; cm. Includes bibliographical references and index. 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, Cortical—An and/or Question? Aisha Cortoos, Elke De Valck and Raymond Cluydts

Chapter II

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

Chapter III

Non-Pharmacological Alternatives for the Treatment of Insomnia – Instrumental EEG Conditioning, a New Alternative? Kerstin Hoedlmoser, Thien Thanh Dang-Vu, Martin Desseilles and Manuel Schabus

Chapter IV

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

Chapter V

Aggression in Older Adult Populations 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 Bingh Tang and Lyn Tiu

Chapter VII

Chapter VIII

A Novel Model Using Generalized Regression Neural Network (GRNN) for Estimating Sleep Apnea Index in the Elderly Suffering from Sleep Disturbance Bingh Tang and Weizhong Yan Hormones and Insomnia Axel Steiger and Mayumi Kimura

1 35

69

103 135

161

191 205

vi Chapter IX

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

Chapter X

Melatonin and Nocturia 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 Rüdiger Hardeland

Chapter XII

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

Chapter XIII

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

Chapter XIV

Sleep Disturbance in Obsessive-Compulsive Disorder Enrico Pessina, Sylvia Rigardetto, Umberto Albert, Filippo Bogetto and Giuseppe Maina

Chapter XV

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

Chapter XVI

Neuroimaging Insights into Insomnia Martin Desseille, Thien Thanh Dang-Vu, Manuel Schabus, Kerstin Hoedlmoser, Camille Piguet, Maxime Bonjean, Sophie Schwartz and Pierre Maquet

227 249

273 291

303 315

329 337

Chapter XVII Neuroimaging Insights into the Dreaming Brain Martin Desseilles, Thien Thanh Dang-Vu, Manuel Schabus, Virginie Sterpenich, Laura Mascetti, Ariane Foret, Luca Matarazzo, Pierre Maquet and Sophie Schwartz

357

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

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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 doesn‘t 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 nonpharmacological 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 today‘s 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 1215Hz 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

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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 sleep–wakefulness 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 30 minutes) or a sleep maintenance problem (wake after sleep onset > 30 minutes) based on a polysomnography. In addition they had to report sleep complaints with a minimum of 3 times per week, and duration of the insomnia complaints of more then 6 months. Impairment in daytime functioning had to be present and all participants had to be medication-free for at least 4 weeks before the start of the study, as well as during the whole study. All psychiatric or medical disorders were excluded, except for a positive response in the M.I.N.I. on dysthymia and/or generalized anxiety disorder when it was clearly related to their sleep complaints. Table 1. Clinical characteristics Insomnia

Duration insomnia (years) Age STAI 1 STAI 2 BECK AIS PSQI PSAS SOM PSAS COG ESS

n=17 ♂=11;♀=6) 12.41 (10.15) 42.65 (9.35) 34.12 (5.56) 42.18 (7.19) 5.65 (5.23) 12.24 (3.53) 11.53 (2.00) 11.41 (4.58) 20.88 (8.53) 7.65 (4.96)

Controls n=12 (♂=7;♀=5) 0 (0) 44.42 (7.68) 27.67 (6.3) 34.58 (9.03) 2.67 (3.08) 2.17 (1.47) 4.00 (1.76) 9.50 (1.62) 11.75 (2.30) 7.08 (2.35)

*indicates significant difference with control group (p. < .05)

Effect size (r)

0.85* 0.09 0.52* 0.39* 0.25 0.83* 0.83* 0.15 0.41* 0.11

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Further exclusion criteria for all subjects: students, shift workers, pregnancy, consumption of more than two alcohol units/ day for woman and three alcohol units/day for men, consumption of more than five caffeine beverages/day, phase delayed or phase advanced syndrome, abnormal bedtime hours (< 09:30 PM) or irregular sleep-wake schedule, parents with newborns, excessive daytime sleepiness (ESS>13 and subjective report of difficulty staying awake during the day), presence of other primary sleep disorders (RLL, PLM, sleep apnea,…), BMI > 30.

Sleep Diary and Actigraphy Before the polysomnography, participants were asked to fill in a sleep diary and wear an actigraphy during the night for 2 weeks, to check for irregular sleep-wake schedules. The morning after the polysomnography, all participants were asked to fill in a morning questionnaire evaluating their night in the sleep lab, consisting of the Brussels Indices of Sleep Quality (BISQ) and a PSAS. Following variables were calculated from the sleep diary: Total Sleep Time (TST), Sleep Latency (SOL), Wake after sleep onset (WASO), Sleep Efficiency (SE), and Time in Bed (TIB).

Wake EEG All participants underwent a full-cap EEG measurement using the Cognitrace (A.N.T.) the evening they came to the laboratory for their sleep night. 19 electrodes were placed according to the international 10-20 system (Fp1, Fp2, F3, F4, F7, F8, Fz, C3, C4, Cz, P3, P4, Pz, T3, T4, T5, T6, O1, O2) and were averaged referenced online. An EOG and EMG submentalis were added to exclude artifacts of eye movements or muscle activity. Sampling rate was 256 Hz and impedances were kept below 10 kOhm. A 5 minute measurement with eyes open and eyes closed was performed. A Fast Fourier Transformation (FFT) Analysis was performed on the wake EEG on a minimum of 90 seconds artefact-free data using Neuroguide software (Applied Neuroscience, Inc.). The spectrum was divided into the following EEG frequency bands: delta (1-3.5 Hz), theta (4-7.5 Hz), alpha (8-12 Hz), beta1 (12-15 Hz), beta2 (15-17.5 Hz), beta3 (18-25 Hz), and high beta (25.5-30 Hz). Both absolute and relative values were calculated and a log transformation was performed to counter normality issues.

Polysomnography A polysomnography was performed at the experimental sleep laboratory at the Vrije Universiteit Brussel. In accordance with the studies of Perlis et al. [66, 67] analysis were performed on the first screening night. The recording montage consisted of 3 EEG electrodes referenced to a single mastoid (F3-A2, C4-A1, O1-A2), 2 EOG electrodes referenced to a single mastoid (LOC, ROC), a bipolar submentalis EMG, tibialis EMG, and EKG. A 32

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channel Embla N7000 recording system was used (Medcare) with a DC offset of 500 mV max and a fixed DC low cut filter at 0.3 Hz. The signal was digitized at a sampling rate of 500Hz using Somnologica Software. The EEG and EOG signals were high pass filtered at 0.5 Hz and low pass filtered at 40 Hz, EMG channels were high pass filtered at 5 Hz and low pass filtered at 70 Hz. All data was scored in 30-second epochs according to the Rechtschaffen & Kales [88] rules by a trained specialist, unaware of group allocation. Outcome variables were Total Sleep Time (TST), Sleep Onset Latency (SOL) defined as lights out to the first minute of stage 1 sleep, Wake After Sleep Onset (WASO), Sleep Efficiency (SE), % Slow Wave Sleep (SWS) of the Sleep Period Time (SPT), % REM sleep of the SPT, % Stage 1 sleep (S1) of the SPT and % Stage 2 sleep (S2) of the SPT. Furthermore, the arousal index defined as the amount of arousals (3-15 seconds) per hour and number of awakenings was calculated. Additionally, the EMG level (Root Mean Square µV) of the first period of wakefulness during the sleep onset period was also analyzed as a measure of baseline tension level. Movement artefacts were excluded from analysis. Spectral analysis was performed on C4-A1 to evaluate both the sleep onset period (SOP) and NREM and REM sleep. SOP was defined as lights-out to the first 5 minutes of stage 2 sleep [60]. Artefacts were removed and the SOP was divided into four quartiles to evaluate the EEG dynamics. FFT analysis was performed using Neuroguide software (Applied Neuroscience, Inc.), in which standard EEG frequency bands were defined: delta (1-3.5 Hz), theta (4-7.5 Hz), alpha (8-12 Hz), beta1 (12-15 Hz), beta2 (15-17.5 Hz), beta3 (18-25 Hz), and high beta (25.5-30 Hz). Regarding the sleep EEG, all epochs containing movements, EMG artefacts, sleep stage transitions or arousals (3-15sec) were excluded from analysis. All artefact-free epochs underwent high-pass filtering and hanning windowing followed by Fast Fourier Transformation in 2-second epochs. Delta (0.5 – 3.5 Hz), theta (4 – 8 Hz), alpha (8.5 – 12 Hz), sigma (12.5 – 16 Hz), beta (16.5 – 30 Hz) and gamma (30.5 – 60 Hz) were the analysed frequency bands. Analyses were performed using Somnologica Science software and data was exported to an excel file. The definition of NREM and REM cycles was adopted from the study of Perlis and colleagues [67]. Relative power spectra were calculated by dividing each frequency band by the calculated total power (sum of power of all frequency bands).

Arousal Parameters The somatic subscale of the PSAS will be used as a measure of subjective physiological arousal, both retrospective, as well as during their stay in our sleep laboratory. Secondly, EMG levels during sleep onset, as well as a cortisol sample the evening of the scheduled polysomnography will be used as an objective measure of physiological arousal. The cognitive subscale of the PSAS will be used as a measure of subjective cognitive arousal. Finally, an evaluation of cortical arousal reflected by the spectral profile of the wake and sleep EEG (SOP-NREM-REM) will be performed.

Conditioned Arousal in Insomnia Patients

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Procedure Before the polysomnography, participants were asked to fill in a sleep diary and wear an actigraphy during the night for 2 weeks, to check for irregular sleep-wake schedules. Subjects came to our sleep lab for the first PSG measurement at the Vrije Universiteit Brussel. They came in around 8:00 pm and received information on the procedure of the evening and purpose of the measurement. Around 8:15 pm the EEG measurement in an experimental room was started. During the eyes open condition, subjects were asked to keep their eyes fixed on a white dot on the floor, approximately 1.5 m from their seat to minimize eye movements. In the eyes closed condition, subjects were asked to visualize the same white dot and try to keep their eyes as still as possible. Afterward the electrodes for the night were applied. Around 10:30 pm cortisol measurement was performed through a saliva sample. Subjects went to bed between 10:30 pm and 12:00 pm, depending on their usual bedtime. Time in bed was approximately 7 hours and 30 minutes and was kept stable for every subject. The next morning they were asked to fill in the Brussels Indices of Sleep Quality (BISQ) and PSAS to monitor their subjective sleep quality.

Statistical Analysis Statistical analysis was performed using STATISTICA 8.0 software. Normality and homogeneity of variances were checked before analysis. To evaluate differences regarding clinical, demographical, PSG and sleep diary data an independent samples t-test was performed. If one of the assumptions was violated, a Mann-Whitney U test was used. The wake EEG was evaluated using a 2x19 repeated measures ANOVA for every EEG frequency band, using group (insomnia vs. controls) as a between subject variable and electrode location (19 locations) as a within subject variable. A 2x4 repeated Measures ANOVA was used for the SOP, with group (insomnia vs. controls) as a between subject variable and quartile as a within subject variable. The first 3 NREM and REM cycles were also examined using an 2x3 repeated measures ANOVA with group (insomnia vs. controls) as a between subject variable and NREM/REM cycle as a within subject variable. The calculated effect size for the repeated measures ANOVA is partial-eta squared (ηp2). Finally, in order to examine possible associations between sleep and arousal, a Spearman Rank correlational analysis was performed.

Results Clinical Characteristics In addition to the data presented in table 1, our insomnia subjects reported significantly more anxiety, both as a state and trait characteristic (STAI-1: z = 2.81; p.20%) [10]. Elementary school students Persistent need to yawn (62%), desire to sleep (58%), desire to lie down (47%), Eyestrain (33%), difficulties to sit straight (29%), memorizing difficulties (28%), irritated (27%), Neck stiffness (26%), low activity (25%), difficulties to concentrate (25%), Hypersensitive (24%), thirsty (21%), make many mistakes (20%) Junior high school students Desire to sleep (boys/girls; 73.8%/80.8%), persistent need to yawn 43.6%/69.1%), Desire to lie down (43.2%/47.2%), eyestrain (40.7%/44.7%), Memorizing difficulties (35.2%/33.6%), neck stiffness (29.3%/35.1%), Lumbago (26.5%/23.2%), low activity (21.3%/28.0%), Hypersensitive (20.0%/27.0%), difficulties to concentrate (21.0%/23.8%), Irritated (20.5%/24.2%),

As mentioned previously, bedtime delay in youngsters reduces total daily sleep duration [8], and approximately 80% of kindergarten and nursery school teachers reported that many children are sleep-deprived [20]. In fact, sleep deprivation has been demonstrated to exert a negative effect on daytime functions [33-35], general well being [36], metabolic and endocrine function [37, 38], and body weight [29]. However, the required sleep duration of an individual person is very difficult to determine, because the need for sleep is variable and depends on several factors [39]. Adults normally sleep for varied lengths of times, and such habits are considered to develop at a young age [32]. Of course, these differences should not mean that one should not take care of their sleep duration. If individuals are alert and active during late morning, then they are more likely to have healthier sleep duration, sleep quality, and life rhythms.

3. Nocturnal Lifestyles and Behaviors Not only a shortage of sleep duration, but also delayed bedtimes and wake-up times are known to produce physical, mental, and/or emotional problems.

3.1. Adults and Older Children Later bedtimes and wake-up times are significantly associated with sub-clinical manictype symptoms among working adults [40], and evening-type medical school students are reported to experience reduced sleep efficiency compared with morning-type students [41]. To determine if an individual is a morning-type or evening-type person, a self-assessment questionnaire was used. According to an original report [42], morning-type people went to bed and arose significantly earlier than evening-type people. Evening-type young adolescents

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in Taiwan exhibited a greater association with mood and anxiety symptoms [43]. Among 6631 adolescents aged 14.1-18.6 years, evening-types were found to exhibit more attention problems, perform more poorly in school, experience more injuries, and were emotionally upset more often than the other chronotype individuals [44]. Japanese junior high school students, with an evening preference, were reported to be more likely to exhibit poorer sleepwake parameters and lifestyle habits than those with a morning preference [45], and there was a greater association between evening-type individuals and impulsivity in students [46]. Compared with morning-type students, evening-type 12- to 13-year old students were reported to be more likely to exhibit behavioral/emotional problems, suicidal behavior and ideation, and habitual substance use [47]. Evening-type children aged 8-13 years have been shown to exhibit a greater tendency towards antisocial behavior, rule-breaking, attention problems, conduct disorder symptoms in boys, and aggression towards others in girls [48]. According to a nationwide survey, students in Japan with regular bedtimes and waking times showed better school performance than those with irregular sleeping times [49]. And conversely, an irregular lifestyle is known to be associated with delayed bedtimes and waking times. Of the college students surveyed, those with poor sleep quality exhibited less regularity in social rhythms relative to those with good sleep quality, and later rising times and bedtimes were reported to be associated with worse sleep quality [50]. Moreover, in adult populations, evening-type people are reported to demonstrate a more irregular daily lifestyle than morning-type people [51]. These reports all suggest an association between delayed waking times, bedtimes and irregular lifestyle with problematic behaviors of older children, adolescents, and adults.

3.2. Studies on Preschoolers Although few studies have described an association between sleep habits and behavior in preschoolers, problematic behaviors among children aged 4 to 6 years have been associated with late and irregular waking times and bedtimes, but not with sleep duration [52]. Suzuki et al. [53] compared the relationship between a 2-week sleep diary and the ability to copy a triangular figure on the first attempt in 222 children aged 5 and 6 years. The children who successfully copied the triangle had significantly earlier mean morning wake-up times, as well as significantly longer mean total sleep duration, compared with children who failed to copy the triangle. Compared with children with regular sleep-wakefulness rhythms, children with irregular sleep-wakefulness rhythms exhibited a 5.9-times greater risk of inability to copy the triangle. A semi-structured interview with 16 teachers identified 48 troublesome episodes in 42 children. The rate of children with irregular sleep-wakefulness rhythms among the children with the troublesome episodes (19/42) was significantly greater than children without troublesome episodes (15/180). These results suggested that children with irregular sleep-wakefulness rhythms exhibit more behavioral problems, as well as problems with integration of cognitive and motor activity. In a separate study, 204 children, aged 12-40 months (mean 22.6 months), were assessed for daily average physical activity counts per minute (PA) [54]. Results showed that increased age, male gender, and early wake-up times exhibited significant positive

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correlations with PA. Among children with a mean age of 7.3 years, higher mean daytime activity counts were reported to be associated with a decrease in sleep latency [55].

4. Nocturnal Lifestyle and Neurological Systems The above-mentioned studies on preschoolers, along with previously cited papers on older children, adolescents, and adults, report problematic behaviors that are associated with delayed wake-up times, delayed bedtimes, and an irregular lifestyle. Although delayed bedtimes also resulted in sleep loss [8], problematic behaviors were found to be more likely associated with delayed wake-up times, delayed bedtimes, and an irregular lifestyle, regardless of sleep duration [52]. In the following section, the presumed neuronal mechanisms associated with these results will be addressed.

4.1. Biological Clock Circadian signals are relayed from the SCN to the hypothalamic dorsomedial nucleus via the subparaventricular zone. The dorsomedial nucleus of the hypothalamus combines inputs from the SCN with inputs from other areas, allowing for flexible control, and sends signals to structures that regulate various circadian rhythms, such as feeding, locomotion, sleep-wake alternation, corticosterone secretion [56], and the autonomic nervous system [57]. Typically, the endogenous period of the circadian clock is longer than 24 hours, and it is through exposure to sunlight in the morning people become accustomed to the 24-hour cycle [58]. Conversely, light exposure at night delays the circadian clock phase [58], or disrupts its function [59-61]. Non-photic cues, such as eating times [62] and activity [63], also serve to synchronize the circadian system to a 24-hour day. In the absence of time cues, daily rhythms become altered, developing their own rhythm. After spending life under such conditions for a considerable period of time, the staging of various biological rhythms changes, such as sleep– wakefulness and temperature [64]. Under such conditions, reciprocal phase interactions within circadian rhythms are disturbed. In general, most people spontaneously awake in the morning when the body temperature begins to rise from its lowest level and, conversely, fall asleep at night when the body temperature begins to decline from its highest level. However, once this reciprocal interaction is impaired, the phase relationship between body temperature and sleep-wake circadian rhythms is disrupted [64], known as circadian desynchronization [65, 66]. This condition might produce various physical and mood disturbances (disturbed nighttime sleep, impaired daytime alertness and performance, disorientation, gastrointestinal problems, loss of appetite, inappropriate timing of defecation, excessive need to urinate during the night). Similar complaints and mood alterations have been observed in patients with jet lag [67], seasonal affective disorder [68], and in astronauts [69]. Endogenous phasing of the circadian biological clock in morning-type individuals varies from evening-type individuals [70], who experience a temperature rise later in the morning and later waking times [71]. Moreover, individuals who are alert in the morning experience an earlier circadian rhythm temperature peak than do individuals who are alert in the evening

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[72]. These reports suggested that evening-type individuals suffer from circadian desynchronization [65, 66]. Those with delayed waking times and bedtimes, and an irregular lifestyle (an evening preference) are hypothesized to suffer from circadian desynchronization. Arendt et al. [67] showed that jet lag recovery rate, which is attributed in large part to temporary circadian desynchronization, varies with individuals, as well as with the direction of time zone change. The susceptibility for developing symptoms, presumably due to desynchronization, is likely to vary in different individuals. In this regard, the following reports suggest that desynchronization susceptibility is affected by biological background. Nilssen et al. [73] compared the prevalence of sleep disorders in two ethnically different populations living in the same extreme arctic climate. More than 50% of the Norwegian population in these studies [73, 74] resided in the northern region of Norway, whereas the Russian subjects were primarily recruited from the southern part of Russia and the Ukraine. The study determined that Russians exhibited a greater prevalence of sleep disorders than Norwegians. A one-year prevalence of self-reported depression was also compared in the two populations [74], with similar results. The authors [73, 74] postulated that insufficient acclimatization after migration to the north resulted in these effects. Susceptibility to these symptoms was presumably due to desynchronization, which was likely affected in part by unknown biological background factors, including acclimatization. However, acclimatization cannot be altered within one generation.

4.2. Melatonergic System Melatonin not only regulates the circadian phase [75], but also acts as a hypnotic, is an effective free-radical scavenger and antioxidant, and directly induces gonadotropin-inhibitory hormone expression [76]. Interestingly, bright light during nighttime decreases melatonin secretion [77]. The existence of immunoreactivity against melatonin was demonstrated in the bacterium Rhodospirillum rubrum, one of the oldest species of living organisms, at possibly 2-3.5 billion years [78]. Bacterial melatonin might provide on-site protection of bacterial DNA against free-radical attack. Melatonin is also known to exert antioxidant effects in the brain [79], and sleep is hypothesized to function as an antioxidant or scavenging process in the brain [80]. Melatonin promotes and synchronizes sleep by acting on SCN-expressing melatonin MT1 and MT2 receptors, respectively. Synthesized melatonin receptor agonists exhibiting increased duration of action are expected to provide significant clinical value for treating insomnia patients [81]. The onset of melatonin secretion begins 14-16 hours after waking, usually around dusk [82]. Exposure to bright, midday light has been shown to increase melatonin secretion during the night, without a circadian phase shift [83]. Although the results are preliminary, in a study of 3-year-old children, early sleepers tended to exhibit higher levels of urinary 6-sulfatoxymelatonin (6SM) (6SM/creatinine ratio), the primary melatonin metabolite, compared with late sleepers [84]. Decreased melatonin levels in aged zebrafish have been shown to correlate with altered circadian rhythms [85]. Danel et al. observed an inversion in melatonin circadian rhythm

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secretion in alcoholics, not only during intake, but also during short- and long-term withdrawal. They concluded that circadian disorganization of melatonin secretion could be responsible for desynchronization in some alcoholic patients [86]. Because melatonin regulates the circadian phase [75], altered melatonin secretion could disturb circadian oscillation, producing various biological alterations. Nevertheless, in the rat, altered melatonin rhythm had no effect on circadian rhythms of locomotor activity and body temperature [87].

4.3. Serotonergic System Exposure to morning sunlight has been demonstrated to activate the serotonergic system [88] and, conversely, a nocturnal lifestyle is unlikely to activate the serotonergic system. Moreover, depression correlates with decreased norepinephrine, serotonin, or both [89]. In addition, selective serotonin reuptake inhibitors, which increase the availability of serotonin at the synaptic cleft, have been widely used to treat depression. Emotional instability, typical in individuals with nocturnal lifestyles, might be associated with insufficient serotonergic activity. The serotonergic system is activated through rhythmic movements, such as gait, chewing, and respiration [90]. Adequate physical activity could, therefore, be important for the activation of serotonin. Exercise-derived benefits for brain function have been demonstrated at the molecular level [91], and physical activity has been reported to decrease the risk of Alzheimer‘s disease [92–95]. Physical activity, which activates serotonergic activity, is one of the key factors in promoting brain function in animals and humans. The concept of low serotonin syndrome, which comprises aggressiveness, impulsivity, and suicidal behavior has been proposed [96]. In adult, male, vervet monkeys, decreased serotonergic activity was reported to be a disadvantage, and enhanced activity an advantage, for attaining high social dominance status [97]. Disturbance in the lateral orbito-prefrontal circuit induces aggressive behavior and loss of sociability [98], and the serotonergic system has been shown to activate this circuit [99]. Serotonin levels, which are increased through exercise, have been shown to enhance learning ability [92]. Serotonergic activity is profoundly affected by the sleep-wakefulness cycle, exhibiting highest activity while waking, and lowest activity during rapid eye movement sleep [100]. Taking these facts together, it has been postulated that irregular sleep-wakefulness rhythm disturbs emotional control and sociability, due to decreased serotonergic activation in the lateral orbito-prefrontal circuit. It is likely that circadian desynchronization results in unsatisfactory physical, mental and/or emotional conditions, presumably leading to decreased physical activity. If physical activity becomes too low, then the serotonergic system will not be activated. This is further confounded by a lack of morning light. The following negative cycles (solid filled lines in Figure 1) can be postulated in those with delayed wake-up times, delayed bedtimes, and an irregular lifestyle.

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Figure 1. Schematic drawing of the development of asynchronization modified from Figure 1 in reference 4.

4.4. Reported Disease Conditions Associated with Circadian Disruption Miike et al. [101] described altered circadian rhythms in childhood chronic fatigue syndrome, and reported that these patients suffered from an atypical, but continuous, jet lag condition. A British cohort study over more than 30 years [102] revealed that sedentary behavior during childhood increased the risk of chronic fatigue syndrome/myalgic encephalomyelitis, for which depression is a major symptom. Selective serotonin reuptake inhibitors have been reported to be effective in treating chronic fatigue syndrome patients [103]. It has been assumed that decreased serotonergic activity is involved in the occurrence of this syndrome. Melatonin has also been shown to be effective for chronic fatigue syndrome patients with delayed circadian rhythm [104]. One third of children with chronic fatigue syndrome exhibited abnormal cardiovascular regulation during postural changes (orthostatic dysregulation), which is characterized by instantaneous orthostatic hypotension, postural, or neural-mediated syncope [105]. Orthostatic dysregulation is a well-established clinical concept among pediatricians in Japan. The characteristic clinical burnout symptoms, first described in 1974 [106], comprise excessive and persistent fatigue, emotional distress, and cognitive dysfunction. These symptoms are common among disorders such as depression, chronic fatigue syndrome, and vital exhaustion [107]. Burnout is positively associated with poor sleep quality, a sensation of not feeling refreshed upon awakening, and sleepiness and/or fatigue during daytime [108]. Burned-out subjects are reported to exhibit a higher frequency of arousal during sleep [107]. A study of University Hospital nurses revealed that daylight exposure for at least 3 hours per day resulted in reduced stress and greater job satisfaction, both of which were favorable

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factors for reducing burnout [109]. Because bright, midday light increases melatonin secretion during the night in elderly individuals [83], the melatonergic system, as well as the serotonergic system [110], might be involved in the pathogenesis of burnout. Appels et al. introduced the terminology of vital exhaustion, which is conceptually akin to burnout [111]. In a prospective study of a large sample of healthy men, vital exhaustion was shown to comprise three factors - fatigue, depressive affect, and irritability - and the risk of subsequent myocardial infarction was attributed to fatigue from vital exhaustion [112]. Vital exhaustion is also associated with sleep disturbances. Polysomnographic recordings indicated that deep sleep stages were significantly reduced in exhausted subjects, compared with control subjects, suggesting that normal restoration processes, which occur while sleeping, are impaired in exhausted subjects [113]. In addition, exhausted subjects presented with a greater number of sleep complaints, shorter sleep duration, frequent napping, and poorer sleep quality [111, 114-116]. Fibromyalgia is characterized by widespread pain and muscle tenderness lasting at least three months, as determined by palpation [32]. Patients with fibromyalgia commonly complain of light and non-refreshing sleep, fatigue, cognitive difficulties, and psychological distress, including symptoms of depression and anxiety. Interestingly, a serotonin and norepinephrine-reuptake inhibitor has been reported to be successful in these patients [117], as well as melatonin for treating the pain associated with fibromyalgia [118]. Decreased circadian rhythm amplitude has also been reported in a more common condition - depression [119]. Moreover, decreased amplitude in circadian core body temperature changes was reported in delinquent student patients diagnosed with a desynchronized condition [120]. External and internal desynchronizations were two of the three major components of jet lag [121]. Another major component was sleep deprivation [121]. External desynchronization refers to the conflict between the internal clock and external time cues. As an individual is exposed to new, external, time cues, the internal clock adjusts to the new time zone, which may take several days. Internal desynchronization, a loss of phase coupling between phenomena revealing circadian oscillation, takes place during readjustment of internal clocks, and each system adjusts itself differently. Internal desynchronization can also be induced by acute manipulation resulting in phase alteration [122], which is the case in jet lag. As a result of internal and external desynchronization, sleep loss occurs, which decreases the quality and quantity of various activities [29, 33-38]. This ultimately results in decreased serotonergic activity. For the transmeridian traveler, both physical cues such as daylight and darkness, and social cues, such as mealtimes and noise, encourage realignment of the circadian system. In contrast, for the shift worker, physical cues are resolutely opposed to nocturnal alignment, as are most social cues stemming from a day-oriented society. Therefore, circadian realignment of shift workers takes longer than realignment from jet lag [123]. In addition, a forced, extraordinary schedule can also induce desynchronization [124]. As previously mentioned, alcoholics have been reported to display an inversion of melatonin circadian rhythm secretion, which could be responsible for their desynchronization [86]. As described in this review, chronic fatigue syndrome, orthostatic dysregulation, burnout, vital exhaustion, fibromyalgia, depression, jet lag, and shift work are likely to be a result of desynchronization and decreased serotonergic, as well as decreased melatonergic activity.

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Although each of these disease conditions possesses its own specific origin, major symptoms, and course, there might be a similar pathophysiology between these disease conditions and the condition that many Japanese preschoolers/students are currently suffering from.

5. Asynchronization More than half of the preschoolers/students in Japan complained of daytime sleepiness, while about one quarter of junior high school students in Japan suffer from insomnia. Moreover, as shown in Table 2, frequent complaints of students in Japan were compatible with associated features of behavioral-induced sleep-deficient syndrome [32], most likely due to inadequate sleep hygiene. If this were the case, these symptoms should be ameliorated following adequate sleep (by exclusion of dotted lines in Figure 1). However, such therapeutic approaches often fail. The students cannot fall asleep, despite sleep loss, and this is partly due to inadequate sleep hygiene consistent with excessive media exposure and lowlevel physical activity. Indeed, delayed wake-up times and bedtimes could be symptoms of a delayed sleep phase form of circadian rhythm sleep disorder. Although this article does not discuss this disorder in detail, it should be noted that there is confusion between this disorder and the biological- and lifestyle-related sleep phase delays that are especially common during adolescence [125]. It is possible that certain factors other than simple sleep loss and inadequate sleep hygiene are involved in many of the young people in Japan that exhibit delayed wake-up times, delayed bedtimes, and an irregular lifestyle. It has been assumed that decreased activity in the melatonergic and serotonergic systems, as well as desynchronization, are candidates for explaining pathophysiology.

5.1. Presumable Pathophysiology In 1976, Aschoff and Wever described [126] that activity rhythm (wakefulness and sleep) and other rhythmic variables (e.g., temperature) often have similar circadian periods of approximately 25 hours. However, on occasions, the activity period may become substantially longer (e.g., 33 hours), while other rhythms continue with a period of about 25 hours. Such a state is termed internal desynchronization. Thus circadian desynchronization is used to indicate a loss of phase coupling between certain phenomena, which lead to circadian oscillation. It should be noted that this term arose from basic studies, and was not originally a clinical-related term. Individuals with delayed wake-up times, delayed bedtimes, and an irregular lifestyle may also exhibit a loss of phase coupling between phenomena, circadian oscillation, and decreased amplitudes of other phenomena, although no concrete evidence has obtained to date. Desynchronization alone is not adequate to describe the clinical conditions that many young people in Japan are suffering from. In addition, many of these individuals likely display reduced serotonergic and/or melatonergic activity. I wonder a novel, clinical entity is required to improve understanding of the pathophysiology of these disturbances [3, 4].

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In 1970, Winfree [5] reported that a specific, dim, blue-light, pulse stimulus, with a unique stimulus time and duration, resulted in unusual broadening of the daily eclosion peaks of the fruitfly, Drosophila pseudoobscura, even to the extreme of obscuring circadian rhythm. This phenomenon was termed ―circadian singularity behavior‖, and has been described in a range of organisms, such as algae, plants, and mammals [127-132]. In humans, Jewett et al. [129] reported circadian rhythms of rectal temperature and plasma cortisol were abolished by a single, long duration, bright-light pulse administered during one or two successive circadian cycles. Huang et al. [133] demonstrated that temperature increases and light pulses can trigger singularity behavior in Neurospora circadian clock gene frequency. In addition, Ukai et al. [59] reported that a critical light pulse (3-hour light pulses delivered at a specific circadian time (CT) ~17 (near subjective midnight (=CT18))) drives cellular clocks to singularity behavior in mammals. Interestingly, this phenomenon is transient [133], although removal of the stimulus is needed. Table 3. Asynchronization. Essence Presumable causes

Symptoms

Therapeutic approaches

Prognosis

Disturbance of various aspects (e.g., cycle, amplitude, phase, and interrelationship) of biological rhythms that indicate circadian oscillation. Light exposure during the night. Lack of light exposure in the morning. Decreased physical activities. Disturbance of the biological clock and/or the serotonergic system. Disturbances related to the Autonomic Nervous System sleepiness, insomnia, disturbance of hormonal excretion, gastrointestinal problems, sympathetic nervous system predominance Somatic Disturbances tiredness, fatigue, neck and/or back stiffness, headache, persistent yawn, desire for sleep, wish to lie down, inactivity, lumbago Disturbances related to Higher Brain Function disorientation, loss of sociality, loss of will or motivation, impaired alertness and performance, difficulties to remember, difficulties to concentrate Neurological Disturbances attention deficit, aggression, impulsiveness, hyperactivity, irritated, hypersensitive Psychiatric Disturbances Symptoms observed in depressive disorders, personality disorders, and anxiety disorders Morning light, an avoidance of nocturnal light exposure, conventional approaches - light therapy, medications (hypnotics, antidepressants, melatonin, vitamin B12), physical activation, chronotherapy and alternative ones - Kampo, pulse therapy, direct contact, control of the autonomic nervous system, respiration (qigong, tanden breathing), chewing, crawling Early phase: Disturbances are functional and can be relatively easily resolved, e.g., through establishment of a regular sleep-wake cycle Chronic phase: Without adequate intervention, disturbances can gradually worsen, involving loss of serotonergic activity, which is difficult to resolve.

Taken together with this basic entity - singularity -, I designed a novel clinical concept asynchronizatiopn-. Asynchronization is the result of disturbed aspects (e.g., cycle, amplitude, phase, and interrelationship) of biological rhythms that normally exhibit circadian oscillation, which presumably involves decreased serotonergic and/or melatonergic activity.

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The major trigger of asynchronization is hypothesized to be a combination of light exposure during nighttime, which reduces melatonin secretion, and a lack of morning light exposure, which decreases serotonergic activity. Thus asynchronization symptoms (Table 3) include disturbances of the autonomic nervous system (sleepiness, insomnia, disturbed hormonal excretion, gastrointestinal problems, sympathetic nervous system predominance, etc.), as well as higher brain functions (disorientation, loss of sociability, loss of will or motivation, impaired alertness and performance, etc.). Neurological (attention deficits, aggression, impulsiveness, hyperactivity, etc.), psychiatric (depressive disorders, personality disorders, anxiety disorders, etc.) and somatic (tiredness, fatigue, neck and/or back stiffness, headache, etc.) disturbances are also putative symptoms of asynchronization. Complaints introduced in this article (Table 2) could be symptoms of asynchronization. To detect the disturbance of biological rhythms, actigraphic recordings [134], as well as diurnal measurements of body temperature, corticosteroids, and melatonin are useful. Takimoto et al. monitored human clock genes in whole blood cells to evaluate internal synchronization [135]. The early phase of asynchronization is hypothesized to be functional and can be relatively easily resolved by establishing a regular sleep-wakefulness cycle. However, without adequate intervention, disturbances can gradually worsen, resulting in decreased serotonergic and/or melatonergic activity, which can be difficult to resolve. In Figure 1, red lines, especially the broad ones, are hypothesized to be involved in asynchronization. A portion of patients with chronic fatigue syndrome, orthostatic dysregulation, burnout, vital exhaustion, fibromyalgia, and depression are thought to suffer from asynchronization.

5.2. Potential Therapeutic Approaches 5.2.1. Basic Principles For synchronization of the biological clock to a 24-hour cycle, exposure to morning light and avoidance of nocturnal light are essential. Therefore, lack of these two behaviors will result in asynchronization. Moreover, light-induced adrenal gene expression and corticosterone release have been demonstrated [136]. Under normal conditions, steroid secretion is greatest in the morning. In addition to light and social factors [124], food [137] is known to affect the circadian clock. The dorsomedial hypothalamic nucleus was determined to be a putative foodentrainable circadian pacemaker in mice, and oscillation of this pacemaker was found to persist for at least 2 days, even when mice received no food during the expected feeding period following establishment of food-entrained behavioral rhythms [62]. Regular mealtimes, as well as participation in social activities, are likely to prevent asynchronization. A daytime nap is known to result in favorable performance [138]. However, eveningtype adolescents were reported to nap more frequently during school days than other chronotypes [44], although improved school performance after an afternoon 15-minute-nap was reported in a Japanese high school [139]. Further studies are needed to determine whether napping affects asynchronization.

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Nevertheless, to prevent asynchronization, the social promotion of favorable sleep hygiene is important [140, 141]. 5.2.2. Conventional Approaches

5.2.2.1. Light therapy

Light therapy has been shown to effectively treat patients with depression [142, 143] and seasonal affective disorder [144]. It has been recommended that patients with seasonal affective disorder initially receive morning light shortly upon awakening [68]. In patients with winter depression (seasonal affective disorder), one week of bright, morning light (2500 lux) treatment produced significantly greater remission rates (53%) than evening (38%) or midday (32%) treatment [145]. A clinical trial [68] that administered 5 weeks of bright, morning light therapy (10000 lux, 60 minutes) to chronic (≥ 2 years) major depression outpatients resulted in a remission rate of 50%, while the control group showed only minor improvements. Light therapy also reduced depression scores in patients with fibromyalgia [146]. The effects of light therapy on chronic fatigue syndrome have, however, been controversial [147, 148]. As described previously, exposure to at least 3 hours daylight per day was suggested to produce favorable effects on burnout patients [109], and light therapy was used to treat patients with shift work and jet lag disorders [149]. However, in animals and humans, short nights attenuate both evening light-induced circadian phase delays and morning light-induced circadian phase advances [150, 151]. In addition, circadian clocks advance phases by inducing earlier waking time and bedtime, while circadian clocks delay phases by pushing waking and bedtime later [152, 153]. Although these light effects should be clues for treating patients with early phase asynchronization, attenuation of light-induced circadian phase delays during short nights results in decreased light therapy effects on individuals suffering from jet lag and night workers engaged in a nocturnal life with a long nocturnal photoperiod (= short nights) [151].

5.2.2.2. Medications 5.2.2.2.1. Hypnotics

There is insufficient evidence to assess the safety and efficacy of hypnotic medication for delayed sleep phase disorder [154]. Data encompassing the safety and efficacy of hypnotics with other types of circadian rhythm sleep disorders are scant [154]. In addition, the effects of hypnotics on shift work disorder patients are inconsistent [149]. However, the use of hypnotics for jet lag-induced insomnia is a rational treatment and is consistent with standard recommendations for treating short-term insomnia. The efficacy of benzodiazepines on patients with fibromyalgia, together with non-steroidal anti-inflammatory drugs, has been inferior to amitriptyline [155]. In addition, ultra-short- or medium-acting hypnotics have been used in children with chronic fatigue syndrome [148], and are widely used to treat insomnia in depression patients [156]. It is likely that appropriate use of hypnotics should be taken into consideration for the management of asynchronization.

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5.2.2.2.2. Antidepressants The efficacy of antidepressants has been reported in depression, as well as chronic fatigue syndrome [103] and fibromyalgia [117, 155]. These agents could also be promising for treating depressive tendencies in asynchronization patients. However, because asynchronization are likely to be involving serotonin depletion, the use of selective serotonin reuptake inhibitors or serotonin and norepinephrine-reuptake inhibitors as the first agent of choice for treating asynchronization needs further studies.

5.2.2.2.3. Melatonin and its Agonists

The effects of melatonin in patients with delayed sleep phase disorder and free-running disorder have been established [154]. Afternoon or evening melatonin administration would be expected to shift rhythms earlier, thereby correcting pathological phase delay. Appropriately timed melatonin administration has been shown to entrain totally blind individuals with free-running disorder. Melatonin or melatonin agonists might benefit daytime sleep in night workers through their hypnotic, as well as phase-shifting, effects [149]. Melatonin, administered at the appropriate time, can reduce symptoms of jet lag and improve sleep following travel across multiple time zones [149]. Melatonin is also effective treatment for some patients with chronic fatigue syndrome [104], as well as pain associated with fibromyalgia [118]. Interestingly, agomelatine, a compound with melatonin receptor agonist properties, has been reported to exert an antidepressant effect superior to selective serotonin reuptake inhibitors and selective serotonin and noradrenaline reuptake inhibitors [157]. However, because melatonin is not regulated by the U.S. FDA, there are a variety of preparations, and its usefulness has been limited [158]. In a 4-year-old boy diagnosed with Smith-Magenis syndrome, Carpizo et al. reported treatment with a beta (1)-adrenergic antagonist in the morning (to suppress diurnal melatonin secretion) and melatonin in the evening (to generate nocturnal melatonin peak), which resulted in improved sleep quality, as evaluated by polysomnographic methods [159]. This approach could be beneficial for asynchronization patients that exhibit altered diurnal melatonin secretion.

5.2.2.2.4. Vitamin B12

Vitamin B12 has been shown to enhance light pulse-induced phase shifts and thus augment entrainability of the circadian clock to light in rats [160]. In fact, high-dose vitamin B12 (3 g/day) proved to be effective in childhood chronic fatigue syndrome patients with free-running disorder [148]. An association between low vitamin B12 status and depression in elderly individuals has been suggested [161]. Because vitamin B12 deficiency causes decreased remethylation of homocysteine and is, therefore, most likely contributing to increased homocysteine levels, Regland et al. [162] measured homocysteine and vitamin B12 levels in cerebrospinal fluid of patients that fulfilled criteria for both fibromyalgia and chronic fatigue syndrome. They measured increased homocysteine concentrations, as well as a correlation between vitamin B12 levels and clinical variables. In other words, decreased vitamin B12 levels resulted in more severe clinical conditions. However, a recent review suggested that vitamin B12 was not an effective treatment for delayed sleep phase disorder

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[154]. Also, vitamin B12 was not recommended for treating jet lag or shift work disorders [149].

5.2.2.3. Physical activity

Physical activity is associated with an antidepressant effect in clinical depression [163]. Exercise leads to improved physical and mental health in fibromyalgia patients [164] and was shown to re-time circadian rhythm in individuals suffering from jet lag or shift work [165]. In patients with chronic fatigue syndrome, graded exercise therapy was shown to be valuable in randomized controlled trials [166]. Exercise induces these effects not only through the serotonergic systems, which is activated by rhythmic movements, such as gait, chewing, and respiration [90], but also through other molecules, such as brain-derived neurotrophic factor [91]. Physical activity or exercise could be potentially used to relieve asynchronization. Each morning in Japan, we have a 10-minute radio program of gymnastic exercises with piano accompaniment. This set of exercises is very familiar to almost all people in Japan, especially those older than twenty years of age. The efficacy of these exercises should be re-evaluated for physical and mental health.

5.2.2.4. Chronotherapy

To resynchronize the circadian clock with the desired 24-hour cycle, chronotherapy has been used in patients with circadian rhythm sleep disorder. This approach assumes that the circadian clock cycle of the majority of people is longer than 24 hours. In a case of delayed sleep phase, a successive delay of sleep onset by 3 hours each day, over a 5-6-day period, is required to achieve desired sleep onset [167]. This shift should be rigidly adhered to establish a set sleep-wake schedule and proper sleep hygiene practice. However, the potential confounding effects of light exposure at inappropriate circadian times might limit the effectiveness and practicality of this approach [168]. 5.2.3. Alternative Approaches The following are potential approaches to manage asynchronization, although the diagnostic standards and methodology, in terms of applicability, remain to be determined.

5.2.3.1. Kampo

Kampo medicine is a traditional Japanese herbal medicine that originated from traditional Chinese medicine. Examples for prescription are listed in Table 4 [169-171]. In addition to these prescriptions, Kanbaku-taisou-to (72) (the value in parentheses is the standardized number for prescription in Japan) and Yoku-kan-san (54) is the author‘s preference for patients with early-phase asynchronization and presumed elevated sympathetic nerve activity. I also use Dai-saiko-to (8) to treat insomnia due to hypertension or tinnitus. In patients with depression [172] and fibromyalgia [173], Kampo or traditional Chinese medicine have been commonly used.

Table 4. Presumable Kampo prescriptions for asynchronization.

fatigue syndrome

chronic fatigue syndrome

child patients with school refusal

Rokumi-gan (88), Hochu-ekki-to (41), and ShoSaiko-to (9) [169] Ninjin-yoei-to (108) [169] [170]

weakness in the lower extremities

systemic hypofunction and/or coldness

glow ing (or heat sensation in the palm or foot)

Hachimiziou-gan (7) [171]

Sinbu-to (30) or Ougiken-chu-to (98) and Ninzin-to (32) [171]

Rokumigan (87) [171]

Rokumigun (87) [171]

apathy,

Seishoekki-to (136) [171]

Number in the parenthesis is the standardized number for prescription in Japan.

aggressiveness or impulsiveness,

Saiko-karyukotuborei-to (12) [171]

depressive tendency

Kamishouyousan (24) [171]

anemia

GI disturbance

fatigue after acute infection

Zyuzentaiho-to (48) and/or Ninjin-yoeito (108) [171] Zyuzentaiho-to (48) and/or Ninjin-yoeito (108) [171]

or insomnia Kihi-to (65) or fatigue Hochu-ekkito (41) [171] or insomnia Kihi-to (65) Hochu-ekkito (41) [171]

Saiko-keishi-to (10) [171]

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5.2.3.2. Rhythmic Movements

As described in the former section, exercise could produce favorable effects on depression [163], fibromyalgia [164] jet lag, shift work [165], and chronic fatigue syndrome [166], presumably not only through the activation of serotonergic system [90] but also by the induction of other molecules [91]. Among rhythmic movements which activate serotonergic system [90], gait must be a part of exercise. In this section, rhythmic movements other than gait –respiration and chewing- will be introduced. Qigong is an ancient, oriental, mindful exercise [174], also described as a mind-body, integrative exercise or traditional Chinese medicine intervention that is used to prevent and cure ailments, as well as to improve health and energy levels [175]. Qigong (or ch'i kung) refers to a wide variety of traditional ―cultivation‖ practices that involve movement and/or regulated breathing [176]. Qigong has recently been designated as an alternative therapy to help meet the increasing demand of non-pharmacologic modalities for achieving bio-psychosocial health in patients suffering from anxiety [174] or pain [177]. Although the metaanalyses to date have been based on low-quality studies and small numbers of hypertensive participants, Qigong and Zen meditation have been shown to significantly reduce blood pressure [178]. Tanden breathing involves slow breathing (range of 0.05-0.15 Hz) into the lower abdomen, and was found to affect cardiac variability, which is controlled by the autonomic nervous system [179]. Although rhythmic respiration has been reported to activate serotonergic activity [90], Arita and Takahashi [180] preliminarily determined that tanden respiration also elevates serotonergic activity. Chewing has also been reported to activate the serotonergic system [90, 181]. This behavior could be used to manage asynchronization by deliberately activating serotonergic activity. Locomotion is a sort of rhythmic movements. Failed locomotion (crawling) during infancy (lack of interlimb coordination between upper and lower extremities) has been reported to be due to hypofunctioning serotonergic and/or noradrenergic neurons [182]. This results in postural atonia by disfacilitating postural augmentation pathways and/or disinhibiting the postural suppression pathway and preventing locomotion [183]. Forcedcrawl training has been described as relieving symptoms resulting from low serotonergic activity [184].

5.2.3.3. Direct Contact

An older generation Japanese pediatrician [185] was quoted to say, ―Holding a baby in the arms (―dakko‖ in Japanese) is the most effective tranquilizer for a baby.‖ Although therapeutic touch is now receiving attention as a method to manage anxiety disorders, including depression [186], dakko is a typical and classic daily behavior that involves direct contact between caretakers and youngsters. With the rapid spread of various types of media, including mobile phones, one concern is that direct contact between people is rapidly diminishing. In fact, concurrent television exposure is reported to correlate with fewer social skills [187]. In addition, hugging and intimate, face-to-face conversations are expected to be promising in the effort to manage and/or prevent asynchronization.

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5.2.3.4. Control of the Autonomic Nervous System To provide adequate cues for the circadian clock, morning activation of the sympathetic nervous system and evening stimulation of the parasympathetic system might be helpful to manage asynchronization. In Japan, some pediatricians recommend scrubbing the skin with a dry towel or cold water in the morning to train the autonomic nervous system in patients with orthostatic dysregulation [188]. However, this approach has not been covered in the recently published guideline [189].

5.2.3.5. Pulse Light In addition to the removal of stimuli that induce singularity effects, adequate stimuli (light pulse at CT 9-15 (transition from subjective day to night) [59]) could also reverse singularity. Further studies are needed to identify adequate stimuli for reversing circadian singularity behavior in asynchronization.

6. Conclusion Many young people in Japan suffer from daytime sleepiness and nocturnal insomnia, and are persistently tired and inactive. This review focused on the association between nocturnal lifestyle and biological clock disorders, as well as the melatonergic and serotonergic systems. However, involvement of dopamine [190] and opioid peptides [101] are also possible. A novel clinical concept – asynchronization - has been proposed, and a similar basic concept singularity - was also introduced. In this review, studies that recommended morning-type behavior to reduce behavioral/emotional problems were introduced [28, 47, 52]. Ayurveda, an ancient system of health care that is native to the Indian subcontinent, suggests that, in addition to good conduct, thought, diet, interpersonal dealings, physical activity, early rising, and early bedtimes are good for a healthy life [191]. Ekken Haibara wrote in his essay, Youzyoukun (1713), that one should awake early in the morning and avoid late bedtime to live a healthy life [192]. Byoukesuchi (Hirano, 1832), a book describing medical practices for the home, stated that one should go to bed early at night and awake before dawn for a healthy life [193]. Thus both traditional wisdoms and recent researches recommend morning-type behavior, and this article reviewed the possible background mechanisms for the favorable effects on physical and mental health. Senior high school students in Korea are reported to go to bed (0:54 on school nights) [194] later than those in Japan (0:06 [11] or 23:50 [12]). Although Chinese senior high school students in Hong Kong went to bed earlier (23:24) than those in Japan, it was concluded that they did not receive sufficient sleep [195]. Many young people not only in Japan but also in the other countries might be potential patients with asynchronization. In addition, some NEET (Not in Employment, Education, or Training) [196] individuals might also suffer from asynchronization. Now we are living in the society with 24-hour activity. I am afraid that this type of society might produce unfavorable effects on the SCN. A quarter of the world‘s population is subjected to a 1 hour time change twice a year (daylight saving time; DST) [197]. DST is

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now known to disturb normal seasonality seen in sleep timing assessed by mid-sleep times [197]. In addition, at the beginning of DST (=spring), the rates of traffic accidents [198] and the attacks of myocardial infarction [199] are reported to increase. I wonder we should be more careful on the property of the biological clock. I hope a novel concept of asynchronization to contribute to noticing the significance of the SCN, and to helping patients suffering from circadian disruptions.

Acknowledgment This study was supported by a grant from the Ministry of Health, Labour, and Welfare of Japan (19231001).

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In: Melatonin, Sleep and Insomnia Editor: Yolanda E. Soriento

ISBN: 978-1-60741-859-7 ©2010 Nova Science Publishers, Inc.

Chapter V

Aggression in Older Adult Populations Sarah E. Parsons1, Luis F. Ramirez1,2, Philipp Dines1,2 Scott Magnuson3 and Martha Sajatovic1,2 University Hospitals Case Medical Center1 Case Western Reserve University School of Medicine2 Cleveland State University3, USA

Abstract 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 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.

Keywords: Elderly, aggression, delirium, dementia

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I. Introduction and Background Aggressive behavior amongst the elderly population is a significant problem in the community and in institutions. The relative paucity of information on the subject and the projected aging trends globally, particularly in developed countries such as the United States, are indicative that there is increasing need for additional research. In 2005, a report from the United Nations Populations Division noted that the number of individuals world-wide aged 60 years and older is expected to nearly triple, increasing from 672 million in 2005 to almost 1.9 billion by 2050 [1]. 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 [1]. According to the U.S. Census Bureau, the percentages of people aged 60 and over are projected to increase from 16.8% of the U.S. population in 2005 to 25.1% in 2030 [3]. Prevalence of aggressive behavior in elderly persons differs drastically amongst studies. In institutional settings, Zimmer reported aggressive behavior occurring in 8.3% of patients [4], whereas Winger reported 91% [5]. Prevalence rates for community settings differ from 1% [6] to 47% [7]. This wide range of prevalence can be attributed to researchers‘ diverse definitions of aggressive behaviors as well as sampling methods and sample composition. The definitions of aggressive behavior amongst studies have included tantrum-like behaviors, physical aggression, self-injurious behavior, property destruction, and verbal abusiveness. The divergence of prevalence reports can also be attributed to the use of differing methods, including standardized scales to evaluate aggressive behaviors. Common standardized measures of aggression include, but are not limited to, the Cohen-Mansfield Agitation Inventory (CMAI) [8], the Rating Scale for Aggressive Behavior in the Elderly (RAGE) [9], and the Ryden Aggression Scale [7]. Additionally, researchers derive their data from varying sources including incident reports [10], caregiver report [11], patient interview [12], or review of the medical record [13]. Aggressive behavior and agitation are a non-specific group of behaviors that can occur in the context of many different clinical conditions. Phenomenologically there are several behavioral syndromes which may overlap with aggression or agitation, including restlessness, hyperactivity, fidgetiness and akathisia as well as vegetative symptoms such as changes in sleep and sleep cycles. The functional nueroanatomy and the neurochemical basis of agitation have not been clearly elucidated. A model proposed by Sachdev and Kruk [14] posits agitation as a disturbance in multiple brain circuits involving the limbic system, the striatum, the globus pallidus, and disinhibition in neurons of the thalamocortical tracts and brain stem. Because of the involvement of multiple and differing parts of the brain, various neurotransmitters may be at least partially responsible for some of the behaviors observed in agitated states. For example, in the case of agitated depression there is an increase in serotonergic responsivity with a decrease in GABA [15]. In mania and acute psychosis there is an increase in dopamine, in dementia there is a decrease in GABA, in panic disorder and GAD there is an increase in norepinephrine and a decrease in GABA with a decrease in dopamine and an increase in norepinephrine in the case of akathisia [15].

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The impact of aggressive behaviors can be very detrimental to the elderly aggressor, as well as caregivers. Studies have indicated that as much as 20% of caregivers for people with dementia report physical violence as a serious problem [16]. These behaviors may result in physical danger to those in close proximity to the aggressor, to the caregiver, or to the aggressor themselves. In addition, those who commit these behaviors often elicit reactions from others that exacerbate the behavior. According to Patel and Hope, aggressive behaviors cause the greatest impact on the elderly and their caregivers [17]. It has been found that caregivers who have been physically abused by their care receivers are more likely to act abusively in return [18]. In addition, aggressive behavior is one of the most frequent causes for institutionalization among the elderly and increases the requirement for drug therapy and hospitalization [19]. The health care professional facing a clinical situation in which aggressive behavior is present is confronted with two tasks: assess the clinical situation and treat the individual/manage the environment. The detail involved in the evaluation is determined by the circumstances surrounding the patient and the urgency demanded by the characteristics of the symptoms. Many times the professional facing these issues has to act quickly without all the information available in order to guarantee the safety of the patient or the people surrounding the patient. The first step is to determine if the patient is suffering a delirium. In general terms delirium can be defined as a transient, potentially catastrophic or life threatening syndrome caused by severe and acute physiological changes in the brain. Delirium is commonly seen in medical conditions or toxic states due to medications or drug interactions. Elderly individuals with chronic impairment in cognition and behavior caused by neurological damage or degeneration may have dementia. Both delirious and demented patients may exhibit a variety of psychiatric and/or neurological signs and symptoms with clear manifestations of irritability, agitation, aggression, fear, anger, suspiciousness, cognitive impairment, sleep-wake cycle disruption and extra sensibility to stimuli. Elderly individuals who exhibit aggression and behavior symptoms may also suffer from mood, anxiety or psychotic disorders as will be discussed in this chapter. Appropriate assessment and treatment of these psychiatric conditions will reduce /resolve aggressive behavior and is generally associated with improvement in symptoms and functional status. Therapeutic approaches aimed to optimize safety and enhance quality of life are needed to address and decrease aggressive behaviors irrespective of underlying cause. It is important for caretakers to uphold the dignity of the care receivers to the maximum level possible and respect their rights of privacy. In summary, population aging is 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 puts individuals at physical risk. Aggressive behavior by older individuals with mental disorders incurs substantial humanitarian and financial burden on patients, families and society at large.

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This review will address aggression in elderly populations with general medical conditions that include delirium, toxic states and drug-drug interactions as well as dementing illness, mood and anxiety disorders and psychotic disorders. A pragmatic approach with 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.

II. Aggression in Elderly Patients with Medical Conditions Elderly patients are more likely than younger patients to have a number of health problems [20]. These medical conditions often lead to an increased number of prescriptions, increased hospitalizations, and an increased number of prescribing medical specialists. The ageing brain has less ―cerebral reserve‖ and is more sensitive to minor and major alterations in physiology. Elderly patients are likely to react differently to a vast array of medical conditions, from minor infections to major surgery, compared to their younger counterparts. The result of multiple medical conditions, medications, and an alteration in physiology is often delirium; aggressive behavior can be a manifestation of this delirium. Understanding delirium and its management is essential to a positive outcome for an aggressive elderly patient with medical conditions.

A. Delirium and Toxic States Delirium is an acute disturbance in consciousness and cognition that is causally linked to physiologic changes and is especially common in older populations. In adults, as age increases, vulnerability for delirium increases as well, with the highest incidence in those aged 60 years and older [21]. Additional factors that increase the risk for delirium are cognitive disorders, recent surgery, specific medical conditions, and certain medications. Delirium is typically transient and reversible, thus the etiology needs to be thoroughly investigated as quickly as possible once a diagnosis is reached. The rate of delirium in the general population is difficult to assess; most studies on prevalence of delirium focus on specific hospital referrals or specialized hospitalized populations. Across these studies, delirium is evident in 5-44% of patients aged 65 years and older on medical/surgical wards or in long term care facilities [22-25]. Specialized populations with higher rates of delirium include those patients with recent coronary artery bypass grafting (CABG), recent hip replacement, advanced cancer, or on mechanical ventilation in the intensive care unit [26-28]. Delirium is important to identify and treat, as it is associated with mortality in 25% of patients [29] and also contributes to longer hospitalizations and increased cost of hospitalization [30, 31]. Delirium is characterized by impairment of consciousness and cognition, developing over a short period of time, and explained by a change in physiologic condition. The disturbance in consciousness can be a decrease in ability to focus and/or difficulty sustaining or shifting attention. The disturbance in cognition can manifest as disorientation, perceptual

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changes, alteration in memory function, or changes in language ability. This cognitive impairment must not be better explained by preexisting, established, or evolving dementia. These changes in consciousness and cognition must have developed over a short period of time (hours to days) and tend to fluctuate over the course of a day. A prodrome is frequently described in the hours to days leading up to florid delirium, characterized by restlessness, irritability, sleep disturbance, and distractibility; a review of the patient record/caregiver report may reveal subtle symptoms building over the course of a few days. A diagnosis of delirium is reached if the changes in consciousness and cognition are noted in response to a physiological change, such as medical condition, administered medication, or illegal substance use or withdrawal. When diagnosing delirium, an etiology needs to be identified (e.g. delirium due to hepatic encephalopathy). Delirium due to multiple etiologies can be diagnosed if several factors seem to be contributing; if no clear etiology is evident, a diagnosis of delirium not otherwise specified is warranted [32]. Delirium can be described as hypoactive or hyperactive, based on psychomotor behavior, and is frequently under recognized and under diagnosed [33]. Delirious patients with relative alertness, though continued clouding of consciousness (hyperactive delirium) are more likely to experience hallucinations, delusions, and illusions, as well as to exhibit agitation [34]. Hypoactive delirium is frequently misdiagnosed as depression, whereas hyperactive delirium is frequently misdiagnosed as new onset psychosis or behavioral problems. Delirium is a reversible cause of mental status changes, thus needs to be explored when evaluating aggression in an elderly patient with medical conditions. When delirium is superimposed on preexisting dementia, patients demonstrate more aggressivity, agitation, delusions, anxiety, and hallucinations as compared to their non-demented counterparts [35]. Although dementia can present with behavioral problems, any abrupt onset of change in aggression or agitation could be delirium and warrants investigation. Diagnosing delirium involves recognizing clinical features, as well as a thorough mental status exam and complete physical and neurological exams. The potential contributing medical factors need to be explored through laboratory tests and brain imaging. Electroencephalogram (EEG) typically shows diffuse slowing, though this is a nonspecific finding and most useful when a previous EEG is available (or repeating EEG after delirium resolves). A mental status exam needs to include attention and concentration tasks, evaluation of short and long term memory, visuoconstructual ability, abstraction, and language tasks including writing and naming. Once delirium has been diagnosed, prompt identification and prioritization of potential contributing etiologies is essential; etiology can be singular (less than 50% of cases) or multifactorial, averaging 2-6 contributing factors per patient [22]. Etiologic categories of delirium include: autoimmune, cardiac, cerebrovascular, drug intoxication, drug withdrawal, hypoxic, infection, metabolic disturbance, neoplastic disease, and traumatic [36]. Medications, especially opiates, benzodiazepines, and drugs with anticholinergic properties, can precipitate delirium. Table 1 illustrates medications commonly associated with delirium.

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Table 1. Medications Commonly Associated with Delirium. Analgesics Antibiotics

opiates (esp. meperidine), salicylates acyclovir, ganciclovir, aminoglycosides, amphotericin B, cephalosporins, interferon, isoniazid, metronidazole, rifampin, sulfonamides, vancomycin

Anticholinergics

antihistamines, antispasmodics, atropine, benztropine, phenothiazines, tricyclic antidepressants

Anticonvulsants

Phenobarbital, phenytoin, valproic acid

Anti-inflammatories

corticosteroids, NSAIDs

Antineoplastic Drugs

asparaginase, 5-fluorouracil, methotrexate, procarbazine, tamoxifen, vinblastine, vincristine

Antiparkinsonian Drugs

amantadine, bromocriptine, levodopa

Cardiac Drugs

beta-blockers, captopril, clonidine, digitalis, lidocaine, methyldopa, procainamide, quinidine, tocainide

Sedative-hypnotics

barbiturates, benzodiazepines

Sympathomimetics

amphetamines, cocaine, ephedrine, phenylephrine, theophylline

Others

baclofen, disulfiram, ergotamines, lithium, propylthiouracil

Compiled from: 1.) American Psychiatric Association. Practice guideline for the treatment of patients with delirium. American Journal of Psychiatry, 1999 156 (supplement), 1-20. 2.) Marcantonio, ER; Juarez, G; Goldman, L. The relationship of postoperative delirium with psychoactive medications. JAMA, 1994 272, 1518-1522. 3.) Trzepacz, PT; Meagher, DJ. The American Psychiatric Publishing Textbook of Psychosomatic Medicine (J.L. Levenson, Ed.). Washington DC: American Psychiatric Publishing Inc; 2005.

Management of Delirium The first step in managing delirium is to treat the underlying medical cause of the symptoms. Depending on the cause and medical condition of the patient, resolution of delirium could take some time; clinical duration is usually 4 days to two months, with an average of 10-12 days [37]. Psychopharmacologic treatment of symptoms may be required as delirium resolves; aggression and agitation of delirious patients are some of the first symptoms requiring treatment due to the need for safety on a medical/surgical unit or in a long term care facility. Antipsychotic medications have been shown to be effective in treating several aspects of delirium, including aggression and agitation. Haloperidol is the most frequently used, as it is a potent antipsychotic with very little anticholinergic or hypotensive side effects; it is also available in intravenous form, allowing for easier administration. Other antipsychotic medications have been shown to be effective in the treatment of delirium: chlorpromazine, droperidol, olanzapine, risperidone, and quetiapine [38]. Short-acting benzodiazepines, preferably lorazepam may be helpful if delirium is related to alcohol withdrawal; longer acting benzodiazepines should be avoided, as they do not seem to improve delirium and can paradoxically worsen aggression and agitation [39]. Other nonpharmacologic treatment can be employed, including redirection and minimizing disruptions to the environment [40]. If the delirious patient is aggressive or agitated, providing a room

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near the nursing station and a sitter may be necessary; restraints may be used if all other attempts to keep the patient and others safe have failed. The severity of the delirium typically correlates with the length of time for the symptoms to resolve; thus, early identification and treatment of the underlying cause should aid in quicker resolution of the delirium and less need for treatment of symptoms.

B. Drug-Drug Interactions One of the most common contributing factors to delirium is drug-drug interactions with associated adverse medication effects. Older patients frequently have multiple medical problems and multiple providers; they are often taking many medications and all providers may not have access to an accurate medication record. Drug-drug interactions are preventable causes of adverse drug events, increased morbidity and mortality, and higher health costs [41, 42]. Studies on the prevalence of drug-drug interactions are scarce, listing the prevalence as 1 to 66% across all age groups [43, 44]. One study focused on drug-drug interactions among the elderly and reported that the average number of prescribed medications per patient was 7.0; each patient had an average of 0.83 drug-drug interactions, with 10% of those listed as major drug-drug interactions [45]. Kohler and colleagues [46] found that the prevalence of drug-drug interactions in the elderly increases as the number of prescriptions increases. Elderly patients often present to the Emergency Department or to their primary care providers when experiencing a drug-drug interaction [47]. The clinical presentation of medication adverse effect and drug-drug interactions are identical to delirium as described above. If a timeline can be established, relating a change in medication (discontinuation, addition, extra dose, etc.) with mental status changes; the observed delirium can be directly related to a medication effect. Management of delirium caused by a suspected drug-drug interaction should consist of careful examination of recent medication administration and discontinuation, including communication with patient‘s providers, caregivers, and pharmacists if possible. Withdrawing or tapering the offending agent or combination is the first step in management of this cause of delirium. Involving the patient‘s entire medical team is recommended, as even slight adjustments in offending medications could cause other health problems. As with any delirious state, medication or environmental interventions may be employed to manage the patient on a medical/surgical floor or in a long term care facility. As the population ages and more drugs are brought to market, the incidence of drug effects and drug-drug interactions may increase. It is important for providers to coordinate care and for patients to have accurate medication information when presenting to providers in emergent or routine settings. The emergence of electronic prescriptions and medical record may help to decrease the incidence; however knowledge of drug-drug interactions is of key importance, especially in treating the older population. Avoidance of drug-drug interactions is one way to effectively prevent delirium in elderly patients. Aggression in the elderly population is a frequent occurrence on medical and surgical inpatient units, as well as in long term care facilities. In any patient with a sudden onset of mental status changes, including increased aggressive behavior, delirium should be considered high on the list of differential diagnoses. Management of delirium needs to consist

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of investigation of underlying cause and treatment of symptoms, often including aggression. Physicians and nursing staff working with an aggressive elderly patient need to work as a team to recognize delirium, determine the cause, and support the patient as symptoms resolve. Drug-drug interactions are easily preventable causes of delirium; physicians need to be aware of dangers of medications in the elderly and of drug-drug interactions in this population. Delirium is one of the few reversible causes of mental status change and has dire consequences if overlooked.

III. Aggression in Elderly Patients with Dementia Dementia is a brain disorder which manifests with clinical deficits in two or more areas of cognition which are of enough magnitude to significantly affect basic and necessary activities of daily living. Impairments typically present with memory loss and difficulties with executive function, judgment, insight, abstract thinking, visualspatial ability or language dysfunction which occurs in the context of a decline from a previous higher level of functioning [48]. The prevalence of cognitive impairment in large, community-based studies is 2.9% in the age group of 65 to 74, 6.8% in the range from 75 to 84 and 15.8% from age 85 and older [49]. Another study reported the prevalence of Alzheimer‘s dementia in the community aged 65 and older to be 10.3%, and in addition, the prevalence appears to increase by age group, with 3% in the age group 65 to 74, 18.7% in the age group 75 to 84 and 47.2% in the age group 85 and older [49, 50]. Thus, it might be anticipated that as the general population ages, the population of those with dementia will continue to grow. Approximately, 67% of dementias are of the Alzheimer‘s type followed by Vascular dementia which constitutes 15% to 25% of dementia syndromes. Lewy Body dementia comprises about 10% of dementia cases [48]. There are many less common degenerative brain disorders which manifest as dementia which include the parkinsonian dementias, as well as frontal dementias with prefrontal executive dysfunction as an earlier feature. Very rapidly progressing frontal dementias include Pick‘s Disease and Creutzfeldt-Jacob Disease [51]. It has been reported that 60% of individuals with dementia living in the community have manifested behavioral or psychiatric disturbances [52, 53]. In the nursing home population, 80% of elderly with dementia exhibit psychiatric or behavioral findings [54, 55]. Lifetime risk of psychiatric symptom or behavioral disturbances in the elderly with dementia is reported to reach 100% [53]. Agitation and aggression are relatively common in demented populations, particularly in the content of psychotic symptoms. Zimmer [4] reported that physical and verbal agitation was seen in 86% of demented elderly and was largely associated with bathing and toileting care, which can result in frequent injury to care giver staff [56]. In general, the prevalence of agitation in dementia is reported to range from 20% to 80% [57-59]. Physical aggression among community- living individuals with dementia occurs in the order of 11% to 46% [58]. Physical aggression can be manifested in association with mood disturbances, cognitive compromise, psychosis or combinations of these phenomena [60]. In Alzheimer‘s disease, major depression has a prevalence rate of 24% contrasted to 7% in

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similar populations without dementia [61]. Psychosis presents with delusions or hallucinations in Alzheimer‘s disease [62]. It has been reported that the prevalence of delusions in Alzheimer‘s disease ranges from 9% to 63% with a median of 36% [58]. Hallucinations in Alzheimer‘s disease are reported to occur at rates of 4% to 41% with a median of 18% [58, 63]. Progressive dementia generally leads to more severe behavioral disturbance, aggression and progressively worsening clinical outcomes. It is known that psychotic features and agitation are associated with decreased quality of life in the elderly [64, 65], and rapidly deteriorating cognitive functioning is associated with more severe psychosis [66-68]. Overall, it has been reported that behavioral disturbances in dementia decrease survival [58, 69]. In addition to profoundly destructive effects on the individual, psychosis and agitation with dementia cause substantial caregiver distress [70-74]. Caregiver burden and behavioral disturbances increase the likelihood of nursing home placement [75]. Additionally, behavioral disturbances in dementia are associated with increased healthcare costs [76].

Management of Behavioral Symptoms of Dementia Both behavioral and neuropsychopharmacological approaches have been applied to manage behavioral disturbances in dementia in elderly individuals. The Omnibus Budget Reconciliation Act (OBRA) of 1987 mandates behavioral management prior to the use of physical or chemical restraints [77]. Behavioral approaches to aggression in institutional care include differential reinforcement of alternative behaviors [77-79]. Limitations in these approaches among individuals with severe memory and cognitive deficits have prompted other approaches including non-contingent reinforcement to treat behavioral disturbances in elderly using a time- based method of reinforcement [77]. This technique has the advantage of higher reinforcement, ease of implementation and rapid response [77]. Other therapies that may hold promise include cognitive stimulation therapy, music therapy and educational approaches [58]. Studies [80, 81] have demonstrated reduced antipsychotic use and reduced behavioral disturbances [82] with educational approaches [58]. Nevertheless, the evidence for the overall effectiveness of psychosocial approaches has, in general, been equivocal [58, 83, 84]. Although behavioral approaches should be a starting point in the management of aggression in the elderly with dementia, pharmacological interventions are indicated when the response to behavioral disturbances is limited. Medication management, sometimes viewed as a ―chemical restraint‖, is the most common approach to aggression and agitation in nursing homes [85]. A more recent report notes that 40% to 50% of residents of nursing homes are treated with psychotropic medications affecting resident ambulation [86]. Even so, the inappropriate excessive use of antipsychotics, sedative hypnotics and anxiolytic to sedate patients has decreased since the implementation of the Nursing Home Reform Act contained in OBRA 87 [87]. Four principal classes of agents used in the management of behavioral disturbances in the elderly with dementia include the cognitive enhancers, antidepressants, anticonvulsants, and the antipsychotics.

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The use of pharmacological interventions, particularly the antipsychotics, are widely used [58]. In general, antipsychotics—particularly aripiprazole, olanzapine, quetiapine, risperidone and haloperidol, have been found in the literature to have modest effectiveness compared to placebo [58]. At the same time the literature currently indicates a higher incidence of mortality, 1% to 2% over 8 to 12 weeks, associated with treatment with atypical antipsychotics as a class [58]. The risks for cardiovascular adverse events and death after 8 to 12 weeks of antipsychotic treatment are unclear [58]. As a result this has lead to an FDA warning for atypical antipsychotics and an increased risk of stroke and adverse cardiovascular events. There have been a paucity of studies looking at comparing the typical and atypical antipsychotics which showed comparable efficacy in most studies and greater efficacy of the atypical antipsychotics in only one study [58]. However, in one study typical antipsychotics have also been reported to have a higher risk of death compared to atypical antipsychotics [58, 88]. The atypical antipsychotics, in addition, were found to be less likely to cause involuntary movement disturbances including dyskinesias and dystonias in individuals with dementia compared to typical antipsychotics [58]. Particularly, high potency typical antipsychotics are most likely to be associated with involuntary movement disturbances in the elderly [58]. The cognitive enhancers include the cholinesterase inhibitors (galantamine, rivastigmine, donepezil) and the NMDA-acting drug memantine. Efficacy of these agents in the treatment of behavioral disturbances in the elderly with dementia appear to be modest, at best, with their overall effectiveness unresolved [58, 89, 90]. Serotonin antidepressants including trazodone and the selective serotonin reuptake inhibitors may diminish aggression and agitation in a subset of elderly individuals with dementia [91-96]. The anticonvulsants have had a spectrum of reports demonstrating limited to no benefit in a subset of elderly with dementia and agitation/aggression [96-99]. With regard to the use of benzodiazepines in elderly populations with dementia, the results have been equivocal relative to therapeutic efficacy and tolerablity [58]. Of concern are reports linking benzodiazepine use and falls in the elderly [100, 101]. Overall, none of the classes of psychotropic agents nor psychosocial approaches have clearly established superior effectiveness in treating agitation and aggression in dementia [58]. All of the currently available psychotropic agents have been employed to treat other illnesses, and then their application has been extrapolated to address symptom complexes of dementia. Currently there are no specifically targeted agents for the aggressive and agitated features of dementia [58]. At the same time, the available psychotropic agents carry newly recognized risks that need to be weighed against unclear benefit. Current clinical practice requires balancing these putative unestablished benefits with known risks in the context of a thoughtful, transparent consenting process with family and patient.

IV. Aggression in Elderly Patients with Mood, Anxiety and Primary Psychotic Disorders Depression, mania, anxiety and primary psychotic illness (such as schizophrenia) at times are associated with agitation, and there is a generally positive relationship between the

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severity of depression and the level of agitation. As a possible explanation for this overlap, a model of based upon brain neurotransmitters, specifically serotonergic sensitivity, has been proposed [15]. The serotonergic sensitivity model has two types,1) a serotonin- sensitive model with manic symptoms and impulsive aggression and, 2.) a serotonin- resistant model with different agitated behaviors [15]. Stahl [102] has proposed the serotonin (5HT1) a receptor as one of the ―links‖ between these effects on emotion and behavior. Additional possible links involve other neurotransmitters such as GABA and noradrenergic transmission. These mechanisms may explain why serotonergic antidepressants drugs (SSRIs such as fluoxetine) and other serotonergic compounds (azapirones) may reduce levels of aggression/agitation. Older patients with depression, mania, severe anxiety or psychosis may have symptoms of agitation with differing components. This can be aggressive physical behavior such as fighting, grabbing, destroying things, or aggressive verbal behavior such as cursing and screaming. Non-aggressive physical behaviors include pacing, and non-aggressive verbal behavior includes constant or repetitive questioning. These symptoms are generally more frequent and prominent when individuals have cognitive impairment [60] due to inability to analyze the environment or feelings experienced during stress.

Geriatric Mood, Anxiety and Primary Psychotic Disorder: Prevalence and Symptoms Depression Geriatric depression is a growing problem which is under-recognized and under-treated. It has been estimated that the prevalence of major depression in the general population is 12% with depressive symptoms affecting as much as 15% of older persons [103]. Major depression is one of the leading causes of disability in adults, and in the elderly may have an additive effect to medical illnesses creating an increase in morbidity, mortality and placement in nursing homes. Late- life depression is a heterogeneous syndrome that may occur in the context of cognitive impairment, structural brain abnormalities, and other psychiatric and medical comorbidities which are frequently associated with poor treatment responses. Medical comorbidities are very common among older adults with depression and are risk factors for the development or worsening of depression, with depression itself being a risk factor for medical illnesses. Depression plus physical problems leads to increased morbidity, high levels of disability with frequent hospitalizations and nursing home placement and an increase in mortality. Currently there is substantial literature documenting the complex relationship between depression, cardiovascular and cerebrovascular disease, with evidence that depression is associated with a greater number of re-hospitalization days after angioplasty or myocardial infarction [104, 105]. Also 20-30% of patients develop depression after stroke with left- sided stroke more likely to be associated with early- onset depression [106]. The diagnosis of depression relies heavily on somatic such as changes in sleep, weight, appetite, levels of energy and psychomotor activities. These symptoms can be caused by medical (non-psychiatric) comorbidities making them ―exclusionary‖ criteria for the

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diagnosis. In these cases it is important to pay attention to the ―psychological‖ symptoms such as sadness, unhappiness, inability to enjoy things (anhedonia), isolation, irritability, anger and delusions/hallucinations. A challenge in the evaluation of geriatric patients with mood disorders is the patient who appears to be suffering a depressive syndrome but denies that s/he is depressed, creating a ―clinical‖ diagnosis of ―masked‖ depression. Aggressive behavior is most generally seen in individuals with the more severe types of depression, but as noted previously are amplified when dementia or cognitive impairment is present. Bipolar Disorders Elderly patients with bipolar disorders represent 5-19% of the patients presenting for acute treatment within geriatric psychiatric services [107]. These patients represent a mixed and complex set of patients with frequent comorbidities, poor outcomes and in many cases, high morbidity and mortality rates. It has been generally accepted that the type and range of manic symptoms in the elderly are similar to the general population but with a tendency to be of lesser severity and intensity. Co-existing symptoms of depression and mania are fairly common in bipolar elders with increasing symptoms of irritability or aggression corresponding to increased illness severity. Some patients have ―mixed‖ presentations with manic symptoms and perceptual abnormalities such as delusions and hallucinations. Some patients will show ―dis-inhibition‖ symptoms such as pathological laughing with lesions of the right side of the brain and pathological crying with lesions on the left side. Secondary manias (mania associated with medical or neurological disease) are associated with other behavioral or physical symptoms indicating head injuries, alcoholism, tumors, endocrine disorders, AIDS, silent cerebral infarctions, medications and multiple sclerosis. Anxiety Disorders The prevalence rates for anxiety disorders in older adults range from 3.5% to 10.2% suggesting a higher prevalence than late-life depression with increased incidence among those who are home-bound, living in a nursing home or those with other comorbidities. The prevalence of anxiety symptoms may be as high as 20% [108]. Generalized anxiety disorder (GAD) is highly prevalent in the elderly, with a reported rate of 7.3% . Panic disorders have a prevalence rate of 0.1-1%. Phobias range from 3.1% to 12%. Older patients with anxiety disorders report similar symptoms as do younger patients, but with the confounding situation of comorbid medical conditions. Patients suffering anxiety disorders may have a series of ―physical‖ symptoms which in many cases are the symptoms causing the patient to seek medical help. Somatic symptoms such as tachycardia, chest tightness, vertigo, tremors, sweating, dizziness, paresthesias are common in medical and anxiety problems. Aggression is uncommon with anxiety disorders unless overall illness severity is relatively high. Schizophrenia Most individuals with schizophrenia first develop the illness in young adulthood, although it is known that some individuals experience a later-onset form (sometimes called ―paraphrenia‖) after age 45 or beyond. Thus older adults with schizophrenia comprise individuals with illness of varying duration and time of onset. In the large scale

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Epidemiological Catchment Area (ECA) survey of psychopathology in the United States general population, the reported 1 year prevalence rates for schizophrenia were 0.6% for people aged between 45 and 64 and 0.2% for those over 65 years [109]. A review done by Harris and Jeste [110] reported that 23.5% of patients with schizophrenia had an onset after the age of 40 with 3% after the age of 60. In several studies reported between 1955 and 1993 it was found that the frequency of late-onset schizophrenia among patients in psychiatric facilities had a range from 3 to 10% [111, 112]. The older person who develops psychotic symptoms represents a diagnostic and management dilemma for the clinician. The aging process is a risk factor for the development of psychosis, and if the patient presents cognitive deficits it is difficult to determine if the psychotic symptoms are part of a dementia process or a primary psychotic disorder such as schizophrenia. Patients with late-onset schizophrenia show a generalized pattern of cognitive deficits that are similar to the patterns of young patients with schizophrenia, but different from cognitive deficits in patients with dementia of the Alzheimer type, with the schizophrenia patents generally preserving their learning capacity. Delusions are the most common presenting symptom of late-onset schizophrenia. Persecutory delusions are most frequent but other delusions are not uncommon. Howard et al [113] reported delusions of reference in 76% of elderly patients, noting that auditory hallucinations are common while formal thought disorders and negative symptoms are uncommon. Arango et al [114] reported that schizophrenic patients posing the greatest risk for violent behavior appear to be those who show suspiciousness and hostility, have more severe hallucinations, show less insight into their delusions, experience greater thought disorder and have poorer control of their aggressive impulses.

Treatment of Elderly Populations with Mood, Anxiety and Primary Psychotic Disorders If a patient suffers an affective disorder it has to be determined if the agitation is caused by a unipolar depression or a bipolar disorder. This differentiation is easy to make in some situations but it becomes more difficult when the diagnosis under consideration is a psychotic depression or an agitated depression. A psychotic depression is defined as the occurrence of delusions or hallucinations in the setting of a major depressive disorder and may occur in as much as 15% of all depressed patients. Patients with agitated depression have increased psychomotor activity and may exhibit pacing, hand wringing, nail biting, hair pulling, incessant smoking, and incessant talking. A similar situation can happen with patients suffering an exacerbation of symptoms of a schizophrenic disorder. The first step in dealing with these patients is to ensure the safety of the individual and those around them. Patients in these conditions should be approached in a non-threatening matter, if necessary with a show of force provided by trained personnel. The cautious use of sedation with intramuscular (IM) medication and seclusion and/or physical restraints may be necessary to guarantee the safest setting in which to administer evaluation and treatment. In cases of severe agitation the use of antipsychotic medication continues to be the first line of treatment despite the ―black box‖ warning in the manufacturer‘s package insert added

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to all antipsychotic (conventional and atypical) specifying the ―Iincreased risk of mortality in elderly patients treated for dementia-related psychosis‖ [115]. A meta-analysis done by Schneider [116] (in elderly with dementia) compared seven studies done between 1966 and 1989 resulting in improvement of 41% for placebo and 59% for active medication. Other studies done after 1990 confirmed these observations, but showed moderate to significant extrapyramidal symptom (EPS) side effects with haloperidol when the dose is 2-3 mg a day. For this reason, most clinicians recommend that elderly patients who require typical antipsychotic drugs receive doses approximately equal to 25-50% of the regular adult dosage. Compared to older, conventional agents, the atypical antipsychotic drugs offer different side effects profiles including less EPS but potentially more orthostatic hypotension, cardiac arrhythmias and/or autonomic dysfunction. Metabolic derangement and propensity for diabetes can occur with longer term use of atypical antipsychotic medications. Among the atypicals the ones which have been most studied are risperidone and olanzapine [58] Risperidone has been shown to reduce psychosis and agitation with relatively few side effects at doses below 2 mg a day [117, 118]. Olanzapine has been shown to be effective in reducing agitation and psychosis with relatively low side effects with doses between 2 and 15 mg per day. Both risperidone and olanzapine can be given orally, utilizing rapid dissolving tablets that may be helpful in the elderly who are unable to swallow pills. In patients that require IM medication the alternatives for treatment are haloperidol, olanzapine, ziprazidone and aripiprazole. The recommended doses for geriatric patients, consistent with most elderly vs. younger populations, are 25-50% of the regular adult dosage. Once the acute clinical state has been treated and resolved, the urgent treatment of the basic psychopathological state needs to be addressed. It is important to decide if the patient is suffering a bipolar disorder or a unipolar depression. This distinction is critical because if the patient is suffering a bipolar disorder the treatments of choice are ―mood stabilizers‖ such as lithium carbonate or valproic acid, but if the patient is suffering a unipolar depression or an anxiety disorder the treatment of choice will generally be antidepressant medications. While the treatment of depression in older patients often requires the use of medication treatment, effectiveness is increased if medication is combined with psychotherapy. According to meta-analysis done by Wilson and Mottram [119] the SSRIs and TCAs have comparable efficacy and tolerability. A similar statement can be made about the efficacy and tolerability of SNRIs. Selegiline, a selective MAO B inhibitor has been studied in older populations with Schneider and Sobin showing improvement in behavior, cognition and mood [120]. The main concern with these medications in the elderly is the potential for interactions with other medications and diet. The availability of a transdermal antidepressant patch may be useful in some patients with difficulties taking medications. Psychotic depression occur in approximately 20-45% of hospitalized depressed elderly patients. Despite its relative frequency, that there is a lack of empirical data in the treatment of patients with depression accompanied by psychotic symptoms. The Expert Consensus Guidelines suggest the combination of an antidepressant and antipsychotic medication or electro convulsive therapy (ECT) as treatments for geriatric psychotic depression [121]. ECT has been found to be particularly effective in moderate to severe depression and depression

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with melancholic features, and in the case of psychotic depression, catatonia or treatment refractory conditions. Bipolar Disorders The literature about the pharmacological treatment of older patients suffering a bipolar disorder is limited. Nemeroff [122] showed in patients 21 to 71 years old that a combination of paroxetine and lithium was more efficacious than lithium alone. Robillard [123] reported that lamotrigine was useful in addition to lithium or divalproex, and also useful in the maintenance of geriatric patients with bipolar disorder. Other alternatives are the use of the combination fluoxetine/olanzapine, the antipsychotic quetiapine or ECT in patients with manic episodes. In terms of the dosing of lithium, some clinicians suggest the utilization of the same lithium blood levels utilized in mixed aged adults, but there are reports of toxic reactions with this strategy motivating others to utilize lower blood levels (between 0.5 and 0.8 mEq/L). It is important to keep in mind drug-drug interaction and comorbid conditions in bipolar elders. Sajatovic and colleagues [124] have reported that older adults with bipolar disorder discharged from a geropsychiatric unit had a mean 3.7 medical illnesses --- a ready setting for drug to drug interactions. There is good evidence that the use of divalproex in the treatment of mania and mixed episodes is efficacious and well tolerated but the studies involving older patients are limited [125]. While medications such as aripiprazole, olanzapine and quetiapine have been approved by the FDA for the treatment of manic episodes in mixed-age populations, there is little data regarding the efficacy of antipsychotic medication in the treatment of geriatric bipolar disorders. Schizophrenia When psychotic patients present with agitation due to an exacerbation of symptoms the treatment of choice must be directed to the management of the agitation in a safe and rapid way. The first step is to ensure that the patient and the people around are safe from physical danger. Patients in these conditions should be approached in a non-threatening matter with a show of force provided by trained personal. Sedation with intra-muscular (IM medication) and seclusion and/or physical restraints under careful supervision may be necessary to guarantee a proper treatment and evaluation. Antipsychotic medications are the most effective symptomatic treatment for both earlyonset and late-onset schizophrenic disorders. Because of age- related bodily changes that may affect the pharmacokinetics and pharmacodynamics of these medications in the elderly it is important to follow the principle of ―start low and go slow‖ when using them. The decision of which antipsychotic to use is very much predicated on the side effect profile of the particular medication in question. Significant improvement of psychotic symptoms has been reported with the typical antipsychotics haloperidol, trifluoperazine and thioridazine [126]. Typical antipsychotics have a wide variety of side effects related to their high affinity for the dopamine receptors. They also have anticholinergic and adrenergic side effects. For example, thioridazine produces the longest prolongation of the QT interval making this medication generally unsuitable for use in the elderly population. Atypical antipsychotics have become the standard of care for their effectiveness with positive and negative symptoms and their relative lack of dopamine- related side effects (parkinsonian syndrome, akathisia, dystonias and tardive dyskinesia) but they are not free of

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side effects. Besides causing sedation and hypotension they may also produce prolongation of the QT interval as well as weight gain and serious metabolic side effects including causing or worsening diabetes [126]. Other medications commonly utilized in these cases are the short- acting benzodiazepines with lorazepam being the most utilized. Once the episode of agitation is controlled most patients are placed on regular, oral antipsychotic medication. Patients with adherence problems must be considerd to be candidates for long acting medications such as haloperidol decanoate and long-acting, injectable risperidone. Howard and Levy [127] reported good outcomes, good adherence, and a reduced amount of medication with long acting- neuroleptics in older patients with psychosis. Anxiety Disorders Naturalistic studies looking at patients treated in primary care clinics for anxiety disorders point toward the use of anxiolytic or antidepressant medications in older patients but there is a lack of systematized studies. Despite side effects and problems with cognition and falls, benzodiazepines remain the mainstay of pharmacological therapy for acute management of anxiety and panic disorders and as an initial adjunct to therapy with SSRIs or SNRIs. These medications are beneficial because they have a rapid onset and little effect on the cardiovascular system. On the other hand the long term use has potential problems such as excessive daytime drowsiness, cognitive impairment, and confusion, increase risk for falls, respiratory problems and dependence potential with withdrawal syndromes. Because of the withdrawal syndromes it is recommended that older patients taking benzodiazepines for 4-6 weeks be tapered off them for at least 2-4 weeks. For the older patient the recommended benzodiazepines are the ones with short half-life such as lorazepam, oxazepam and temazepam as they are inactivated by direct conjugation in the liver which is a mechanism minimally affected by normal aging. Several studies have shown the efficacy of antidepressants in the treatment of anxiety disorders in the elderly. Sheik [128] found that imipramine and alprazolam were better than placebo in the treatment of anxiety. In another study the same authors showed that sertraline had a significant effect in the symptoms of anxiety. In one of the few prospective, randomized trails, Lenze and colleagues, demonstrated that citalopram was better than placebo in the treatment of generalized anxiety (GAD) (65% -vs- 27%) [129]. In a secondary analysis evaluating individuals age 60 and older, from several multicenter studies, Katz and colleagues [130] found a significant positive effect by venlafaxine in the treatment of symptoms of GAD. Azapirone and buspirone, as reported by Rickels and colleagues [131] have efficacy comparable to diazepam in patients with generalized anxiety disorder. Boehm and colleagues [132] reported that buspirone is well tolerated by geriatric patients and is effective for the remediation of chronic anxiety. Despite the results of some of these clinical studies the experience in ―real world‖ clinical settings has not been satisfactory, creating the impression of inconsistence therapeutic results. Finally, other drugs utilized for the management of anxiety are antihistaminics such as hydroxyzine, beta blockers and antipsychotics but there are no good placebo controlled studies or the presence of side effects has precluded their use in the older patients.

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Non-Pharmacological Interventions Elderly individuals suffering depressive, anxiety or bipolar disorders may benefit from psychotherapeutic interventions. A wide variety of therapies have been utilized with these patients but there is a scarcity of systematic, prospective studies. At present there is evidence showing that cognitive behavioral therapy and interpersonal therapy are probably the first line of non pharmacological intervention, and it is generally accepted that the utilization of psychotherapy plus medication is better that one of the two modalities alone. This has been studied for cognitive behavioral therapies [133]. Interpersonal therapy (IPT) has been studied and shown that is as effective as nortriptyline in older adults with fewer drop-outs [134]. Other therapies utilized but less studied are: Reminiscence Therapy, Brief Dynamic Therapy, Problem-Solving Therapy, Group therapy and Couple and Family therapy [135].

V. Future Outlook and Needed Research Unfortunately, as is evident from the preceding text, treatment research on late-life aggressive behavior has lagged behind the pace of the growing population. Without appropriate management, aggressive behavior in the elderly has profound personal and societal consequence. For example, the older individual with dementia might be placed in a nursing home because his elderly spouse is unable to manage transient aggressive behavior. There is a critical need for greater understanding of biological and psychological underpinnings and precipitants of late-life aggression. Additionally expansion of evidence – based assessment protocols as well as treatments are essential. Treatments should ideally minimize both adverse effects on the individual as well as reduce burden to caregivers and families. Three main types of interventions to manage aggression in older adult populations are currently being utilized. They are behavioral interventions, educational interventions and pharmacological interventions. All of these avenues both separately and in combination should be explored in order to refine and improve outcomes.

VI: Final Commentary Aggressive behavior in elderly populations is common and can be associated with acute medical conditions, toxic states, neurodegenerative conditions and acute or chronic psychiatric disorders. It is clear that population trends predict growing numbers of older adults and it is anticipated that there will be a great need for effective treatment approaches that minimize aggressive behavior and the effects of aggression in elders with a variety of medical, neurological and psychiatric disorders. Current treatments appear to have efficacy in clinical trial settings, but have limited effectiveness in real-world, clinical settings. Public awareness of this growing problem, and large-scale exploration of treatment methods and technologies are essential in order to meet future healthcare needs of this population.

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In: Melatonin, Sleep and Insomnia Editor: Yolanda E. Soriento

ISBN: 978-1-60741-859-7 ©2010 Nova Science Publishers, Inc.

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 唐秉輝 Bingh Tang1 and Lyn Tiu2 1

New York College of Traditional Chinese Medicine, Mineola, Long Island, NY USA 2 Danville, California USA

Abstract 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 article 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.

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With advancing age, age-related changes have been described for sleep–wakefulness 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.

Keywords: Asian, Body weight, Body Mass Index, Sleep Disturbance, Older adults

Selected Abbreviations ad Acronyms Apnea-Hyperpnoea-Index (AHI), Body Mass Index (BMI) Coronary heart disease (CHD) National Cholesterol Education Program (NCEP) National Heart Lung and Blood Institute's (NHLBI's) guidelines for body weight Spearman's rank correlation coefficient (rs)

Introduction Sleep Disturbance in the elderly population is not uncommon. One of the most common complaints of sleep disturbance is insomnia.. Whether it is a solitary disorder or merely a symptom is still unclear. In the Philippines, it is noted that, for exa,ple, insomnia has its prevalence in non-governmental community dwelling elderly individuals in a dwelling facility in Quezon City was 43%, and they were mostly females (Kamble 1979): Philippines poverty assessment). The prevalence of chronic insomniac (>4 weeks) in that facility was enormous female predominance, which was accredited to the much larger proportion of females in the dwelling association, about 92% of 2,200 members. Table 1. The relationship of BMI in the elderly people in the Philippines and Taiwan Country Age (y) The year of survey Prevalence Underweight, BMI< 14.8 Overweight, BMI > = 30

The Philippines 69.3 (7.2) 1996

Taiwan 69.9 (7.2) 1999

29.9 % 12.2%

6.4% 29.3%

As per Jenkins et al (Jenkins et al 2007), the data from two nationally-representative surveys of older adults (aged 60 and older) in the Philippines (1996) and Taiwan (1999) to assess the prevalence of underweight and overweight and examine associations between body weight and demographic, socioeconomic, and health characteristics in these populations. The reverse is observed in Taiwan (6.4 and 29.3%, respectively).

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Table 2. Comparison of Different Sleep Studies between two Societies in three hospitals Setting

Number of participants Age range (yr) Gender F/M Mean age Exclusion criteria

Health insurance coverage Height cm Weight kg [[190.5, 46.31 BMI kg/m2 Neck circumference cm

AHI events/hr 60 Taichung area Taiwan Liu and Liu

Oregon State The US Tractenberg et al

The literature estimates the prevalence of snoring from 25 to 83%, with that of insomnia from 10 to 69%.

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Snoring As a comparison, it is interesting to notice that in the U S, a) on Tractenberg et al's reports (2003, 2006), the criteria of the frequency of snoring is defined as: 0 for never; 1 for less than once per month; 2 for at least once per month; 3 at least once per week; and 4 nearly everyday per day/night. b) those reports encounter the issue of the level of awareness of the sleep disturbance problems in the reporters at nights. Conversely, the literature estimates the prevalence of habitual snoring in general population ranges from 3.6% to 35.7%. (Rice et al, 1986; Koskenvuo et al; Young et al, 1993) In one of the studies in Taiwan (Tang, 2007), it investigated the subjects of a sleepmedicine-laboratory based cohorts, who lived in the dwelling communities of Changhua area, Mid-Taiwan, which is adjacent to Taichung area. The snoring prevalence in Taichung area, Taiwan is 47.8 % for males, whereas 37.2 % for females with age ranging from 10 to older than 60 years, all together 1,252 people who were successfully interviewed, whereas 606 were males and 646 were females, according to a report by Liu and Liu (2004) on the prevalence of snoring in a regional area of Mid-Taiwan. Snoring as a risk factor for stroke has been reported in the Philippines as well. Sawit (2006) has extensively reported with its relevance to sleep apnea. Snoring is a not only an independent risk factor for acute vascular disease, but also a factor for stroke and myocardial infarction. In addition, habitual snorers are more at risk for acute vascular disease compared to occasional snorers. Taiwan is short of such studies except one by Liu & Liu (2004). They merely reported the prevalence of snoring in a regional area of Mid-Taiwan. Further studies to inquire on the relationship of sleep apnea with snoring in Taiwan should be done.

BMI and Environment BMI has been affected by urbanicity and obesigenic nature of environment. For example, I-lan County, located at the northwestern region of Taiwan, is a rural area with high labor work (e. g. farming). There, body weight tends to be lower. Urbanites tend to have higher BMIs than their rural counterparts. As rural area became more urbanized in I-lan County, the relationship between urbanicity and obesigenic nature of environment merits further consideration. In Taiwan and the Philippine societies, modernization of certain rural areas leads to an increase in their body weight. This aspect of modernization has exerted a strong influence on the debates on the role of agriculture as a prerequisite for developing countries. Ishikawa (1967), Johnston ( 1969), Kelley and Williamson ( 1971), and Hayami (1974) to contribute to this debate.

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The Comparison of BMI among Three Sleep Studies between Two Societies Three studies between two societies are contrasted. BMI was marginally not significant upon independent sample t test (p= 0.069) in the Taiwanese (Tang, 2007) study, whereas that of the Filipinos Conde-Corpuz's study was significant (p=0.001) as tabulated in Table 2. In Table 2, the t test instead of the Mann Whitney test was used in the Filipino CondeCorpuz's study. The updated census data for Taiwanese BMI (2000) was 18.5-24 (applied to all ages), issued by the Health Department of Taiwan ( http://www.doh.gov.tw/ ). An earlier (19931996) survey conducted by the same department concluded that BMI for subjects with 19-44 years old > 26.4 would be classified as obese. The census data of BMI in the period from 2001 to 2003 was 20-24.9 ( http://www.doh.gov.tw/ ). With respect to the comparison of BMI (and other basic parameters) between non-snores and snorers in two different societies, by examining Table 1 of this article, it is, as well, noted that in the Taiwanese study (Tang, 2007), the difference of BMI between non-snores and snorers is 2.02; that in the Filipino study in Table 1 is 4.3, twice that of Taiwanese study (Table 2). All AHI values in Table 3 have been dichotomized at a level of 5. BMI was a result has become marginally not significant upon independent sample t test (p= 0.069) in the Taiwanese study, whereas that of the Filipino Conde-Corpuz's study (Conde-Corpuz) was significant (p=0.001) (Table 3).

The Significance of Marginally Not Significant (P Value = 0.069, Instead Of 0.05) in Measurement (Table 3) With regard to the fact that AHI values in Table 3 have been dichotomized at a level of 5 and BMI was a result has become marginally not significant upon independent sample t test (p= 0.069) in the Taiwanese study, it merits evaluation as follows. The p value suggests a "very small amount of evidence in support of the null hypothesis". It does not suggest that the difference (the alternative hypothesis) is true, because p-values are strictly related to the null, and not the alternative, hypotheses. Thus, a p value = 0.069 is "marginally not significant" is the most appropriate; one should not attribute any characteristic apart from marginality to the p-value.

The Importance of Gender Factor The prevalence of OSA in patients up to the age of 60 is two times higher in men than in women (Franco, 2004). The gender data on BMI in one of the Taiwanese study (Tang, 2007) is consistent with the literature.

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The Importance of Who was Doing Measurement of Height and Weight In Denmark and the U S, a self-reported measurement of height and weight is strongly i practiced. The height and weight data are predictors of health outcomes (Stunkard & Albaum, 1981; Troy et al., 1995). Most studies involving BMI are in conjunction with data of height and weight. The key issue is whether they are self-reported or not. In a Taiwanese studies (Tang, 2007), a clinical research was carried out on individuals aged from 65 to 88.5 years; PSG technologists measured 117 individuals‘ height and weight before PSG testing. BMI was then calculated. There was no chance for self-reported bias. Anthropometric indicators of height measures may underestimate BMI because people of short people may over report their height, and heavy individuals may under report their weight (Black, Taylor, & Coster); this aforementioned can happen in any society regardless of cultures.

The Significance of Asian BMI Researchers modified WHO expert committee‘s suggestion and used the criterion of > = 27 instead of >= 30 for Asian BMI. The upper limit of normal BMI in Far-East Asian is 23.5 kg/m2 from new WHO data. Obesity in Asia, as in Singapore nationwide, is defined as BMI >23. Asian nutritionists are inclined to apply a limit of BMI > 23kg/m2 for obesity due to lower stature and body weight in Asians. Asian BMI allows for a smaller skeleton (physical) frame, of most Asians. For every height, weight is set lower to compensate for the smaller frame. The current WHO data the upper limit of the normal Asian BMI is 23.5 kg/m2; this been as well applied in Singapore nationwide. Singapore nationwide protocol reveals that the scales that have been compiled using a nationwide survey data in Singapore. If one is not an Asian or an Asian descendent, Asian BMI will not be applicable. For example, census data of BMI from 2001 to 2003 in one of Taiwanese studies (Tang & Chen, 2003) is 20-24.9 kg/m2 . Obstructive sleep apnea (OSA) may not be uncommon in Asian and Southern Pacific patients (Tan W. C., 2004) compared to what has been reported for Western patients (Duran J et al, 2001; Redline, S. et al, 2004). Several studies comparing OSA between Caucasians and Asians have shown that Asian subjects have a greater severity of illness, as indicated by high AHI, when contrasted with Caucasian patients matched with age, gender, and BMI (Fletcher, 1995; Pawer et al, 1996). Asians generally have a higher percentage of body fat than Caucasians. Hence, making cross-ethnic comparison of body structures by using absolute BMI values may be misleading. Obesity is associated with an increased risk of OSA. (Young, Peppard, Gottlieb, 2002; Fletcher, 1995; Pawer et al, 1996; Hoffstein et al, 1991). Therefore, OSA‘s association with BMI in Asia should be evaluated with Asian BMI criteria.

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Underweight The risk of being underweight (instead of normal weight) increases with age in the Philippines and Taiwan. In one Taiwanese Sleep Study (Tang 2007), 3.22% of the studied cohort was underweight. Another Taiwanese cohort of 778 cases was recruited in the multinational Global Lower Extremity Amputation (LEA) Study. Risk factors included age, sex, smoking, BMI, hypertension, systolic (SBP), diastolic blood pressure (DBP), and LEA level. Mortality was ascertained from the National Death Registry. With a follow-up period of up to 6.5 (median: 4.0) years and 1239.17 patient-years, 214 patients died. The underlying cause of death was recorded as diabetes mellitus; 57.9% died. After adjustment for age and sex twp variables, then smoking, SBP and underweight are predictive for mortality. (Tseng, 2007)

Underweight and Overweight A sleep-laboratory-based Taiwanese study, using Asian BMI criteria, for those subjects who were underweight: with the BMI of 18.5 included 0.85% of the population. For those with the BMI< 18.5, it was three times greater, 2.56 % (Tang, 2007). Tang stressed the importance of Asian BMI, the upper limit of normal BMI in Far-East Asian is 23.5 kg/m2. (Table 6) Table 6. The data of a national survey in Taiwan that was conducted in 1999 * Variables Age (years) Height (cm) Weight (kg) BMI (kg/m2)

Male (n = 1,243)

Female (n = 1,189)

72.7 (72.1–73.2) 162.9 (162.6–163.3) 61.4 (60.7–62.1) 23.2 (23.0–23.5)

73.0 (72.5–73.4) 149.9 (149.3–150.5)* 53.9 (53.0–54.8)* 24.0 (23.7–24.4)*

* Elderly Nutrition and Health Survey in Taiwan (1999–2000): research design, methodology and content' was not published until 2005.

Among other studies that adapt Asian BMI criteria, in Taiwan, there is a study for checkup population in 2001 used mean BMI in Asian criteria compared with socioeconomic status (SE) for the elderly aged 65 years and over. (Chien, K.L., 2004) Due to changes in socioeconomic status and dieting habit, there are other publications that employ Asian BMI criteria. There were reports on dietary changes from 1978 to 2003 in the Philippines. The relationship between BMI and Sleep Apnea has been identified. Trends of dietary changes from 1978 to 2003 in the Philippines might affect the composition of BMI, and thus secondarily influence sleep apnea. The expanding Filipino economy from 1998 to the 2003 reduced the consumption of starchy roots and tubers from 37 g/day in 1978 to 19 g/day in 2003. (Jenkins at el, 2007). Conventional and cultural food consumption is primarily from yams and tubers is diminishing. A double burden of malnutrition and high food costs

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was illustrated in case studies carried out in six developing countries (FAO Corporate Document Repository of the Philippines). Such a trend might affect the composition of BMI, and thus consequently affect sleep apnea. In Taiwan, there is the higher proportion of underweight people among the elderly (70+) than among the near elderly (53-69 y). In Taiwan, an analysis reveals that with a sample size for the elderly cohort (70+ years) and near elderly cohort (53-69 years) 1855 subjects, and near elderly cohort (53-69 years) 2014 subjects , the number of was 211 for the elderly and 65 for the near elderly respectively. When expressed as a percentage, the values are 1.13% for the former, and 0.32% for the latter (SA and Larsen, 2007). Based on clinical studies, body weight peaks in the 50s and remains stable or decreases after the mid- or late 60s. The weight data for Taiwanese elderly data seem to fit this pattern. Underweight is more prevalent in the Philippines (29.9%) than in Taiwan (6.4%). By comparison, overweight is more prevalent in Taiwan (29.3%) than in the Philippines (12.2%) (Jenkins et al 2007) This difference can be attributed to the level of economic development and their impact on nutrition transition of the two societies. Different sets of factors are related with the two extremes of body weight. The risk of being underweight instead of normal weight increases with age in both countries. Old adults aged from 70 to 80 years have had less exposure to the nutrition transition towards the Western diet than those aged from 50 to 70 years. A cohort effect might explain why 50 to 69 year Taiwanese adults have a greater risk than the older old Taiwanese adults, aged from 70 to 80 years of being overweight instead of normal weight. The absence of this pattern in the Philippines may be due to its lower economic development relative to what in Taiwan. Men are generally less likely than women to be either underweight or overweight. In the Philippines, almost 30% of older adults are underweight. (Table 1) A study of under-nutrition in Taiwan follows. A simple questionnaire adopted from the Mini Nutritional Assessment (Sa & Larsen, 2007) was recently employed as a preliminary screening method for Taiwanese elderly individuals who were at increased risk of nutritional inadequacy. The proportion of Taiwanese elderly who were regarded at the high risk of under-nutrition increased with age, ranging from 0.88% for 53 to 60 year-old subjects, 1.86% for those subjects aged 60 to 70 years, 3.6% for those from 70 to 80-year-olds, and 5.3% for those subjects aged older than 80-year-old (Tsai, A). Not surprisingly, different sets of factors are related with the two extremes of body weight. There are both similarities and differences in predictors across settings. The risk of being underweight instead of normal weight increases with age in both settings, because of a cohort effect; the older old adults have had later and lesser exposure to the nutrition transition towards the Western diet than have the younger old adults. A cohort effect might also explain why younger-old (50 to 69 year old) Taiwanese adults have a greater risk than the older old (70 years and over) Taiwanese adults of being overweight instead of normal weight. The absence of such a pattern in the Philippines may be due only to its lower level of economic development relative to Taiwan. (Table 1) Several studies comparing OSA in Caucasians and Asians have shown that Asian subjects have a greater severity of illness, as indicated by higher AHI, contrasted with Caucasian patients matched with age, gender, and BMI. Asians generally have a higher percentage body fat than Caucasians of the same matched items. Hence, making cross-ethnic

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comparison of body habitués using absolute BMI values may be misleading as previously mentioned. Culture and eating habit have to be taken into account. For example, the people in Gujarat state of India are mostly merchants, instead of farmers; they are fond of food made from sweets. Generally, the prevalence of being overweight will become much greater in urban areas and among the rich. The relationship between obesity and socio-economic status (SES) has been altered as countries develop. Likewise, that between obesity and urbanicity will change as countries grow. Urbanites are inclined to have higher BMI than their rural counterparts. Other studies have found differences by age and gender. Therefore, BMI has been affected accordingly, which in turn influences sleep apnea. The drawback of one of the Taiwanese studies (Liu & Liu, 2004) is the lack of BMI data. Both Taiwanese and the Filipino other studies cover weight, height and BMI data. Nevertheless, there are still some issues that bear further studies. There are clues to determine and to find the subgroups that are most vulnerable to abnormal weight, which is affecting BMI, but not height. Adequate attention should be paid to the localities where economic development that benefits only the urban elite, such as in Brazil (Jenkins et al, 2007). Visceral fat accumulation of obese and overweight patients should be considered. The secondary increase of the negative intrathoracic pressure by respiratory efforts may play a role in the pathophysiology of SDB. The standard PSG used in most of sleep studies does not include the measurement of esophageal pressure (Pes), which represents the intrathoracic pressure. Hence, the upper airway resistance syndrome is often overlooked because the severity of OSA has already been evaluated by the AHI. Obesity, BMI and socioeconomic status (SES) are important issues. Huang et al (2005) report on obesity in the elderly and its relationship with cardiovascular risk factors in Taiwan. Conversely, there is a study that assesses the association between socioeconomic status (SES) and overweight and obesity among near elderly (aged 53-69) and elderly (age 70+) people, using a longitudinal survey data in Taiwan. In mainland China, status and current income were positively related with BMI among near elderly and elderly men. SES was not associated with BMI in elderly women, while education was inversely related with BMI among near elderly women. The shifting of paradigm in the relationship between SES and overweight/obesity between near elderly and elderly women suggests a budding social inequality in overweight and obesity in Taiwan. The signs indicate that prototypes of social gradients in obesity are acclimatizing to socioeconomic and cultural background (Sa and Larsen , 2007). There is some complementary provision that the desirable body image may also become more westernized. A propensity in the cultural insight of body weight is currently affected on the younger generation by fashion-models. This prevails in societies that where the younger generation wants to be more fashionable, while among the older generation wants to be 'slimmer'. The above tendency is found in the Philippine, Taiwan, in other Asian countries like India. The traditional culture of Taiwanese and the Philippines tend to recognize a more appealing physical body structure. Such structure contrasts to the existing Western physical standard to be socially acceptable, presentable and desirable. Working through examples can help highlight the issues involved and demonstrate how to conduct a possible solution. More extensive comparisons may assist in recognizing the

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subset groups that are most susceptible to abnormal body weight, and consequently, lead to hypertension and then to sleep apnea. It would be practical and educational to account for the role of public health and sleep hygiene together with National Cholesterol Education Program (NCEP). Conceivably, nutrition programs that keep a tight rein on hypertension and excessive weight will prevent sleep apnea for all the steps of the social-class ladder and the rich and poor in both societies. Obviously, both developed and underdeveloped countries conceivably need more sleep studies (See Tables 1-5). Patterns of being underweight and overweight, which affect sleep apnea, should be studied in more details in both societies.

Cigarette Smoking In the Philippines, the population is predominantly young. Cigarette smoking is a problem. In the Philippines, cigarettes can be bought one at a time, which makes them easily accessible to adolescents and children. Increasing fat intake, diabetes, high cholesterol levels, and CHD are now increasing health problems in the adult population. The population is spread over many islands, and there are diverse ethnic groups. Thus collecting epidemiological data is difficult. One of the unusual strengths in gathering data is that the Philippines are well supplied with dietitians. Filipino experts are committed to continuing health education. In Taiwan, the elderly people are increasing in number. Unfortunately, the problem of sleep disturbance in the elderly has not been sufficiently studied. However, there is a repot on 6,406 adult subjects (41.4% women) from January to December 2001 from the healthscreening program in a tertiary hospital. C reactive protein (CRP) was found positively related to smoking status (Chien K. L. et al, 2003) High CRP levels were strongly associated with metabolic syndrome. CRP significantly associated with smoking and metabolic syndrome. Inflammation, smoking and atherosclerotic risks were interrelated among healthy young and elderly Taiwanese. (Chien KL et al, 2003) For elderly adults, CRP's relationship with sleep disturbance needs further evaluation in the two societies. It is unclear which metabolic syndrome risk factor components could predict CRP levels and possible interaction with smoking. Elderly smoking at nights may be related to insomnia; this should to be evaluated. Sleep apnea syndrome is an important risk factor for atherosclerosis, cardiovascular morbidity, and cigarette smoking. Smoking interacts with sleep apnea to increase cardiovascular risk (Lavie et al, 2007).

Latent Clinical Factors for the Elderly People The elderly, a factor that is worthy of discussion in relation to the height distribution is the latent clinical factor. It is the rate people, mostly the elderly, have height loss due to ageing. The elderly people have hormonal changes, which are related to loss of bone density. Latent Clinical Factors are clinically unobservable. In the current work of this author‘s observation of the height loss, there is a lack of knowledge about their rate of height loss. On

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the parlance of the latent variable modeling, there might be a true nature, as whether a fast or slow shrinker of height in the elderly people - and this is what really causes subjects to fall into one or the other statistical distribution that one can possibly observe. The latent variable should explain the observable variability. In addition, the latent variable should have a theoretically sound basis. There are many equivalent models of the correlations among observed variables. Hence, a latent variable (or more than one) requires some serious hypothesizing to link the possible relationship of height to sleep disturbance in the elderly people.

Health Insurance Coverage and its Effect on Sleep Education and Sleep Studies For Taiwanese, the National Health Insurance plan in Taiwan provided and provides the expense of PSG, with 1/10 of its co-payments to be paid by a patient per test. Therefore, the subjects were not particularly richer than the average, for any full payment of the expensive PSG. Prior to March 1995, 12.7 million people, about 60 percent of the Taiwanese population were eligible to benefit from thirteen public health insurance plans. More than 8.5 million were uninsured. Many were children and half were over sixty-five. After six years of planning, the Taiwan government launched the National Health Insurance (NHI) program on March 1, 1995. In 2008, 99% of the Taiwanese population are insured. By comparison, National health insurance is not available in the Philippines. There are other issues: urban-learned Western eating habits, patterns of life style, nightlife and entertaining activities into rural parts, versus those in rural areas that either directly or indirectly affect sleep patterns.

The Poor Elderly Get Less Sleep The elderly people living in poverty get less sleep than those in higher SES group. This is an important societal problem, regardless of the various cultural backgrounds. Examples of the influence of poverty on the elderly people can be found, even in advanced countries like U S A. There is recent evidence that the obesity burden tends to shift towards the poor as countries develop (Monteiro, 2004). Obesity has an adverse effect on sleep apnea, and is more prevalent in males than females. Furthermore, many health disparities even are linked to inequalities in education and income (Drewnowski, 2004). Over 47 million Americans uninsured and even more underinsured. Approximately, 18 million Americans suffer from obstructive sleep apnea (OSA). Unfortunately 10-20% of these people are aware of that they have OSA and are being treated. An increasing number of an aging population and obeseity will lead to an increase in OSA. Elderly people who are living in poverty get less sleep than those in higher SES group; this will exacerbate a bad situation ( McCamy Taylor, 2007). In the Mindanao region of the Philippines, women cried out 'we boil bananas for our children when food is not available.‘ In

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some cases, when the Department of Agriculture distributes corn seeds, we cook these seeds instead of planting them. Ironically, they borrow money to acquire these seeds. The cycle of poverty continues, as they are unable to pay for these loans. Moreover, some indigenous people feel that they are 'gradually losing control over their ancestral lands. In some areas, non-indigenous people get titles to indigenous people's lands in connivance with unscrupulous government representatives.' In the Philippines, approximately 16 to 27% of the population would remain poor in 2010. As a result, the Philippine will have to move rapidly if poverty is to be reduced perceptibly.

Poverty and Obesity There are interrelations between socioeconomic factors and obesity when taste, heavy dietary energy, and food prices are employed as superseding factors. Increasingly Americans are becoming overweight and obese while consuming more added sugars and fats and spend a lower portion of their throwaway earnings on food (Drewnowski, 2004). A similar trend occurs in the Philippines and Taiwan. Biofuel production drives up the food price, and damages the environment and speeds up global warming. Food should not be so expensive that many elderly, disabled and homeless people will be unable to feed themselves and their children. The increase food prices can raise people‘s anxiety and adversely affects their sleep quality (Braun and Pachauri, 2006).

National Health Insurance As previously mentioned, by 2005, nearly 99 percent of the Taiwanese population was covered by National Health Insurance (NHI). Despite public satisfaction rates of over 70 percent, an increasing number of elderly people has given rise to changing patterns of health problems. As the proportion of elderly people increased, chronic cardiovascular diseases have replaced infectious diseases as the major health problem among adults. In Taiwan, the Ministry of the Interior is planning to alter its immigration policy by adding a program aimed at attracting foreign white-collar professionals. According to ministry statistics, the Taiwanese birth rate in 2002 was 11.02 percent, compared to 49.97 percent in 1951. The number of children in the average family was 1.34 in 2001, down from 7.04 in 1951. The Ministry of Interior of Taiwan deals with an increasing number of elderly people, developing ways to raise the birth rate and altering the immigration policy. With such an increasing number of elderly people, the problem of sleep disturbance has not been addressed. Like many developing countries, the Philippines are experiencing both rapid urbanization and an ageing population. In the Philippines, with such an increasing number of elderly people, the problem of their sleep disturbance has not been suitably attended.

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Limitations of Cross-Cultural Sleep Studies There is no definite information of the prevalence and severity of obstructive Sleep Apnea in Asian snorers, including Taiwan and the Philippines. Conversely, the relationship between the AHI scores and the immediate consequences in the asymptomatic and/or undiagnosed general elderly population needs more study (Tang 2005, Tang 2006a, Tang 2006b). It is important to have both subjects and controls in the same age group in a sleep study. Due to the lack of WHO reports on Taiwan, together with the delay of publishing a national survey in Taiwan, some sleep studies had no choice but to analyze two different samples (participants) from two different time periods. For example, in a study, the subjects were from 2002 to 2003, while controls were from 1993 to 1996 (Tang, 2007). The limitations of studies such above include the selection of study subjects might be challenged. Such as the above is also potentially subject to sources of bias and variation, and the generalization of the results may be limited. Therefore, the findings in such studies might underestimate the prevalence of sleep-disordered breathing (SDB) in the entire population in a certain country. Hence the relationship between the AHI scores and the immediate consequences in the asymptomatic and/or undiagnosed general elderly population needs more study. The comparison data from a national survey (1993-1996, Taiwan) was used in one of the studies of Taiwanese. Participants in that survey were not taking the nocturnal PSG. The survey reported on the population a few years earlier than the beginning of the sleep study in Taiwan (Tang, 2007), but survey was not published until 1999 for public reference in Taiwan, which was merely two years before the beginning of the sleep study (Tang, 2007). The height and weight measurements should have been obtained from the census data to have validity in any comparison. Unfortunately, comparative year to year comparative data do not exist. The report of 'Elderly Nutrition and Health Survey in Taiwan (1999 to 2000): research design, methodology and content' was not published until 2005, three years and eleven months after the conclusion of a Taiwanese sleep study (Tang, 2007). Most of the sleep studies discussed in this article are cross-sectioned. Most of such variables studied are restricted by the application of a dichotomous measure of urbanicity. Modifications do happen in sleep disturbance and apnea, along with metabolism and dieting habit during the life span; such modifications may decrease the odds of being overweight for those who survive to the age of 70 years and over. Given the cross-sectional nature of most of the studies referred here, elderly participants who live long enough to join the studies naturally were the survivors. On the tapis of such a cross-sectional nature of studies cited in this article, it is difficult to justify that changing metabolism, dieting and nutrition habits across the life span may mitigate the effects of being obese or overweight for those who survive to the older age. Hence, there is a need for the proper longitudinal survey for the future work in this area. Associations between obesity and urbanicity will alter as countries develop, as has the relationship between socio-economic status (SES) and obesity. Current studies are restricted not only to cross-sectional studies as outlined in the aforementioned section, but also in the use of a dichotomous gauge of urbanicity. The measurement of the latter needs improvement. The application of a dichotomous description of urbanicity, while convenient and frequently

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helpful, can as well be challenging (Champion 2004, McDade 2001, Vlahov 2002, and Yach 1990).

Conclusion The study of sleep disturbance in the elderly is a new area of scientific research. This is a research field that has largely been neglected for this age group. Probable reasons for this are numerous. One of the most likely factors may be due to a combination of the lack of documented data, together with the complexity of human sleep itself. This field is an undiscovered entity, especially in sleep research on the age groups mentioned in this article. All patients are vulnerable, especially those who are elderly. Thus, the difficulty is due to the problem faced in obtaining volunteers as well as the philosophical and theological undertones people associate with ''the sleep when they are at the end stage of their life‖. Moreover, there is as well the misconception of sleep study on 'those who haven't many years left anyhow' in general. Additionally, there is difficulty in recognizing cross-cultural differences among the elderly people's sleep disturbance. Hence, as aforementioned, the objective of this article was to provide a broader understanding of the complicated relationship of various aspects of sleep apnea in the age group studied. Results from this article may provide direction for fruitful areas of future research. National differences in epidemiology of sleep apnea may be helpful for better understanding of triggers and pathogenesis of this condition. Thus this article can be used to help establish proper concepts, to improve the wellbeing of the elderly people with sleep disturbance in countries regardless of developing status of the nation. 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. Finally, society helps keep a person 'up to the times', and enables her/him to refurnish her/his ‗mental shop with the latest wares‘, see the 1904 statement by William Osler (18491919) (Osler, 1904).

References American Academy of Sleep Medicine Task Force (1999): Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research: the report of an American Academy of Sleep Medicine Task Force. Sleep; 22:667-89 American Society for Clinical Nutrition , http://www.ajcn.org/contents-by-date.0.shtml Accessed 30 August 2009. Baron, R.C., Thacker, S.B., Gorelkin, L, et al (1983) Sudden death among southeast Asian refugees: an unexplained nocturnal phenomenon. JAMA 1983;250:2947-2951 Barbara, Cavalla-Sforza, Cutter, & Darnton-Hill ; National Heart, Lung, and Blood Institute 1998

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In: Melatonin, Sleep and Insomnia Editor: Yolanda E. Soriento

ISBN: 978-1-60741-859-7 ©2010 Nova Science Publishers, Inc.

Chapter VII

A Novel Model Using Generalized Regression Neural Network (GRNN) for Estimating Sleep Apnea Index in the Elderly Suffering from Sleep Disturbance 唐秉輝 Bingh Tang 1 and Weizhong Yan2 1

New York College of Traditional Chinese Medicine, Mineola, Long Island, NY, USA 2 GE Global Research Center, Niskayuna, NY, USA

Abstract Objective: The main objective of this paper 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