Somatizationand Psychosomatic Symptoms

Kyung Bong Koh Editor
Somatiza
tion and
Psychoso
matic
Symptom
s
Somatization and Psychosomatic Symptoms
Kyung Bong Koh
Editor
Somatization and
Psychosomatic Symptoms
Editor
Kyung Bong Koh
Department of Psychiatry
Yonsei University College of Medicine
Seodaemun-gu, Seoul, Korea
ISBN 978-1-4614-7118-9 ISBN 978-1-4614-7119-6 (eBook) DOI

10.1007/978-1-4614-7119-6
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Preface
After working successfully as chairperson of the Organizing Committee at the

21st World Congress on Psychosomatic Medicine held in Seoul in August 2011, I
planned to write a book entitled Somatization and Psychosomatic Symptoms with
my distinguished colleagues from all around the world. Most of them who have
been interested in the fi eld of psychosomatic medicine and actively involved in the
academic as well as clinical activities for a long time accepted my proposal for
publishing this book. Over a period of one and a half years, our efforts fi nally bore
fruit in the form of this book . I am very proud of this book because it is not only a
collection of up-to-date knowledge by many international professionals as the prod
uct of our collaboration, but it reveals the vision for the future of psychosomatic
medicine. Furthermore, this book deals with a variety of interesting and controver
sial issues relevant to psychosomatic medicine.
Psychosomatic medicine has tried to integrate biopsychosocial factors in assess
ment and treatment of illnesses or diseases and played a central role in leading
medicine to “personhood.” This fi eld has also provided a theoretical framework
for effective and desirable clinical practice and helped physicians to overcome
obsta cles to the development of medicine, such as dualism and reductionism.
Currently, there are many patients distressed by a variety of somatic symptoms
along with psychosocial problems. In particular, although the number of patients
with medically unexplained somatic symptoms is increasing, a considerable num
ber of patients are still wandering without seeking appropriate management. In
addition, a number of patients with serious diseases, such as cancer, are surviving
longer than before with the development of cutting-edge therapeutic modalities.
Thus, they are struggling to live with chronic poor quality of life.
Somatization is a process in which there is inappropriate focus on physical
symptoms which are medically unexplained. Somatization is highly prevalent in
primary care. Somatoform disorders are representative of somatization. These dis
orders tend to be chronic and can cause signifi cant personal suffering and social
problems as well as fi nancial burden. Treatment of somatoform disorders is chal
lenging because they cannot be effectively treated according to the existing bio
medical model. Psychosomatic symptoms refer to physical symptoms of physical
v
vi Preface
diseases affected by psychosocial factors. Both patients with somatization and

those with psychosomatic symptoms tend to show resistance to psychiatric or
psychologi cal assessment and treatment in common. These patients are good
models for medi cal students and health-care professionals, such as physicians,
nurses, psychologists, and social workers, to learn about the biopsychosocial
approach to patient-centered care because their symptoms cannot be biomedically
explained. Therefore , the pro fessionals need to learn specifi c assessment skills
and treatment techniques in order to deal with these patients more effectively. This
book deals with a variety of issues relevant to mechanisms, education, assessment,
and treatment of such disorders in terms of biopsychosociocultural perspectives.
The book consists of 22 chapters. Twenty-three distinguished experts from
different countries participate in this project as contributors.
The book is composed of seven parts: I. Basic understanding of somatization ,
II. Theoretical approaches to mind and body, III. Biopsychosociocultural mecha
nisms in psychosomatic medicine, IV. Practical approaches to patients and family,
V. Specifi c psychosomatic symptoms, VI. Specifi c psychosomatic disorders, VII.
Specifi c therapeutic interventions and biological effects of interventions . The fi
rst part deals with the identity of somatoform disorders because, currently, there is
an identity crisis related to the survival of the terms of some subgroups as well as
“somatoform disorders.” In the second part, evolution of philosophy underpinning
personhood in medicine is reviewed. Moreover, the recent trend of reductionism in
medicine calls for such philosophy. The third part deals with genes, memes, alexi
thymia, culture, and the molecular mechanism of sleep-wake regulation. In particu
lar, the relationship between memes, stress, and psychosomatic disorders is
explored and meme-oriented therapies are introduced in treatment of stress-related
disorders. On the other hand, our understanding of molecular aspects of sleep-
wake regulation will help expand areas of traditional psychosomatic medicine.
In the fourth part, the need for psychosomatic assessment and approach to clini
cal practice is emphasized in terms of cost-benefi t, especially in chronic diseases.
The effect of assessment of alexithymia and emotional intelligence on the quality
of the doctor-patient relationship is reviewed. How to integrate cognitive therapy
into medical care and how to refer medically unexplained patients are presented.
Differences between Western medicine and Oriental medicine and the role of com
plementary and alternative medicine in psychosomatic medicine are discussed. In
addition, a variety of family assessment tools are introduced and problem-centered
systems therapy of the family is described in detail.
The fi fth part includes psychosomatic symptoms, especially pain: “pain as a
common language of human suffering,” “fi bromyalgia,” and “a psychosomatic
approach to diffi cult chronic pain patients.” In the sixth part, specifi c psychoso
matic disorders such as “stress-induced cardiomyopathy”; “cancer,” especially
“breast cancer”; and “poststroke depression” are reviewed. In the past, the mecha
nism of stress-induced cardiomyopathy was not addressed in books related to psy
chosomatic medicine. This topic will help medical students to understand the
relationship between stress and heart problems. In the chapter related to breast
cancer , a variety of therapeutic modalities, including cognitive behavioral therapy
Preface vii
and psychopharmacotherapy, are presented. Poststroke depression can be a good

candidate for an integrative or biopsychosocial approach. Herein, mechanisms and
management of poststroke depression are mainly addressed, focusing on biological
and psychological therapies (including cognitive behavioral therapy).
The last part deals with “motivational interviewing,” “wisdom and wisdom psy
chotherapy,” and “advanced psychopharmacology” as therapeutic interventions in
psychosomatic medicine. Motivational interviewing is reviewed as a cost-effective
and culturally sensitive intervention for domestic violence victims. The usefulness
of wisdom therapy in coping with stress is addressed as a way of strengthening
resilience. In addition, the effects of interventions, such as relaxation, mindfulness
based stress reduction, and cognitive behavioral therapy, on immunity are
reviewed. These results will provide a rationale for clinical applications of these
interventions to improve immunity in patients with immune-related disorders.
I believe this book will be a good guide for medical students, nurses, psycholo
gists, social workers, as well as psychiatrists and physicians who want to learn
about psychosomatic medicine or an integrative approach to medicine.
First and foremost, I wish to thank my contributors for sharing their clinical
experience, research, and insights. I am truly grateful to Ms. Janice Stern, senior
editor, and Ms. Christina Tuballes , editorial assistant, for their assistance through
out the process of editing and publication of this book. In addition, I thank my
wife, Sungsook Cho, for her constant encouragement and emotional support. I
also thank God for enabling me to fi nish this hard work without giving up.
Seoul, Korea Kyung Bong Koh
Contents
Part I Basic Understanding of Somatization
1 Identity of Somatoform Disorders: Comparison

with Depressive Disorders and Anxiety Disorders .............................. 3
Kyung Bong Koh
Part II Theoretical Approaches to Mind and Body
2 Toward a Philosophy of Life to Underpin

Personhood in Medicine ........................................................................ 19
Osborne P. Wiggins and Michael Alan Schwartz
Part III Biopsychosociocultural Mechanisms

in Psychosomatic Medicine
3 Genes, Memes, Culture, and Psychosomatic Medicine: An Integrative

Model ............................................................................. 33 Hoyle Leigh
4 Alexithymia and Somatic Symptoms ................................................... 41 Gen
Komaki
5 Culture and Somatic Symptoms: Hwa-byung,
a Culture-Related Anger Syndrome ..................................................... 51
Sung Kil Min
6 Molecular Mechanism of Sleep–Wake Regulation:
From Basic to Translational Research ................................................. 61
Yoshihiro Urade
ix
x Part IV Practical Approaches to
Patients and Family
Contents
7 Psychosomatic Approach to Clinical Practice ..................................... 75

Eliana Tossani and Giovanni Andrea Fava
8 Emotional Intelligence, Alexithymia,
and the Doctor-Patient Relationship .................................................... 91
Arnstein Finset
9 An Effective Approach to Somatization Assessment
and Management .................................................................................... 99
Kyung Bong Koh
10 Role of Complementary and Alternative Medicine
in Psychosomatic Medicine ................................................................... 113
Sae-il Chun
11 Family Assessment and Intervention for Physicians .......................... 129
Gabor I. Keitner
Part V Specifi c Psychosomatic Symptoms
12 Pain, Depression, and Anxiety: A Common Language of Human

Suffering ............................................................................... 147 Tatjana
Sivik and Matteo Bruscoli
13 Psychosomatic Aspects of Fibromyalgia .............................................. 165
Masato Murakami and Woesook Kim
14 A Psychosomatic Approach to the Treatment
of the Diffi cult Chronic Pain Patient .................................................... 175
Jon Streltzer
Part VI Specifi c Psychosomatic Disorders
15 Stress-Induced Cardiomyopathy: Mechanism

and Clinical Aspects ............................................................................... 191
Jun-Won Lee and Byung-il William Choi
16 Poststroke Depression: Mechanisms and Management ..................... 207
Kyung Bong Koh
17 Cancer in a Psychosomatic Perspective ............................................... 225
Adriaan Visser
18 Psychosocial Aspects of Breast Cancer:
Focus on Interventions .......................................................................... 239
Kyung Bong Koh
Contents
xi
Part VII Specifi c Therapeutic Interventions

and Biological Effects of Interventions
19 Motivational Interviewing in Psychosomatic Medicine ...................... 261

Sung Hee Cho
20 Wisdom and Wisdom Psychotherapy in Coping with Stress ............. 273
Michael Linden
21 Current Advances in the Psychopharmacology
of Psychosomatic Medicine ................................................................... 283
Amarendra N. Singh
22 Emotion, Interventions, and Immunity ............................................... 299
Kyung Bong Koh
Index ................................................................................................................ 317
Contributors
Matteo Bruscoli, M.D. Societa Italina Medicina Psichosomatica, Italy, Affi liated
to Institute of Psychosomatic Medicine, Sweden
Sung Hee Cho, Ph.D. Christian Studies Division , Baekseok University, Cheonan
, Chungnam Province , Korea
Byung-il William Choi, M.D. Division of Cardiology , Medical College of
Wisconsin , Milwaukee , WI , USA
Sae-il Chun, M.D. Department of Integrative Medicine, The Graduate School of
Integrative Medicine , CHA University, Sungnam City , Kyeonggi Province ,
Korea
Giovanni Andrea Fava, M.D. Laboratory of Psychosomatics and Clinimetrics,
Department of Psychology , University of Bologna, Bologna , Italy Department
of Psychiatry, State University of New York at Buffalo , Buffalo , NY , USA
Arnstein Finset, Ph.D. Department of Behavioural Sciences in Medicine,
Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo,
Blindern, Oslo, Norway
Gabor I. Keitner, M.D. Department of Psychiatry, Rhode Island and Miriam
Hospitals , Brown University , Providence , RI , USA
Woesook Kim, Ph.D. Clinical Psychology , College of Nursing Art and Science,
University of Hyogo , Akashi, Hyogo , Japan
Kyung Bong Koh, M.D., Ph.D. Department of Psychiatry , Yonsei University
College of Medicine, Seodaemun-gu , Seoul , Korea
Gen Komaki, M.D., Ph.D. School of Health Sciences at Fukuoka , International
University of Health and Welfare, Ohkawa, Fukuoka , Japan
Jun-Won Lee, M.D. Division of Cardiology, Department of Internal Medicine ,
Yonsei University Wonju College of Medicine, Gangwon Province , Korea
xiii
xiv Contributors
Hoyle Leigh, M.D. Department of Psychiatry , University of California , San

Francisco , USA
UCSF Fresno, Fresno , CA , USA
Michael Linden, M.D. Research Group Psychosomatic Rehabilitation at der
Charité University Medicine Berlin
Department of Behavioral and Psychosomatic Medicine at the Rehabilitation
Center Seehof , Lichterfelder Allee 55, Teltow/Berlin , Germany
Sung Kil Min, M.D., Ph.D. Yonsei University College of Medicine, Seoul
Metropolitan Eunpyeong Hospital, Eunpyeong-gu, Seoul , Korea
Masato Murakami, M.D., Ph.D. Department of Psychosomatic Internal
Medicine , Nihon University Hospital, Itabashi-ku, Tokyo , Japan
Michael Alan Schwartz, M.D. Departments of Humanities in Medicine and
Psychiatry , Texas A&M Health Science Center College of Medicine, Round Rock
, TX , USA
Amarendra N. Singh, M.D. Psychopharmacology, Department of Psychiatry,
Pharmacology and Neurosciences, Queen’s Univeristy, Kingston, ON, Canada
Tatjana Sivik, M.D., Ph.D. Department of General Medicine , Institute of
Psychosomatic Medicine, University of Göteborg , Fridkullagatan, Göteborg ,
Sweden
Jon Streltzer, M.D. Department of Psychiatry , University of Hawaii at Manoa,
John A. Burns School of Medicine, Honolulu , HI , USA
Eliana Tossani, Ph.D. Department of Psychology , University of Bologna,
Bologna , Italy
Yoshihiro Urade, Ph.D. Department of Molecular Behavioral Biology , Osaka
Bioscience Institute, Osaka , Japan
Adriaan Visser, Ph.D. Knowledge Center Innovations in Care , Rotterdam
University of Applied Sciences, Rotterdam , The Netherlands
Osborne P. Wiggins, Ph.D. Philosophy Department , University of Louisville ,
Louisville , KY , USA
Part I
Basic Understanding of Somatization
Chapter 1
Identity of Somatoform Disorders:
Comparison with Depressive Disorders and
Anxiety Disorders
Kyung Bong Koh
1.1 Introduction
Somatoform disorders are among the most prevalent psychiatric disorders in

general practice. Somatoform disorders were diagnosed in 16.1 % of consecutive
consulting patients [ 1 ]. Patients with somatoform disorders are often referred to
as “medical orphans” [ 2 ], because correct diagnosis is not made by physicians
and the patients end up “shopping” for diagnoses by visiting many physicians.
The term “somatoform disorders” was introduced in the third edition of
Diagnostic and Statistical Manual (DSM) in recognition that many patients present
with somatic distress that does not fi t in the rubric of physical diseases, anxiety,
mood, or psychotic disorders. Somatoform disorders represent heterogeneous sub
groups of patient presentations, ranging from conversion disorder to
hypochondriasis to somatization disorder to pain disorder [ 3 ].
1.1.1 How to Get Labeled as Misdiagnosed Somatoform

Disorder
The diagnosis of somatoform disorders relies on the presence of subjective

distress in the absence of objective fi ndings. As a result, there is always the
possibility that a diagnosis will be missed or altered later. In addition, patients are
sometimes mis diagnosed with somatoform disorders, because the doctor has
simply missed the diagnosis by insuffi cient attention to the history, physical
examination, or labora tory tests and by not relying on contemporary diagnostic
techniques. In addition,
K. B. Koh , M.D., Ph.D (*)

Department of Psychiatry , Yonsei University College of Medicine ,
50 Yonsei-ro, Seodaemun-gu , Seoul 120-752 , Korea
e-mail: [email protected]
K.B. Koh (ed.), Somatization and Psychosomatic Symptoms, 3 DOI 10.1007/978-1-4614-7119-

6_1, © Springer Science+Business Media New York 2013
4 K.B. Koh
symptoms have the potential to be worsened by iatrogenic factors. New diseases,

unknown in past years, have also come to light (e.g., hepatitis C with fatigue and
depression) [ 3 ]. However, the rate of misdiagnosis for somatoform disorders (less
than 10 %) is not as high as expected, because it is in the range of misdiagnoses
that are found for other mental disorders or physical diseases [ 4 ].
1.1.2 Shortcomings of Somatoform Disorders as Diagnoses
Although retained and enlarged in the DSM-IV, somatoform disorders have been
the subject of continuing criticism by both professionals and patients [ 5 ]. Many
clinicians believe that the current terminology and classifi cation system performs
poorly in respect to the functions of diagnosis [ 5 ]. First, the terminology is
unacceptable to patients. Second, the category is inherently dualistic. Third,
somatoform disorders do not form a coherent category. Fourth, somatoform
disorders are incompatible with other cultures. Fifth, there is ambiguity in the
stated exclusion criteria. Sixth, somatoform disorders are unreliable. Seventh,
somatoform disorders lack a clearly defi ned threshold. Finally, somatoform
disorders cause confusion in disputes over medical-legal and insurance
entitlements.
1.1.3 Shortcomings of the Specifi c Somatoform Disorder

Subcategories
Many of the diagnostic subcategories currently housed within the somatoform

disorders either lack validity as separate conditions or may be better housed
elsewhere [ 5 ]. Shortcomings of the specifi c somatoform disorder subcategories
have already been outlined in previous studies. In somatization disorder, doubts
have been expressed about both its clinical value and conceptual basis [ 6 ] because
it has substantial overlap with personality disorders, particularly borderline person
ality disorder [ 7 ]. This diagnosis has shown a low stability in longitudinal
surveys, because the diagnosis relies on a lifetime history of symptoms, that is,
patients’ recall of past symptoms [ 8 ]. Moreover, the diagnosis is based simply on
counting the number of “unexplained” somatic symptoms. Such diagnosis merely
represents an extreme of severity on what appears to be a continuum of distress [ 9
]. As such, the threshold of the criteria for somatization disorder is too high, and
patients with this diagnosis are so rare. Therefore, somatization disorder has little
clinical validity. Hypochondriasis also remains controversial as a diagnostic
category. Although there is good evidence of the co-occurrence of the triad of
disease conviction, asso ciated distress, and medical help-seeking, these symptoms
are better conceived of as a form of anxiety that happens to focus on health
matters and is closely related to other forms of anxiety disorder [ 10 , 11 ].
Conversion disorder has long been a problem for diagnostic classifi cation. DSM-
III placed this disorder with other diagnoses in
1 Identity of Somatoform Disorders…
5
the somatoform section because of the shared characteristic of somatic symptoms

that are not intentionally produced [ 12 ]. However, the DSM-IV workgroup recog
nized it has a close relationship with dissociative disorder [ 13 ]. The prevalence of
undifferentiated somatoform disorder is high, ranging from 10 % to 30 % [ 1 , 14 ,
15 ]. However, there have been few studies on undifferentiated somatoform
disorder. Its existence represents the need to have a diagnosis for a very large
group of patients not easily classifi ed elsewhere, even though this diagnosis is not
widely used in clinical practice [ 5 ]. Despite revision of pain disorder between
DSM-III and DSM-IV, there remain problems both in its defi nition and in
establishing it as a separate disorder [ 16 ]. Body dysmorphic disorder might be
better grouped with obsessive-compulsive disorder [ 17 ].
The heterogeneous classifi cation of somatoform disorders according to the
DSM-IV and the International Classifi cation of Diseases (ICD-10) has been found
to be insuffi ciently useful for therapeutic and scientifi c purposes [ 18 – 22 ].
Therefore, the identity of somatoform disorder is confusing. Currently, there is an
identity cri
sis related to the survival of somatoform disorders. Some scientists have proposed
that these diagnostic categories should be abolished and that a new term for
somatic symptoms be adopted [ 5 ].
The diagnostic group should be made more homogeneous and its biopsychoso
ciocultural characteristics should be elucidated in order to resolve the identity con
fusion. For this purpose, the author compared somatoform disorders with other
major mental disorders, such as depressive disorders and anxiety disorders in terms
of biopsychosociocultural perspectives, including incidence and specifi city of psy
chosociocultural and behavioral features and biological features. Therefore, the
similarities and differences in these biopsychosociocultural aspects between the
three disorders will help to clarify whether somatoform disorders are independent.
1.2 Incidence and Specifi city of Psychosociocultural and

Behavioral Features in Patients with Somatoform
Disorders
1.2.1 Severity of Somatic Symptoms, Depression,

and Illness Anxiety
Patients with depressive disorders have higher levels of depression, illness
anxiety, and somatic symptoms than patients with somatoform disorders. Patients
with anxi ety disorders have higher levels of illness anxiety than patients with
somatoform disorders. However, there are no differences in the severity of
somatic symptoms and depression between patients with anxiety disorders and
somatoform disorders [ 23 ]. In this study, diagnoses of mental disorders were
made by general practitio ners. In another study [ 29 ], patients with depressive
disorders have higher levels of depression than patients with somatoform disorders
or anxiety disorders, but there
6 K.B. Koh
are no signifi cant differences in the levels of somatic symptoms and anxiety
among the three disorders. These diagnoses were made by psychiatrists.
Therefore, somatoform disorders are similar to anxiety disorders in the severity of
somatic symptoms and depression, but both disorders are different from
depressive disorders in the levels of depression.
1.2.2 Attribution
Patients with somatization report fewer normalizing symptom attributions than

nonclinical subjects [ 24 ]. Somatization patients have more organic attributions
than depressed patients [ 24 , 25 ], but they usually do not have monocausal
simplistic explanations [ 24 ].
1.2.3 Health Anxiety/Illness Worry
Somatization patients show elevated health anxiety scores [ 26 ]. It has been

shown that different chronic pain syndromes share health anxiety as a common
feature [ 27 ]. Health anxiety is elevated in somatization and hypochondriasis as
compared to mixed clinical controls [ 26 ]. However, it is possible that the content
of worry is dif
ferent in somatization versus hypochondriasis [ 28 ].
1.2.4 Anger and Anger Management Style
Patients with somatoform disorder scored signifi cantly higher on the Stress
Response Inventory (SRI) anger subscale than normal controls [ 29 ]. Somatoform
disorder or anxiety disorder patients are less likely to have high levels of anger
than depressive disorder patients [ 29 ]. Somatic symptoms in anxiety disorder [
30 ] and somatoform disorder [ 31 ] patients are associated with anger
suppression, whereas somatic symp
toms in depressive disorder patients are more associated with anger expression [ 31
] (Figs. 1.1 , 1.2 , and 1.3 ). Therefore, in terms of anger levels and the relationship
between anger management style and somatic symptoms, somatoform disorders
are similar to anxiety disorders but are different from depressive disorders.
1.2.5 Alexithymia
Alexithymia is signifi cantly more prevalent in somatizers without organic pathol

ogy than in healthy subjects [ 32 ]. Adolescents with persistent somatoform pain
disorder have higher levels of alexithymia than healthy adolescent controls [ 33 ].
1 Identity of Somatoform Disorders…0.57 0.84 0.84
7
Anger-In Depression Anxiety Somatic Symptoms −0.22*
Anger-Out
Bentler’s comparative fit index : 0.93 R2= 0.70
* Indicates coefficients of Pearson correlation
Fig. 1.1 The relation between anger management style, mood, and somatic symptoms in anxiety
disorders (From Koh et al. [ 30 ])
Anger-In
0.52*
0.81* Depression Anxiety 0.37 0.52 Somatic Symptoms
Bentler’s comparative fit index : 1.00 R2= 0.71

* Indicates coefficients of Pearson correlation
Fig. 1.2 The relation between anger management style, mood, and somatic symptoms in somato
form disorders (From Koh et al. [ 30 ])
0.84 0.80
Depression Somatic Symptoms
*−0.20
*0.59
Anxiety Anger-In
Bentler’s comparative fit index : 0.93 R2= 0.65 * :
Indicates coefficients of Pearson correlation
Anger-Out
Fig. 1.3 The relation between anger management style, mood, and somatic symptoms in depres
sive disorders
In patients with somatoform pain disorder, alexithymia was negatively correlated
with quality of life [ 34 ]. Patients with tension headache were signifi cantly more
alexithy mic than patients with anxiety disorders and depressive disorders [ 35 ].
However, the correlation between alexithymia and somatization has not been
established [ 32 ].
8 1.2.6 Cognitive Factors
K.B. Koh
Somatization patients over-interpret minor physical symptoms as possible signs of

illness and have a self-concept of being “weak” [ 26 ]. The catastrophizing of physi
cal symptoms is specifi c to somatization and hypochondriasis but is not seen in
patients with depressive and anxiety disorders. The self-concept of being “weak” is
a distinguishing characteristic between somatoform disorder patients and patients
suffering from other mental disorders [ 26 ].
1.2.7 Somatosensory Amplifi cation
Increased somatic symptom reports are associated with higher somatosensory

amplifi - cation [ 24 , 36 ]. However, there are contradictory results regarding the
specifi city of somatosensory amplifi cation in somatoform disorders, especially
concerning the differentiation from patients with anxiety disorders and depressive
disorders [ 24 ].
1.2.8 Illness Behavior
Increased health-care use in somatization [ 24 , 37 ] and signifi cant differences in

somatization patients compared to controls were found in various aspects of illness
behavior (e.g., body scanning, expression of symptoms) [ 38 ]. In addition, chronic
pain syndromes are associated with reassurance-seeking behavior [ 27 ]. Increased
health-care use also occurs in hypochondriasis, depressive disorders, and anxiety
disorders [ 36 ]. However, evidence of the ability of single aspects of illness
behavior to differentiate between patients with somatization, depressive disorders,
and anxiety disorders is still inconclusive [ 38 ].
1.2.9 Culture
Sociocultural restraints may play a role in the somatic symptoms of somatoform

disorders by blocking emotionally charged feelings or ideas from being expressed
[ 39 ]. Hwabyung , an anger syndrome specifi c to Korean culture and
characterized by a variety of somatic symptoms, is associated with anger
suppression [ 40 – 43 ].
In East Asian societies, the Westernized “medically unexplained” concept of
the somatoform disorders is not easily accepted due to the strong infl uence of the
non- dualistic and syndromal approach of traditional medicine [ 44 ]. Hwabyung is
not considered to be “medically unexplained” in traditional medicine practitioners
in Korea. Therefore, we need to address the future diagnostic utility of somatoform
disorders in a broader cross-cultural conceptual and contextual framework [ 45 ].
9
1.3 Why Are Biological Findings Important in Establishing

the Identity of Somatoform Disorders?
A better understanding of the underlying neurobiological underpinnings of

frequently co-occurring disorders may help to determine whether they are
independent entities [ 46 ]. In particular, biological fi ndings may be helpful to
address the limit of self reporting when diagnosing somatizing patients. Such
biological fi ndings include neural imaging, along with neural immune and genetic
studies.
1.3.1 Incidence and Specifi city of Biological Features

in Patients with Somatoform Disorders
1.3.1.1 Brain Imaging
Somatoform disorder patients showed hyperperfusion in the left hemisphere at the

superior temporal gyrus, inferior parietal lobule, middle occipital gyrus, precentral
gyrus, and postcentral gyrus and in the right hemisphere at the superior temporal
gyrus, as compared to the healthy controls. Hyperperfusion in the left superior
temporal gyrus and hypoperfusion in the right parahippocampal gyrus were found
in patients with undifferentiated somatoform disorder and panic disorder when
compared to healthy controls [ 47 ]. Together, these fi ndings suggest that two
disorders share neural activities (Fig. 1.4 ). In addition, in pain disorder patients,
when compared with healthy controls, there was reduced gray matter in the
anterior cingulate cortex, posterior cingulate cortex, lateral prefrontal cortex,
ventromedial prefrontal cortex, and anterior insular cortex [ 48 ].
Another study also found that panic disorder patients showed increased gray
matter in the left superior temporal gyrus when compared with healthy controls [
49 ]. However, another report found that the gray matter in the right middle and
superior temporal gyrus regions was reduced in anxiety disorder patients when
compared with healthy controls [ 50 ]. In contrast, increased cerebral blood fl ow
in the amygdala and medial orbital areas was found in major depressive disorder
patients when compared with healthy controls. In addition, major depressive disor
der patients showed reduced metabolism in the prefrontal cortex [ 51 ], as well as
reduced gray matter in the right inferior frontal gyrus [ 50 ] when compared with
healthy controls. Therefore, major depressive disorder is likely to differ from
somatoform disorders and anxiety disorders in terms of neural activity.
1.3.1.2 Genetic Findings

One study examined serotonin-related gene polymorphisms in patients with undif
ferentiated somatoform disorder and healthy controls. However, no signifi cant
differ ences were found in serotonin-related gene polymorphisms between the two
groups.
10 K.B. Koh
Fig. 1.4 Hyperperfused ( red/gray ) or hypoperfused ( green/white ) brain regions in panic

disorder ( a ) and undifferentiated somatoform disorder ( b ) patients compared with healthy
controls From Koh et al. [ 47 ]. Adapted and Reprinted by permission of Physicians Postgraduate
Press
Therefore, serotonin-related gene pathways are unlikely to be genetic risk factors

for undifferentiated somatoform disorder [ 52 ].
In contrast, some serotonin-related gene polymorphisms, such as tryptophan
hydroxylase (TPH)1 A218C gene [ 53 ], variants of TPH2 gene [ 54 ], and
serotonin receptor 2A (5-HTR 2A) gene [ 55 ], were regarded as candidate genes
for major depressive disorder. In addition, a functional polymorphism located in
the promoter region of the serotonin transporter gene (5-HTTLPR) has been
shown to be associated with seasonal affective disorder [ 56 ].
On the other hand, it was reported that aggression in major depressive disorder
patients is more susceptible to an excess of TPH1 CC homozygote than in undif
ferentiated somatoform disorder patients, though the two disorders are high-risk
groups for aggression [ 53 ].
More than 350 candidate genes have been examined in association studies of
panic disorder. However, most of these results remain negative or have not been
clearly repli cated. Only Val158Met polymorphism of the catechol-O -
methyltransferase gene has been implicated in a susceptibility to panic disorder by
several studies in independent samples and was confi rmed in a recent meta-
analysis [ 57 ].
1.3.1.3 Immunological Findings
There have been few studies on the comparison of immune function between
somatoform disorder patients and healthy controls. One study showed reduced lym
phocyte proliferation in patients with undifferentiated somatoform disorder com
pared with normal controls [ 58 ].
11
When compared with normal controls, panic disorder patients were found to
have a wide range of lymphocyte proliferative response to mitogens: decreased [
59 ], normal [ 60 , 61 ], or increased [ 62 ]. However, several additional studies
observed reduced blas togenic response to the mitogens PHA [ 63 , 64 ] and PWM
[ 59 ], as well as reduced serum IL-2 production level [ 64 ] in patients with
anxiety disorders, especially panic disorder. Moreover, patients with panic
disorder had signifi cantly lower levels of CD4+ than depressive disorder patients
[ 65 ].
In patients with depressive disorders, meta-analytic approaches to the literature
showed statistically reliable decreases in T cell responses [ 66 , 67 ], although there
have been both successful and unsuccessful replication attempts.
1.4 Considerations for a New Classifi cation

of Somatoform Disorders
Converging evidence from the biopsychosocial data should be used for

establishing any new classifi cation of somatoform disorders. It is possible to
consider reestab lishing the relationship between somatoform disorders and
psychosomatic disorders in a new classifi cation. For example, functional
psychosomatic disorders (somatic syndromes) such as irritable bowel syndrome,
tension headache, and functional dyspepsia may be included in the new classifi
cation of somatoform disorders (e.g., autonomic somatoform disorder).
In addition, there may be an immediate need to specify an undifferentiated
somatoform disorder, due to its high prevalence among somatoform disorders. This
diagnosis may be included in somatization disorder by lowering threshold for diag
nosing somatization disorder. Future diagnostic concepts and somatoform disorder
criteria should be meaningful and useful in both Western and non-Western coun
tries. Potential new classifi cation of somatoform disorders is proposed and pre
sented in Table 1.1 .
Table 1.1 Controversial subgroups of somatoform disorders and potential new classifi cation
DSM-IV Potential new classifi cation Hypochondriasis Anxiety disorder (e.g., illness anxiety
disorder) Body dysmorphic disorder Obsessive-compulsive disorder Conversion disorder
Dissociative (conversion) disorder (ICD-10) Pain disorder Somatoform pain disorder (DSM-III)
Somatization disorder
Undifferentiated somatoform disorder Somatization disorder
Functional psychosomatic disorders Autonomic somatoform disorder (e.g., IBS, tension
headache, functional dyspepsia)
Somatoform disorder not otherwise specifi ed Nonspecifi c somatoform disorder DSM-IV
Diagnostic and Statistical Manual, 4th edition, ICD-10 International Classifi cation of Diseases,
10th revision, IBS irritable bowel syndrome
12 1.5 Conclusions
K.B. Koh
The identity of somatoform disorder is confusing due to the heterogeneous classifi

- cation of somatoform disorders according to the DSM-IV and the ICD-10. In
order to resolve the identity confusion, we need to elucidate more about the
biopsychoso ciocultural characteristics of somatoform disorders. For this purpose,
somatoform disorders were compared with other major mental disorders, such as
depressive disorders and anxiety disorders, in terms of biopsychosociocultural
perspectives. Biological fi ndings, as well as psychosocial fi ndings, may help to
differentiate between somatoform disorders and other mental disorders, such as
depressive dis orders and anxiety disorders. Somatoform disorders are
biopsychosocially more similar to anxiety disorders than to depressive disorders,
especially major depres sive disorder. However, somatoform disorders may be
more affected by sociocul tural factors than anxiety disorders. Among many
factors relevant to somatoform disorders, anxiety disorders, and depressive
disorders, there are some factors show ing clear differences between the three
disorders, including psychosociocultural factors, such as attribution, anger levels,
anger management style, cognitive factor, and cultural difference, as well as
biological factors, such as neural activity and genetic factors. The converging
evidence from the biopsychosociocultural data may help resolve the identity
confusion of somatoform disorders and establish a new classifi cation of
somatoform disorders.
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Part II
Theoretical
Approaches to
Mind and Body
Chapter 2
Toward a Philosophy of Life to
Underpin Personhood in Medicine
Osborne P. Wiggins and Michael Alan Schwartz
2.1 Introduction
2.1.1 Modern Heritage and the Puzzle About Persons

in Medical Practice
Hans Jonas has broken new ground in the history of Gnosticism [ 1 ] and
modernity [ 2 ], medical ethics [ 3 ], and philosophical biology [ 4 ]. He has been
embraced by people on the political left and others on the political right. Our
presentation draws on his interpretation of modernity and his attempt in his
philosophical biology to provide a new path out of some of the dead ends of
modernity. As Jonas knew, these concerns have a direct bearing on how we think
about medicine.
Modern medicine has enjoyed much success by drawing on those sciences
which study the most elementary components of living beings, namely, the
sciences of physics, chemistry, genetics, and others. There can be no doubt that
these basic sciences do and will play large roles in helping to explain and treat
diseases and injuries of various kinds. However, such sciences fall far short in
providing for medical practitioners, especially clinicians, a conception of the
patient as a living human self that is needed for the practical purposes of
healthcare.
O. P. Wiggins , Ph.D.
Philosophy Department , 313 Bingham Humanities Building,
University of Louisville , Louisville , KY 40292 , USA
M. A. Schwartz , M.D. (*)
Departments of Humanities in Medicine and Psychiatry ,
Texas A&M Health Science Center College of Medicine,
Round Rock Campus , 3950 North A. W. Grimes Blvd , Round Rock , TX 78665 ,
USA e-mail: [email protected]

20 2.1.2 Approaches to This Puzzle
O.P. Wiggins and M.A. Schwartz
In its approach this chapter is divided into two main sections: historical
background and conditions for life. The two sections are continuous with one
another by drawing on the philosophy of living beings developed by Hans Jonas.
In historical background, we shall briefl y sketch the history of modern
conceptions of human life which lead to our present-day puzzlement. This sketch
will lead to the recognition of the mind/body problem as the persistent intellectual
framework from which we still have not succeeded in escaping. As the new
sciences of nature emerged in the seventeenth and eighteenth centuries, a
philosophical framework for trying to unify the ever-expanding multiplicity of
theories and concepts took shape. This framework consisted in a hierarchy of the
sciences, each higher level science being theoretically dependent upon the
concepts and laws of sciences of the lower levels. This hierarchy of the sciences,
however, gave rise to an attempt to simplify them all by proposing an all-
encompassing naturalism, the philosophy that all the sciences would (and must)
someday be reduced to physics. Reductionistic naturalism has never proven to
fully satisfy the modern mind, however, and consequently the mind/body dualism
persisted to thwart attempts to see living beings – human beings in particular – as
unifi ed wholes. Present-day efforts in medicine to make overall sense of the
patient as a person thus encounter road blocks.
2.2 Historical Background
2.2.1 The Modern Hierarchy of the Sciences

and Reductionism
By placing its confi dence in the ability of physics, chemistry, and other such
funda mental sciences to furnish its conceptual base, medicine adheres to an
understanding of the relations among the sciences that is at least a century and a
half old. In the middle of the nineteenth century, Auguste Comte was the fi rst
thinker to explicitly set forth an ordering of the sciences into a hierarchy that is
tacitly taken for granted today [ 5 ]. According to this hierarchy mathematics is the
most fundamental of the sciences. It is the most fundamental because it articulates
the formal relations of the elements of any science whatsoever. Founded on
mathematics and logically presup posing it is physics. Based on physics and
presupposing it is chemistry. Based on chemistry and logically rooted in it is
biology. Founded on all of these natural sci ences are the social sciences, such as
psychology and sociology. The social sciences differ from the natural sciences
because the social sciences fall into no particular rank ordering among themselves;
logically and conceptually they seem to reside on the same level. Comte claimed
that this hierarchy followed two principles: (1) a science
2 Toward a Philosophy of Life to Underpin Personhood in Medicine
21
was more basic if it was more comprehensive or more inclusive and (2) a science
was more basic if its components were simpler. Hence, to illustrate the fi rst
principle, physics was more comprehensive than chemistry because all chemical
realities are physical, but not all physical realities are chemical. And, to illustrate
the second prin
ciple, the constituents of physical realities that physics studies are simpler in their
makeup than are the constituents of chemical realities; the elements of chemistry
include elements of physics plus something more, something that renders them dis
tinctively chemical.
This conception of the hierarchical dependencies among the sciences continues
to dominate our thinking to the present day. Because the hierarchy entails that the
higher level sciences are conceptually based on the lower level ones, repeated
attempts have been made to simplify the overall picture of the universe by showing
how the higher level sciences can be reduced to the lower level ones.
Now “reductionism” in the sciences can be understood in different senses. The
way in which we understand it here is that a higher level science is reduced to a
lower level one if the higher level science can be logically derived from the con
cepts and laws of the science just below it. Ideally such a reductionism implies that
all the concepts and laws of all the sciences should be reducible to the concepts
and laws of mathematical physics.
A less stringent notion of reductionism is very prominent today. It is called
“naturalism.” It stipulates that any entity that is not physical, chemical, or biologi
cal will ultimately be logically explainable in terms of these natural sciences. In
other words, all realities that are not yet considered natural realities will be in the
future fully explained by the natural sciences. In other words, the natural sciences
will ultimately provide the concepts and laws that explain the whole of reality,
even those parts that are now studied by the social sciences and humanities.
Moreover, it is incumbent on scientists at work today to search for possible
reductionistic con nections. For example, neuroscience is today thought to hold out
the hope for a reduction of mental processes of all sorts to brain structures and
processes, a reduc tion that would ideally eliminate all need to even use the terms
“mental” or “psychological.”
Much of the resistance to such a reductionism arises from the fact that thinkers
in the social sciences and humanities persist in talking about realities and events
that seem to be irreducible. For social sciences to speak of mental processes such
as ideas, emotions, purposes, or moods is for them to use a terminology not
derived from the natural sciences. Modern-day naturalism has a response to such
an “unscientifi c” way of speaking. Talk about mental events of all sorts is thought
by naturalists to be merely a holdover from “folk psychology.” Folk psychology is
simply a prescien
tifi c, commonsensical way of speaking. As genuine science develops, it will
progressively eliminate the need to resort to such nonscientifi c terms, and in their
place we can refer to events and structures in the brain. In other words, the
vocabulary of neuroscience will entirely replace the words of everyday speech,
“folk psycho
logical” words.
22 O.P. Wiggins and M.A. Schwartz
2.2.2 The Mathematization of Nature and Mind/Body Dualism
The depositing of all words and concepts of mental events into the despised
category of “folk psychology” illustrates merely the most recent case of having to
fi nd some separate sphere for mind. Since we cannot avoid referring constantly to
mental processes, we seek to circumvent our dependence on them by drawing
strict lines of demarcation between mental events and “true reality,” that is, natural
reality. We are historically familiar with these determined attempts at strict
separation through our troubled heritage of “the mind/body problem.”
From the moment Descartes sought to defi ne the external world as res extensa,
he had to admit that it bore little resemblance to that other, equally real “reality,”
res cogitans [ 6 ]. Thus began the dualism of the two metaphysically different
realms, physical body and nonphysical mind. And, according to some
philosophers of the seventeenth and eighteenth centuries, not only were the
physical and the mental fundamentally different but also they were completely
separate in their operations and laws. For these thinkers, mind did not determine
matter, and matter did not determine mind. On the other hand, some writers sought
to locate a point of mutual interaction – Descartes’ “pineal gland” being the most
well known – while still others recognized the hopelessness of the attempt.
Descartes also defi ned the model of pure nature that the new science of nature
would study. By defi ning the metaphysical basis of the physical realm as res
extensa, Descartes strips it of all properties except its mathematizable ones. Res
extensa means “extended thing” or “extended substance.” By categorizing physical
matter as exclusively extended, Descartes defi nes it as possessing solely
geometrical properties. No other properties belong to it. The mathematization of
reality had at fi rst to take the form of geometrization because analytical geometry
was the most advanced mathematics of Descartes’ time. In other words, what
Descartes was saying was that true nature possesses solely mathematical
properties. The laws of nature must then be formulatable as algebraic equations
and geometrical fi gures. This set the program for future natural science; one can
arrive at the ultimate truth about nature when one can conceptualize its
movements and constituents with mathematical formulae alone. All other
properties of nature were abstractly disre garded. What happens to these abstractly
discarded properties? Do they simply vanish? No, they stubbornly remain in some
form that has now, with the abstraction, been rendered mysterious. But at this
juncture the usefulness of positing a separate domain of res cogitans becomes
clear; everything that was excluded from the sphere of nature can be conveniently
deposited in the sphere of mind.
Let us cite just two examples of the abstractions that were necessary to constitute
the domain of “pure matter,” that is, matter stripped of all properties except mathe
matical ones. Our fi rst example of disregarded features is teleology and, with the
exclusion of goal-directed behavior, the discarding of teleological explanations.
All changes in nature, including alterations in biological organisms, must be
explained as the results of antecedent causal conditions. Already Francis Bacon
had branded teleological explanations as anthropomorphic fallacies: human
23
investigators were all too prone to understand natural events in terms of the human
mind. To avoid this, scientists must carefully check this human weakness in
themselves and systematically refrain from seeing goal-directed behavior in things.
The appearance of teleology was an anthropomorphic illusion [ 7 ].
Our other example is the abstraction that systematically disregards values and
norms. The fact/value distinction was fi rmly in place at least by the time of David
Hume (1711–1776). Science was “empirical” only to the extent that it studied a
nature of pure facts [ 8 ]. At this stage, the time of the European Enlightenment,
val
ues were not banished; they were simply confi ned to other disciplines such as
moral or political philosophy.
The usefulness of this modern dualism cannot be overestimated for the early
devel opment of the natural sciences. It allowed these natural scientists to abstract
from everything mental, social, political, economic, and religious and to attend
exclusively to what remained, matter and the physical forces that determined it.
Moreover, natural scientists could apply various idealizations to this matter if
applied to the mind and its workings. The most obvious example here is the
idealization of strict causal determination. If we assert that the changes in matter
are strictly determined by antecedent causal events, we can proceed to seek out
these prior events and their law-governed relations to the ensuing changes.
However, if we apply this idealiza
tion to the investigation of mental changes, we implicitly – if not explicitly – deny
any freedom to the will. If, on the other hand, we conceive of the will as a faculty
of the mind alone, then our dualism of mind and matter allows us to place free will
in the mental realm and strict causal determinism in the physical.
Human thinkers seem, however, to remain unhappy with dualistic systems
which so sharply divide reality into metaphysically different spheres. The thinking
intellect appears to long for a monism, a single unifi ed system into which all of
reality can at least potentially fi t. And therefore as dissatisfactions grew more
troubling in the early modern period, monisms were proposed: idealism, the
monism of mind, and materialism, the monism of matter. But a monism satisfi es
fi nally only if it can absorb the other reality into itself. So idealism must explain
our persistent experi
ences of matter as somehow ultimately a mental reality itself. And similarly, mate
rialism works only if it can successfully account for the persistence of our own
subjective experiences with purely physical concepts. Each, of course, has proven
itself unable to prevail over the other. But it should be remembered that there are
versions of “naturalism” prominent today which still strenuously aspire to a
monism and seek to account for our subjective experiences as somehow or other
merely natural processes in the brain.
2.2.3 Darwinism and the Need to Rethink Life
In the middle of the nineteenth century, Darwin’s theory of evolution disturbed

the peace that metaphysical dualism had sought to establish [ 9 , 10 ]. The
Darwinian approach explained the human mind as having evolved through the
same regular
processes of chance mutation and natural selection that had produced all other
living beings. Hence, the human mind was incorporated back into the physical
domain, and as a consequence the mind required no other explanation than that
which natural science could now offer. Natural science was thereby seen as
universal: all of reality could be understood in the same basic scientifi c terms and
laws [ 4 ].
This universalizing of scientifi c conceptualization seemed to betoken the
victory of metaphysical materialism. If all of reality could be explained by
science, then all of reality could ultimately be explained in terms of the most basic
constituents that science had uncovered, namely, inorganic matter. Hence, we
need not speak of “mind,” “spirit,” or “soul” anymore except to demonstrate how
even these phenom
ena could be accounted for fully by a law-governed physical causality. Such a
metaphysical materialism, if it could be developed, would signal the victory of
what Gabriel Marcel has called “the spirit of abstraction” and what Alfred North
Whitehead labeled “the fallacy of misplaced concreteness” [ 11 – 13 ]. The “spirit
of abstraction” consists in mistaking parts of reality that have been intellectually
separated out from other parts of the same reality and treating the abstract parts as
actually existing as separate from the other parts. The fallacy of misplaced con
creteness goes one step further and seeks to explain all the other parts of reality as
produced or caused by this privileged part. The intellectually abstracted part is thus
treated as the most “concrete” dimension of reality from which the other
dimensions are derived. In metaphysical materialism this is precisely what has
happened; the part of reality which is inorganic, purely physical matter, the part
studied by physics, has been intellectually abstracted from the other parts of
reality and deemed the primary, fundamental, or basic part.
Hans Jonas’ approach opposes such a privileging of one part of reality and
deeming it the most “concrete” or formative part. Indeed, he opposes all forms of
reduction ism. And he does this precisely by interpreting the Darwinian
breakthrough in a different way. If, in this post-Darwinian age, we must now
account for everything living and nonliving in a unifi ed system of thought, then
we should be able to draw on everything we know about the living and nonliving
in our account of reality. In other words, the Darwinian victory reincorporates into
our understanding of living beings the entire human realm which materialism had
excluded, and it does so with the demand that we now see the living world as a
unifi ed whole. Hence, we seem to be called on to develop a theory of this unitary
whole which is life in both its mental and physical dimensions.
Still it seems we cannot heed this call. We cannot because we in the West have
inherited a centuries-long understanding of life that is dualistic, and this heritage is
not easily discarded. Just as in the past, the unacceptability of dualism has led
merely to the reduction of one side to the other, to either materialism or idealism,
so today the most popular attempt to construct a monism is naturalism which is
nothing other than materialism in a new guise.
This leaves the reality of life, most obviously human life, inconceivable except
by reducing it to one monism or the other. And it is human life, in illness and
health, which centrally concerns medicine. What medicine needs is a non-
dualistic, a post- dualistic, theory of life.
25
Hence, the question arises of how to develop such a theory. Obviously we must
fully appreciate what the separate sciences have taught us, but we should view
them all, the natural sciences, the social sciences, and the humanities, as equally
impor tant contributions to the general theory. And yet it is the sprawling
multiplicity of these disciplines that must be overcome. Overcoming it will require
overcoming the one-sidedness and exclusivity that limits each.
What should be the starting point of our inclusive, unifi ed philosophy of life?
Beyond abstract theories, an indispensable beginning for the development of a non
dualistic philosophy of life can be found in the directly and constantly felt reality
of being alive in ourselves. This determines our starting point because here we can
claim privileged access: since we are living beings ourselves, we know what it
means to be alive from our own fi rst-hand experience. Every moment of our lives
we directly expe rience life, life in ourselves and in others. Our most intimate
experience of life is in our own individual lives. But this constant experience of
our own being alive makes it pos sible for us to make sense of the being alive of
other people and, to some extent, of animals. We move beyond abstract theories
here because we cannot imagine a datum more concrete than the experience of
ourselves in our constant living reality. Direct refl ection on this experience
reveals to us the basis of any other experience of life. And such a concrete given is
certainly more basic than any of our theorizing about life [ 14 ].
Quite independently of Jonas, the zoologist Adolf Portmann has put forward
the same idea. In order to develop a non-reductionistic view of all forms of life,
Portmann writes,
… we must, then, also emphasize – more than is usually done –what we owe to the
knowledge of our own inner life for the understanding of all animal existence. There is
also a continu ous stream of interpretation fl owing from our own experience into our
biological work with animals, a stream that can only come from that special wellspring of
our own experience. This subjectivity should not be perfunctorily deemed suspect for
being all too human, but, rather, should be made use of in a meaningful way. The vision
of life looking down from above, from the point of view of the human being is a
necessary complement to the attempt at building from beneath, to proceeding from the
simplest forms. [ 15 ]
Hence, we should be able to start from both sides – from the side of what
science can tell us about inorganic, organic, psychological, and social realities and
from the side of our own direct experience of life in ourselves and in others – and
show how these realities meet in the living being. If dualism is to be discarded,
then we must strive for a unifi ed understanding of life, an understanding that fully
appreciates both the natural processes of the organism and the inward-felt
experiences of being alive. Hence, aiming at their intersection, we shall reason
from both directions.
We do this in the confi dence that life is ultimately one reality, however
complex. Human beings are psychosomatic wholes, and therefore, a theory that
reintegrates psyche with soma can be developed as long as no component of the
whole is short changed. We shall search for features that characterize life as such,
whether “objective” or “subjective.” These features of living beings in general
emerge, in our view, as condi
tions for being alive. If the organism ceases to meet the conditions we shall outline,
it will cease to live. Hence, they might be called “necessary conditions of life.” We
shall now, drawing on Jonas, attempt to describe some of these vital conditions [ 4
, 11 ].
26 2.3 Conditions for Life
In this second part of this chapter, we employ the method sketched just above and
seek to lay out conditions for being alive that are found in both the mental and the
more physical dimensions of life. These conditions are the following: (1) the
necessity for living individuals to constantly act in order to sustain their ongoing
existence; (2) the separateness of the individual living being from its environment
while at the same time maintaining an openness to the environment and engaging
in transactions
with it; (3) the necessity for the organism to undergo constant change while always
making a sameness of self throughout this change; (4) the directedness of the organ
ism’s activity toward its own future being, hence the teleological orientation of
organic processes; (5) the origin of feelings in higher life forms. These fi ve
conditions of life can serve as a framework within a unifi ed conception of the
person which for the purposes of medicine includes both the more physical and
the more mental dimensions of patients.
2.3.1 The Need for Self-Preservation
The existence of every living being is sustained through metabolism. Unlike inor
ganic matter, the very being of a living entity is contingent upon its own ceaseless
activity. As a result the existence of the organism from moment to moment is its
own dynamic achievement. Inorganic matter need not actively do anything in order
to endure as the being it is, but organisms must. This inescapable need to persis
tently bring about their own continuation through their own metabolic functioning
proves that organisms are threatened beings: if they do not actively achieve and
repeatedly re-achieve their own reality, they die. Ceaselessly dependent on their
own functioning for their survival, organisms hang suspended over the abyss of
nonbeing. Hence, we can acknowledge one of the conditions that necessarily defi
ne life: always threatened by nonbeing, the organism must constantly reassert its
being through its own activity [ 2 , 4 ].
2.3.2 Enclosed Within the Self and Open to the World
This activity, however, must be an organized activity. Metabolic processes are

structured processes, and it is this very structure of the processes of the organism
that must be maintained as such. When the structure fails to determine the direction
of the processes, the organism dies. Accordingly, the identity of the organism
depends on the maintenance of its internal structure. We might even say that the
identity of the organism is the identity of the structure. This becomes even more
obvious when we note that the components that constitute the organism are con
stantly changing. The material components of the organism come and go, but it is
27
important that the organism remains as the same one. To “remain as the same one”
is to maintain the same structure even in the midst of constant change of compo
nents. In order to maintain this constant change of its components, however, the
organism must to some extent be open to its environment, the ultimate source of
the components. We are now in a position to appreciate another one of the distinc
tive conditions of being alive. Living beings are both enclosed within themselves,
defi ned by the boundaries that separate them from their environment, while they
are also ceaselessly reaching out to their environment and engaging in
transactions with it. This vital feature is found even in the single cell [ 2 ], and it
continues in dif ferent forms all the way up to social institutions.
On the one hand, the cell membrane determines the cell’s boundaries: the
reality of the cell extends no farther than this membrane. And indeed these
boundaries must be maintained if the cell is to continue to be. Hence, the
membrane must main tain the separation of the cell from the rest of reality. Death
consists in the loss of this separation. This need to remain bounded and distinct
from that which is outside is observed at all levels of life. From the single cell,
through the different organs of animal bodies, to the level of human beings as
whole persons, “self” and “other” are defi nitely distinguished. This distinction
between self and other is demonstrated most clearly, of course, in the immune
system. The immune system is geared to detect what is nonself, and once this
detection of otherness occurs, the immune system actively opposes the invader.
On the other hand, the membrane is semipermeable so that the cell may
continually exchange its material with realities outside of it. Literally through its
membrane the cell metabolically carries on transactions with that which is not
itself. Indeed, this transac tion with other entities is necessary if the cell is to
maintain its existence; the cell is physically dependent upon the outside for its
continuation in being. This dependency on what is not itself in order to survive
evinces the organism’s neediness; lacking self suffi ciency, the living being must
of necessity acquire the means for its existence from its environment. However,
this unavoidable exposure to the environment, born out of need, manifests again
the riskiness of organic existence. The environment can prove harmful and even
deadly. Moreover, the unfamiliar and uncontrollable nature of the environment
poses an additional threat to the already precarious venture, that is, organic life.
Hence, the cell is enclosed within its own boundaries in order to maintain its sepa
rate and autonomous being while it is also open, constantly engaging in
transactions with outside realities and indeed even exchanging its own matter with
them.
2.3.3 Change and Sameness
Through the metabolic exchange of material components, the cell undergoes

ceaseless change in its physiochemical makeup. But this change is, as we have
seen, an orga nized change: it is determined by the internal structure of the cell.
Through the change, then, the cell maintains its own separate identity while it also
changes the physicochemical parts that compose it. It is both in fl ux and stable.
Maintaining its
stable identity through constant turnover in its material constituents, the being of
the organism is both independent of and dependent on these constituents. Some
material constituents are always necessary for the existence of the organism, hence
the dependence of the organism. But since these constituents will eventually be
exchanged for others as the organism continues to live, the organism is
independent of precisely these constituents, that is, of whichever constituents
compose it at any given time. We can therefore recognize one of the other
conditions of life in organ
isms: they are both dependent on the material components that constitute them at
any given moment and independent of any particular groupings of these compo
nents across time. These conditions of dependence and independence always defi
ne organic existence [ 2 ].
2.3.4 The Organism’s Teleology and the Basis for Value
As we have said, the metabolic activity of the organism is geared toward

sustaining the existence of the organism. This being geared toward the sustaining
of its own being shows that the metabolism of the organism is “for the sake of” its
own con tinuation in being. The being that the transactions are geared toward
preserving is the organism’s future being. The metabolic functioning is for the
sake of bridging the temporal gap that separates the organism in the present from
its own existence in the future. In slightly different terms, metabolic activity
serves the temporal enduring of the organism. Hence, it is temporal duration that
poses the main threat to the organism’s contingent existence; the question of
whether the organism will endure from moment to moment remains unanswered
until the future becomes the present and the organism still lives. And the threat
can be defeated only if the activity of metabolism is sustained. Life is thus
teleological : the present activity of the living being aims at its own future being [
10 , 16 ].
If we can speak of the metabolic transactions of the organism as occurring “for
the sake of” the organism’s future being, this means that at some fundamental
level the organism posits its own continuation in reality as “good.” In other words,
the organ ism posits its own existence as having a positive value. Value is thus
built into the reality of being alive; it is organic life itself that places value there. It
is not human beings and certainly not human agency that introduces value into an
otherwise value-free universe. Living beings themselves, by striving to preserve
themselves, already signal that, at least for the being involved, its own life is good
[ 3 , 4 , 17 ].
We can see, then, that the values that motivate medical practice are grounded in
organic life itself. While only human beings can develop and practice medicine, it
is not human beings who introduce into the world the values that call for and
justify it. The same would be true for suffering and pain, at least for those
organisms that can feel . Felt suffering and pain are posited by the organism
feeling them as bad. Hence, the moral need to relieve and even eradicate pain
through medical treatment arises at the most basic levels of life, even if only
human beings can recognize this value as a moral requirement and develop the
medical techniques to respond to it [ 3 , 4 ].
29
2.3.5 The Origin of Feeling in Higher Life Forms
Since we have mentioned feeling, we would like to conclude by indicating its

importance for any philosophy of life. Although it is diffi cult to pinpoint the
precise level, at some level of life, the organism’s relationship with the world
becomes a relationship of feeling; many organisms are sensitive to elements in
their environ
ments. Again this applies to individual cells as well as to conglomerates of cells
and whole organisms. Sensitivity is the fi rst glimmering of subjectivity in
organisms, if we may apply the word “subjectivity” to even the most primitive and
elemental kinds of feeling. Moreover, as we move up the living kingdom to more
and more complex organisms, sensitivity too becomes more complex, and at a
certain point we can speak of organisms perceiving items composing the
environment. It would, of course, be diffi cult to mark the progressive difference
between an elemental sensitivity to the outside and an actual perception of it, for
any form of felt sensitivity may already count as an experience, at least of a very
basic sort. Our point here is, however, that the fi rst glimmerings of subjectivity
arise relatively early in the phylogenetic scale. And once subjectivity appears, it
grows in complexity, refi ne ment, and acuity. “Mind,” then, is certainly not the
exclusive privilege of human beings. It is not even the exclusive possession of the
higher animals. Mental life begins where sensitivity to the outside is felt [ 3 ].
This birth of subjectivity marks another aspect of the selfhood of living beings.
For as subjectivity grows and becomes more complex, the organism is able to
sense its environment across spatial distances and to feel a desire for things across
time. If we add to this subjectivity the movement of the organism’s body, then the
living being can move across the spatial distances and pursue objects as long as
desires for them are felt. With growing experience and motility, then, living
beings confront a world that grows in its spatial extent and its temporal duration.
Mind renders organic world-relatedness richer and more encompassing, even if
this larger exposure to the outside also expands the realm from which threats to
life can emerge [ 3 ].
2.4 Conclusions
Medicine’s laudable attempt to orient its activities toward the patient as a person
encounters the problem that confounds all such attempts in the modern era; the
centuries-long persistence of mind/body dualism renders it extremely diffi cult to
conceive of persons as integral wholes. Obviously if such reconceiving of patients
is to serve medicine, it must incorporate what we know from present-day biology
and other natural sciences as well as what we know about persons as psychological
and spiritual beings. The way we have suggested for incorporating the two facets is
to reason from both points of view at once and to thereby uncover conditions for
life found in each. This integral view supports a medicine that is able to
comprehend the personhood of a patient as well as his or her biological being.
30 References
1. Jonas, H. (1958). The gnostic religion: The message of the alien God and the beginnings of
Christianit . Boston: Beacon Press.
2. Jonas, H. (1974). Philosophical essays: From ancient creed to technological man . Chicago:
University of Chicago Press.
3. Jonas, H. (1984). The imperative of responsibility: In search of an ethics for the technological
age . Chicago: University of Chicago Press.
4. Jonas, H. (1966). The phenomenon of life: Toward a philosophical biology . Chicago:
University of Chicago Press.
5. Comte, A., & Ferré, F. (1988). Introduction to positive philosophy . Indianapolis, IN: Hackett
Publishing Company.
6. Gurwitsch, A. (1974). Phenomenology and the theory of science . Evanston, IL: Northwestern
University Press.
7. Bacon, F. (2009). In L. Jardine, M. Silverthorne (Eds.), The new organon . Cambridge
University Press, Cambridge.
8. Putnam, H. (2004). The collapse of the fact/value dichotomy and other essays . Boston:
Harvard University Press.
9. Darwin, C. (1897). The origin of species by means of natural selection . New York: D.
Appleton and Company.
10. Jonas, H. (1996). Mortality and morality: A search for the good after Auschwitz . Chicago:
Northwestern University Press.
11. Schwartz, M. A., & Wiggins, O. (1985). Science, humanism and the nature of medical
practice: A phenomenological view. Perspectives in Biology and Medicine, 28 , 331–361. 12.
Marcel, G. (1962). Man against mass society (G. S. Fraser, Trans.). Chicago: Regnery. 13.
Whitehead, A. N. (1948). Science and the modern world . New York: New American Library.
14. Schwartz, M. A., & Wiggins, O. P. (2010). Psychosomatic medicine and the philosophy of
life. Philosophy, Ethics, and Humanities in Medicine, 5 , 2.
15. Portmann, A. P. (1990). A zoologist looks at humankind . New York: Columbia University
Press. 16. Thompson, E. (2007). Mind in life: Biology, phenomenology, and the sciences of
mind . Boston: Harvard University Press.
17. Grene, M. (1974). The understanding of nature: Essays in the philosophy of biology .
Heidelberg: Springer.
Part III
Biopsychosociocultural Mechanisms
in Psychosomatic Medicine
Chapter 3
Genes, Memes, Culture, and Psychosomatic
Medicine: An Integrative Model
Hoyle Leigh
3.1 Evolution of Memes from Memory
The brain evolved as a specialized organ dedicated to processing information.

Information is stored as memory, which may be a result of learning, or may be
intrinsic, derived from genes. The evolution of the brain facilitated learning,
survival, reproduc tion, and further enlargement of the brain. Learning through trial
and error created information that facilitated individual and species survival, but
the information contained in the memories died with the organism until the brain
developed imitation as a learning tool [ 1 ].
With imitation, which is robustly in evidence in primates and in songbirds,
infor mation (memory) could be transferred from one brain to other brains in the
form of memes (which is a term coined by Dawkins, which I use here to denote
any portable memory, i.e., information).
Prior to the advent of language, however, most memes residing in individual
organisms died with the organisms. Chimpanzees could observe a bright
chimpanzee cracking a nut with a stone, and this information could spread, but
only to a limited degree. First, they had to be in visual contact with the bright
chimpanzee, and second, the bright chimpanzee must engage in the behavior for
the meme (how to crack a nut) to spread, and this presupposes that there are nuts
and stones around. If chimpanzees had language, one who observed the behavior
could describe it even when there were no nuts and stones, and such a meme could
spread much faster and wider. Such was the case with humans.
H. Leigh , M.D. (*)

Department of Psychiatry, University of California , San Francisco , CA , USA
UCSF Fresno , 155 N. Fresno St , Fresno , CA 93701 , USA

34
H. Leigh
With the development of the written word, memes found an abode outside of
brains. Now they could reside in patterns of indentations in clay, stone, and ink in
paper, and eventually as electronic signals in magnetic tapes and optical media.
Now, more memes reside outside of human brains than inside them, in printed
form in libraries and homes, in electronic media, and in digital form in computers,
CDs and DVDs, and in the cloud. The acquisition of language by Homo sapiens
was instru
mental in memes’ attaining dominance over genes for the fi rst time on planet
earth. In fact, memes in the form of moral codes have suppressed gene-derived
sexual drive in many cultures, and memes in the form of scientifi c knowledge
provides humans with the ability to control gene propagation.
3.2 Neural Memes and Natural Selection

Kandel described a sequence of events in long-term memory formation in Aplysia
. With repeated stimulus of a neuron, a sequence of chemical reactions causes
gene activation in the nucleus of the neuron, resulting in release of messenger
RNA in a dormant form. Further stimulation of the neuron causes a prion-like
protein, cytoplas
mic polyadenylation element-binding protein (CPEB), which is present in all
synapses, to become activated to an infectious form, which in turn activates the
dormant messenger RNA, which in turn makes protein to form a new synapse.
The prion-like infectious form of CPEB infects adjacent CPEB and thus
perpetuates itself and the protein synthesis, maintaining and reenforcing the new
synaptic connection [ 2 ].
In higher organisms, the stimulus that reaches a neuron resulting in this series
of events is itself modifi ed in several interneurons which have their own
connections, that is, stimulus (perception) is modifi ed by existing memory
(memes). Furthermore, neurons are capable of generating impulses without
external stimulus, which may stimulate and reinforce connected neural clusters. A
reinforced neural cluster may be represented as a binary neural code [ 3 , 4 ],
which represents a meme complex, that is, information that is connected and
potentially processed as a unit.
An important aspect of the concept of memes as proposed by Dawkins is that
memes are replicators. Originally, Dawkins pointed out that memes are replicated
in the brains of those who learn by imitation. As these replications are not always
exact, memes undergo Darwinian natural selection and evolution. How about the
memes within the brain?
Edelman described Darwinian natural selection of certain clusters of reinforced
neurons in the brain in somatic time [ 5 ]. Neuronal groups may be reinforced by
signals from other similarly fi ring neuronal groups (forming memes) and thus
gain survival advantage . One might say that neurons thrive on memes. When a
compet
ing meme becomes dominant, neural clusters underlying it are enhanced, that is,
better fed, with more synapses. Thus, some memes will become dominant with
repeated exposure and rehearsal and proliferate, that is, recruit other neuronal
groups; others will become dormant, not forming new connections or recruiting
others. The process resulting in new parallel connections may be seen to be a
process of replication of the meme, a prion-like replication by contact through
synaptic and/or
3 Genes, Memes, Culture, and Psychosomatic Medicine...
35
dendritic connection. This is not to imply that one neuron serves only one meme.
In fact, a neuron has many connections and may be a component of a number of
different memes and memetic connections. Meme replication in the brain,
therefore, does not necessarily involve reproducing new neurons, but rather occurs
through recombination of component memes in existing neuronal groups. Such
replication may occur through meme-processing mechanisms such as cognition,
often stimulated by the entry of new memes into the brain.
3.3 Memeplexes, Development, and Psychopathology
Why are our brains full of thoughts? According to Blackmore [ 6 ], the answer lies
in the fact that memes are replicators, and the thoughts we have are expert
replicators that survived Darwinian selection.
While most of the memes in our brains come from outside of the brains, some
memes are created or cobbled together in new combinations within our brains in
the form of new memeplexes. Our brain is full of memes and memeplexes that we
have acquired over time. Some examples of memeplexes include the following: “I
am intel
ligent,” “good,” “evil,” “health,” “God,” “Devil,” “socialism,” and “psychosomatic
medicine.” Memeplexes may be complexes of ideas, sounds, and other perceptual
memories, for example, songs, scenes, posters, and jingles.
Humans live in niches of memes called culture. Culture consists of memes such
as language, rules, morals, religion, beliefs, traditions, and esthetics. It also
consists of matter-meme complexes like food, buildings, and edifi ces. In any
meme pool we call culture, there are prevalent or dominant memes and non-
prevalent, recessive, and/or latent memes.
Niches, by defi nition, tend to be stable habitats, and memes that form a
particular niche are those that made stable copies of themselves over time, that is,
did not change much. Memetic niche culture, therefore, tends to be conservative,
that is, resistant to change. The conservative meme pool incorporated, over time,
memetic infrastruc
tures to support the existing gene-meme social power structure, such as hereditary
caste, wealth, and access to information. Social customs, religions, rituals, and
other codes of conduct are such memeplexes that support the dominant culture.
Cultural artifacts such as books, scripture, churches, and tombs all embed such
memes.
The environment consists of memes and potential memes like a culture medium
in a Petri dish. The culture medium consists of molecules, some of them nutrients,
others toxins, and yet others inert. Some enter the organism and become part of it
or give it energy. Others may simply enter and stay without much effect. Under
certain conditions, such as an increase in the concentration of the toxic molecules,
some such molecules will penetrate the protective barrier of the organism and
cause a reac
tion in the host – perhaps an immune reaction that gets rid of the toxic molecule, or
the organism may succumb to the toxin. The shape and nature of the toxic
molecule play important roles in whether it enters the host and what happens
afterwards. So with memes. The shapes and other characteristics of the vehicles of
memes are physical in nature such as printed words, spoken words, melodies,
rhythm, scenes,
36 Fig. 3.1 Memes in environment and brain
H. Leigh
movements, facial expressions, and touch. Those memes that are endemic are the
cultural memes that enter the brain in early life.
A person is the net result of gene × meme × environment interaction that we
call development. Except in rare cases where the environment interacts directly
with genes as with environmental toxins and climate, genes interact with memes
in the brain, which may have been absorbed directly from the environment as
information or may have been induced through experiential learning. Some newly
introduced memes may confl ict with existing memes in the brain and may either
die or become dormant (unconscious). Others may combine with existing dormant
memes and activate them (Fig. 3.1 ).
While the aggregate of these memes and memeplexes constitute our
personalities, some such acquired memes are pathogens and in interaction with
genes and other “host factors” may cause mental or psychosomatic illness.
Treating such an infection may require the equivalents of either a pathogen-specifi
c antibody or a broad-spectrum antibiotic therapy. Prevention may also be
possible through appropriate immunization.
3.4 Gene × Meme × Environment Interaction

in the Pathogenesis of Stress-Related Disorders
A single gene that codes for the vulnerability to multiple stress-related disorders is
the serotonin transporter gene (SERT) and its promoter region polymorphism
(5HTTLPR). SERT is highly evolutionarily conserved and regulates the entire
serotonergic system
37
Fig. 3.2 Epigenetic cascade

and its receptors via modulation of extracellular fl uid serotonin concentrations.
5HTTLPR polymorphism consists of short (s) and long (l) alleles, and the presence
of the short allele tends to reduce the effectiveness and effi ciency of SERT. The
short allele has been identifi ed as the underlying variation for increased anxiety,
increased neuroticism, smoking behavior, especially to reduce negative mood and
feel stimu
lated, diffi culty in quitting smoking, social phobia, major depression, and irritable
bowel syndrome [ 7 – 10 ].
Genes may create an environment in the brain that is more hospitable to certain
types of memes than others. For example, in the presence of the short allele of the
serotonin transporter promoter gene (5HTTLPR), the amygdala tends to be more
sensitive to threatening stimuli (memes) [ 11 , 12 ] In spite of the gene, if the child
experiences abundant nurturance, the gene may be turned off. On the other hand, if
the child is mistreated, the brain will respond with increased fear, anxiety, and help
lessness, generating corresponding memes, which are likely to epigenetically
activate the vulnerability gene. Such a brain would be more susceptible to
infection by depressive and dysphoric memes and memeplexes coming from
social interactions, learning, and even the media. A stressful event in adulthood
may then infuse the brain with a massive dose of depressive memes. Thus, a brain
that is already inhabited with a large number of depressive memes (most of which
may be unconscious) may be overwhelmed by addition of new infection resulting
in a depressive syndrome, a state of total control by the depressive memes (Fig.
3.2 ).
38
H. Leigh
Ross postulated that a person becomes vulnerable to “psychosomatic memes”

when in distress [ 13 ]. He writes, “the anguish of distress compels the sufferer to
give it a name…a meaning…Like a virus that incorporates into a cell by fi tting a
forged protein into a cell receptor, a psychosomatic meme incorporates into a host
by providing the “key” to the suffering.”
Explanatory concepts of symptoms and disease are all memeplexes and
undergo evolution within and across cultures. Somatic sensation may be amplifi
ed by memes (“I have a serious disease”) to the point of hypochondriasis.
Psychosomatic memes may be epidemic, as in the case of pseudohypoglycemia in
the 1970s [ 14 ].
Posttraumatic stress disorder (PTSD) may be likened to a tumor of event-
related memes. In massive traumatic stress, there may be an invasion of massive
amounts of memes both representing the trauma (visual, auditory, tactile
perceptions) as well as the meaning of the trauma (anxiety/fear memes, anger
memes, regret memes, guilt memes). The massive infusion of memes results in
massive stress hormone activation.
Hippocampus plays an important role in shutting off the HPA activation – any
damage or atrophy of the hippocampus attenuates this resulting in a prolonged
HPA activation to stress [ 15 , 16 ]. Certain types of acute stress and many chronic
stressors suppress neurogenesis or cell survival in the hippocampus.
Glucocorticoids, excitatory amino acids acting on N -methyl- d -aspartic acid
(NMDA) receptors, and endogenous opioids mediate the suppression [ 17 ]. Stress
also affects the shape and abundance of dendrites in the hippocampus, amygdala,
and prefrontal cortex. Generally, stress results in retraction and simplifi cation of
dendrites.
In sum, stress hormones tend to disconnect incoming memes from existing
memes (memories), which in turn attenuates resident protective memes, allowing
unchecked replication of newly introduced stress memes. These unchecked stress
memes fi nd every opportunity to reinforce themselves and replicate as in fl
ashbacks and nightmares. Hypervigilance and avoidance in PTSD may be
compensatory mechanisms to reduce the stress meme replication.
3.5 Treatment Approaches
Treatment of depression and stress-related disorders should be geared to (1)

attenuating or reversing the brain state that is hospitable to pathologic memes, (2)
attenuating or eradicating the strength of the pathologic memes that have taken
control of the brain, and (3) regulating the memes in the environment, that is,
reducing noxious memes and increasing benefi cial memes.
Pharmacologic and surgical (e.g., deep brain stimulation) treatments are
primarily geared to changing the brain state. Psychotherapies are essentially
treatment modalities geared toward memes, but without the conceptualization of
memes, they tend to be haphazard and imprecise and seem mutually exclusive or
contradictory. Among extant psychotherapies, cognitive-behavioral therapy (CBT)
comes closest to a more explicit understanding of the memes, particularly when
the underlying “delusions,” which are pathogenic memes, are identifi ed.
39
As with antibiotics, meme-oriented therapies may be classifi ed into broad-

spectrum and specifi c therapies. Broad-spectrum anti-meme therapies suppress
replication of all memes through activities such as meditation, mindfulness,
relaxation training, autogenic training, music, dance, and exercise therapies.
Specifi c anti- meme therapies include psychotherapies specifi cally geared to
delusions, phobias, confl icts, etc. The concept of memes may lead to more specifi
c and direct methods of identifying and neutralizing specifi c memes, for example,
through introduction of counter-memes which may be in the form of images,
melodies, or sounds.
Placebo is an excellent example of meme-oriented therapy that can result in
robust physiologic and brain changes [ 18 – 20 ]. Non-deceptive placebo, in which
patients are told that they will be taking a “sugar pill” that has been shown to help
symptoms, has been shown to be effective in treating irritable bowel syndrome
patients [ 21 ]. Virtual reality may be used to create conducive memetic
environments, and avatars, images of oneself, may be used as memetic identifi
cation fi gures [ 22 , 23 ].
In this gene × meme × environment interaction model of epigenetic
development, prevention must play a key role. Prevention of epigenetic changes
that cause vulnera bility to illness, such as childhood abuse, as well as prevention
through strengthening of the effective meme-fi ltering activity of critical thinking
is essential in preventing mental, psychosomatic, and stress-related illnesses.
3.6 Conclusions
The brain evolved as a specialized organ for processing information. Information

was stored in the brain as memory and died with the organism. With the
acquisition of language in humans, memory became portable and spreadable –
memes . Memes can be stored outside the brain in books and electronic media and
spread widely. There are endemic memes we call culture that are introduced into
the brains of children from early life. Such endemic memes may be protective or
pathogenic. Memes associated with early stress and nurturance cause epigenetic
changes and determine genetic vulnerability/resilience for later stress. In the
course of develop ment, memes that are stored in the brain as reinforced neural
clusters undergo Darwinian natural selection, and some memes become dominant
while others become attenuated or dormant. Later stress may result in hormonal
changes leading to an attenuation of hippocampal function resulting in an
attenuation of protective dominant memes, allowing a massive infusion of stress
memes that in turn awaken dormant pathologic memes. This cascade may result in
mental and stress-related psychosomatic illness. Treatment of psychosomatic
illness should thus be geared to the suppression of pathologic memes as well as
toward the prevention and treatment of pathogenic epigenetic changes. Broad-
spectrum and specifi c memetic therapies should be considered. Childhood
nurturance, prevention of abuse, and enhancement of meme processing through
education are important factors in psychosomatic health.
40 1. Dawkins, R. (1976). The selfi sh gene . New
York: Oxford University Press. 224pp.
H. Leigh
References
2. Kandel, E. R. (2006). In search of memory: The emergence of a new science of mind (1st ed.).
New York: WW Norton & Co. 510pp.
3. Yang, G., Tang, Z., Zhang, Z., et al. (2007). A fl exible annealing chaotic neural network to
maximum clique problem. International Journal of Neural Systems, 17 , 183–192. 4. Lin, L.,
Osan, R., & Tsien, J. Z. (2006). Organizing principles of real-time memory encoding: Neural
clique assemblies and universal neural codes. Trends in Neurosciences, 29 , 48–57. 5. Edelman,
G. M. (1987). Neural Darwinism: The theory of neuronal group selection . New York: Basic
Books. 371pp.
6. Blackmore, S. J. (1999). The meme machine . Oxford/New York: Oxford University Press.
264pp. 7. Lotrich, F. E., & Pollock, B. G. (2004). Meta-analysis of serotonin transporter
polymorphisms and affective disorders. Psychiatric Genetics, 14 , 121–129.
8. Hu, S., Brody, C. L., Fisher, C., et al. (2000). Interaction between the serotonin transporter
gene and neuroticism in cigarette smoking behavior. Molecular Psychiatry, 5 , 181–188. 9.
Lerman, C., Carporaso, N. E., Audrein, J., et al. (2000). Interacting effects of the serotonin
transporter gene and neuroticism in smoking practices and nicotine dependence. Molecular
10. Yeo, A., Boyd, P., Lumsden, S., et al. (2004). Association between a functional
polymorphism in the serotonin transporter gene and diarrhoea predominant irritable bowel
syndrome in women. Gut, 53 , 1452–1458.
11. Caspi, A., Hariri, A. R., Holmes, A., et al. (2000). Genetic sensitivity to the environment:
The case of the serotonin transporter gene and its implications for studying complex diseases
and traits. The American Journal of Psychiatry, 167 , 509–527.
12. Sugden, K., Arseneault, L., Harrington, H., et al. (2010). Serotonin transporter gene
moderates the development of emotional problems among children following bullying
victimization. Journal of the American Academy of Child and Adolescent Psychiatry, 49 ,
830–840.
13. Ross, S. E. (1999). “Memes” as infectious agents in psychosomatic illness. Annals of
Internal Medicine, 131 , 867–871.
14. Welch, M. (1971). Hypoglycemia. Ladies Home Journal, 88 , 98–103. 15. McEwen, B. S.
(2007). Physiology and neurobiology of stress and adaptation: Central role of the brain.
Physiological Reviews, 87 , 873–904.
16. McEwen, B. S., & Milner, T. A. (2007). Hippocampal formation: Shedding light on the infl
uence of sex and stress on the brain. Brain Research Reviews, 55 , 343–355.
17. Gould, E., McEwen, B. S., Tanapat, P., et al. (1997). Neurogenesis in the dentate gyrus of the
adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. Journal
of Neuroscience, 17 , 2492–2498.
18. Benedetti, F., Mayberg, H. S., Wager, T. J., et al. (2005). Neurobiological mechanisms of the
placebo effect. Journal of Neuroscience, 25 , 10390–10402.
19. Stein, D. J., & Mayberg, H. (2005). Placebo: The best pill of all. CNS Spectrums, 10 , 440–
442. 20. Mayberg, H. S., Silva, J. L., Brannan, S. K., et al. (2002). The functional neuroanatomy
of the placebo effect. The American Journal of Psychiatry, 159 , 728–737.
21. Kaptchuk, T. J., Friedlander, E., Kelley, J. M., et al. (2002). Placebos without deception: A
randomized controlled trial in irritable bowel syndrome. PLoS One, 5 , e15591. 22. Bailenson, J.
N. (2006). Transformed social interaction in collaborative virtual environments. In P. Messaris &
L. Humphreys (Eds.), Digital media: Transformations in human communica tion (pp. 255–264).
New York: Peter Lang.
23. Bailenson, J. N., Yee, N., Blascovich, J., et al. (2008). The use of immersive virtual reality in
the learning sciences: Digital transformations of teachers, students, and social context.
Journal of the Learning Sciences, 17 , 102–141.
Chapter 4
Alexithymia and Somatic Symptoms
Gen Komaki
4.1 Introduction
A person’s limited ability to understand, process, or describe his/her feelings is

referred to as alexithymia, literally “no words for feelings.” This concept was fi rst
introduced by Sifneos [ 1 ] and was formulated from observations of
psychosomatic patients who had defi cits in their ability to identify, describe, and
work with their own feelings as well as having diffi culty in distinguishing
between their feelings and their bodily sensations. In addition to these defi cits, the
concept of alexithymia also includes a very limited fantasy life and a cognitive
style that is excessively focused on external details.
Although the term “alexithymia” was in the past mainly used for patients
suffering from psychosomatic disorders, the concept of alexithymia is currently
being used to refer to defi cits in the emotional functioning of broader populations
with common medical diseases and psychiatric disorders. Assessment of
“alexithymia,” as reported in the medical literature, is generally based on the
Toronto Alexithymia Scale (TAS)-20 [ 2 ]. This self-reported alexithymia scale,
however, refl ects “subjective” diffi culties in identifying and describing feelings
that can differ from “objectively” identifi ed diffi culties. Consequently, it is
possible that patients with neuroticism and/or soma tization are being identifi ed
rather than those who are truly alexithymic. As Sifneos emphasized at every turn,
what is really needed is for physicians to learn to recognize the difference between
neurotic and alexithymic patients [ 3 ].
G. Komaki , M.D., Ph.D. (*)

School of Health Sciences at Fukuoka , International University of Health and
Welfare , 137-1 Enokizu , Ohkawa , Fukuoka 831-8501 , Japan

42 4.2 Alexithymia and Somatic
Symptoms
G. Komaki
Because of their inability to communicate their feelings, people with alexithymia

are prone to communicate through their bodily sensations, seeking help from
primary care physicians rather than getting the psychological treatment they need.
A quanti tative review of the literature showed a small to moderate association
between the total score of TAS-20 and somatic symptoms [ 4 ]. In many studies,
signifi cant asso ciations have been found between alexithymia and somatoform
disorder symptoms or somatic symptoms in clinical [ 5 – 7 ] and nonclinical
samples [ 7 ]. However, contra dictory fi ndings have also been reported [ 8 , 9 ].
When trait anxiety and depression were controlled, no signifi cant association
between alexithymia and somatic com plaints was found in a community sample [
10 ]. Patients with a tendency to over report physical symptoms scored signifi
cantly high on the TAS-20 “diffi culty in identifying feelings” and “diffi culty in
describing feelings” subscales [ 7 ], whereas another subscale, “externally oriented
thinking,” was not related to somatic symp toms but rather to fewer medical
outpatient visits [ 8 ]. Because the above studies were dependent on self-reported
symptoms and “externally oriented thinking” may truly refl ect a tendency toward
alexithymia [ 11 ], it is diffi cult to draw concrete conclusions about the
relationship between specifi c dimensions of alexithymia and somatic symptoms,
regardless of whether or not the symptoms can be medically explained. As
discussed later in 4–5, alexithymia may be associated with a “decoupling” of
subjective emotional experience from physiological reactivity in emotionally
arousing situations [ 12 ]. Neuroimaging studies may help to elucidate the
relationship between alexithymia and somatic symptoms [ 13 ].
4.3 Alexithymia and Depression
The so-called dimensions associated with diffi culties in communicating feelings

have been positively related to negative affects such as depression and anxiety [ 11
, 14 ]. Studies have shown that “diffi culty in identifying and describing feelings”
is associated with depression. Several studies showed a relationship between “mea
sured alexithymia” and depression [ 15 – 18 ]. One study found that the “diffi culty
in identifying feelings” and “diffi culty in describing feelings” subscale scores
were signifi cantly correlated with scores of the Beck Depression Inventory (BDI)
[ 18 ]. In fact, depressed mood may potentiate alexithymia [ 19 ], but alexithymia
differs from the cognitive distortions of depression as measured by the BDI.
People who score high on the “diffi culty in identifying feelings” and “diffi culty
in describing feel
ings” subscales may be viewed by others as emotionally aware, or they may use
emotional language in relatively complex ways [ 20 ]. Clearly, people with high
neg ative affect differ substantially from those with alexithymia who are much less
interested in their own psychological and emotional lives.
4 Alexithymia and Somatic Symptoms
43
4.4 Alexithymia and Personality
People with high neuroticism make fewer and less effective attempts at emotional
regulation [ 21 ], and neuroticism itself is considered to be a stable dimension of
normal personality [ 22 ]. Although the concept of neurosis has been excluded
from the Diagnostic and Statistical Manual of Mental Disorders (DSM), it
encompasses a vari
ety of clinical manifestations: depression, anxiety (panic, phobia), hysterical symp
toms, hypochondriasis, depersonalization, irritability, and abnormal eating
behavior [ 23 ]. Neurotic people are aware of their predisposition to experience
negative affect and are concerned about negative affect-eliciting situations, and
they prefer to avoid them. Neuroticism is a trait that involves a predisposition to
experience negative affect and that is considered to have a biological basis [ 24 ],
whereas alexithymia is a person ality trait that refl ects a defi ciency in emotional
experience [ 20 ]. Similar to the fi ndings for depression, as stated above, subjects
with high TAS-20 scores are prone to show signifi cantly more neurotic traits [ 25
]. However, whether or not a patient’s alexithymia scores are truly associated with
this personality dimension should be carefully deter mined. Scores of the “diffi
culty in identifying feelings” and “diffi culty in describing feelings” subscales of
TAS-20 showed signifi cant and positive correlations with the neuroticism scores
of both the NEO-Five-Factor Inventory (FFI) [ 26 ] and the Eysenck Personality
Questionnaire [ 2 , 26 , 27 ]. However, for the subscale that assessed “exter nally
oriented thinking,” no signifi cant association with neuroticism was shown [ 2 , 26
]. In contrast with the “diffi culty in identifying feelings” and “diffi culty in
describing feel ings” of TAS-20, “externally oriented thinking” is the cognitive
section of TAS-20 and is more accurately rated because the items related to this
subscale ask people to rate themselves on a skill or habit that they are easily aware
of [ 28 ]. Externally oriented thinking is also less infl uenced by depression or
anxiety [ 29 ]. Although some research ers have questioned if it represents a salient
feature of the alexithymia construct [ 24 , 30 ], there is a signifi cant and moderate
negative correlation between “externally oriented thinking” of TAS-20 and
“openness” of the NEO-FFI, which coincides with the results of a previous study [
2 ]. People with low openness are defi cient in imaginative ability, so it must be
remembered that alexithymic patients have diffi culty in fi nding the appropriate
words to describe their feelings. Therefore, this impairment may be due to their
impov erished fantasy life [ 3 ]. The negative association between “openness” and
“externally oriented thinking” also supports the latter as corresponding to a
passive and negative attitude toward observing, analyzing, and coping with
unknown events and confl icts. Thus, the evidence indicates a strong overlap
between the alexithymia construct and “openness to experience,” which may be
the key personality dimension [ 22 ].
4.5 Alexithymia and Interoceptive Awareness
As noted by Craig [ 31 , 32 ], individual differences in emotional awareness are

directly related to differences in the capacity for interoceptive feeling. Alexithymia
is considered to be inversely associated with the processing and perception of
44 G. Komaki
interoceptive signals, because the characteristics of alexithymia are negatively

associated with emotional awareness. However, there are contradictory fi ndings
on the interoceptive awareness of subjects with alexithymia.
Researchers have hypothesized that people with alexithymia may be
excessively aware of or attuned to their bodies or the undifferentiated arousal that
generates somatic sensations, which results in amplifi cation of the sensations as
symptoms of physical illness [ 33 , 34 ]. Further, studies on the relationship
between alexithymia and panic disorders have confi rmed such tendencies [ 35 –
37 ]. Of the dimensions of TAS-20, however, “diffi culty in identifying feelings”
had a positive correlation with the severity of anxiety and panic symptoms, which
suggests that “high” alexithymia may be associated with the amplifi cation of
panic symptoms in patients with panic disorder. In contrast, the experimental
studies on alexithymia by Näring et al. [ 38 ] and Herbert et al. [ 39 ] found rather
poorer or blunted perception of heart rate changes, which suggests a lack of
interoceptive awareness (e.g., subjects with vary ing degrees of alexithymia and
anxiety/depression). Because heart rate perception correlates with the ability to
detect changes in other autonomically innervated organs, it can be said that this
variable refl ects a general sensitivity to visceral processes, i.e., interoceptive
awareness. In fact, these fi ndings showed that, in con
trast with the fi ndings for panic disorder patients [ 36 , 37 ], there was no signifi
cant difference in the strength of association between interoceptive awareness,
affective alexithymia component related to “diffi culty in identifying and
describing feelings,” and cognitive alexithymia component related to “externally
oriented thinking” [ 39 ]. Although the cognitive pathways, i.e., neural dysfunction
of frontolimbic circuits, have been reported to possibly underlie the panic with
“high” levels of alexithymia and hyperarousal toward emotionally related bodily
stimuli [ 37 ], it remains unknown if and how alexithymia is associated with either
physiological hyper- or hypoarousal in the different stages of emotional
processing [ 39 ]. Further studies are necessary to examine the interaction between
interoceptive awareness and the various aspects of alexithymia during
physiological arousal with and without different emotional processing. In relation
with this, it will be interesting to do neuroimaging studies to examine the
relationship between alexithymia and interoceptive awareness [ 13 ].
Ikemi Y [ 40 ] fi rst coined the term “alexisomia” to designate a condition
wherein certain people have diffi culty in expressing how their bodies feel. He
noted that many people with alexithymia seemed to have reduced awareness of
and diffi culty in expressing their feelings about both normal and abnormal bodily
sensations. This concept of impairment in the awareness of somatic feeling may
overlap or be identical to alexithymia, i.e., a defi cit in interoceptive awareness.
4.6 Validity Issues in the Assessment of Alexithymia
Recent studies on the relationship of TAS-20 scores with performance-based mea

surement of emotional ability and the developmental aspects of the emotional
aware ness in adolescents suggest that the assessment of “alexithymia” based on
4 Alexithymia and Somatic Symptoms 45
self-reported questionnaires should be reexamined [ 41 , 42 ]. To prevent false-

positive alexithymia, it would be better to use TAS-20 in combination with non-
self- report measures of alexithymia. The non-self-report measures include the
Modifi ed Beth Israel Questionnaire, which is based on an interview [ 43 ];
Haviland’s California Q-Set alexithymia Prototype [ 44 ] and his Observer
Alexithymia Scale [ 45 ], which are rated by collateral informants; and Lane’s
Levels of Emotional Awareness Scale (LEAS). The LEAS is a tool for assessing
the complexity of emotional responses to vignettes and contains performance
subtests of various emotional abilities [ 46 ].
Igarashi et al. [ 41 ] investigated the relationship between the LEAS and TAS-
20 scores among college students and found that only the “externally oriented
thinking” subscale score of TAS-20 was signifi cantly and negatively correlated
with the LEAS scores. This is consistent with the fi ndings of other studies for
somatoform disorder patients [ 11 , 47 ]. Furthermore, “externally oriented
thinking” has been more closely associated with various objective measurements
regarding emotional regulation, such as physiological indices (e.g., baseline heart
rate) [ 47 ] and the Affect Consciousness Interview, than the two dimensions
related to diffi culties in communicating feelings [ 14 , 48 ]. Therefore, the
“externally oriented thinking” subscale may be more fi t than the other subscales
for the measurement of alexithymia in college students [ 41 ] because it is signifi
cantly associated with objective measures of emotional awareness (e.g., LEAS)
and emotional regulation of bodily functions (e.g., baseline heart rate), as
mentioned above.
One study [ 26 ] examined the relationship between the alexithymia subscales
and age in a normative sample of more than 2,700 people and found that the TAS-
20 total score and the “diffi culty in identifying feelings” and “diffi culty in
describing feelings” subscale scores were highest in teenagers, thereafter declined
with age, and from the 30s did not change signifi cantly (Fig. 4.1 ). In contrast,
“externally oriented thinking” subscale scores showed an almost linear, positive
correlation with age. “Diffi culty in identifying feelings” subscale scores were
higher for women, while “externally oriented thinking” subscale scores were
higher for men, without any interaction between gender and age differences. Such
age-related differences in TAS-20 subscale scores indicate developmental aspects
of emotional regulation; alexithymia has two components with different
developmental paths: “diffi culty in identifying feelings/diffi culty in describing
feelings” and “externally oriented thinking.” In particular, this age-related
difference in “diffi culty in identifying feelings” and “diffi culty in describing
feelings” might refl ect age-related alteration (linear decline with age) of self-
consciousness, an aspect of neuroticism that is related to the discrete-emotion
construct of shame [ 49 ].
Another study [ 42 ] indicated that alexithymia in early adolescence is not ade
quately assessed by self-report questionnaires such as the TAS-20, particularly the
“diffi culty in identifying feelings” and “diffi culty in describing feelings”
subscales. More than half of the items of TAS-20 had to be eliminated after
exploratory factor analysis due to low factor loading, which indicates the necessity
of modifying the content of these subscales or perhaps the need to create a new
item pool. As described above, even when teenagers score signifi cantly high on
the “diffi culty in identifying feelings” and “diffi culty in describing feelings”
subscales, the scores still might not
46 G. Komaki
Fig. 4.1 Age-related comparison of TAS-20 total score and subscales scores (mean ± SE) in men
and women. DIF diffi culty in identifying feelings, DDF diffi culty in describing feelings, EOT
externally oriented thinking. TAS-20 total score and the DIF and DDF subscale scores were
highest for teenagers, thereafter declined with age, and from the 30s did not change signifi cantly.
In contrast, EOT subscale scores showed a positive correlation with age ( p < 0.05). DIF subscale
scores were higher in women, while EOT subscale scores were higher in men ( p < 0.05) (From
Moriguchi et al. [ 26 ])
represent a tendency toward alexithymia. Therefore, self-reported questionnaires

for alexithymia need to be carefully constructed and examined, for both
adolescents and adults.
4.7 Conclusions
Whether or not somatic symptoms can be medically explained, many studies have
indicated that somatoform disorders, depression, panic symptoms, and neuroticism
are associated with alexithymia. However, critical analysis of the current methods
of assessment shows weaknesses in that alexithymia has been defi ned only by its
affective aspects, such as diffi culty in identifying and/or describing feelings, and
that assessment has been based on self-reported measurements, such as TAS-20.

Because affect and cognition are not ontologically separate, but perhaps phenome
nologically distinctive, future studies need to examine how the affective and
cognitive aspects of alexithymia are associated with diffi culty in distinguishing
between feel ings and emotional arousal-related bodily sensations.
To determine the relationship between alexithymia and somatic symptoms, it is
necessary to use a package that can cover all the aspects of the alexithymia
construct: self-reported questionnaires (e.g., TAS-20), performance-based
measurements, expert judgments, and the ratings of collateral informants. In
addition, neuroimaging studies may help to elucidate the relationship between
alexithymia and somatic symptoms.
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Chapter 5
Culture and Somatic Symptoms: Hwa-byung
, a Culture-Related Anger Syndrome
Sung Kil Min
5.1 Introduction
Many psychiatric illnesses or symptoms are known to evolve in a sociocultural

context. Culture may not only affect the labeling of certain illnesses or symptoms
but also affect people’s belief in the occurrence of a certain illness or symptom
according to their reaction pattern via modulation of sensitivity to a particular
stressor as well as susceptibility to a particular organ [ 1 ]. Culture is closely
related to the clinical history or the precipitants of a certain health problem.
Accordingly, understanding the infl uence of culture on psychiatric disorders is
critical to the biopsy
chosocial formulation and treatment planning for patients with such disorders.
Particularly, somatic symptoms are probably the most typical symptoms that refl
ect the infl uences of culture on psychiatric symptoms. For example, somatic
symptoms are frequently described in different names according to different
cultures, as if they are really different illnesses, although they are substantially
identical. The opposite is possible, too: the same label of symptoms or illnesses
for a substantially different pathology. However, there have been limited studies
on how a particular culture affects the development of symptoms along with their
labeling. In Korea as well, a few studies have been reported to date regarding the
infl u ences of culture on the occurrence of somatic symptoms, on the labeling of
somatic symptoms, and on the explanation of etiology. In the study of such culture
infl uences, a culture-related psychiatric syndrome may be the most suitable
subject. In Korea, hwa-byung is the case.
In this chapter, several studies will be reviewed on how somatic symptoms are
differently manifested, described, and explained according to the traditional and
contemporary cultures of Korea in general; a case of hwa-byung , a culture-related
syndrome will also be analyzed.
S. K. Min , M.D., Ph.D. (*)

Professor Emeritus, Yonsei University College of Medicine, Seoul Metropolitan
Eunpyeong Hospital , 90 Baengnyeonsan-ro, Eunpyeong-gu , Seoul 122-913 ,
Korea e-mail: [email protected]

52 Koreans
5.2 Somatization in Koreans S.K. Min
5.2.1 Somatizing Tendency of
It has been argued that Koreans have a high tendency to express their
psychological or emotional problems in somatic terms, not only in psychiatric
illnesses, but also in an ordinary conversation. Kim [ 2 ] related such high
somatization tendency to old primitive concepts based on shamanism and Asian
ancient medicine. In an ordinary conversation, Koreans frequently use somatic,
especially visceral, terms in order to express their psychological or emotional
matters. For example, there is a frequently stated Korean proverb which says,
“when one’s cousin buys a piece of land, they get sick to their stomach.” In this
proverb, the major characteristics of the traditional Korean culture are refl ected,
including traditional agrarian culture, historical poverty, emotional reaction to
unfairness, and people’s utmost concern for eating (gastroin testinal function) [ 3 ].
In Korea, the greeting “Good morning” used to be “Did you eat breakfast?” Min
and Kim [ 4 ] reported that Korean depressives tended to somatize their
depression, especially in visceral symptoms including indigestion, abdominal
discomfort, heart pounding, and respiratory stuffi ness.
5.2.2 Biology and Culture

Based on the biopsychosocial model of human behavior, research has suggested
the complex interactions between the body, mind, and sociocultural environments.
This complexity has been attributed to a marked increase in the number of neurons
in the human brain. Additionally, the increase of interconnections among neurons,
which are shaped by an environmental input of long-term evolutionary changes as
well as by development after birth, also affects the complexity. Certain somatic
symptoms may be localized in the brain where culture may exert infl uence. An
example illustrating the influences of culture on brain localization is handedness.
Handedness may be developed differently according not only to the genetic
predisposition but to the cultural pressure on handedness. Min and Lee [ 5 ]
reported the differences of the lateralized pattern of somatic symptoms in Korean
patients with depression, anxiety disorders, and somatization disorders in relation
to handedness.
5.2.3 International Comparative Studies
In an epidemiological study in Korea [ 6 ], using the original American version of

DIS-III, the lifetime prevalence of somatization disorders was reported to be 0.06
% of the general population. However, when the Korean version of DIS-III was
used, including the Korean culture-related somatic symptoms (i.e., heat sensation,
respira
tory stuffi ness, and a feeling of something pushing up in the chest) in the diagnostic
53
5 Culture and Somatic Symptoms: Hwa-byung , a Culture-Related Anger Syndrome
criteria of somatization disorders, the prevalence rate increased to 5.45 %. This

result suggested not only a high tendency of somatization in Koreans along with
the infl uence of Korean culture on naming of certain symptoms or a selection of
symptomatic organs but a necessity for modifi cation of the diagnostic criteria
according to different cultures since the occurrence of somatization symptoms and
naming of symptoms are strongly infl uenced by culture.
An international comparative study on the differences in the prevalence rate of
symptoms of depression in three Asian countries, Japan, China, and Korea [ 7 ],
reported that Korean depressives were more likely to show a depressive mood,
psychic anxiety, somatic anxiety, and gastrointestinal and genital symptoms in
comparison with the Japanese and Chinese depressives. In addition, Koreans had
relatively more frequently complained of palpitation, indigestion, general
weakness, and loss of libido.
However, Kim et al. [ 8 ] reported a different fi nding. They compared
depressive symptoms among the three groups of depressed patients: Koreans
residing in Seoul, Korea; Korean Chinese in Yanbian, China; and Chinese in
Yanbian, China, using the rating scales for depression. The results revealed that
Korean depressives in Korea complained of more psychological symptoms,
Chinese depressives of more somatic symptoms, and Korean Chinese depressives
of symptoms that lie between the other two groups on a somatic–psychological
continuum. The differences between the two studies may be explained by time
differences of the studies. During the 1991–1999 period, the Korean society had
been signifi cantly changed in its cultural context.
5.2.4 Comparative Studies Within Korea
Within the same ethnic group, somatic symptoms can transform in quantity and
quality in relation to a cultural change over time. For example, Min and Suh [ 9 ]
reported that, during a period of 15 years between the 1950s and 1970s, the
number of admitted patients with hysterical disorder had decreased. Moreover, the
classical symptoms such as convulsion, fainting, or other motor–sensory
symptoms had decreased in patients with this disorder, whereas pain or visceral
symptoms had increased. These changes were considered related to the cultural
changes in the Korean society, from a simple agrarian undeveloped culture to a
more industrialized, educated, and sophisticated culture.
5.3 Korean Culture-Related Syndrome, Hwa-byung
5.3.1 Clinical Correlates of Hwa-byung
Symptoms of hwa-byung , especially its somatic symptoms, reveal how the

Korean culture is related not only to the concept and naming of a certain disorder
and its symptoms but to the explanation of the cause and development of the
disorder and
54 S.K. Min
to its treatment [ 10 ]. The name hwa-byung itself is cultural: Hwa (火) in hwa-
byung means anger and fi re in Korean, and byung (病) means disease or illness;
accord ingl y, hwa-byung literally means “anger disorder” or “fi re disease.”
Self-labeled hwa-byung was reported in 4.2 % of the general population in
Korea; it was most frequently reported in middle-aged or older women of lower
socioeconomic status, who seem to have kept the Korean traditional culture [ 11 ].
When diagnoses were made according to the criteria of the DSM-III-R or
DSM-IV in patients with self-labeled hwa-byung , many of them were diagnosed
with a major depressive disorder, generalized anxiety disorder, an atypical
somatization disorder, or their comorbid state [ 11 ]. However, in a study using the
research diagnostic crite
ria for hwa-byung [ 12 ], only about 16.8 % of the patients with the so-called “neu
rotic” disorders were found to have only hwa-byung [ 13 ], suggesting the
existence of a new category of “anger” disorder [ 14 ].
Regarding the biology of hwa-byung , Lee et al. [ 15 ] reported that in a study
using functional magnetic resonance imaging (fMRI) on neural responses to
neutral, sad, and angry facial stimuli, the effect of anger suppression resulted in an
aberrant function of the brain regions related to the visual pathways. Moreover,
this func
tional impairment in the anterior cingulate cortex may contribute to the pathophysi
ology of hwa-byung .
The precipitating factors of hwa-byung were reported to be traumatic experi
ences to one’s self-esteem. The most common typical factor was domestic
violence: husbands and/or mothers-in-law committing violent acts toward
wives/daughters in- law [ 10 ]. According to the patients’ explanation, anger
reactive to the unfairness should be “suppressed” in order not to jeopardize
harmonious familial and/or social relationships [ 16 ]. However, if the anger-
provoking situation is repeated, then the suppressed anger accumulates and
becomes dense(鬱), which patients usually describe as wool-hwa (鬱火), meaning
dense hwa (anger or fi re), and fi nally resulting in hwa-byung .
Hwa-byung has been argued to be the result of incomplete suppression and
somatization of anger [ 10 ]. Defense style or coping strategies include oral con
sumption, avoidance of stimulus, externalization (projection), help-seeking
behavior, impulsiveness (acting out), pseudo-altruism, omnipotence, fatalism, self-
pity, and fantasy [ 17 ]. Roberts et al. [ 18 ] suggested that hwa-byung is charac
terized by anger, hopelessness, general health problems, and gastrointestinal
symptoms. Lee et al. [ 19 ] examined the temperament of patients with hwa-byung
and suggested that hwa-byung was positively correlated with impulsiveness, harm
avoidance, and self- transcendence; hwa-byung was negatively related with self
directedness, self-acceptance, and acceptance. Moreover, global severity of hwa
byung showed positive association with self-transcendence, its subscale being self-
forgetfulness, and anticipatory worry, but negative association with attachment
and compassion.
Hwa-byung was reported to be a chronic illness [ 20 ]. Supportive
psychotherapy, family therapy, and selective serotonin reuptake inhibitors (SSRIs)
are suggested as effective treatments for h wa-byung [ 20 , 21 ].
55
A Case Vignette
A 49-year-old housewife visited the outpatient clinic with the chief complaint of
pent-up anger, “ hwa ,” which was intermittently accompanied by a hot sensation,
which had to be cooled with a fan, along with a feeling of something pushing up
in her chest. The other symptoms were “many things accumulated” in the
epigastrium and respira
tory stuffi ness that used to be relieved by frequent sighs. At times, she felt so
angry and so “ uk-wool ” (a feeling of unfairness) that she almost felt like losing
control or losing her mind. Her self-diagnosis was hwa-byung . The reason for her
anger was her family situation with her husband and her mother-in-law. Her anger
began 15 years ago just after her marriage, when she realized that she had been
deceived by her husband regarding his past history. He had never been in college
and was in a much worse economic condition than what he had claimed before
marriage. Since then, she lived with an angry feeling, with a frustration related to
her hard life. Moreover, her mother-in-law had lived together with her family only
because her husband was the fi rst son. Her mother-in-law began to treat her
unfairly and, furthermore, she inter fered in her everyday private and marital life.
To keep peace in the family, the patient had to suppress her anger and hide her
hatred toward her husband and mother-in-law; she obeyed her husband and his
mother. While living with her husband, she found her husband to be a truly good
man, and that is why she kept their marriage intact until now. Nevertheless, she
gradually became irritable and nervous. She recently became more irritable and
began to beat her husband and even throw things at her children to the point that
she abused them. She said the children never understood why she was so angry.
When she recently stood up against her mother-in-law for the fi rst time in her life,
she felt “cool” (relieved) at the moment.
During the interview, she talked extensively, with sighs and tears, about how
she had suffered from a life of “ uk-wool and anger” and with “much haan .”
However, she said she did not feel depressed and had never thought about suicide.
Rather, she has tried to live enthusiastically and actively; she regularly worked as
an employee (cleaning buildings). She attempted to avoid being isolated from her
fellow workers since she believed they might think of her as a “good” person. She
revealed her painful past memory of how she had been discriminated by her
mother for being a daughter. Finally, her mother’s favoritism to sons and her
gender discrimination did not allow the patient to complete her middle school
education.
5.3.2 Symptoms of Hwa-byung
Symptoms of hwa-byung have been studied in patients who self-labeled

themselves with hwa-byung [ 10 , 22 ] and in hwa-byung patients diagnosed with
the Research Diagnostic Criteria for hwa-byung [ 12 , 23 ]. The typical
psychological symptoms of hwa-byung include subjective pent-up anger ( hwa ), a
feeling of unfairness, uk-wool
(抑鬱) and boon (憤), and hate/hostility and revengeful mind toward someone who
caused the anger. Patients also typically complain of haan , which means grudge,
embitterment, or distress ( haan will be described in detail later). Other
psychological
56 S.K. Min
symptoms are many thoughts ( 雜念 , rumination), irritability, being easily

frightened, sad and pessimistic mood, nihilistic ideas, and guilt feeling. Hwa-
byung patients sometimes report “cannot fi nd what to do” or “absentmindedness,”
which seems to be a feeling of losing control. Typical hwa-byung patients work
hard, eat well, sleep well, and associate well with others as seen in the case
history. They usually express a strong will to live and do not have any thoughts
about suicide.
The most typical factor is somatic symptoms including a heat/hot sensation in
or on the body, appearing mainly in the upper trunk. Heat may appear as a hot fl
ush on the head, a feeling of boiling inside, or by sweating. Sometimes, a hot
sensation in the trunk is accompanied by a cold sensation with cold sweat on the
limbs. Other typical somatic symptoms include palpitations, the feeling of
something pushing up in the chest, and dry mouth. The “something” used to be a
mass of fi re/anger. The “pushing up” usually extends up to “the end of the head”
and causes the head to become hot, resulting in a headache. These symptoms seem
to refl ect the symbolical relation between anger and physical nature of fi
re/smoke. Patients with hwa- byung sometimes complain of respiratory stuffi ness
(chest oppression or chest tightness), which is relieved by letting out a deep sigh.
This action of sighing seems to symbolize the release of suppressed anger/fi re as
well as the choking smoke. Less frequent but typical factor is epigastric mass or a
feeling of mass formation in the neck, chest, or abdomen. This mass is referred to
as dung-u-ri , like a piece of stone, which seems to symbolize suppression,
accumulation, and increased density of anger/fi re; it is also attributed to
respiratory stuffi ness.
Behaviorally, hwa-byung patients are generally polite and docile, but at times,
they show irritability, ill temper, aggressive words, violent gestures, or, rarely,
aggressive action such as throwing things or quarreling. They are generally
reluctant to talk about their inner and familial life, suggesting a suppression of
anger. But once the talk is ignited, their talk on their life distress and haan is
extended for a long period of time accompanied by frequent tears and sighs (
hasoyeon ); it becomes hard for them to stop the conversation. Talking, tears, and
sighing seem to be symbolic measures of releasing suppressed anger and feeling
of unfairness ( uk-wool ). Patients with hwa-byung are intolerant to a warm and
closed space. To cool down the heat, they use fans and ice cubes, ventilate the air,
or go out to feel the cool air. At times, they walk around without a destination, or
they get on a bus, go to the last stop, and come back. These behaviors seem to
symbolize their intention to avoid or release anger/fi re/smoke.
Other less frequent symptoms include insomnia, anorexia, headache, and
general aches, all of which seem to symbolize a general psychological distress.
5.4 The Relationship Between Somatic Symptoms

and Korean Culture
Traditional shamanism and Asian traditional medicine has provided Koreans with
concrete and physical explanation for nature, emotion, and human suffering
(disease), whereas the traditional philosophy like Confucianism has taught a way
of
57
life in which people suppress emotional reaction not to jeopardize harmonious

interpersonal relationships. In this culture, Koreans have learned to express their
suppressed emotion in somatized form while saving their face.
5.4.1 Shamanism
Shamanism has provided people with an explanation of the world, life, and
disease. Traditionally in Korea, shamanism used to relate suffering or symptoms
of any diseases with physical harming of spirits who died from unfairness ( “uk-
wool” ), and thus, they became evil spirits because of their unresolved anger and
revengefulness [ 24 ].
5.4.2 Traditional Asian Medicine
Somatization tendency of Koreans, particularly the frequentness of visceral or

gastrointestinal symptoms, can be related to the traditional medicine. In traditional
medicine, based on traditional philosophies, the human body can be explained in
physical terms of fi ve cosmic elements including fi re, water, wood, metal, and
earth. The body is also operated with cosmic positive or negative energy ( qi ), yin
and yang, of fi ve elements . In this medicine, emotions were also understood as
energy, which is related to fi ve major body organs including the liver, heart,
stomach, spleen, and kidney. According to this theory, Koreans’ body image has
been formed, with which they believe that health can be kept in harmonious
balance between those kis in these visceral organs; unbalanced impact of emotion
may disturb the function of the autonomic nervous visceral organs. In particular,
the impact of anger has been identifi ed with the energy of fi re ( hwa-qi ), and
such emotion is supposed to affect the visceral organs, mostly the heart and liver,
resulting in a disease such as hwa- byung , fi re disease.
5.4.3 Traditional Social System
Traditional philosophies including Confucianism and the traditional patriarchal

authoritative culture have supported the development of unique familial
collectivism in Korea. In this culture, fathers, teachers, and kings are identifi ed to
be in the same authority. People have been taught to suppress anger and not to
jeopardize social or familial harmony with those authority fi gures, engendering a
suppression of anger. These traditional cultures have also been supportive in the
development of gender discrimination and social class-related oppression, which
has contributed to the social unfairness for women and lower-class people in their
sociopolitical life. Under the infl uence of such traditional cultures, the socially
weak, especially
58 S.K. Min
women, have adopted somatization or hwa-byung presentation as a way for a

nonverbal communication of their suffering and also as a help-seeking method in
order for the people around them to understand their feeling or suffering, while
saving their faces, in the Korean cultural context.
5.4.4 Traditional Affect of Haan
Haan (恨) has been defi ned as a chronic mixed mood of missing, sadness, and
“everlasting woe,” [ 25 ] beyond its literal meaning [ 26 ], and is known to be a
unique traditional collective sentiment or pathos for Koreans. Similar to hwa-
byung , haan has been said to be resulting from the accumulation of suppressed
anger, feeling of unfairness ( uk-wool ), and/or even revengeful mind.
Haan has been argued to have developed in the psyche of Koreans, who have
endured repeated traumas from international violence (invasion of China,
Mongolia, Japan and, recently, communist North Korea) and domestic violence
throughout not only their nation’s history but also from their personal lives. Their
haan includes haan of poverty, haan of the weak, haan of not being educated, and
women’s haan
[ 18 , 27 , 28 ]. Accordingly, the Korean history of 5,000 years used to be referred
to as a history of haan. Accordingly, hwa-byung and haan are frequently found in
the socially weak group of people, especially among women. Haan has been
suggested as a within normal range of emotion providing positive energy for
survival or cre
ativity, while hwa-byung seems to be a personal illness, a negative or illness form
of haan [ 29 , 30 ].
Naturally, haan and hwa-byung have many common factors in clinical
correlates including etiological emotion of anger and feeling of unfairness,
precipitating factors in sociocultural context, and defense styles including
suppression and somatization [ 17 , 30 ], and clinical signs such as sighing, tears,
respiratory stuffi ness , hasoyeon, and lamenting with frequent deep sighs and
tears and eung-u-ri , a feeling of a mass in the chest (a bit vague concept
compared to the more concrete dung-u-ri in hwa-byung ).
Metaphorically, hwa-byung is like an inactive volcano, from which fi re,
smoke, and lava leak. In this metaphor, an anger attack or intermittent explosive
disorder is like an active volcano with an explosive eruption of the fl ame and
lava. Haan is like an extinct volcano; the crater became a lake which is
surrounded by a forest. The volcano may look peaceful and beautiful; yet the fl
ame under it is ready to erupt at any time [ 14 ].
It is natural that Koreans have developed social devices for solving haan,
generally referred to as “ haan-puri .” Collectively, historical haan of poverty has
been solved by working hard and educating children. Haan of the socially weak
was solved by protesting against the oppression of rulers, by sublimation through
satirizing them, through artistic activities including humorous paintings by
unknown people, or elegant ceramics making by unknown masters. Therefore, the
Korean traditional culture is called as a culture of haan .
59
Personal haan-puri includes wish fulfi llment, revenge, shaman ritual, or

achieving fi nal success after longtime effort and endurance of the hardship. For
example, a mother’s haan-puri can be achieved by a divorce or more desirably by
the success of her son whom she has nurtured with long-term sacrifi ces of herself
despite unfair treatment from her husband and/or mother-in-law. Productive and
creative haan- puri may provide a theoretical frame for the treatment of hwa-
byung.
Koreans’ passion to overcome their historical haan , especially the haan of
poverty, has stimulated modern Koreans to educate their children enthusiastically
(education fever) and work very hard, resulting in the recent rapid economic
growth. However, their children, who had been educated on democracy and
human rights, began to protest against the military dictators in order to solve haan
of the politically suppressed. At the same time, such economic growth and high
competitiveness in the society had produced many losers and stimulated a new
anger or unfairness reaction, or a new haan among them and a new form of acute
hwa-byung , contrasting to tradi tional chronic hwa-byung.
5.5 Conclusions
The review of research on somatization in Koreans and unique somatic symptoms

of hwa-byung , a culture-related anger syndrome of Korea, suggests the signifi cant
infl uence of culture on somatic symptoms. Further, the review on the specifi c his
torical and cultural experiences as national and personal traumas may contribute to
understanding specifi c emotional reaction patterns as well as specifi c
somatization symptom patterns in Koreans to evolve. Also, the symbolic meaning
of names of such somatic symptoms as well as the dynamic analysis of such
symptom develop ment could be explained by a traditional view on nature, body,
and, most impor tantly, the emotions of the Korean, which still continues up to the
present time. Further research is needed in order to develop the culture-relevant
treatment methods for Koreans with health problems.
References
1. Tseng, W. S. (2001). Handbook of cultural psychiatry . San Diego: Academic Press. 2. Kim,
K.-L. (1977). A study on somatization tendency of Koreans. New Medicine, 15 , 1440–1443.
3. Min, S. K. (1981). Psychodynamic in somatization. In Kang, S. H., et al. (Eds.), Tao and
Human Science (pp. 413–428). Seoul, Korea: Samil-dang.
4. Min, S. K., & Kim, K. H. (1988). Somatic symptoms in depression. Journal of Korean
Neuropsychiatric Association, 17 , 149–154.
5. Min, S. K., & Lee, B. W. (1997). Laterality in somatization. Psychosomatic Medicine, 59 ,
236–240.
60 S.K. Min
6. Lee, H. Y., Namgoong, K., Lee, M. H., et al. (1989). The psychiatric epidemiological study of
Kanghwa Island (III). The prevalence of major psychiatric disorders. Journal of Korean
7. Nakane, Y., Ohta, Y., Radford, M., et al. (1991). Comparative study of affective disorders in
three Asian Countries. II. Differences in prevalence rate and symptom presentation. Acta
Psychiatrica Scandinavica, 84 , 313–319.
8. Kim, K.-I., Li, D., & Kim, D.-H. (1999). Depressive symptoms in Koreans, Korean-Chinese
and Chinese: A transcultural study. Transcultural Psychiatry, 36 , 303–316. 9. Min, S. K., &
Suh, S. Y. (1979). A clinical study on hysterical neurosis and change of its symptom pattern for
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K., Lee, M. H., Kang, H. C., et al. (1987). A clinical study of hwa-byung. Journal of the Korean
Medical Association, 30 , 187–197.
11. Min, S. K., Namkoong, K., & Lee, H. Y. (1990). An epidemiological study of hwa-byung.
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12. Min, S. K., Suh, S. Y., Hur, J. S., et al. (2009). Development of the hwa-byung scale and the
research criteria of hwa-byung. Journal of Korean Neuropsychiatric Association, 48 , 77–85. 13.
Min, S. K., & Suh, S.Y. (2010). Anger syndrome, hwa-byung and its comorbidity. Journal of
Affective Disorders, 124 , 211–214.
14. Min, S. K. (2008). Clinical correlates of hwa-byung and a proposal of a new anger disorder.
Psychiatry Investigation, 5 , 125–141.
15. Lee, B. T., Paik, J. W., Kang, R. H., et al. (2008). The neural substrates of affective face
recog nition in patients with hwa-byung and healthy individuals in Korea. The World Journal
of Biological Psychiatry, 10 , 552–559.
16. Min, S. K. (1989). A study on the concept of hwa-byung. Journal of Korean
17. Min, S. K., Park, C. S., & Hahn, J. O. (1993). Defense mechanisms and coping strategies in
hwa-byung. Journal of Korean Neuropsychiatric Association, 32 , 506–516. 18. Roberts, M. E.,
Han, K. H., & Weed, N. C. (2006). Development of a scale to assess hwa- byung, a Korean
culture bound syndrome, using the Korean MMPI-2. Transcultural Psychiatry, 43 , 383–400.
19. Lee, J., Min, S. K., Kim, K. H., et al. (2012). Differences in temperament and character
dimen sions of personality between patients with hwa-byung, an anger syndrome, and
patients with major depressive disorder. Journal of Affective Disorders, 138 , 110–116.
20. Min, S. K. (2004). Treatment and prognosis of hwa-byung. Psychiatry Investigation, 1 , 29–
36. 21. Min, S. K., Suh, S. Y., Jeon, D. I., et al. (2009). Effects of paroxetine on symptoms of
hwa- byung. Korean Journal of Psychopharmacology, 20 , 90–97.
22. Min, S. K., & Kim, K. H. (1998). Symptoms of hwa-byung. Korean Journal of
Psychopharmacology, 37 , 1138–1145.
23. Min, S. K., Suh, S.Y., & Song, K. J. (2009). Symptoms to use for the diagnostic criteria of
hwa-byung. Psychiatry Investigation, 6 , 7–12.
24. Rhi, B. Y. (1970). The legend of won-ryung and psychology of haan. In H. K. Kim (Ed.),
Traditional society and people’s art (pp. 95–107). Seoul, Korea: Min-um Sa. 25. Kim, L (1997,
May). Haan and hwabyung . Presented at the 150th Annual Meeting of the American psychiatric
Association, San Diego, pp. 14–17.
26. Han, W. S., & Kim, S. K. (1980). An essay on haan in popular sociological concept . Seoul,
Korea: Hankil-sa.
27. Lee, H. J. (1978). Haan of Korean women . Seoul, Korea: Chungwoo-sa. 28. Chung, H. K.
(1991). Struggle to be the sun again . Maryknoll, NY: Orbis Books. 29. Min, S. K. (1991). Hwa-
byung and the psychology of haan. Journal of Korean Medical Association, 34 , 1189–1198.
30. Min, S. K., Lee, J. S., & Hahn, J. O. (1997). A psychiatric study on haan. Journal of Korean
Chapter 6
Molecular Mechanism of Sleep–Wake
Regulation: From Basic to Translational
Research
Yoshihiro Urade
6.1 Introduction
Sleep gives our body its needed rest, which prepares us for the next day’s
activities. In our modern society, people suffer from sleep deprivation, which
leads to an inability to concentrate, to a loss of judgment, and to an increased risk
of accidents. It is reported that 1 in 4–5 Japanese has a sleep problem and that 1 in
9 Japanese uses sleeping pills regularly. Hypnotic drugs are prescribed for
insomnia patients. The current sleeping pills developed from tranquilizers are
much safer than the ones used in the past, as the latter were developed from
anesthetic agents, which brought death in case too many pills were taken.
However, the current type of sleeping pills causes a coma in case of an overdose.
Such pills are sometimes used in crimes such as coma robbery cases.
What people demand now is some methods to adjust the sleep–wake rhythm
based on our innate sleep–wake regulatory system and sleeping pills that induce
natural sleep without any side effects. To develop such sleep aids, it is necessary
that we understand the mechanism of sleep–wake regulation. However, there is
still much mystery regarding sleep and questions to be answered, such as why we
sleep and how to gain comfortable sleep. Sleep research has only a 90-year history
and is currently being advanced due to highly interdisciplinary input based on
recent fi ndings from brain science, genetic engineering, and computer and
information– communication technology.
Y. Urade , Ph.D. (*)
Department of Molecular Behavioral Biology , Osaka Bioscience
Institute , 6-2-4, Furuedai , Suita-shi, Osaka 565-0874 , Japan

62 Adenosine
6.2 Sleep–Wake Regulation by 6.2.1 Prostaglandin (PG) D 2 as an

Endogenous Sleep Substances: Endogenous Sleep Substance
Prostaglandin (PG) D2 and Y. Urade
Many endogenous molecules have been isolated and proposed to act as sleep-
promoting substances. Among them, PGD 2 is the most potent endogenous sleep-
promoting substance, and its sleep-induction mechanism is best characterized in
terms of pro duction and action sites, and signal transduction system, whose
characterization has been made by the use of various pharmacological tools and
gene- knockout mice for the synthases or receptors.
In the 1980s, PGD 2 was found to be the most abundant PG in the brains of rats
[ 1 ] and other mammals including humans [ 2 ], thus suggesting that it has an
important function in the central nervous system. The sleep-promoting effect of
PGD 2 was then discovered after the microinjection of nano-molar quantities of
PGD 2 into the rat brain, which causes profound enhancement of both non-rapid
eye movement (non
REM, NREM) and REM sleep [ 3 ]. Based on electrophysiological and behavioral
cri teria, PGD 2 -induced sleep is indistinguishable from physiological sleep.
During the infusion of PGD 2 , for instance, rats are easily aroused by a clap sound,
and their sleep is episodic, indicating that PGD 2 does not interfere with the basal
wakefulness crucial to the survival of the animal. The somnogenic effect of PGD 2
was later confi rmed in a nonhuman primate, when PGD 2 was infused via the
intracerebroventricular (i.c.v.) route into a rhesus monkey ( Macaca mulatta ) [ 4
]. The electroencephalogram (EEG) power spectrum of NREM sleep during the
PGD 2 infusion into monkeys was the same as that of their natural sleep at night,
but clearly different from benzodiazepine
induced sleep, which is characterized by a decrease in the theta range and the
appear ance of a rapid wave with a peak at around 20 Hz. In addition, PGD 2 was
reported to be involved in the pathogenesis of mastocytosis, a disorder
characterized by episodic production of endogenous PGD 2 , which accompanies
deep-sleep episodes [ 5 ]. Also, the PGD 2 concentration, but not that of PGE 2 or
IL-1ß, is elevated time-dependently in the CSF of patients with African sleeping
sickness, which is a disease caused by an infection with Trypanosoma [ 6 ]. These
fi ndings suggest that PGD 2 induces sleep in humans as well as in rodents and
monkeys.
To study the molecular mechanism of PGD 2 -induced sleep, we established a
sleep bioassay system using the EEG to monitor brain waves, and the electromyo
gram to monitor the muscle tension, of freely moving mice during the continuous
i.c.v. infusion of drugs (Fig. 6.1 ). We also developed SLEEPSIGN software
(Kissei Comtec Co., Ltd., Nagano, Japan) for automatic scoring of the vigilance
states of rats and mice, based on the fast Fourier transform (FFT) analysis of the
EEG [ 7 ].
When PGD 2 is infused into the lateral ventricle of wild-type mice at a rate of
50 pmol/min during a wake period at night, it induces potent NREM sleep (about
35 min/h) almost equal to the maximum level of NREM sleep during a sleep
period in the morning, but induces only a small amount of REM sleep (about 5
min/h, Fig. 6.2 ). In contrast, DP 1 -knockout mice do not respond to the PGD 2
infusion at all,
6 Molecular Mechanism of Sleep–Wake Regulation…
63
Fig. 6.1 Sleep bioassay system EMG, electromyogram

Fig. 6.2 Sleep induction by i.c.v. infusion of PGD 2 in wild-type ( WT ) and DP 1 receptor-
knockout ( DPR KO ) mice (From Mizoguchi et al. [ 8 ], reprinted by permission of Proceedings
of the National Academy of Sciences )
64 15:00 for 6 h, as indicated by the horizontal bars
(From Qu et al. [ 9 ], reprinted by permission of
Proceedings of the National Academy of
Fig. 6.3 DP 1 antagonist inhibits sleep in rats.
Sciences )
ONO-4127Na was given between 09:00 and Y. Urade
indicating that the remarkable NREM sleep induction by PGD 2 is completely

dependent on DP 1 receptors [ 8 ].
Ono Pharmaceutical Co., Ltd. (Osaka, Japan) developed a novel DP 1
antagonist, ONO-4127Na, which exhibits a highly specifi c binding affi nity ( Ki =
2.5 nM) for and excellent antagonistic effects (pA 2 = 9.73) on DP 1 receptors. We
examined the effect of ONO-4127Na on sleep in rats by infusing it into the
subarachnoid space under the rostral basal forebrain, where DP 1 receptors are the
most abundant [ 9 ]. The antagonist infusion reduces NREM sleep by 23 % and 28
% and REM sleep by 49 % and 63 % at 100 and 200 pmol/min, respectively,
during perfusion for 6 h and post-infusion for 1 h. ONO-4127Na infusion at 200
pmol/min decreases NREM sleep by 30–40 % per hour and REM sleep by 60–90
% 2 h after the start of ONO 4127Na infusion, as compared with the baseline (Fig.
6.3 ). Due to the low solubility of ONO-4127Na, the antagonist cannot be used at
doses higher than 200 pmol/min. These results clearly show that the DP 1
antagonist dose-dependently attenuates NREM and REM sleep, suggesting that
endogenous PGD 2 acting via DP 1 receptors is essential for the maintenance of
physiological sleep.
6.2.2 Adenosine as a Paracrine Sleep-Promoting Molecule

The infusion of PGD 2 into the subarachnoid space of wild-type mice increases the
extracellular adenosine concentration in a dose-dependent manner. This PGD 2 -
induced increase in extracellular adenosine is absent in DP 1 receptor-knockout
mice,
65
Fig. 6.4 Caffeine-induced arousal in adenosine receptor gene-manipulated mice. Caffeine (15
mg/kg, i.p.)-induced arousal in wild-type ( WT ) and A 1 receptor-knockout mice, but not in A 2A
receptor knockout ( A2AR KO ) mice (From Huang et al. [ 10 ], reprinted by permission of Nature
Publishing Group)
indicating that DP 1 receptors are required for this increase [ 8 ]. Adenosine has
also been proposed to be an endogenous sleep substance, because a number of
stable ade nosine analogues induce sleep when administered to rats and other
animal species. For example, when CGS21680, an A 2A receptor agonist, is infused
into the lateral ventri cle of wild-type mice, NREM sleep is induced dose-
dependently. Comparatively, CGS21680 is tenfold or more potent than PGD 2 , the
unstable natural ligand, in terms of the potency to induce NREM sleep. The
infusion of CGS21680 at a dose of 5 pmol/h increases NREM sleep to 35 min/h.
In contrast, N6-cyclopentyladenosine, an A 1 receptor-selective agonist, is totally
inactive even when infused at 5 nmol/h, indicating
that A 2A , but not A 1 , receptors play a major role in NREM sleep regulation.
Caffeine is a nonselective antagonist of adenosine A 1 and A 2A receptors. Caffeine
induces complete insomnia in wild-type mice (Fig. 6.4 ) for 2–3 h after an intraperi
toneal (i.p.) injection at a dose of 15 mg/kg, a dose corresponding to an intake of
approximately three cups of coffee in humans. Earlier we used knockout mice for
A 1 or A 2A receptors and their respective wild-type littermates of the inbred
C57BL/6 strain to test which subtype of the adenosine receptor is involved in the
caffeine induced wakefulness [ 10 ]. The caffeine-induced arousal in A 1 receptor-
knockout mice was observed to have the same intensity and duration as that in the
wild-type mice. In contrast, A 2A receptor-knockout mice did not show any change
in time spent in wakefulness after the caffeine administration, indicating that A 2A
receptors are crucial for the caffeine-induced wakefulness and that these receptors
play an important role in the regulation of the sleep–wake cycle.
The DP 1 antagonist ONO-4127Na inhibits sleep in rats and caffeine, a nonselec
tive antagonist of adenosine A 1 and A 2A receptors, induces complete insomnia in
wild-type mice, suggesting that the PGD 2 /adenosine system is important for the
maintenance of physiological sleep, as described above. However, knockout mice
for DP 1 , A 1 , and A 2A receptors show essentially the same circadian profi les and
daily amounts of sleep as wild-type mice. These results suggest that a defi ciency
of one system in a complicated sleep–wake regulatory network is effectively
compensated by collateral systems formed during embryonic development.
Therefore,
66 Y. Urade
Fig. 6.5 Effects on caffeine-induced arousal of focal deletion of adenosine A 2A receptors in the
core ( a ) or shell ( b ) of the NAc of rats. Caffeine (15 mg/kg, i.p.)-induced arousal in rats with A
2A receptors in the NAc shell ( a ), but not after removal of A 2A receptors in the NAc shell ( b )
(From Lazarus et al. [ 11 ], reprinted by permission of Journal of Neuroscience )
pharmacological approaches, such as receptor antagonists, and conditional gene

suppression based on the Cre/loxP system or the focal RNA interference strategy
are useful to minimize functional compensation in sleep–wake regulation.
Adenosine A 2A receptors are densely expressed in the basal ganglia of the
brain, which contains the caudate putamen, which is involved in locomotion; the
nucleus accumbens (NAc), which is important for motivation and addiction; and
the olfactory tubercle, a structure involved in olfaction. To identify the active
center of the caffeine-induced insomnia, we used focal knockdown of A 2A
receptors by microin
jecting adeno-associated virus-carrying short-hairpin RNA into the A 2A receptor
expressing brain regions of rats [ 11 ]. As shown in Fig. 6.5 , caffeine-induced
wakefulness in rats is not affected by the focal removal of A 2A receptors from the
NAc core or other A 2A receptor-positive areas of the basal ganglia, but is
remarkably decreased by their removal from the NAc shell. These results indicate
that caffeine promotes arousal by activating pathways that traditionally have been
associated with motivational and motor responses in the brain.
6.3 Translational Sleep Research for Sleepless

Modern Society
6.3.1 Sleep Condition of Modern Society
Figure 6.6 summarizes the sleep length in the Asia-Pacifi c region, surveyed by
The Nielsen Company, New York, USA, in 2004. As clearly seen, Japanese and
Korean people are increasingly suffering from sleep deprivation which has
pronounced
67
Fig. 6.6 Sleep length in Asia-Pacifi c regions (The Nielsen Company 2004) (Depicted from data
of the Nielsen Company 2004). Th e number in the rectangle indicates the percentage of
hours of sleep
negative effects on performance and increases the risk of accidents as well as

negatively affects the health outcome in the case of cardiovascular disease and
certain forms of cancer. However, there seems at present to be no way to eliminate
most of the nega tive effects of insomnia on human physiology and cognition.
Therefore, the devel opment of products that are safe and effective for the
treatment of insomnia is demanded. Toward this end we have used our sleep-
scoring system to identify sleep-promoting components in various foods and
herbal raw materials.
6.3.2 Identifi cation of Natural Sleep-Promoting Components
6.3.2.1 Hastatoside and Verbenalin from Herbal Tea Verbena offi cinalis
Herbal tea made from Verbena offi cinalis has traditionally been used for the treat
ment of insomnia and other nervous conditions. Oral administration of hastato side
or verbenalin (0.25 and 0.5 g/kg of body weight, respectively), two major iridoid
compounds of V. offi cinalis , increases NREM sleep in rats during a 9-h period in
the dark time (when rats are active) 1.8- and 1.4-fold, respectively, with a lag time
of about 3–5 h after the administration at the lights-off time. Both com pounds also
increase the delta activity during NREM sleep. However, verbasco side, a major
polyphenol of V. offi cinalis , has no effect on the amount of sleep, indicating that
hastatoside and verbenalin are major sleep-promoting components of this herb [
12 ].
68 6.3.2.2 l -Stepholidine from Chinese
Herb Stephonia
Y. Urade
l -Stepholidine is an active ingredient of the Chinese herb Stephonia , the fi rst
compound with mixed dopamine D 1 receptor agonist/D 2 antagonist properties, and
is used as a treatment medication for schizophrenia. When stepholidine is adminis
tered i.p. to mice at doses of 20–80 mg/kg, it shortens the sleep latency to NREM
sleep, increases the amount of NREM sleep, and prolongs the duration of NREM
sleep episodes, with a concomitant reduction in the amount of wakefulness [ 13 ].
Stepholidine also increases the number of state transitions from wakefulness to
NREM sleep and subsequently from NREM sleep to wakefulness. However, step
holidine has no effect on either the amount of REM sleep or EEG power density of
either NREM or REM sleep. These results suggest the potential application of this
herb for the treatment of insomnia.
6.3.2.3 Ornithine
Ornithine supplementation has recently been used for attenuation of physical

fatigue in healthy people. When we examined the effects of this molecule on the
sleep– wake cycle of freely moving mice after oral administration at lights-off
time, we found that ornithine (1.0 and 3.0 g/kg of body weight) increases the
amount of NREM sleep 1.6- and 2.0-fold, respectively, for 2 h after its
administration, with a peak at 1 h post administration compared with that of the
vehicle-administered mice, without changing the amount of REM sleep [ 14 ].
Ornithine may also be con
sidered to improve human sleep.
6.3.2.4 Crocin, Crocetin, and Safranal from Crocus sativus L . (Saffron)
Crocus sativus L. (saffron) has been traditionally used for the treatment of
insomnia and other diseases of the nervous systems. Two carotenoid pigments,
crocin and crocetin, are the major components responsible for the various
pharmacological activities of C. sativus L . When crocin (30 and 100 mg/kg, i.p.)
is administered to mice, it increases the total time of NREM sleep 1.6- and 2.7-
fold, respectively, during a 4-h period after administration at a lights-off time [ 15
]. When crocin is given to histamine H1 receptor-knockout mice, its sleep-
promoting effects are attenuated, suggesting that the histaminergic system is
involved in crocin-induced sleep. Crocetin (100 mg/kg, i.p.) also increases 1.5-
fold the total time of NREM sleep after its administration. These compounds do
not change the amount of REM sleep or show any adverse effects, such as
rebound insomnia, after the induction of sleep. In hypnotic-model mice treated
with a low dose (20 mg/kg) of pentobarbital, oral administration of safranal (100–
300 mg/kg), another component of C. sativus L. , increases the duration of NREM
sleep, shortens NREM sleep latency, increases the number of stage transitions
between episodes of NREM sleep and wakefulness, and enhances the delta power
activity of NREM sleep [ 16 ]. These fi ndings indicate that crocin, crocetin, and
safranal may be useful for the promotion of sleep in humans.
69
6.3.2.5 Honokiol and Magnolol from Chinese Herb Houpu (

Magnolia offi cinalis )
Decoctions of the Chinese herb houpu ( Magnolia offi cinalis ) contain honokiol
and magnolol and are used to treat a variety of mental disorders including
depression. Honokiol (10 and 20 mg/kg, i.p.) signifi cantly shortens the sleep
latency to NREM sleep in mice and increases the amount of NREM sleep [ 17 ]
and the number of state transitions from wakefulness to NREM sleep and
subsequently from NREM sleep to wakefulness. However, honokiol has no effect
on either the amount of REM sleep or EEG power density of either NREM or
REM sleep. Magnolol (5 and 25 mg/kg, i.p.) also increases NREM sleep in mice [
18 ]. Pretreatment with fl umazenil (1 mg/kg, i.p.), an antagonist of the
benzodiazepine-binding site of GABA A receptors, completely abolishes the
somnogenic effects of honokiol and magnolol, indicating that these compounds
promote NREM sleep through the GABA A /benzodiazepine receptor complex.
Therefore, these compounds may be used for the treatment of insomnia, espe cially
for patients with diffi culty in falling asleep, as well as for sleep maintenance.
6.3.3 Development of Portable 1-Channel EEG Device

and a Simple Scoring System for Human Sleep
To measure sleep stages in hospitals, a polysomnographic test is normally used, in

which data are analyzed with major devices and many electrodes to measure brain
waves, eye movement, electromyogram, breathing, and snoring. However, we have
established a simple sleep-scoring system for animals by using an EEG system
with only two electrodes. Based on this unique technology, we developed a
portable 1-channel EEG device and a simple sleep-scoring system for measuring
the human EEG at home or while traveling. This device is the smallest in size in
the world, weighing only 60 g, and it is easy to wear and does not bring about any
uncomfort able feeling (Fig. 6.7a ).
This portable EEG device is used daily to evaluate the quality of a person’s
sleep easily, so that the wearer can detect intrinsic sleep problems as soon as they
occur in the early stages of mental disorders such as depression. We have started a
col laborative research project with the National Institute of Polar Research of
Japan and Japan Aerospace Exploration Agency (JAXA). Our device was used by
mem bers of the 50th and 51st Antarctic observation teams to evaluate an effect of
a long stay in the polar regions on their psychological implication and their
biological rhythm. Our device was also used by a Japanese astronaut, during his
long stay in the International Space Station (Fig. 6.7b ).
This device and sleep-scoring system will make it possible to improve the
quality of sleep, thus providing a safer environment, as well as prevent traffi c
accidents and, eventually, improve the mental health of the wearer. It is hoped that
people’s quality of life will also be improved. Importantly, this portable EEG
device allows a person to evaluate quite easily the quality of his or her daily sleep.
70 Y. Urade
Fig. 6.7 Portable 1-channel EEG device used for evaluation of sleep-promoting health foods ( a
) and daily sleep of Japanese astronaut, Mr. Furukawa, while staying in the International Space
Station ( b ) (Reprinted by permission of Sleep Well Co., Ltd., and Mr. Satoshi Furukawa,
JAXA)
6.4 C onclusions
PGD 2 is the most potent endogenous sleep-promoting substance, and its action
mechanism is the best characterized at a molecular level among various
endogenous sleep-promoting substances. PGD 2 stimulates DP 1 receptors, which
increases the local concentration of extracellular adenosine. Adenosine acts as a
paracrine sleep
promoting molecule to activate adenosine A 2A receptor-expressing sleep-
promoting neurons in the brain. The administration of a DP 1 antagonist (ONO-
4127Na) or an adenosine A 1/2A receptor antagonist (caffeine) suppresses sleep,
indicating that the PGD 2 -adenosine system is crucial for the maintenance of
physiological sleep.
Earlier we established a sleep-scoring system to measure the EEG of various
gene-manipulated mice. This system is used to identify sleep-promoting compo
nents in various food and herbal raw materials, such as hastatoside and verbenalin
from Verbena offi cinalis ; l -stepholidine, an active ingredient of the Chinese herb
Stephonia ; ornithine, a noncoding amino acid in the urea cycle; crocin, crocetin,
and safranal from Crocus sativus L. (saffron); and honokiol and magnolol from
the Chinese herb houpu ( Magnolia offi cinalis ). These fi ndings will contribute to
the production of health foods and pharmaceuticals that improve the quality of
sleep.
By using sleep-scoring technology for animals, we also developed a small
portable device for measuring human EEG activity at home or while traveling.
This EEG device is useful to allow an individual to self-evaluate easily his or her
quality of daily sleep. This “self-diagnostic system” as well as “supplements for
good sleep” will make it possible for one to improve his or her quality of sleep in
addition to proper exercise, an appropriate bathing practice, and selection of the
best kinds of food.
Acknowledgments We thank Drs. Michael Lazarus and Zhi-Li Huang for helpful comments on
this manuscript. This work was supported by grants from the Japan Society for the Promotion of
Science, Japan Science and Technology Agency, Takeda Science Foundation, Sankyo
Foundation, the Program of Basic and Applied Researches for Innovations in Bio-oriented
Industry of Japan, Takeda Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd, and Osaka
City.

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Kyung Bong Koh Editor

ISBN 978-1-4614-7118-9 ISBN 978-1-4614-7119-6 (eBook) DOI

© Springer Science+Business Media New York 2013

Printed on acid-free paper

Springer is part of Springer Science+Business Media (www.springer.com)

After working successfully as chairperson of the Organizing Committee at the

diseases affected by psychosocial factors. Both patients with somatization and

and psychopharmacotherapy, are presented. Poststroke depression can be a good

Seoul, Korea Kyung Bong Koh

Part I Basic Understanding of Somatization

1 Identity of Somatoform Disorders: Comparison

Part II Theoretical Approaches to Mind and Body

2 Toward a Philosophy of Life to Underpin

Part III Biopsychosociocultural Mechanisms

3 Genes, Memes, Culture, and Psychosomatic Medicine: An Integrative

7 Psychosomatic Approach to Clinical Practice ..................................... 75

Part V Specifi c Psychosomatic Symptoms

12 Pain, Depression, and Anxiety: A Common Language of Human

Part VI Specifi c Psychosomatic Disorders

15 Stress-Induced Cardiomyopathy: Mechanism

Part VII Specifi c Therapeutic Interventions

19 Motivational Interviewing in Psychosomatic Medicine ...................... 261

Index ................................................................................................................ 317

Hoyle Leigh, M.D. Department of Psychiatry , University of California , San

Kyung Bong Koh

Somatoform disorders are among the most prevalent psychiatric disorders in

1.1.1 How to Get Labeled as Misdiagnosed Somatoform

The diagnosis of somatoform disorders relies on the presence of subjective

K. B. Koh , M.D., Ph.D (*)

K.B. Koh (ed.), Somatization and Psychosomatic Symptoms, 3 DOI 10.1007/978-1-4614-7119-

symptoms have the potential to be worsened by iatrogenic factors. New diseases,

1.1.2 Shortcomings of Somatoform Disorders as Diagnoses

1.1.3 Shortcomings of the Specifi c Somatoform Disorder

Many of the diagnostic subcategories currently housed within the somatoform

the somatoform section because of the shared characteristic of somatic symptoms

1.2 Incidence and Specifi city of Psychosociocultural and

1.2.1 Severity of Somatic Symptoms, Depression,

Patients with somatization report fewer normalizing symptom attributions than

1.2.3 Health Anxiety/Illness Worry

Somatization patients show elevated health anxiety scores [ 26 ]. It has been

1.2.4 Anger and Anger Management Style

Alexithymia is signifi cantly more prevalent in somatizers without organic pathol

0.81* Depression Anxiety 0.37 0.52 Somatic Symptoms

Bentler’s comparative fit index : 1.00 R2= 0.71

Indicates coefficients of Pearson correlation

Somatization patients over-interpret minor physical symptoms as possible signs of

1.2.7 Somatosensory Amplifi cation

Increased somatic symptom reports are associated with higher somatosensory

1.2.8 Illness Behavior

Increased health-care use in somatization [ 24 , 37 ] and signifi cant differences in

Sociocultural restraints may play a role in the somatic symptoms of somatoform

1.3 Why Are Biological Findings Important in Establishing

A better understanding of the underlying neurobiological underpinnings of

1.3.1 Incidence and Specifi city of Biological Features

1.3.1.1 Brain Imaging

Somatoform disorder patients showed hyperperfusion in the left hemisphere at the

1.3.1.2 Genetic Findings

Fig. 1.4 Hyperperfused ( red/gray ) or hypoperfused ( green/white ) brain regions in panic

Therefore, serotonin-related gene pathways are unlikely to be genetic risk factors

1.3.1.3 Immunological Findings

symptoms are many thoughts ( 雜念 , rumination), irritability, being easily