Early Trauma as the Origin of Chronic Inflammation: A Psychoneuroimmunological Perspective 3662667509, 9783662667507

Table of contents :
Foreword
Preface
Contents
About the Author
1 The Long Shadow of Early Trauma—Look!
1.1 Mental Illness
1.2 Pain in Childhood—and What Comes Later?
1.3 How can I Sleep While My Bed is Burning?
1.4 Teeth Suffer
1.5 Target Variable: Weight
1.6 Cardiovascular Diseases
1.7 Chronic Lung Problems
1.8 And then Chronic Inflammation
1.9 To the Point
References
2 What is a Child’s Psychological Trauma?
2.1 Origins and Important Protagonists
2.1.1 Urie Bronfenbrenner, a Psychologist (1917–2005)
2.1.2 John Bowlby, a Child Psychiatrist (1907–1990)
2.1.3 Michael Rutter, Psychiatrist (1933–2021)
2.1.4 David Barker, Social Medicine and Epidemiologist (1938–2013)
2.1.5 Vincent J. Felitti, an Internist (Born 1938)
2.1.6 Robert J. Plomin, a Psychologist (Born 1948)
2.1.7 W. Thomas Boyce (Born 1943), a Pediatrician, and Jay Belsky (Born 1952), a Psychologist
2.1.8 Summary
2.2 The Different Types of Early Traumatic Experiences
2.3 Time Windows for Bad Childhood Experiences
2.4 Frequency of Bad Childhood Experiences
2.5 Compensating Positive Factors Against Trauma Experiences
2.5.1 Resilience
2.5.2 Unfavorable Versus Favorable Childhood Experiences
2.5.3 Orchid or Dandelion
2.5.4 Favorable or Unfavorable Genetic Predisposition
2.5.4.1 Phase 1—Twin and Adoption Studies
2.5.4.2 Phase 2—The Candidate Genes
2.5.4.3 Phase 3—Combination of Candidate Genes
2.5.4.4 Phase 4—Human Genome-Wide Association Studies
2.5.5 Favorable or Unfavorable Epigenetic Changes
2.5.5.1 Phase A—The Candidate Genes are Epigenetically Modified
2.5.5.2 Phase B—Polygenic Approaches in Epigenetics
2.5.5.3 Summary—Epigenetics
2.6 Child Disadvantages and Steeling Effects
2.7 Transmission of Behavior from Generation to Generation
2.7.1 Genetic Transmission
2.7.2 Epigenetic Transmission
2.7.2.1 The Dutch Hunger Winter—An Example of Intergenerational Transmission (F0 to F2)
2.7.3 Transmission—without Genetic and Epigenetic Explanations
2.8 An Evolutionary Medicine Perspective
2.8.1 Historical Development
2.8.2 Childhood Trauma and Evolutionary Medicine—the Results
2.8.3 Gender Differences—an Evolutionary Medicine Perspective
2.9 To the Point
References
3 Consequences of Early Traumatic Experiences
3.1 Many Places are Affected
3.2 The Brain Probably Suffers the Most
3.2.1 Alcohol, Nicotine and Drugs
3.2.1.1 Where in the Brain is the Problem?
3.2.2 Depression
3.2.2.1 Where is the Problem in the Brain?
3.2.3 Anxiety Disorders
3.2.4 Personality and Childhood Trauma
3.2.5 More Psycho- and Neuropathology
3.2.6 More Sleep Disorders as a Result of Previous Trauma
3.2.6.1 Where in the brain is the problem?
3.2.7 More Pain after Childhood Adversities
3.2.8 Summary
3.3 The Body Periphery Suffers as Well
3.3.1 High Body Weight
3.3.1.1 Fat-Making Eating Behavior
3.3.2 Heart Attack and Co.
3.3.3 Chronic Lung Diseases
3.3.4 The Stomach Aches and the Stool Consistency Bothers
3.3.5 And When We Get Old?
3.3.5.1 Accelerated Aging
3.3.5.2 Cancer Disease
3.4 And Finally the Immune System is Activated
3.4.1 Early Trauma and Autoimmunity
3.5 To the Point
References
4 Chronic Immune System Activation
4.1 Egoistic Brain and Egoistic Immune System are Fourfold Interconnected
4.1.1 Areas in the Brain that Stimulate Direct and Indirect Connectors
4.2 Direct Connectors Chronically Activate the Immune System (No. 1)
4.2.1 The Sympathetic Nervous System
4.2.1.1 Hans Selye and the Pro-inflammatory Response of the Sympathetic Nervous System
4.2.1.2 The Tone of the Sympathetic Nervous System Promotes Inflammation
4.2.1.3 The Tone of the Sympathetic Nervous System Inhibits Inflammation
4.2.1.4 The Sympathetic Nervous System Promotes Inflammation Through Various Adaptation Reactions
4.2.2 The Parasympathetic nervous system
4.2.3 The HPA Axis
4.2.3.1 What is the Tone and Stress Reactivity in Previous Early Traumas
4.2.3.2 The Increased Tone of the HPA Axis Increases Inflammation
4.2.3.3 Glucocorticoid Receptor Resistance Increases Inflammation
4.2.3.4 An Increased Breakdown of Cortisol Increases Inflammation
4.2.3.5 Cortisol Mobilizes Important Elements of Inflammation
4.2.3.6 Summary of the HPA Axis and Inflammation
4.2.4 Disruption of the Circadian Rhythm
4.2.4.1 Circadian Rhythm After Early Traumatic Experiences
4.2.5 Tone of the Pain Pathways
4.2.6 Tone of the Sex Hormone Axis
4.2.6.1 Influence of Early Trauma on the World of Sex Hormones
4.2.6.2 HPA Axis and Sex Hormones
4.2.6.3 Differential Effects of Sex Hormones on Inflammation
4.3 Indirect Connectors Activate the Immune System Chronically (No. 2)
4.3.1 Adipose Tissue is Pro-inflammatory
4.3.2 The Insulin from the Pancreas Promotes Inflammation
4.3.3 Reduced Physical Activity—Anti-inflammatory Factors are Missing
4.3.4 Microbiome and Inflammation
4.3.5 The Permeability of the Gut is Pro-inflammatory
4.3.6 The Skin Itches Chronically and is Inflamed
4.4 Environmental Factors Chronically Activate the Immune System (No. 3)
4.4.1 Where There’s Smoke, There’s Fire
4.4.2 Where Fine Particles are Flying, It Gets Uncomfortable
4.4.3 Asthma
4.4.3.1 Environmental Factors (Extra-corporeal Connectors, 90% of All Forms)
4.4.3.2 The Brain Promotes Non-allergic Asthma (Indirect Connector, 10% of All Forms)
4.4.3.3 Asthma Makes Chronic Inflammation
4.4.4 Infections are Extra-corporeal Connectors
4.4.5 Risk Behavior
4.5 Gene Mutations as Pleiotropic Connectors (No. 4)
4.5.1 The Search in the Gene Databases Leads to Pleiotropic Connectors
4.6 Summary
4.7 To the Point
References
5 Energy, Early Traumatic Experiences and Chronic Immune System Activation
5.1 Brain and Immune System Define Energy Expenditure
5.2 The Trauma Reaction can Use a Lot and a Little Energy
5.3 Is there a Trauma and Energy Provision Memory?
5.4 Energy and Chronic Immune System Activation
5.4.1 How High is Inflammation in People with Early Traumatic Experiences Really?
5.4.2 How High is Energy Expenditure at Different Levels of Inflammation?
5.4.3 The Quintessence
5.5 To the Point
References
Glossary

Citation preview

Early Trauma as the Origin of Chronic Inflammation A Psychoneuroimmunological Perspective Rainer H. Straub

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Early Trauma as the Origin of Chronic Inflammation

Rainer H. Straub

Early Trauma as the Origin of Chronic Inflammation A Psychoneuroimmunological Perspective

Rainer H. Straub Division of Rheumatology Department of Internal Medicine University Hospital Regensburg, Germany

ISBN 978-3-662-66750-7 ISBN 978-3-662-66751-4  (eBook) https://doi.org/10.1007/978-3-662-66751-4 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer-Verlag GmbH, DE, part of Springer Nature 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Responsible Editor: Christine Lerche This Springer imprint is published by the registered company Springer-Verlag GmbH, DE, part of Springer Nature. The registered company address is: Heidelberger Platz 3, 14197 Berlin, Germany

Dedicated to my doctoral students and pupils

Foreword

Life events in childhood and adolescence have a lasting impact on a person's personality development, both in a positive and a negative sense. These functional connections are not only postulated by the various psychological schools and psychotherapeutic approaches from psychoanalysis to cognitive behavioral therapy, but are now also confirmed by many empirical studies. As an experimental behavioral scientist and clinically active behavioral therapist, even after more than 30 years of therapeutic work, I am always impressed by the close connections between the current psychological problems my patients report and the described experiences and events from their childhood and adolescence. It is not always only traumatic experiences such as sexual abuse, physical abuse or emotional neglect that are related to the acute psychological complaints such as anxiety, depressive symptoms or somatoform dysfunctions. Often, divorce of the parents and the resulting insecurity or high performance expectations of the parents cause the development of psychological problems in later adult life. These stressful childhood experiences affect not only mental health, but also physical processes. Since its beginnings, psychosomatic medicine has postulated the connections between traumatic childhood experiences and the development of physical illnesses such as chronic inflammatory processes. For a long time, however, only speculation was possible about these connections, since too little was known about the functions of the immune system and the corresponding connections with the nervous and hormonal systems. Through the new academic and research field of psychoneuroimmunology, the interactions between systems have become known in increasing detail in recent years, and the interplay between systems appears to be much closer and more complex than previously thought. For example, a recent high-profile publication in the journal Cell showed that information from a subsided inflammatory response in the gut is stored in a special brain area called the insular cortex. When the neurons in the insular cortex are reactivated in the mice using chemogenetic methods, a renewed inflammatory response in the intestinal tissue occurs in the animals (Koren et al. 2022, Cell, 184 5902).

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Foreword

As a physician and one of the internationally recognized protagonists of psychoneuroimmunology, Professor Rainer H. Straub has contributed groundbreaking basic scientific findings on bidirectional communications between the nervous, endocrine, and immune systems, which have significantly contributed to a better understanding of these interactions between the systems for the development and course of immunologically related diseases. In this book, Rainer H. Straub uses his profound knowledge accumulated over many years to provide an excellent summary of previous knowledge and empirical findings on the functional connections between traumatic experiences in childhood and adolescence and the development of chronic inflammatory diseases in later adulthood. Rainer H. Straub describes the psychological foundations just as competently as the historical development, the evolutionary-biological background, the genetic-epigenetic and, of course, the endocrinological and immunological correlations that prove to be responsible for chronic inflammatory diseases after early traumas. The author does not merely loosely string together individual empirical findings; rather, he understands how to bring these sometimes complex interrelationships to the reader in an understandable way in an entertaining narrative style. Overall, this is an impressive book that presents this exciting topic in a unique way, and I wish it a wide range of readers. Essen 25 February 2022

Manfred Schedlowski

Preface

The population on this earth is growing and growing, and this is the cause of many problems. New large populations are joining the globalized work force. Resources are being consumed, the environment is being increasingly polluted and the world of work is being seriously changed. The family with two working parents is the norm. This brings an increase in stressful life situations, especially in families with precarious circumstances. In addition, there are mental illnesses as a result of stress and environmental influences. The migration of people seeking protection and the confrontation with the local population is another stress factor. The difficulties cannot all be listed here in detail, but the major victims are often the children and young people. The Corona pandemic also shows this. The famous American dancer Isadora Duncan (1877–1927) once wrote: “As long as little children are allowed to suffer, there is no true love in this world.” Karl Menninger (1893–1990), American psychiatrist, added: “What’s done to children, they will do to society.” Already around conception, during the time in utero, through childhood and in adolescence, people are exposed to more and more stress factors. These stressful situations influence individual development in different time windows, which can be linked to problems in adulthood. Throughout life, these stress factors accumulate, and this can lead to lasting psychological and physical problems in later stages of life. My goal in writing this book was, first, to raise public awareness of the important long-term physical and psychological effects of early trauma in children and adolescents. While this is a central task of psychotraumatologists, it also concerns the interested immunologist, as you will see in the next paragraph. It is not a question of “What is wrong with this child?” but a question of “What happened to this child?” And another question is, “Why can there be such long-term problems that extend into adulthood?” My second goal as a psycho-neuro-endocrine oriented immunologist was, on the other hand, to shed light on the often detectable increased inflammatory state after early traumas. This chronic immune activation is shown by increased inflammation levels in the blood. It may lead to an increased incidence of autoimmune diseases such as

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rheumatoid arthritis (the most common form of chronic joint inflammation) later in life, and this concerns the rheumatologist. However, it is not yet well understood why an early traumatic event or stressful situation should cause a higher inflammatory situation in the long run. There must be some kind of programming that originates in the brain and subsequently affects the body periphery in the form of increased inflammation. The reader is introduced to the topic of trauma through examples in the first chapter. In the second chapter, the different trauma situations, the time of occurrence and the frequencies of childhood adversities in the population are pointed out. Furthermore, those factors that can protect against long-term consequences are mentioned. Indeed, it is by no means just a “one-way street from trauma to late problems,” as there are many protective elements (the subject of resilience research, among others). This attitude reflects the view of those affected who put the trauma behind them and yet look positively to the future. This part is concluded by an evolutionary medical view. In Chap. 3, I deal with the consequential problems found in the brain and body periphery. Pathophysiological pathways are outlined, and this requires some medical depth. This discussion transitions into the presentation of the elevated inflammatory situation, with a focus on the chronic situation, also known as autoimmune disease. Epidemiological studies show a clear link between childhood/adolescent trauma and later onset of these autoaggressive diseases. The fourth chapter now explains step by step how a problem in the brain can affect the body periphery to cause chronic inflammation there. The brain and immune system are intertwined via “connectors,” and these contribute to chronic immune activation. The Chap. 5 looks into the future. On the basis of energy considerations, a hypothesis is put forward which reads: Mild inflammation exists, but it does not decisively stimulate the late problems. This last statement may be surprising for one or the other reader, because he understands inflammation as the supporting pillar of all subsequent problems, particularly in the periphery. This mild inflammation is for me only a concomitant phenomenon in the context of the energy regulation of the body, a support of the immune system for an overactive brain. This book is intended for researchers already studying psychological trauma and late effects, as well as those who wish to engage in this growing area of research, including students, and individuals who wish to improve the lives of vulnerable children. Professionals in medicine, psychology, psychiatry, social work, education, sociology, nursing, pediatrics, public health, applied economics, humanitarian aid, and disaster planning may find useful ideas and background for their work. A basic understanding of medicine is beneficial for reading. As in my previous books, I do not make any suggestions for therapy, because that is presumptuous, because there are specialists in psychotraumatology for that. If you read the book carefully, you can see approaches to therapy in abundance. Often these therapy options consist of preventing the bad and stimulating the good.

Preface

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A book like this is never created single-handedly, so a few very helpful people have given good advice here. The book was critically read by my wife Verena Straub. Another big thank you goes to Dr. Volker von Baehr, IMD Institute for Medical Diagnostics, Berlin, who supported the printing of the book. From the Springer-Verlag, valuable help came from Dr. Christine Lerche. If inclined readers provide further tips, I am grateful. Improvements will be collected and added to a later edition. Regensburg Summer 2022

Rainer H. Straub

Contents

1 The Long Shadow of Early Trauma—Look!. . . . . . . . . . . . . . . . . . . . . . . . . . 1 1.1 Mental Illness. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1.2 Pain in Childhood—and What Comes Later?. . . . . . . . . . . . . . . . . . . . . . . 2 1.3 How can I Sleep While My Bed is Burning?. . . . . . . . . . . . . . . . . . . . . . . . 3 1.4 Teeth Suffer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 1.5 Target Variable: Weight. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 1.6 Cardiovascular Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 1.7 Chronic Lung Problems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 1.8 And then Chronic Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 1.9 To the Point . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 2 What is a Child’s Psychological Trauma? . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 2.1 Origins and Important Protagonists. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 2.1.1 Urie Bronfenbrenner, a Psychologist (1917–2005). . . . . . . . . . . . . 13 2.1.2 John Bowlby, a Child Psychiatrist (1907–1990). . . . . . . . . . . . . . . 14 2.1.3 Michael Rutter, Psychiatrist (1933–2021). . . . . . . . . . . . . . . . . . . . 15 2.1.4 David Barker, Social Medicine and Epidemiologist (1938–2013). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 2.1.5 Vincent J. Felitti, an Internist (Born 1938) . . . . . . . . . . . . . . . . . . . 16 2.1.6 Robert J. Plomin, a Psychologist (Born 1948). . . . . . . . . . . . . . . . . 18 2.1.7 W. Thomas Boyce (Born 1943), a Pediatrician, and Jay Belsky (Born 1952), a Psychologist. . . . . . . . . . . . . . . . . . . . . . . . . 18 2.1.8 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 2.2 The Different Types of Early Traumatic Experiences. . . . . . . . . . . . . . . . . 19 2.3 Time Windows for Bad Childhood Experiences. . . . . . . . . . . . . . . . . . . . . 22 2.4 Frequency of Bad Childhood Experiences. . . . . . . . . . . . . . . . . . . . . . . . . . 24 2.5 Compensating Positive Factors Against Trauma Experiences. . . . . . . . . . . 26 2.5.1 Resilience. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 2.5.2 Unfavorable Versus Favorable Childhood Experiences. . . . . . . . . . 29 xiii

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2.5.3 Orchid or Dandelion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 2.5.4 Favorable or Unfavorable Genetic Predisposition. . . . . . . . . . . . . . 33 2.5.5 Favorable or Unfavorable Epigenetic Changes. . . . . . . . . . . . . . . . 41 2.6 Child Disadvantages and Steeling Effects. . . . . . . . . . . . . . . . . . . . . . . . . . 44 2.7 Transmission of Behavior from Generation to Generation. . . . . . . . . . . . . 47 2.7.1 Genetic Transmission. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 2.7.2 Epigenetic Transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 2.7.3 Transmission—without Genetic and Epigenetic Explanations. . . . 51 2.8 An Evolutionary Medicine Perspective. . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 2.8.1 Historical Development. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 2.8.2 Childhood Trauma and Evolutionary Medicine—the Results. . . . . 55 2.8.3 Gender Differences—an Evolutionary Medicine Perspective. . . . . 57 2.9 To the Point . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 3 Consequences of Early Traumatic Experiences. . . . . . . . . . . . . . . . . . . . . . . . 71 3.1 Many Places are Affected . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 3.2 The Brain Probably Suffers the Most . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72 3.2.1 Alcohol, Nicotine and Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72 3.2.2 Depression. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 3.2.3 Anxiety Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 3.2.4 Personality and Childhood Trauma. . . . . . . . . . . . . . . . . . . . . . . . . 81 3.2.5 More Psycho- and Neuropathology. . . . . . . . . . . . . . . . . . . . . . . . . 82 3.2.6 More Sleep Disorders as a Result of Previous Trauma. . . . . . . . . . 84 3.2.7 More Pain after Childhood Adversities. . . . . . . . . . . . . . . . . . . . . . 86 3.2.8 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 3.3 The Body Periphery Suffers as Well . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 3.3.1 High Body Weight. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 3.3.2 Heart Attack and Co.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 3.3.3 Chronic Lung Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 3.3.4 The Stomach Aches and the Stool Consistency Bothers. . . . . . . . . 100 3.3.5 And When We Get Old?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 3.4 And Finally the Immune System is Activated. . . . . . . . . . . . . . . . . . . . . . . 108 3.4.1 Early Trauma and Autoimmunity. . . . . . . . . . . . . . . . . . . . . . . . . . . 109 3.5 To the Point . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 4 Chronic Immune System Activation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135 4.1 Egoistic Brain and Egoistic Immune System are Fourfold Interconnected. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135 4.1.1 Areas in the Brain that Stimulate Direct and Indirect Connectors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137

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4.2 Direct Connectors Chronically Activate the Immune System (No. 1). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140 4.2.1 The Sympathetic Nervous System. . . . . . . . . . . . . . . . . . . . . . . . . . 141 4.2.2 The Parasympathetic nervous system . . . . . . . . . . . . . . . . . . . . . . . 153 4.2.3 The HPA Axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154 4.2.4 Disruption of the Circadian Rhythm. . . . . . . . . . . . . . . . . . . . . . . . 164 4.2.5 Tone of the Pain Pathways. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166 4.2.6 Tone of the Sex Hormone Axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169 4.3 Indirect Connectors Activate the Immune System Chronically (No. 2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174 4.3.1 Adipose Tissue is Pro-inflammatory . . . . . . . . . . . . . . . . . . . . . . . . 174 4.3.2 The Insulin from the Pancreas Promotes Inflammation. . . . . . . . . . 177 4.3.3 Reduced Physical Activity—Anti-inflammatory Factors are Missing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179 4.3.4 Microbiome and Inflammation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180 4.3.5 The Permeability of the Gut is Pro-inflammatory. . . . . . . . . . . . . . 182 4.3.6 The Skin Itches Chronically and is Inflamed. . . . . . . . . . . . . . . . . . 183 4.4 Environmental Factors Chronically Activate the Immune System (No. 3). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184 4.4.1 Where There’s Smoke, There’s Fire. . . . . . . . . . . . . . . . . . . . . . . . . 184 4.4.2 Where Fine Particles are Flying, It Gets Uncomfortable. . . . . . . . . 187 4.4.3 Asthma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 4.4.4 Infections are Extra-corporeal Connectors . . . . . . . . . . . . . . . . . . . 192 4.4.5 Risk Behavior. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195 4.5 Gene Mutations as Pleiotropic Connectors (No. 4). . . . . . . . . . . . . . . . . . . 196 4.5.1 The Search in the Gene Databases Leads to Pleiotropic Connectors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198 4.6 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201 4.7 To the Point . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204 5 Energy, Early Traumatic Experiences and Chronic Immune System Activation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 5.1 Brain and Immune System Define Energy Expenditure . . . . . . . . . . . . . . . 234 5.2 The Trauma Reaction can Use a Lot and a Little Energy . . . . . . . . . . . . . . 238 5.3 Is there a Trauma and Energy Provision Memory?. . . . . . . . . . . . . . . . . . . 239 5.4 Energy and Chronic Immune System Activation. . . . . . . . . . . . . . . . . . . . . 240 5.4.1 How High is Inflammation in People with Early Traumatic Experiences? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240 5.4.2 How High is Energy Expenditure at Different Levels of Inflammation? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241

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5.4.3 The Quintessence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243 5.5 To the Point . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246 Glossary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249

About the Author

Prof. Dr. med. Rainer H. Straub is Professor of Experi­ mental Medicine and Internal Rheumatologist. He heads the Laboratory of Experimental Rheumatology and Neuroen­ docrine Immunology, Internal Medicine, at the University Hospital Regensburg. His non-fiction books “Understanding Aging, Fatigue and Inflammation” (2018) and “Three Mem­ ories for the Body” (2020) have been published by Springer.

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1.1 Mental Illness Children are particularly vulnerable because everything can still take shape and change. The problems affect a sensitive, constantly changing brain that is open to everything. Scientists speak of plasticity of the brain. This plasticity can be bad and good, but in any case it contributes significantly to the individual development of the person. Serious stress-inducing constellation can be drug or alcohol abuse by parents, separation of parents, physical and sexual abuse, death of close relatives (parents, siblings), mental illness in one parent, emotional neglect or overburdening, deprivation of liberty of the child, hospital stays, separation from the parental home, long-term unemployment of parents, arrival of a new adult household member (step-parents), change of school and bullying at school, low socio-economic status, observation of a criminal act or imprisonment of a parent, etc. A detailed list will be presented in the next chapter. These mental and physical injuries lead to severe child stress, which affects children differently. In comparison to control groups, children with such traumas attempt suicide 5 times more often, injure themselves 3 times more often, have an attention deficit 2 times more often, suffer from anxiety disorders 2 times more often and depressions 3 times as often, almost 3 times as often from psychotic symptoms (loss of reality), are more addicted to alcohol and drugs and stand out due to social behavior disorders (Danese 2020). When scientists investigate mentally ill offenders of a forensic psychiatric department, as was done, for example, in Scotland in 2013, almost 80% of the inmates reported having had severe traumatic experiences in childhood. Often there were chaotic family relationships because one parent left the family (32%) or took alcohol/drugs (25%). In total, 23% of the affected were sexually abused, bullied at school (21%), or had to change schools several times (21%). These stressed children and later offenders have a

© The Author(s), under exclusive license to Springer-Verlag GmbH, DE, part of Springer Nature 2023 R. H. Straub, Early Trauma as the Origin of Chronic Inflammation, https://doi.org/10.1007/978-3-662-66751-4_1

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very high risk of suicide and death shortly after release from prison. The risk of death is 29 times higher than in the comparable group of healthy people (Karatzias et al. 2019). The matter goes even deeper because transmission from one generation to the next can be observed. If, for example, mothers were themselves exposed to stressful episodes during childhood, their children also had more stressful circumstances during childhood and psychological and emotional abnormalities later in life (Negriff et al. 2020). The misconduct is programmed during childhood and continues into adulthood. However, not all adults with psychiatric problems have childhood trauma. Childhood stress is not an absolute prerequisite for psychiatric illness, but it can significantly favor it.

1.2 Pain in Childhood—and What Comes Later? We have neuronal pathways for exactly localized pain in the area of muscles, ​​ bones, ligaments, tendons and skin (we call them somatic pain pathways). Another group of pain-sensing nerve fibers comes from the intestines such as lungs, heart, stomach, intestine, bladder, etc. (we call them visceral pain pathways). The paths for somatic and visceral pain are different, but all paths end up in the brain, and so pain from different areas comes into consciousness. Interestingly, we can create a pain memory, which is most clearly seen when we think of phantom pain. This form of pain exists in an amputated body part as if that region still belonged to our body. Think of a soldier in a hospital whose foot had to be amputated due to healing disorders and wound pain and who still suffers from these wound pains— the phantom pains—many years later. This memory provides an unpleasant reminder, and here we see a long-term programming, a long-term memory. What does it have to do with childhood adversities? Sometimes newborns have to be treated in an intensive care unit if, for example, they were born too early or have a serious illness. Here they experience various pains during blood withdrawal, when an infusion is applied, after surgery, in connection with wounds, with dry and strained skin and some other painful situations. Up to 14 painful events can occur per day (Maxwell et al. 2019). Newborns are particularly vulnerable, but can hardly defend themselves. This is a special form of childhood stress that is comparable to the early childhood stress situations already mentioned. These pains lead to chronic changes in a slowly developing brain that functions differently in newborns than in adults. If longer-lasting pain exists during this phase, a memory for this pain can develop. So two-thirds of the children with a longer period on a newborn intensive care unit have chronic pain at the age of 10 years (Bhatt et al. 2019). They show anatomical changes in brain structures and disorders of brain function in later childhood and young adulthood. Adults who have experienced traumatic events more often suffer from fibromyalgia, a disease with pain in the area of tendinous attachment points and bony prominences

1.3  How can I Sleep While My Bed is Burning?

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(Ortiz et al. 2016), which is usually treated by rheumatologists. In addition, these children more often suffer from migraine in adulthood, and there is a dose-response effect, as more trauma leads to more migraine. Physical activity can reduce the problem (Hammond and Colman 2020). In addition, the fear of pain increases in those affected, and they are more likely to have depression and anxiety (You et al. 2019). In a study of middle-aged women, pain in the pelvic area was examined, and this problem was significantly more common in women with negative childhood experiences (Krantz et al. 2019). Although women more often complain of pain, the link between bad childhood experiences and chronic pain was also observed in men (Yamada et al. 2017). In addition to somatic pain, adults who have experienced childhood trauma also suffer more from visceral pain, which manifests itself as irritable bowel syndrome or as urogenital problems (Khandker et al. 2019; Berens et al. 2020; Epperson et al. 2020). It looks as if those affected experience a kind of long-term increased pain sensitivity or stronger pain transmission from the periphery to the brain.

1.3 How can I Sleep While My Bed is Burning? This formulation comes from a song by Australian rock musicians who wanted to draw attention to the fate of indigenous people. The group Midnight Oil sang in the original: “How do we sleep while our beds are burning?” This question can also be asked when we look at the sleep problems of abused children or adolescents. Because severe stress constellations at this time lead to sleep disorders. This connection has already been shown many times. A systematic review presented the situation in 2015. The authors found a clear relationship between sexual abuse in childhood or family disputes on the one hand and clinically relevant sleep disorders in adulthood on the other (Kajeepeta et al. 2015). So it seems that the accumulation of stressful episodes, i.e. the increase in the number of experiences over time, is more important for triggering sleep disorders than the time or type of stressful event (Sheehan et al. 2020). In a large-scale study, the authors examined 22403 adults with an average age of 47 years, and 14587 people had a normal sleep time of 7–9 hours, whereas 2069 people had a very short sleep time of less than 6 hours. If the scientists now compared the people with normal sleep with those with short sleep, the number of negative childhood experiences was significantly higher in the short sleepers. The more negative experiences there were, the more pronounced the phenomenon was (Sullivan et al. 2019). Here I think involuntarily of Napoleon’s statement: “Four hours sleeps the man, five the woman, six an idiot.” Probably Napoleon was brought up very harshly. These analyses were confirmed in many other studies. These include the work of Ketrell McWhorter, who works at the epidemiological center of the National Institute of Health in Durham, North Carolina. She described results in 40082 women, and those with a history of childhood trauma slept significantly shorter than those without

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comparable life circumstances. In addition, the affected people took longer to fall asleep, woke up several times at night and showed short sleep episodes during the day (McWhorter et al. 2019). Since sleep quality is closely linked to subsequent problems such as cardiovascular diseases, this results in an important factor for increased mortality in affected people.

1.4 Teeth Suffer If children come from a household where financial constraints and low education are present, they show more tooth decay, an increased serum levels of the stress hormone cortisol and more typical tooth decay-inducing bacteria. The most severe caries findings were found in those children who had the highest levels of the stress hormone cortisol and the largest amounts of caries-inducing bacteria. In addition, a clear relationship was found between the stress hormone cortisol and inflammatory changes in the gums (Boyce et al. 2010). For example, if children experienced more than four different adverse events, tooth loss and -treatments were more common in them than in comparable control groups. In addition, it bothers them throughout their lives, because tooth loss and dental treatments were particularly present in older adults between the ages of 60 and 69 (Ford et al. 2020). This finding also speaks for a kind of long-term programming. In primates, the researchers were able to establish a connection between tooth enamel changes in older animals and stress situations in younger years based on dental examinations, with things like separation from the mother, pregnancy of the mother, relocation to a new enclosure, physical examination by humans or death of a sibling being of importance (Davis et al. 2020). Thus, it affects animals and humans when they are exposed to early stress experiences. Tooth problems can be accompanied by chronic inflammation phenomena, and so they are often the starting point for chronic diseases (more on this in Chap. 4).

1.5 Target Variable: Weight Children sometimes experience considerable stress even before birth (Fig. 1.1). Poor nutrition among mothers during pregnancy can be problematic, as was the case in the Dutch Hungerwinter of 1944–1945. Children of these mothers were heavier and more prone to diabetes mellitus type 2 Altersdiabetes and metabolism problems later in life. Similar studies on rats showed identical findings (Jackson et al. 1996). In an earlier book (“Altern, Müdigkeit und Entzündung verstehen”), I already spoke of the BarkerHypothese (Straub 2018), which linked intrauterine stress due to malnutrition with later increased weight development and increased mortality from heart attacks (see also in Chap. 2, Origins and Important Protagonists) (Barker et al. 1989). In a similar way,

1.5  Target Variable: Weight

Life of the mother until fertilization of an egg (later child)

From fertilization of an oocyte until birth of the child prenatal

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Early childhood

Childhood

Adolescence

perinatal (0–2 mo)

(4–11 yrs)

early A. (11–14 yrs)

very early childhood (0–12 mo) early childhood (1–4 yrs)

medium A. (15–18 yrs) late A. (18–21 yrs)

Time of the Adults early (21–35 yrs) Medium (35–65 yrs) higher (65–80 yrs) high (>80yrs)

Timeline of mother and child Fig. 1.1   The time of exposure to stress. This figure shows the different time windows when traumatic events can occur (events and episodes are illustrated by the lightning bolt icon above the boxes). The curved arrow below the boxes indicates the propagation of problems from one time window to the next. (A: adolescence; yrs: years; mo: months)

children of mothers who were exposed to psychological stress during pregnancy suffer in a very similar way (Burgueno et al. 2020). They are overweight, which points to a more general stress mechanism. The hormone of the adrenal gland released by stress—cortisol—is important for weight development because it influences decisive neuronal pathways in the brain that are important for long-term programming of eating behavior (Spencer 2013). Children experience stress-inducing events and situations after birth, as reported in the preceding subchapters. These children are often obese in later life with the corresponding metabolic consequences such as metabolic syndrome and diabetes mellitus (Burgueno et al. 2020). The important neuronal pathways for adjusting eating and reward behavior are still very pliable before and after birth (Spencer 2013). The early programming of the corresponding centers by exaggerated stress serves to protect against energy shortages (accumulation of energy-rich fatty acids in fat tissue), but it leads to problems in the long term. This is particularly the case when the accumulated energy reserves are no longer needed in later life because physical activity decreases with age (Straub 2018). With regard to addictive behavior, I refer to Chap. 3, Subchapter “Alcohol, nicotine and drugs”. These early childhood influences also seem to be determined by a subsequent change in the genetic makeup through so-called epigenetic processes (Explanation 1). In this scenario, environmental influences in different time windows can permanently change

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the normally existing and stable genetic program. This creates an increased risk of age-related diabetes and cardiovascular diseases (Hanson and Gluckman 2015).

1.6 Cardiovascular Diseases In Sweden, a group of scientists conducted a very large study of more than 14,000 people born in 1953. Data from people were stored in the databases of the Swedish health system who were placed in institutions outside their family of origin or who had conditions in the parental home that were contrary to the welfare of the child. Those children who experienced these forms of childhood trauma had a higher mortality rate compared to control persons who were not affected. The risk of higher mortality was particularly high if the children grew up outside their family of origin (Jackisch et al. 2019). Does death from cardiovascular disease play a role in these affected persons? In a very large American study, the connection between childhood trauma and heart attack was established. In total, more than 34,000 people took part in the studies, and those with childhood abuse had almost twice the risk of a heart attack. The risk was highest in people after sexual abuse and physical abuse (Chou and Koenen 2019). This can be contributed by obesity, age-related diabetes, high blood uric acid or high blood lipid levels. In fact, people who have been abused as children have more age-related diabetes, which typically occurs after the age of 40. There is also a direct relationship between dose and effect, as a higher number of child abuses contributes to a higher likelihood of age-related diabetes. In one study, it was shown how childhood trauma is more often associated with severe alcohol abuse, smoking and high body weight (Lown et al. 2019), further risk factors for cardiovascular disease. Explanation 1: Epigenetics

By means of epigenetic changes of the genes the readability of the same is promoted or impeded by chemical modifications. The composition of the genes (the sequence of the nucleic bases) is not changed hereby. If for example a methyl group (a C-atom with three hydrogen atoms, thus -CH3) is attached to certain sections of the DNA, the associated gene cannot be read in the same way anymore. If an acetyl group (-C(O) CH3) is attached to the known packaging proteins of the DNA (to the histones), the DNA becomes better accessible and a gene can be read more easily. Thus an extra-cellular stimulus can act on the cell and start the gene reading, but due to the epigenetic changes by the methyl group the gene reading may be blocked. The attaching of a methyl group or an acetyl group is controlled by different enzymes. All this is very complex and we have only understood it in approaches. Thus the gene reading can be manipulated retrospectively during the course of life. Besides these two mentioned possibilities of the retrospective change—methylation and acetylation—there are further epigenetic mechanisms (Kegel 2015), which cannot be mentioned here because this goes beyond the scope of the book. ◄

1.7  Chronic Lung Problems

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Between 1959 and 1961 the “three-year great Chinese famine” was a disaster. In this time under Mao Tse-tung in China between 20 and 40 million people died of malnutrition. Wenqiang Zhang and Rongsheng Luan from Szechuan analyzed the data of a largescale health study of three different groups. They included persons who were born after the famine (control) and persons who were affected as a fetus or in early childhood. The persons affected in the fetal stage showed in comparison to the other groups in adulthood high blood levels of uric acid. This connection remained when the physicians included the risk factors smoking, high body weight, alcohol, hypertension and diabetes mellitus additionally in the statistics (Zhang and Luan 2020). Since a high uric acid is a risk factor for the heart attack this study points to a significant problem. Furthermore adults after early childhood traumas showed higher cholesterol levels, which are a risk factor for the development of cardiovascular diseases (Cubbin et al. 2019). The different risks can occur independently from each other and reinforce each other.

1.7 Chronic Lung Problems Childhood stress experiences are more often associated with the onset of an asthma disease and allergy in adolescents. In one study, the observed persons were between 13 and 18 years old. They experienced blows from the educator, from other people, threats from weapons, rape, sexual abuse, stalking (obsessive pursuit), violence in the family or they observed severe injury or death events. All these things can lead to an increased risk of an allergic disease or asthma (McLaughlin et al. 2016). This problem can persist into adulthood, as was shown in a study in Tucson, Arizona (Oren et al. 2017). It goes even further. If pregnant women experienced domestic violence, were afraid during the pregnancy, suffered from financial constraints, showed symptoms of depression and had a generally higher stress level, their children—especially the male offspring—showed more asthma up to the age of 6. Here, a early time window from Fig. 1.1 is important. It does not stop at asthma, there’s more like allergic rhinitis, neurodermatitis (atopic eczema), welts on the skin (urticaria) and other hypersensitivity reactions are observed. This relationship has now been observed in 30 different studies and recently summarized (Flanigan et al. 2018). However, paternal stress does not affect the offspring’s risk of asthma. And if you think we have reached the beginning of a causal chain, there is an escalation of the problem. If mothers themselves were victims of domestic violence in their childhood or were exposed to traumatic life events from an early age to adulthood and then became pregnant, their male offspring more often had asthma. Interestingly, the mothers often also had asthma during this pregnancy, smoked more often and were significantly overweight (Rosa et al. 2018). A combination of factors increases the risk. For example, the presence of chemicals together with the stress situations leads to an

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amplification of the problem. And again and again it is mainly boys who are affected by the allergic disease (Rosa et al. 2018).

1.8 And then Chronic Inflammation There are large epidemiological studies that show the connection between childhood stress and the later onset of autoimmune diseases. If there were traumatic experiences in childhood, one form of inflammatory joint disease—rheumatoid arthritis—can occur more frequently (Kopec and Sayre 2004). Similar relationships have also been reported for other autoimmune diseases (Feldman et al. 2019). When the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, is not busy with the consequences of the Corona infection, they investigate there, among other things, the consequences of childhood psychological trauma. Shanta Dube of the CDC is an epidemiologist with a focus on child welfare. Some of her informative studies shed light on the connection between childhood trauma and later chronic inflammatory diseases. For this she was able to access large CDC data sets. If only one type of childhood trauma is present, the risk of an inflammatory disease is still low, if several are present at the same time, the risk of such a disease increases 2.5-fold. On average, the diseases do not occur until after the 30th birthday (Dube et al. 2009). Children with early trauma suffer more frequently from a childhood form of arthritis. The risk of developing this chronic joint inflammation is up to 6 times higher in affected children if they had to experience the death of a parent (Neufeld et al. 2013). Likewise, in the less inflammatory osteoarthritis, which we typically attribute to wear and tear (for example, due to occupational stress), the connection between childhood trauma and illness was found (Fuller-Thomson et al. 2009). Although osteoarthritis is relatively non-inflammatory, it is still associated with significant local inflammatory phenomena and pain. Since pain is more often observed in adults who were under stress in childhood, we are not surprised by increased osteoarthritis pain. Even if it does not lead to an open chronic inflammatory disease, adults with childhood trauma have a generally higher inflammatory constellation. They have an increased C-reactive protein in the serum, which is associated with various problems of the adult such as osteoporosis, stroke, heart attack or depression (Danese and Lewis 2017). If the investigators challenge depressive adults with previous childhood trauma to a stress situation, the already increased blood levels of inflammatory parameters increase even more. The childhood stress, the consequences of which we would only suspect in the adult brain (e.g. depression, anxiety, fatigue, etc.), is also transferred to many physical ailments in the periphery. The brain and the body are in close interaction, and that is why such problems arise in adulthood also outside the brain. A key theme of the book is the connection between early childhood stress on the one hand (problem in the brain) and chronic immune activation in adulthood (problem in the periphery). Since I have worked in the field of chronic inflammatory diseases and psycho-neuro-endocrine immunology

References

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for many years, I am particularly interested in this connection. The book will deal with this transmission of problems from the brain to the body periphery and to the immune system.

1.9 To the Point • Prenatal, early childhood and childhood trauma often leads to psychiatric illnesses, anxiety disorders and increased suicide rates. • Consequences of stress-inducing experiences are transmitted by mothers to children, who then suffer from this problem again and can pass it on. • Pain in early childhood increases the likelihood of chronic pain later in life. Traumatic life circumstances also increase the likelihood of chronic pain. • Negative childhood experiences lead to sleep problems later in life. People sleep too little, often wake up at night and need short naps during the day. • Childhood stress episodes worsen dental health in later life. • Child abuse is often associated with a high body weight. This often leads to an unfavorable metabolic state, which in turn often leads to diabetes mellitus in old age. • These metabolic disorders programmed in childhood can be the platform for cardiovascular diseases. The connection between childhood stress and heart attack has been clearly demonstrated epidemiologically. • In the same way, the connection between early traumatic experiences and allergic diseases such as hay fever, asthma or neurodermatitis has been described. Here, the problem of transmission from mother to child becomes clear. • Finally, the link between bad childhood experiences and chronic inflammatory diseases shows the extent of the problem. Since chronic activation of the immune system is an important topic for this connection, it is dealt with in more detail in this book.

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Burgueno AL, Juarez YR, Genaro AM, Tellechea ML (2020) Systematic review and meta-analysis on the relationship between prenatal stress and metabolic syndrome intermediate phenotypes. Int J Obes 44:1–12 Chou PH, Koenen KC (2019) Associations between childhood maltreatment and risk of myocardial infarction in adulthood: results from the national epidemiologic survey on alcohol and related conditions. J Psychiatr Res 116:172–177 Cubbin C, Kim Y, Panisch LS (2019) Familial childhood adversity is associated with chronic disease among women: data from the geographic research on wellbeing (GROW) study. Matern Child Health J 23:1117–1129 Danese A (2020) Annual research review: rethinking childhood trauma-new research directions for measurement, study design and analytical strategies. J Child Psychol Psychiatry 61:236–250 Danese A, Lewis SJ (2017) Psychoneuroimmunology of early-life stress: the hidden wounds of childhood trauma? Neuropsychopharmacology 42:99–114 Davis KA, Mountain RV, Pickett OR, Den Besten PK, Bidlack FB, Dunn EC (2020) Teeth as potential new tools to measure early-life adversity and subsequent mental health risk: an interdisciplinary review and conceptual model. Biol Psychiatry 87:502–513 Dube SR, Fairweather D, Pearson WS, Felitti VJ, Anda RF, Croft JB (2009) Cumulative childhood stress and autoimmune diseases in adults. Psychosom Med 71:243–250 Epperson CN, Duffy KA, Johnson RL, Sammel MD, Newman DK (2020) Enduring impact of childhood adversity on lower urinary tract symptoms in adult women. Neurourol Urodyn 39:1472–1481 Feldman CH, Malspeis S, Leatherwood C, Kubzansky L, Costenbader KH, Roberts AL (2019) Association of childhood abuse with incident systemic lupus erythematosus in adulthood in a longitudinal cohort of women. J Rheumatol 46:1589–1596 Flanigan C, Sheikh A, DunnGalvin A, Brew BK, Almqvist C, Nwaru BI (2018) Prenatal maternal psychosocial stress and offspring’s asthma and allergic disease: a systematic review and meta-analysis. Clin Exp Allergy 48:403–414 Ford K, Brocklehurst P, Hughes K, Sharp CA, Bellis MA (2020) Understanding the association between self-reported poor oral health and exposure to adverse childhood experiences: a retrospective study. BMC Oral Health 20:51 Fuller-Thomson E, Stefanyk M, Brennenstuhl S (2009) The robust association between childhood physical abuse and osteoarthritis in adulthood: findings from a representative community sample. Arthritis Rheum 61:1554–1562 Hammond NG, Colman I (2020) The role of positive health behaviors in the relationship between early life stress and migraine. Headache 60:1111–1123 Hanson MA, Gluckman PD (2015) Developmental origins of health and disease – global public health implications. Best Pract Res Clin Obstet Gynaecol 29:24–31 Jackisch J, Brännström L, Almquist YB (2019) Troubled childhoods cast long shadows: childhood adversity and premature all-cause mortality in a Swedish cohort. SSM Popul Health 9:100506 Jackson AA, Langley-Evans SC, McCarthy HD (1996) Nutritional influences in early life upon obesity and body proportions. CIBA Found Symp 1996(201):118–129 Kajeepeta S, Gelaye B, Jackson CL, Williams MA (2015) Adverse childhood experiences are associated with adult sleep disorders: a systematic review. Sleep Med 16:320–330 Karatzias T, Shevlin M, Pitcairn J, Thomson L, Mahoney A, Hyland P (2019) Childhood adversity and psychosis in detained inpatients from medium to high secured units: results from the Scottish census survey. Child Abuse Negl 96:104094 Kegel B (2015) Epigenetik – Wie unsere Erfahrungen vererbt werden. DuMont Buchverlag, Köln Khandker M, Brady SS, Rydell SA, Turner RM, Schreiner PJ, Harlow BL (2019) Early-life chronic stressors, rumination, and the onset of vulvodynia. J Sex Med 16:880–890

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Kopec JA, Sayre EC (2004) Traumatic experiences in childhood and the risk of arthritis: a prospective cohort study. Can J Public Health 95:361–365 Krantz TE, Andrews N, Petersen TR, Dunivan GC, Montoya M, Swanson N, Wenzl CK, Zambrano JR, Komesu YM (2019) Adverse childhood experiences among gynecology patients with chronic pelvic pain. Obstet Gynecol 134:1087–1095 Lown EA, Lui CK, Karriker-Jaffe K, Mulia N, Williams E, Ye Y, Li L, Greenfield TK, Kerr WC (2019) Adverse childhood events and risk of diabetes onset in the 1979 National longitudinal survey of youth cohort. BMC Public Health 19:1007 Maxwell LG, Fraga MV, Malavolta CP (2019) Assessment of pain in the newborn: an update. Clin Perinatol 46:693–707 McLaughlin KA, Basu A, Walsh K, Slopen N, Sumner JA, Koenen KC, Keyes KM (2016) Childhood exposure to violence and chronic physical conditions in a national sample of US adolescents. Psychosom Med 78:1072–1083 McWhorter KL, Parks CG, D’Aloisio AA, Rojo-Wissar DM, Sandler DP, Jackson CL (2019) Traumatic childhood experiences and multiple dimensions of poor sleep among adult women. Sleep 42:zsz108 Negriff S, Palmer Molina A, Hackman DA (2020) Parental exposure to childhood maltreatment and offspring’s mental health: investigating pathways through parental adversity and offspring exposure to maltreatment. Child Maltreat 25:422–432 Neufeld KM, Karunanayake CP, Maenz LY, Rosenberg AM (2013) Stressful life events antedating chronic childhood arthritis. J Rheumatol 40:1756–1765 Oren E, Gerald L, Stern DA, Martinez FD, Wright AL (2017) Self-reported stressful life events during adolescence and subsequent asthma: a longitudinal study. J Allergy Clin Immunol Pract 5:427–434 Ortiz R, Ballard ED, Machado-Vieira R, Saligan LN, Walitt B (2016) Quantifying the influence of child abuse history on the cardinal symptoms of fibromyalgia. Clin Exp Rheumatol 34:S59–S66 Rosa MJ, Lee AG, Wright RJ (2018) Evidence establishing a link between prenatal and early-life stress and asthma development. Curr Opin Allergy Clin Immunol 18:148–158 Sheehan CM, Li L, Friedman EM (2020) Quantity, timing, and type of childhood adversity and sleep quality in adulthood. Sleep Health 6:246–252 Spencer SJ (2013) Perinatal programming of neuroendocrine mechanisms connecting feeding behavior and stress. Front Neurosci 7:109 Straub RH (2018) Altern, Müdigkeit und Entzündungen verstehen – Wenn Immunsystem und Gehirn um die Energie im Körper ringen. Springer, Berlin/Heidelberg Sullivan K, Rochani H, Huang LT, Donley DK, Zhang J (2019) Adverse childhood experiences affect sleep duration for up to 50 years later. Sleep 42:zsz087 Yamada K, Matsudaira K, Tanaka E, Oka H, Katsuhira J, Iso H (2017) Sex-specific impact of early-life adversity on chronic pain: a large population-based study in Japan. J Pain Res 10:427–433 You DS, Albu S, Lisenbardt H, Meagher MW (2019) Cumulative childhood adversity as a risk factor for common chronic pain conditions in young adults. Pain Med 20:486–494 Zhang W, Luan R (2020) Early-life exposure to the Chinese famine of 1959–61 and risk of Hyperuricemia: results from the China health and retirement longitudinal study. BMC Public Health 20:15

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What is a Child’s Psychological Trauma?

2.1 Origins and Important Protagonists The connection between adversity in childhood and later problems in adulthood has been known for a long time. Sigmund Freud generated great theories with the experiences of his time, in which childhood conflicts and trauma had a significance in the formation of personality and the development of neuroses. Although his considerations at that time had no modern empirical platform, he earned the merit of popularizing the connection between childhood trauma and difficulties in adulthood. However, his focus on psychosexual aspects had a very exclusive character, which is now obsolete (Westen 1998). In addition, he used case studies of individual sufferers, which are not suitable for a generalized statement. Some called Freud’s theories and those of others “the grand theories of personalities” (Westen 1998). Before the Second World War, this view was very much shaped by Freud and his students or followers, and only afterwards did different paths lead to a wide empirical investigation of a serious problem—that was and is the Anglo-American direction. The number of scientists who have examined this connection since Sigmund Freud has become innumerable today. Nevertheless, I would like to briefly mention a few important representatives with different professional orientations. The chronologically determined selection is subjective and does not claim to be complete.

2.1.1 Urie Bronfenbrenner, a Psychologist (1917–2005) Bronfenbrenner (1917–2005) was born in the turmoil of the Russian Revolution in 1917 in Moscow. His family moved to the United States when he was six years old. He studied psychology at Cornell University, Harvard and Ann Arbor. Immediately after the Second © The Author(s), under exclusive license to Springer-Verlag GmbH, DE, part of Springer Nature 2023 R. H. Straub, Early Trauma as the Origin of Chronic Inflammation, https://doi.org/10.1007/978-3-662-66751-4_2

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World War, he became interested in child development. So over the course of his life he generated a model with the following content: The environment has an influence on child development on different levels of society (norms, values), via relationships (e.g. the mother’s workplace, the importance of the neighbors), and up to the immediate interpersonal relationships of the child. The different levels are closely related to each other. In addition, he recognized the enormous importance of socio-economic burden, and he campaigned with Lady Bird Johnson (1934–1973)—the wife of President Lyndon B. Johnson (1908–1973)—for a government support program for economically disadvantaged children. In this program, 20 million children were promoted over decades (Woo 2005). So he earned the merit of having drawn attention to the socio-economic bottlenecks that represent a significant childhood burden.

2.1.2 John Bowlby, a Child Psychiatrist (1907–1990) John Bowlby (1907–1990) was the son of a surgeon of the royal household under King Edward VII of England. As was customary in this social class at that time, Bowlby’s mother Mary hardly took care of her son’s education. This was the responsibility of a nursery maid who took on the role of the mother. In Bowlby’s situation, this nanny left the family in his fifth year of life, which he later described as “a tragic loss of a mother” (van Dijken 1998). At the age of seven, he went to boarding school, a bad time for him, which he later commented on as follows (Bowlby 1966): “At the age of seven, I wouldn’t even send a dog to boarding school.” Finally, he lost a beloved godfather, another separation trauma for Bowlby. We are now not surprised that John Bowlby became interested in the topic of “separation” and “attachment” after he had completed his medical studies. During the Second World War, he was confronted with children who, because of the war turmoil in London, in Cambridge separated from their parents. In the local children’s clinic, he examined boys who had been caught stealing. He found out from 17 of these 44 small thieves how they had lived separated from their parents for a longer period of six and more months before their fifth year of life. In the control group, this fate of separation was experienced by only 2 of 44 children (Bowlby 1946). Separation seemed to lead to delinquent behavior. In the Tavistock Clinic northwest of London’s city center, he initiated the “Sanatorium Study” in 1948, in which children between the ages of one and three were hospitalized in a clinic due to illness or in an orphanage and long-term separated from their mother. Together with James Robertson he described the severe consequences of early separation. The first two phases of separation—protest and despair—are characterized by a very consuming struggle that only in the third phase leads to a seemingly less strenuous situation of denial. Robertson made two films in the 1950s that soon afterwards led to radical changes in the care of these children (Robertson and Bowlby 1952).

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The concept of separation from the mother went down in the history of science as “maternal deprivation”, which today is a recognized early childhood trauma. Furthermore, these works were the platform for attachment research and for animal experiments with similar forms of separation experiences. Another important representative on the topic of maternal deprivation was Michael Rutter (1933–2021) from London (Rutter 1999). Offshoots of this line of research are studies on children who have been exposed to maternal deprivation for a long time. These include the studies on children evacuated to the other places during the Second World War, e.g., in Finland (Eriksson et al. 2014) and the studies on children from Romanian orphanages that made headlines in the early 1990s (e.g. Nelson 2013).

2.1.3 Michael Rutter, Psychiatrist (1933–2021) Sir Michael Rutter (1933–2021) worked at King’s College in London. He was born in Lebanon, as his father worked there as a doctor in the 1930s. During the Second World War, at the age of seven, he lived in London, and there the German bombing took place. In this context, Michael Rutter and his younger sister were evacuated from London to the USA, and he experienced a painful separation experience, because the parents remained in the war-torn London. After attending school in New Jersey (USA) as well as Wolverhampton and York in England, he attended the University of Birmingham, England, after the war, where he graduated in 1955. After training as a neurologist, psychiatrist and pediatrician, Rutter did a research stay at the Albert Einstein College of Medicine in New York, where he dealt with child development (Kolvin 1999). He was the first professor of child psychiatry in England, and he has been doing this until recently. He received many awards for his scientific work in the fields of child development, autism, separation experiences (deprivation), resilience (psychological resistance after trauma), psychopathology as a result of traumatic childhood experiences, genetic causes of behavior and long-term effects of bad childhood experiences in older adults. In 1992 he was knighted by Queen Elizabeth II. (Kolvin 1999). An important study was initiated by him and colleagues after the fall of the Iron Wall in Romania. There he initiated an adoption program of Romanian children and adolescents to England, who were accommodated in orphanages of Bucharest by the wrong policy of the communist leader Ceauşescu at an early stage under unimaginable poor conditions. These investigations were groundbreaking in many ways. He is the author of several seminal books and textbooks (e.g. Rutter’s Child and Adolescent Psychiatry) (Thapar et al. 2015). Various descriptions of the person of Sir Michael Rutter are exuberant, and the interested reader may find out more there (Kolvin 1999).

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2.1.4 David Barker, Social Medicine and Epidemiologist (1938–2013) As the son of an engineer and a concert cellist, David Barker (1938–2013) was initially more interested in natural sciences than in medical studies. Nevertheless, he studied medicine in London, graduated in 1962 and started training as a social medical doctor and epidemiologist at the University of Birmingham in England. Between 1969 and 1979 he worked in Uganda and discovered the cause of a nasty skin ulcer in a combination of cuts with reed grass and colonization with mycobacteria (so-called Buruli ulcer). In 1979 Barker was appointed professor of clinical epidemiology at the University of Southampton, and there he remained for the rest of his life. In the role of epidemiologist, Barker observed in certain northwestern regions of England and Wales a correlation between increased newborn and infant mortality in the early 1920s and increased mortality from heart attacks 75 years later in the same population (Barker and Osmond 1986). The connection apparently resulted from the poor nutrition and living conditions in these regions. That wasn’t the whole truth. Soon Barker became aware of the connection between body weight after the first year of life and the heart attack rate in middle-aged adults. If a child weighed little at the first birthday (8.2 kg), it had a significantly higher risk of suffering from a heart attack many decades later compared to children with a higher body weight of 12.3 kg. His hypothesis was: There must be important factors for healthy aging to be found in newborns and infants (Barker et al. 1989a). Since newborns were affected, Barker and his team were finally able to point to a possible problem during pregnancy (Barker et al. 1989b). The supply situation in the uterus sensitized people in old age to heart attacks, strokes, high blood pressure, age-related diabetes and childhood infectious respiratory diseases (Barker et al. 1993). The Barker phenomenon clearly points to epigenetic changes in the uterus (explanation 1), which can cause a kind of adaptation reaction with negative longterm consequences. In an earlier book (“Altern, Müdigkeit und Entzündung verstehen”), I described the Barker phenomenon (Straub 2018). Indeed, this finding was a clear indication of prenatal stress factors and therefore of an early traumatic experience that can cause chronic problems in adulthood. Here, I further mention the harmful influence of alcohol and nicotine during pregnancy, which also causes long-term problems in offspring (Stroud et al. 2018; Wozniak et al. 2019). Furthermore, animal experiments with prenatal stress by Ingeborg Ward were enlightening, as they demonstrated a reduction in male sexual behavior in the offspring of stressed mothers (Ward 1972).

2.1.5 Vincent J. Felitti, an Internist (Born 1938) After studying medicine at the University of Minnesota in Minneapolis and at Johns Hopkins University in Baltimore, which we got to know through the Corona Dashboard

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in times of COVID-19, Felitti (born 1938) completed his medical studies in 1962. After training as an internist, he came to Kaiser Permanente in San Diego in 1968. This organization is still a private special form of a certain health insurance and care model that is subsidized by the US government and private sponsors. At Kaiser Permanente, Felitti was responsible for prevention research, and one of the programs was used in the 1980s to prevent obesity. In the context of this work, he cared for a young woman who weighed more than 200 kg and lost 66 kg during controlled weight reduction. Unfortunately, this weight loss was not of long duration, and shortly before the patient broke off contact with Felitti, she had gained a lot of weight. She explained that she was a sleepwalker and a night-time glutton. The sleepwalking-eating problem began when she was sexually abused by her grandfather from the age of 10 for more than a decade (Felitti 2019). Since a similar case was presented to the attentive Felitti shortly after this episode, the prevention physicians of Kaiser Permanente began to systematically ask about sexual abuse at his instigation. In a first study of 286 obese people, they were able to document a history of sexual abuse in 55% of the people (Felitti 2019). That was an alarming number. Felitti presented the data of the 286 people at an American conference on obesity, but the findings were not accepted or sharply attacked by those present. During a dinner, an epidemiologist from the Centers for Disease Control and Prevention in Atlanta recommended that he conduct a large epidemiological study and convince his opponents by sheer numbers. During a visit to this research facility, he began a very fruitful interaction with Robert Anda. Together they were able to start a large-scale study of men and women in 1995 (Felitti 2019). The first results were published in 1998 as the Adverse Childhood Experiences Study, which showed that among patients who experienced four or more adverse stress events in their childhood, the risk of health problems such as alcoholism, drug use, depression, suicide, nicotine abuse, promiscuity, sexually transmitted diseases, physical inactivity, and obesity increased by a factor of 2–12 depending on the follow-up problem (Felitti et al. 1998). Thus, the first epidemiological study was published, which showed the connection between childhood trauma and follow-up problems in adulthood in more than 17,000 people. In this survey, a questionnaire was developed that systematically recorded the child abuse. However, all possible childhood burdens were not included in the aforementioned questionnaire, and a revision of the questionnaire was necessary later (see Sect. 2.2). Since the study was designed prospectively, Felitti and colleagues were able to follow up with numerous follow-up studies to date. This resulted in a truly far-reaching new view that left no doubt about this problem in children and adolescents. This epidemiological study was not published until 1998, and that is already astonishing. Were the people before that blind? No, of course they were not, as Bronfenbrenner, Bowlby, Rutter and others showed, but the studies only illuminated individual aspects and were small in scale. Felitti and his team of researchers were able to raise the issue to another platform, and the public in the USA felt affected.

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2.1.6 Robert J. Plomin, a Psychologist (Born 1948) When it comes to the heritability of behavior, the name of Robert Plomin comes first. Plomin (born 1948) earned a bachelor’s degree from Vincent DePaul University in Chicago in the state of Illinois in 1970. He then went to Austin, Texas, to earn a doctorate in psychology there in 1974. After several stops at various universities in the USA—for example Boulder, Colorado and PennState University—he moved to King’s College in London in 1994 to Sir Michael Rutter, a flagship of psychological research in England. There he began his very successful studies of 10000 twin pairs, which were observed from early childhood to adulthood over 25 years. This study was very important for the field of behavioral genetics. He published together with colleagues over 1000 articles, book chapters and books and received many awards for his research work. He was the youngest president of the International Society for Behavioral Genetics, which was only founded in 1970. By the way, the year of foundation of a society often indicates when a scientific field really gets going. Although in the early years of such societies turbulent finding phases are still typical, things begin to stabilize after about ten years. This was the case, for example, in the field of behavioral genetics. In the presidential year 1989 of Robert Plomin, the proponents had reached a stable platform. I take up the topic of genetics again in the Sect. 2.5 below.

2.1.7 W. Thomas Boyce (Born 1943), a Pediatrician, and Jay Belsky (Born 1952), a Psychologist In 2019, Thomas Boyce (born 1943) summarized his findings in a recommended book entitled “Orchid or Dandelion” (Boyce 2019). From his own family history he learned how he himself was a robust dandelion and his later schizophrenic sister was a sensitive orchid in contrast. He was until recently a pediatrician in California and taught at the universities of San Francisco, Berkeley and Vancouver (University of British Columbia). Boyce distinguished children according to their sensitivity to trauma, and he called the sensitive “the orchids” and the robust “the dandelions”. He recognized the practical clinical connection between sensitivity and physical reactions of the stress axes to adverse life events, and orchids showed a much stronger stress reaction than dandelions. The dandelion was so to speak cool and did not get upset, no matter where it was planted. Orchids can fail under strong child stress, and they are sick all their lives, whereas they can thrive very well under caring stress-avoiding conditions—with higher and more creative performance than dandelions (Boyce 2019). The different sensitivities described by Boyce are not based solely on genetic differences in DNA, but also on so-called epigenetic influences (explanation 1). The geneticist

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speaks of epigenetic influences when the reading of the genes is promoted or inhibited by environmental changes at the DNA. These epigenetic influences begin during embryonic development in the womb and remain until adulthood. There they may lead to longterm follow-up problems. This explanation is particularly important because it means that the “offender” can be a victim of adverse circumstances in childhood. Another important representative of the “different sensitivities” theory is Jay Belsky (born 1952), who recognized this fact somewhat later than Boyce in the 1990s (Belsky 1997). In contrast to Boyce, Belsky had a much stronger connection to evolutionary theory. So he can probably be credited with the authorship of a theory that brings together the “different sensitivities” and the evolutionary theory. He first described this in a short editorial from 1997 (Belsky 1997). At the end of Chap. 1, I will go into evolutionary medicine aspects.

2.1.8 Summary The list of these protagonists is incomplete and nevertheless enlightening, because we recognize the entangled paths of different disciplines that aim at the childhood trauma and its consequences. So please forgive the author if he does not list all the participants at this point, because there was not enough space for that. A list of the most eminent psychologists of the 20th century—and this is only a group of scientists—hardly lists any representatives from the non-Anglo-American language area (Haggbloom et al. 2002). We realize: The research has been mainly from the USA and England since 1945. In the next subchapter, the different forms of traumatic experiences will now be addressed.

2.2 The Different Types of Early Traumatic Experiences The important questionnaire on childhood trauma (ACE-Questionnaire:adverse childhood experiences) comes from the large epidemiological study by Vincent Felitti (Felitti et al. 1998). There were similar questionnaires before Felitti’s publications (e.g. Masten et al. 1988), but because of the epidemiological character of the mentioned study, I would like to particularly highlight the ACE-Questionnaire. There are ten main categories mentioned there, which are listed in Table 2.1. Although this ACE-Questionnaire covers many points, it is by no means complete, which was not the claim of Felitti and colleagues. From the answers in the questionnaire, the investigator can assess the severity of the traumatic experiences. Meanwhile, extensions of these questionnaires have been made, and many of them can be accessed via relevant websites. An important German website is the Working Group of Scientific Medical Societies (2019), and from there you can access helpers. This website is supported by various German medical societies.

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Table 2.1  Childhood trauma according to Felitti (ACE-Questionnaire) • Physical abuse (pushing, hitting, grabbing, throwing, cutting, injuring, etc.) • Sexual abuse (at least 5 years older heterosexual person forces against their own wishes to sexual acts or tries to force) • Emotional abuse (insult, accuse, degrade, humiliate, scare) • Physical neglect (little food/hunger, dirty clothes, nobody protects, nobody cares and takes care, nobody provides medical care) • Emotional neglect (lack of love, feeling of unimportance, family members do not take care of each other, lack of proximity to family members) • Violence against the mother (shove, hit, grab, throw, kick, bite, threaten with weapon) • Substance abuse by a family member (alcohol, drugs, medication) • Mental illness or suicide by a family member • Separation of parents • Incarceration of a family member According to Vincent Felitti et al. (1998)

In addition to the elements mentioned in Table 2.1, further trauma has been recognized in recent years that go far beyond the ACE questionnaire (Table 2.2). The points of Table 2.2, for example, come from extensions of the Centers for Disease Control and Prevention, Atlanta (Centers for disease control and prevention 2018) and many working groups that regularly publish on this topic (Gest et al. 1999; Cohen et al. 2006; Burgermeister 2007; Tonmyr et al. 2011; Cronholm et al. 2015; Finkelhor et al. 2015; Ellis and Dietz 2017; Mersky et al. 2017; Oh et al. 2018; Anand et al. 2019). Prenatal stress situations for the mother (Graignic-Philippe et al. 2014) and the unstable socio-economic conditions in the parental home are particularly important in this context (Poulton et al. 2002). In addition, adverse childhood experiences often occur together and at the same time, and so the same person is often exposed to multiple traumas. This phenomenon has been called the “snowball effect” when one problem leads to the next (Masten 2014). In science, a line of four childhood traumas has been established, above which the trauma burden is considered to be severe. However, this line of demarcation depends on the questionnaire and can therefore vary. When children experience multiple childhood traumas, they often have so-called “best friends” in young adulthood who have a high rate of mental problems. In addition, the psychopathology of the “best friends” is a starting point for their own depressive symptoms. So the affected person chooses his environment according to his own needs and thus takes damage himself (Raposa et al. 2015). In addition, it is said that childhood traumas often go hand in hand with mental sequelae of the affected persons and that difficult economic conditions in the parental home

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Table 2.2  Further traumas in childhood and adolescence that are outside the ACE questionnaire • Stress of the mother during pregnancy or before (prenatal stress) (Graignic-Philippe et al. 2014; Frasch et al. 2018) • Prenatal toxins such as alcohol, smoking, hormone-active substances, heavy metals • Early medication treatments (e.g. with glucocorticoids) of the mother during pregnancy or of the child shortly afterwards (McGowan and Matthews 2018) • Mother’s fear of the experience of childbirth (Rothenberger et al. 2011) • Malnutrition of the mother during pregnancy (see David Barker) • Low birth weight or premature birth (see David Barker) • Malnutrition, hunger (Liu et al. 2003; Stickley et al. 2018; Jackson et al. 2019) • Depression of the mother after childbirth (Murray et al. 1996) • Young age of mother at first child • Difficult operations and long-term hospital stays of the child • Life as an orphan with institutionalization (example Romania) (see Michael Rutter) • Life as an adoptive child with stepmother/stepfather • Death of a parent or sibling • Illnesses of parents and/or siblings with/without long-term separations • Children who are left completely alone at home by their parents during the development phase for hours (Wong et al. 2018) • Loss of an important contact and reference person outside the parental home • Loss of work by father or mother • Single mother or father • Low level of parental education • Difficult economic conditions in the parental home, poverty (socio-economic disadvantages) • Frequent change of place of residence and thus of the peer group (Anderson and Leventhal 2017) • Living in homelessness (Patterson et al. 2014; Labella et al. 2019) • Sexual abuse with same-age, same-sex persons (presses against one’s own wishes for sexual acts or tries to press with/without the use of alcohol or drugs) • Victims of child trafficking/human trafficking (Reid et al. 2017) • Emotional abuse by schoolmates, for example for ethnic reasons (insult, accuse, denigrate, humiliate, frighten) • Problems at school with repeating a grade • Life with intellectual disability, impairment of cognitive performance (cognitive disorder) • Belonging to a group of people with a special sexual orientation (LGBT: lesbian, gay, bisexual and transgender) (McLaughlin et al. 2012) • Separation from a life partner • Difficult neighborhood (criminal acts, no security or mutual assistance, etc.) (continued)

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Table 2.2   (continued)

• Witnessing a fire in one’s own household • Witnessing criminal acts against/by loved ones or strangers • Witnessing of war actions and terrorism • Separation of parents due to military service (Turner et al. 2017; Fear et al. 2018) • Separation of asylum-seeking parents from their children (Miranda and Legha 2019) • Natural disasters such as earthquakes, storms, tsunamis, etc. (Inoue et al. 2019) • Expulsion, ethnic cleansing, crime against groups (e.g. Holocaust)

are more closely linked to physical sequelae in adulthood (Wickrama et al. 2015; Sheikh et al. 2016). Whether this separation can be made so clearly is, in my opinion, uncertain. If a parental home suffers from economic problems, other traumas also occur more frequently. You remember the “snowball effect”. A similar question that has been raised by scientists for a long time concerns the connection between trauma subtype—for example, physical abuse as opposed to physical neglect—on the one hand and subsequent problems in the future on the other. Does the special trauma dimension play a role in future specific trauma sequelae? So the observer can take the position: “All traumas trigger similar consequences.” In contrast, the following statement stands: “Each specific trauma triggers its own long-term effect.” With regard to this distinction, the researchers are not in agreement, and I do not want to go into it here (Smith and Pollak 2021). Animals such as monkeys, pigs, sheep, guinea pigs, rats and mice can be exposed to similar stress factors under natural conditions and have to fight similar sequelae (sequelae in the next chapter). There are therefore animal models in which animals are “exposed to prenatal or childhood stress” in order to uncover important factors for the development of disease in later life and to find therapeutic approaches. If, for example, scientists do not provide enough nest material to rat mothers, the rat mothers take care of their offspring less well, which in turn leads to anxiety in the growing and adult young animals (Ivy et al. 2008). This is an emotional and physical neglect. Most questionnaires for the assessment of trauma are based on only one survey. These are usually retrospective and do not allow a study of the connection between trauma and time windows of brain development. Therefore, there have been good suggestions for the assessment of trauma over a longer period of time in order to bring together trauma subtype and time of exposure (Teicher and Parigger 2015).

2.3 Time Windows for Bad Childhood Experiences Due to the sensitivity of structures in the brain and in the body periphery (e.g. immune system), long-term programming of embryos, fetuses, infants, children and adolescents can occur at different times (Nederhof and Schmidt 2012; Slopen et al. 2013; Strøm

2.3  Time Windows for Bad Childhood Experiences

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et al. 2013; Schalinski et al. 2019; Luby et al. 2020). Even the time before or during fertilization of the egg is considered by some authors to be a sensitive phase in which this programming takes place (Shachar-Dadon et al. 2009; Li et al. 2010; Strata et al. 2015; Fleming et al. 2018). We have known for a long time how smoking and alcohol can have a significant negative effect on the child during pregnancy (Stroud et al. 2018; Wozniak et al. 2019). During pregnancy, mothers’ psychotraumatic life experiences can have an adverse effect on the child. Other toxins can cause harm. These prenatal toxins can have long-term effects into adulthood, as we saw in Table 2.2. Different time windows of exposure are important for the subsequent problems. To illustrate the principle of time windows, the view of the development of language is helpful (Fig. 2.1). With regard to the uptake of information, on the one hand the brain must be prepared by appropriate maturity, i.e. the corresponding nerve cell networks must exist, and on the other hand the corresponding experiences must be offered by the environment (Werker and Hensch 2015). In the brain, different regions have the highest degree of sensitivity at different times (Luby et al. 2020). There are limits to the various functions, after which the time windows are closed and learning a function is either not possible or hardly possible at all. For example, the time window for language comprehension closes after 15 months, for feelings of security and attachment (Bowlby!) after 24 months, and for later reading after 24 months (Nelson et al. 2019). Time windows are important when acquiring normal functions. Typical time windows are prenatal (first, middle and last third of pregnancy), around birth (0–2 months), infancy (2–12 months), early childhood (13 months to 4 years), childhood (4–11 years), adolescence and adulthood (Fig. 1.1) (Hambrick et al. 2019). Not always are these time windows well defined for later behavior because the functions under consideration are complex and learned in different time windows.

phonological categories

Formation of word forms in the mother tongue

native phonetic categories Preference for the mother tongue differentiation of foreign speech sounds

Fig. 2.1   Time windows of language development in years. There are critical time windows in early brain development for sensitive, cognitive and affective dimensions. Early trauma can disrupt development and cause lasting disorders. (Information from Werker and Hensch 2015)

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Disruptions within the time windows through various trauma situations, as mentioned in Table 2.1 and 2.2, can strongly influence and affect normal behavior in the future (Nelson et al. 2019). Scientists find similar time windows in animal models (Mueller and Bale 2006; Matsumoto et al. 2009; Nishi et al. 2013; Andersen 2015). Perhaps you yourself have witnessed such events. However, if you are one of the people to whom none of this has happened, you may have no idea how common trauma is in children, adolescents and young adults. In the next section, I would like to briefly illustrate the frequency of child abuse.

2.4 Frequency of Bad Childhood Experiences Absolute numbers of abuse vary widely when looking at both the actually reported cases and a dark field. In 2019, the German Federal Criminal Police Office recorded 13670 definitive cases of sexual abuse of persons under 14 years of age. The offenders are almost 94% male and more than 60% are adult. The crimes mainly take place in small towns with up to 20000 inhabitants and medium-sized towns (up to 100000 inhabitants). The other consolidated cases of abuse of children under 14 years of age amounted to 3430 definitive cases. The offenders are predominantly adults (97.4%) and 45.5% of the offenders are female. The numbers for the different years can be seen on the official website of the German Federal Criminal Police Office (Federal Criminal Police Office 2019). In a book chapter in 2013, Becker and Schulz described the dark field (Becker and Schulz 2013): The official statistics can only give an indication of the actual prevalence of traumatization in childhood. The clarification of the dark field is possible to a certain extent by collecting empirical data [note by the author: mostly retrospective].

In the following text, I refer to such retrospective studies on the dark field from three different countries. In addition, these publications further break down the individual forms of abuse. The most common are the separation of parents or carers and economic hardship in the family mentioned in large population-based studies (Table 2.3). Children are particularly affected if they belong to an ethnic minority, are disabled or sick, are in economic difficulties, are raised by one parent, or live in rural areas (Crouch et al. 2019). Parents most often divorce when the children are between 13 and 17 years old, just at a time of maximum orientation. If two partners live together but are not married, there is more violence compared to a situation with married couples (Crouch et al. 2019). The study conducted in Germany of students in Table 2.3 also shows a very dark picture. The numbers are approximately comparable in all analyses, although the study groups and survey periods differ and, therefore, a direct comparison is not allowed. In the German study, 24.6% of respondents had 4 or more bad childhood experiences

2.4  Frequency of Bad Childhood Experiences

25

Table 2.3  Frequencies of bad childhood experiences Type of abuse* Physical abuse

USA1. N = 45,287.

3.3–17.9 %

Germany2. N = 1466.

3.9 %

Australia3. N = 7432.

5.2–8.2 %

Sexual abuse

10.6–22.0 %

12.3 %

1.1 %

Emotional abuse

3.3–34.4%

19.6%

6.5%

Physical neglect

24.2%

4.6%

1.6%

Emotional neglect

9.4%

19.1%

1.6%

Physical violence by family members

5.0–17.5%

34.0%

5.5%

Substance abuse in the family

8.1–27.6%

12.5%

5.7–18.4%

Mental illness or suicide in the family

7.1–18.8%

32.1%

17.8–23.8%

Separation/divorce of parents

21.9–27.6%

28.1%

14.4%

Parent was incarcerated

3.4–7.9%

not examined

not examined

Death of a parent

2.9%

18.5%

not examined

Economic difficulties of the parents

22.5%

9.8%

11.6%

*When “parents” is used here, the same applies to protective/caregiving adults who are not the parents. N is the number of people studied. 1) (Felitti et al. 1998; Afifi et al. 2011; Merrick et al. 2018; Crouch et al. 2019); 2) (Wiehn et al. 2018) of students (!); 3) (Rosenman and Rodgers 2004)

(Wiehn et al. 2018). In other words, one in 4 students had serious experiences in his childhood/youth. This immediately leads to health-damaging behavior, because 18.9% of the students examined drank alcohol regularly, 11.2% smoked daily, 17.9% took drugs, 17.5% had early sexual experiences, 5.3% had many sexual partners and 11.4% showed signs of suicidality (Wiehn et al. 2018). The conclusions of the German study on students make the problem clear: There is a need for much more education and protection for those (especially children) who cannot speak for themselves. Political and therapeutic consequences are discussed elsewhere (e.g. Spitzer and Grabe 2013; Masten 2014; Berens and Nelson 2015; Black et al. 2017). In the third, Australian study of more than 7000 people, 15.3% of those examined had four or more bad childhood experiences (Rosenman and Rodgers 2004). In this analysis, the age of the respondents—whether 20 to 24 years, 40 to 44 years or 60 to 64 years— had an influence on the reported frequencies, as the 40- to 44-year-olds had higher numbers than the other groups. The causes of this phenomenon are unknown according to the authors, but it may be due to the higher stress levels of people in middle age. Because

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2  What is a Child’s Psychological Trauma?

current stress worsens the assessment of the burden made when looking back (retrospective) (Colman et al. 2016). Many publications are retrospective and unique in the sense of a cross-sectional study, in which the adult respondents only look back on their childhood/adolescence at one single point in time. In this regard, there may be distortions of the statements because the problem is either increased or reduced in memory. For example, if the respondents are suffering from a current depression or other stressful episodes, the hardships of childhood are often presented more dramatically (Colman et al. 2016). Some prospective and retrospective studies show encouragingly similar results with regard to the statements (Patten et al. 2015; Reuben et al. 2016; Jivraj et al. 2020). Accordingly, scientists can rely on a good data base when using retrospective data. This subchapter made it clear how common the problems are. One fifth to one quarter of the population experienced negative childhood experiences, and we must ask ourselves whether there are positive elements in childhood that can offset the negative factors.

2.5 Compensating Positive Factors Against Trauma Experiences 2.5.1 Resilience The definition of resilience is diverse, since the word is used in different places. So the engineer speaks of resilience when a system returns to its original state despite massive disruptions. Resilience in energy management is the ability to not completely fail in the event of breakdown and to return to the starting point before the collapse. In dental medicine, the doctor means the suppleness of the mucous membranes under stress. The material scientist means the elastic property after deformation, which allows a return to the original form (rubber as opposed to dough). The German dictionary Duden essentially assigned resilience to psychology and defined it as the ability to overcome difficult life situations without lasting impairment. Since this is a somewhat long explanation, most people in German use the term “psychological resistance” instead of resilience. Resilience is a process to find a functional balance after trauma. An excellent book on resilience was written by Ann S. Masten, professor at the Institute of Child Development at the University of Minnesota, Minneapolis (Masten 2014). Ann Masten divides the systematic research work on resilience into four temporally separate episodes (explanation 2): Explanation 2: The four episodes of resilience research

1. Descriptive episode: Search for a definition of resilience, measurement of childhood trauma (variables), observation of the consequences of trauma and recognition of mental resistance

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27

2. Episode of clarification of processes leading to resilience and recognition of protective factors 3. Episode of therapeutic resilience promotion: Therapeutic approaches have been tested that promote resilience in the affected person. They are based on the measurement methods from episode 1 and the recognition of the protective factors of episode 2. 4. Episode of integrated considerations (from the 2000s): With the help of many new techniques from neuroscience and elsewhere such as imaging, genetics, epigenetics, omics1 and statistics, an integrated view of resilience is taken. Furthermore, the dynamics of events, the entire system including many body functions (including immune system and metabolism), genes and the environment—the context—play a major role in the multidisciplinary analysis. ◄ Resilience research recognizes childhood trauma and wonders why, despite adverse sometimes unspeakable childhood experiences, often surprisingly gratifying developments in childhood , during adolescence, in young adulthood and later are still to be observed. It recognizes the many follow-up problems after childhood trauma and tries to promote resilience in a therapeutic sense. Resilience research was mainly interested in the causes of the favorable development of a person affected, whereas risk research was more concerned with the risks for the unfavorable child development and the follow-up problems. If these things were strictly separated in the early years of both research lines, the two camps come together in particular with the new multidisciplinary approach of episode 4 (explanation 2). A key statement from the resilience research is as follows: Mental resistance is often present, very strongly developed and based on basic protective mechanisms that were positively selected during evolution. In other words, we can say: During the evolution mechanisms were retained and developed to provide protection in the event of adverse early life conditions. These mechanisms are “adaptive”, like everything that was positively selected during evolution to maintain the adaptation of the individual to the environment. Here they are, “the compensating positive factors against trauma experiences” in the sense of the subchapter heading. What are the favorable factors in detail? See Table 2.4. There the focus is on competence, which is very important for the development after bad childhood experiences. Because the more competent an affected person is, the more gratifying is the later development (Masten 2014). Competence and resilience are dynamic processes that change over time. Some people experience an early favorable

1 Omics:

The scientific disciplines informally known as omics are various disciplines in biology and medicine whose names end in the suffix -omics, such as genomics, proteomics, metabolomics, microbiomics, glycomics, etc. There typically very many—sometimes all—variables are measured and analyzed at the same time.

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2  What is a Child’s Psychological Trauma?

Table 2.4  Factors for resilience and importance for an evolutionarily positively selected, adaptive system Resilience factors (if present, then favorable)

Adaptive systems

Effective care and good parenting by parents or Attachment system; attachment to parents, carcaregivers egivers, mentors, family, fellow human beings Close relationships with other caring adults (mentor)

Attachment system; attachment to fellow human beings and creating social networks

Close friends and romantic loving relationships Attachment system; attachment to family and fellow human beings High intelligence and problem-solving skills (competence)

Learning and thinking systems of the brain, executive functions*

High self-control, emotion regulation, planning, Self-regulation systems of the brain, executive good working memory and good conscious functions* attention control (competence) Highly success-oriented motivation (competence)

Motivation and reward systems

High self-efficacy expectation, high self-confidence (competence)

Motivation and reward systems

Strong belief (religiosity), great hope and enormous trust in the meaningfulness of one’s own life

Spiritual and cultural social systems

Effective schools

Educational systems

Effective neighborhoods; good collective control of behavior within a community

Systems of fellow human beings in a social network

Personality traits such as openness to experience (openness), conscientiousness, agreeableness, and low emotional instability or low vulnerability (no neuroticism)

Is associated with multiple adaptive systems

List according to Ann Masten (Masten 2014). * Executive functions include self-control, emotion regulation, planning ability, working memory, and conscious attention control

development (early bloomers) after the traumatic time, and others go only relatively late in a favorable direction (late bloomers are more often women). In competent and resilient people, the positive aspects of one adaptive system can cascade to the next and create a positive overall picture. As Table 2.4 suggests, personality—formerly called temperament—is of great importance. By the way, temperament was already recognized by Immanuel Kant as a fundamental element of human nature (Kant 1833). Openness to experience (openness and curiosity), conscientiousness (perfectionism), agreeableness (consideration, willingness to cooperate, empathy) and low emotional lability or vulnerability (opposite of neuroticism) are very favorable factors for competence and resilience. Children and adolescents with these properties are more stable and have a high emotional, social and motivational

2.5  Compensating Positive Factors Against Trauma Experiences

29

control over a long period of time (Shiner and Masten 2012). In addition, there seem to be reciprocal effects between personality and competence. Competence problems lead over time to negative personality traits, which are unfavorable in the further course (snowball effects). On the other hand, favorable personality traits can lead to high competence and stabilize the personality (Masten 2014). In the assessment of personality traits, the researchers found strong cultural differences. So children with positive traits like agreeableness and friendliness were not the preferred children in studies of Masai groups because the Masai valued higher the ”difficult“ children with a strong perseverance and intensive self-assertion. Interestingly, children with the latter properties survived a drought period in 1974 better than the agreeable and friendly children (deVries 1984). Is it with the Masai like with the aggressive bird children who by their appearance snatch the food away from the others in the nest? Maybe, but the number of Masai children studied was small, and reliable findings can only be gained with caution. Table 2.4 also lists self-control, emotion regulation, planning ability, working memory and conscious attention control, which are all important elements to plan and control one’s own behavior while taking into account environmental conditions. In neuroscience, the term ”executive functions“” has established itself for this range of tasks. Furthermore, self-motivation, will formation and action initiative belong to this block of executive functions. The better the executive functions are, the higher the competence and resilience. In the brain, this is essentially the frontal lobe, which is in close interaction with other areas (Masten 2014). Furthermore, children learn stress management and avoid the stressor, actively seek support, plan problem solutions, seek balance in religion (culturally dependent), and control the stress reaction. Motivation and reward are important factors (Geschwind et al. 2010), which are located in the dopaminergic reward areas in the brain, such as the core areas of the Nucleus accumbens and other places. Motivation/reward, resilience, and the personality trait “openness to experience” are closely related. However, the incorrect or maladaptive use of this system is associated with addiction—reward and addiction are causally linked (Masten 2014). Thus, every human being has “compensatory positive factors” that were developed and maintained during the course of evolution. Why are most studies only investigating the risk factors for poor development and not the positive factors for favorable development? Only in the last 5–10 years, work groups have begun to take both factors into account equally under the strong influence of resilience research.

2.5.2 Unfavorable Versus Favorable Childhood Experiences First, I want to give a concrete example of how bad childhood experiences (ACE, adverse childhood experiences, Table 2.1) can lead to a later dilemma. Girls with hardships in childhood have early menstrual periods and are often pregnant as teenagers. This

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2  What is a Child’s Psychological Trauma?

is an important topic because these teenagers often do not graduate from high school, are disadvantaged throughout their lives, and pass similar behavior on to their own children (Hillis et al. 2010). The working group of Vincent Felitti and Robert Anda wanted to examine whether parallel positive family experiences regarding early unwanted pregnancy in teenage years protect these girls with early traumatic experiences (Hillis et al. 2010). Family/parents/caregivers are important for resilience, as we have seen in Table 2.4. To do this, the authors used a questionnaire in the well-known way, which examined the following positive family factors: family cohesion, family support, family cares for its members, family protects members, family gives self-confidence and mental strength, family members like each other and family cares for the health of members. These questions were examined together with the ACE questions from Table 2.1. The focus was therefore on negative and at the same time compensating positive factors in childhood. In the survey of more than 3500 participants, the risk of a trauma-related early pregnancy was lower in those women with a large number of positive family factors, even if they had previously made bad childhood experiences. In addition, the women with a positive family situation had fewer job problems, less family and financial problems, less intense stress experiences, and outbursts of anger (Hillis et al. 2010). For girls without bad childhood experiences, the positive family factors are unimportant for the frequency of pregnancies during adolescence. This is illustrated in Fig. 2.2. In the years 2015–2018, another questionnaire emerged from resilience research, which was similar to the ACE questionnaire by Vincent Felitti (Table 2.1) (Narayan et al. 2018). The authors called it BCE, which stood for benevolent childhood experiences (Chung et al. 2008). If you look at the factors in Table 2.5, you will see the similarity with the resilience factors from Table 2.4. The first author had a lot of experience with resilience, as she had previously worked with Ann Masten. Similar questionnaires developed in different places (Chung et al. 2008). This provided an opportunity to test the favourable and unfavourable influence factors at the same time. A study of pregnant women demonstrates this possibility. Expectant mothers with previous adversities in childhood did not reveal the typical symptoms of post-traumatic stress disorder and had less stress experiences if they also had positive childhood experiences. The unfavourable experiences were offset by favourable childhood experiences, and pregnancy was less stressful (Narayan et al. 2018). Since stress factors during pregnancy affect the child, favourable childhood experiences can serve both the mother and the unborn child. Similar studies of more than 1200 college students with unfavorable childhood experiences showed how protective factors had positive effects on physical and psychological health on the one hand and social interactions on the other (Powell et al. 2020). Further studies confirm this view (Atzl et al. 2019; Bethell et al. 2019; Crandall et al. 2019). Regardless of abuse in childhood, positive experiences in childhood lead to a lower cardiovascular risk in middle adulthood (54 years) (Slopen et al. 2017).

2.5  Compensating Positive Factors Against Trauma Experiences

31

With bad childhood experiences (+ACE)

50

Frequency of pregnancy during adolescence (%)

Without bad childhood experiences (–ACE) 40

30

20

10

0

0–1

2–3

4–5

5–6

Number of positive family factors in childhood Abb. 2.2   Pregnancy in adolescence. This figure shows the relationship between positive family factors in childhood and the frequency of pregnancies in adolescence. The red bars show the situation with bad childhood experiences and the white columns the constellation without unfavorable childhood experiences.—Abbreviation: ACE, adverse childhood experience (bad childhood experience). The more positive family factors there were in children with trauma (red bars), the less likely it was to become pregnant in young years

Table 2.5  Questions about benevolent childhood experiences (BCE questionnaire) As you grew up (during the first 18 years of your life) • did you have at least one carer (e.g. parents) who made you feel safe? • did you have at least one good friend? • did you feel like you were growing up in a safe environment? • did you like school? • did you have at least one teacher who cared about you? • did you have a pleasant neighbourhood? • was there an adult (not a parent or carer) who could support or advise you (e.g. teacher, mentor, coach, neighbour or friend)? • did you feel that you were living a “good life” overall? • did you like yourself or find yourself pleasant? • were there typical routine activities at home, such as regular meals and a regular bedtime?

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2  What is a Child’s Psychological Trauma?

In another study, an impressively better result was observed with regard to life expectancy in adulthood when children grew up in an environment with a low socioeconomic status (and were disadvantaged as a result), however, a lot was invested in their education, and they achieved a high level of education (Montez and Hayward 2014). In this section we were able to see how favorable experiences in childhood can offset the hardships in the same life phase to some extent. In recent years, in addition to resilience and positive childhood experiences, another favorable aspect has been considered that scientists described with child sensitivity to negative environmental experiences. It’s about orchids and dandelions.

2.5.3 Orchid or Dandelion When scientists look at their data, they often see a large variation. This situation is illustrated in the completely fictional example in Fig. 2.3. The scattering is enormous in the left subfigure, and the scientist does not see any connection between the two variables on the X and Y axes. If it is possible to find an important characteristic or several important characteristics to form two clearly different groups from a single group (Fig. 2.3, middle and left), the previously large variation can be eliminated and relationships between the variables can be observed. However, these things are rare in science, but sometimes there is a big “aha” moment. Thomas Boyce had such an “aha” event. In terms of child trauma, Boyce early on pointed to a different sensitivity of children (Boyce et al. 1977). If an affected person is very sensitive (orchid), the child trauma will have a stronger effect than if the person has a low sensitivity (dandelion). Boyce has defined the feature SENSITIVITY with different criteria, and in this way he was able to divide a total group like in Fig. 2.3 into a subgroup A and B with different sensitivity. In fact, he found clear clinical and laboratory evidence for a different sensitivity (Boyce 2019). Sensitive children reacted much more strongly to stress stimuli than non-sensitive boys and girls, because they showed a stronger stress response in the form of a cortisol release by the adrenal gland and an increased sympathetic reaction with adrenaline release. The two increased reaction patterns are very important for the chronic immune activation that is at the center of the book (Chap. 4). For Boyce, in the 1980s and 1990s, genetic factors were most likely responsible for the different sensitivity. At that time, the focus was on DNA, the genetic substance, with fixed and unchangeable information. At the same time, behavioral genetics experienced a strong boom (Plomin and Colledge 2001). Boyce, Plomin, Belsky suspected genetic variants in the genome that were supposed to make the difference. From father and mother, we each receive a copy of the DNA of a gene, and this copy can differ in some aspects. It is not fundamentally different—no completely different gene product (=protein) is produced—but there are variants that change the function of a protein. In these variants, the

2.5  Compensating Positive Factors Against Trauma Experiences Group A only

Stress (points)

Stress (points)

Group B only

Reaction to stress (points)

Group total = Group A + Group B

33

Stress (points)

Fig. 2.3   Variation in scientific studies between stress and stress reaction. In this example, the relationship between stress on the X axis and stress reaction on the Y axis is shown. All the people studied are represented in a single graph on the far left (total group), and the correlation between the two variables is almost zero. We do not see any connection between stress and stress reaction. If it is possible to distinguish the entire group based on an important characteristic into group A (with characteristic) and group B (without characteristic), the situation can look completely different, as shown in the two other subfigures in the middle and on the right. Now there is a positive linear relationship for group A and a completely reversed, negative linear relationship for group B. Unfortunately, in reality it is not so easy to find a distinguishing characteristic

observers saw the key to explaining different sensitivity at that time. But before investigating a single gene product, twin and adoption studies came first.

2.5.4 Favorable or Unfavorable Genetic Predisposition When the structure of the genetic substance was published by Watson and Crick in 1953, it took almost 50 years to decode the human genome in 2000. The Human Genome Project involved 12 American, 3 German, 2 Japanese, 1 English and 1 Chinese institute, and between 2001 and 2003, the key aspects of the genome were published in the journal Nature (summarized in: U.S. Department of Energy—Office of Science and Office of Biological and Environmental Research 2019). Nevertheless, genetic influences on diseases or behavior were already well known before these important publications. In the field of behavioral genetics, primarily twin studies and adoption studies contributed to findings.

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2  What is a Child’s Psychological Trauma?

2.5.4.1 Phase 1—Twin and Adoption Studies Robert Plomin, whom we already know, wrote the following in an article from 2001 with a retrospective view on 40 years of research (Plomin and Colledge 2001): Many diseases, such as schizophrenia, were explained on the basis of environmental influences only in the 1960s [AU: although it is different]. (…) Even in the 1970s, there was a great controversy in psychology about behavioral genetics. (…) While in the 1980s and especially in the 1990s psychology accepted the genetic influence on individual behavior (…), today any behavior is determined genetically in some way.

I quote Arthur Schopenhauer on the subject of truth (Schopenhauer 1819), “which is only granted a short victory celebration between the two long periods when it is condemned as paradoxical and underestimated as trivial”. This way to truth in behavioral genetics was experienced by twin and adoption researchers like Robert Plomin. In these studies, the study leaders chose the child participants in order to clearly separate genetic from environmental influences. Typically, these are long-term studies in which children are observed for many years or decades. For example, if the researchers looked at identical twins, these children had a 100% match of their genes. If they grow up with their own parents and differ later in their adolescence or adulthood in their individual behavior, this is due to the environmental share that they did not experience at the same time (this is called non-shared environment). These environmental influences may have been exerted, for example, in kindergarten, at school, in everyday life, or in different circles of friends, etc. (Plomin 2018). In contrast, when the researchers looked at genetically different adoptees who grew up in the same family with genetically unrelated parents, they were able to make a statement about the identical environmental influence of this family. You can imagine how further comparison groups can be formed (e.g. identical twins who grow up in separate families and are brought together later, etc.), and in fact the studies with twins and adoptees are very sophisticated and well thought out (Plomin 2018). The results from these studies are based on a solid foundation because thousands of children were included in these analyses. Under such circumstances, positive and negative influence variables could be worked out that have a positive or negative effect on behavior. For example, parents may prefer one child and negatively influence the other child. The favored are later prosocial and sympathetic, whereas the disadvantaged are often antisocial and depressed (Neiderhiser et al. 1999). In this way, parents can act in a compensatory or divisive way, and thus attenuate or amplify a childhood trauma. With these experiences of twins or adoptees, no statements can be made about individual genes because these things were not investigated. However, the statements of behavioral geneticists are very clear due to the large epidemiological approach with many children (Plomin 2018). Plomin says: “50% of behavior is inherited when considering different dimensions.” The consideration of individual genes could only be carried out after their systematic discovery, starting in the late 1990s. The consideration of gene

2.5  Compensating Positive Factors Against Trauma Experiences

35

variants experienced a strong upswing with the publication of the human genome at the beginning of the 2000s.

2.5.4.2 Phase 2—The Candidate Genes In the early phase of this research approach (1990s and 2000s), certain genes identified as candidates were chosen because they fit well to a disease mechanism or to a behavior for biological reasons. The candidates were biologically plausible. The most important candidate genes that fit to behavioral aspects are summarized in Table 2.6, and the meaning of the respective factor is listed there. Often, the receptors for neurotransmitters or hormones came into the center of investigations. In part, their transport proteins were considered, which are important for the uptake of neurotransmitters or hormones into cells. In addition to the neurotransmitter candidates that are associated with brain performance, the scientists examined hormonal factors from the area of cortisol ​​ control and cortisol action. Cortisol is the stress hormone of the adrenal gland. In the brain, a cascade is set in motion by psychological stress, which begins in the hypothalamus with corticotropin-releasing hormone (CRH), which in turn releases adrenocorticotropic hormone (ACTH) from the pituitary gland, which stimulates cortisol from the adrenal glands. Cortisol inhibits its own release by a negative feedback mechanism at the level of the hypothalamus (blockade of CRH) and at the level of the pituitary gland (blockade of ACTH). This hormone axis was called the HPA axis (hypothalamus, pituitary gland, adrenal gland), at the end is the hormone cortisol, which in turn has a inhibitory effect on the other hormones (negative feedback). The feedback is important because otherwise an excessive cortisol level would damage the brain and the rest of the body (inhibition of brain function and negative influence on the immune system). A high activity of the HPA axis has often been related to depression and anxiety disorders, because the lack of negative feedback does not lead to an inhibition of CRH in the hypothalamus, therefore cortisol remains constantly elevated and thus causes follow-up problems (Dwyer et al. 2020). The matter will be picked up in more detail below. The first significant study of these candidate genes in the context of childhood adversity from Table 2.6 appeared in the scientific journal Science in 2003 (Caspi et al. 2003). There the serotonin transporter from Table 2.6 (top) was examined in more detail for the first time. But there is a history to it, which is briefly summarized in the explanation 3 together with the results. The variant of the serotonin transporter was a big thing at the beginning, a fantastic find, an egg of Columbus. If scientists believe they have found something great, the ravages of time often damage the results because there are always other scientifically active groups that confirm or refute things. This is good scientific practice, which often seems strange to the lay observer. Our virologists have demonstrated this in the corona crisis because the statements depended on and changed with new studies. The confirmation/refutation is a ­necessary

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Table 2.6  Candidate genes*, which were chosen for the studies Candidate genes (observable changes)

Significance with biological plausibility

Neurotransmitters Serotonin transporter (with lower serotonin function)

Serotonin is an important neurotransmitter that is significant in depression. Less released serotonin means more depression.

Monoamine oxidase type A (with low or high activity)

Important enzyme that breaks down serotonin, noradrenaline, and dopamine. Little released serotonin and noradrenaline means more depression. Too much noradrenaline means aggression.

Catechol-O-methyltransferase (with low or high activity)

Important enzyme that breaks down noradrenaline, adrenaline, and dopamine. Little released noradrenaline means more depression. Too much noradrenaline means aggression.

Dopamine transporter (with lower dopamine function)

Dopamine is an important neurotransmitter that is important for reward behavior, motivation, and attention. A lot of dopamine released means high attention, motivation, and reward experience. Little of this neurotransmitter makes the opposite.

Dopamine receptor type D2 Dopamine is an important neurotransmitter that plays a role (with lower dopamine function) in reward behavior, motivation, and attention. Little dopamine action means less of these functions. Dopamine receptor type D4 Dopamine is an important neurotransmitter, is relevant to (with lower dopamine function) reward behavior, motivation and attention. Less dopamine action means less of these functions. Nerve growth factors BDNF (with lower function)

BDNF is an important nerve growth and survival factor for nerve cells. A reduced function would lead to disturbances of nerve growth and survival—with the consequence of nerve cell death.

Hormones CRH receptor (with increased activity)

CRH releases adrenocorticotropic hormone (ACTH) from the pituitary, which in turn stimulates cortisol from the adrenal glands. Much CRH function means high cortisol. Too much cortisol is unfavorable because it contributes to depression, anxiety disorders and brain dysfunction and negatively affects the immune system.

Glucocorticoid receptor (with high or low sensitivity to cortisol)

The glucocorticoid receptor is the receptor for the stress hormone cortisol of the adrenal glands. If there is a low function, the negative feedback is low and more cortisol is released (and vice versa with strong function). Too much cortisol is unfavorable because it contributes to depression, anxiety disorders and brain dysfunction and negatively affects the immune system. (continued)

2.5  Compensating Positive Factors Against Trauma Experiences

37

Table 2.6   (continued)

Candidate genes (observable changes)

Significance with biological plausibility

FK506 binding protein 5–1 (FKBP51) (with low or high amount)

Cortisol must bind to a cortisol receptor in the cell for its effect, which is composed of various subunits. FKBP51 is part of the complex of the cortisol receptor and is decisive for its effect in the cell. If a lot of FKBP51 is present in the cell, cortisol is less effective (and vice versa if there is less FKBP51).

Oxytocin receptor (with low or high function)

Oxytocin is a hormone that initiates the birthing process and activates the milk glands. In addition, it has a supportive role in the relationship between mother and child, the sexual partners and in the interaction between people. If a lot of oxytocin is present, these things are more pronounced (and vice versa if there is less oxytocin).

*From (Strauss et al. 2004; Bakermans-Kranenburg and van Ijzendoorn 2011; McQuaid et al. 2013; Zhang and Belsky 2020). Abbreviations: BDNF, brain-derived neurotrophic factor; CRH, corticotropin-releasing hormone.

process that only stabilizes a result when it has been confirmed many times. The observers must be very patient until something is confirmed, and many do not have this patience. If the politician has a legislative period of 4 or 5 years ahead of him, he necessarily has less patience, which is why science and the promotion of science must be kept out of the usual time frame of a legislative period. Those who do not understand this damage science. Explanation 3: Serotonin Transporter, Childhood Trauma and Depression

At scientific congresses, a few chosen ones are allowed to give a presentation, most only show a poster with contents of their own research work. The poster is typically attached to a display board. At certain times, interested scientists gather in front of this poster. Being chosen as a speaker does not have to be an advantage. The interaction with other scientists is much better at the poster than around a lecture, because only the truly interested meet at the poster. I found my best friends at posters and hardly after lectures. The lecturer, however, floats on a cloud and doesn’t really find any contact with the audience, even if listeners come to the lectern after the lecture. I know both perspectives and summarize: The egocentric concentration on the lecture blocks the social interaction that is possible at the poster. This type of happy, poster-dependent contact took place with the later couple of Avshalom Caspi from a kibbutz in the Negev desert in Israel and Terrie Moffitt from North Carolina. The two newly minted doctors had a scientific poster side by side in St. Louis in 1987. Today they are two widely known psychologists who deal with the influence of genes on behavior and who also take into account the influence of environmental factors.

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In the 1990s, they started these considerations together with a New Zealand group from Dunedin and an English team at King’s College in London (Caspi et al. 2003). But how did it come about? In 1972–1973, Phil Silva from New Zealand examined 1037 children who were born in a certain hospital in Dunedin. After the initial examination, he and the further team followed the history of the children at regular intervals at the ages of 3, 5, 7, 9, 11, 13, 15, 18, 21 and 26. The examined group remained constant in the relatively isolated Dunedin, as 96% of the original group was still available at the age of 26. This is a highlight of a longitudinal study that was highly interesting for Caspi and Moffitt and others. In a study, Caspi, Moffitt and colleagues then showed how the rate of depressive episodes and suicidal thoughts increased with the number of early traumatic experiences. It increased especially in those who had a serotonin transporter with less serotonin function. Since serotonin is an important “mood-enhancing” neurotransmitter, less serotonin released from the nerve cell means more depression. This was the first study to show a link between a gene and an environmental factor in the field of childhood trauma. ◄ Back to the candidate gene of the serotonin transporter by Caspi and Moffitt (explanation 3), which was put to a 10-year patience test. Despite numerous attempts at repetition, some studies were unable to reproduce the same effect. Sometimes the study leaders observed no or even opposite results! In so-called meta-analysis, which summarizes many studies on the same subject, the matter remained unclear and led to considerable criticism of the investigation of individual candidate genes (Manuck and McCaffery 2014; Sharpley et al. 2014; Plomin 2018; Zhang and Belsky 2020). This is true for all of the factors listed in Table 2.6, which went through a similar history. There are no clear relationships between a gene variant and adverse childhood experiences, both of which influence a later health problem in adulthood, for the large number of affected individuals (Plomin 2018). However, there may well be candidate genes that are essential for a certain disease or for a particular behavior. There are examples of this with the so-called monogenic diseases. A genetic change with a deficiency of the monoamine oxidase type A mentioned in Table 2.6, for example, leads to aggressive and autistic behavior with more frequent crime (Brunner syndrome) (Kniffin and McKusick 2018). This is a clear connection between a single gene and a behavior. In most cases, more than just one gene is behind complex behavior. Many genetic factors influence behavior (Plomin 2018) or, in the sense of Boyce, sensitivity (orchids versus dandelions), which is why the search for the sole genetic factor is always difficult. This knowledge has now become more and more established, which is why the people in this research landscape use two other methods that take into account the combination of several genes (Plomin 2018). These are described in the next subchapters as phases 3 and 4. Phase 3 describes the candidate approach with a hypothesis and phase 4 the hypothesis-free genome-wide human approach.

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2.5.4.3 Phase 3—Combination of Candidate Genes If you look at Table 2.6, you will get the idea of how to combine several gene variants in a combined risk factor. If a child with adverse living conditions has several unfavorable gene variants at the same time, it has a high combined risk of suffering from an unfavorable consequence later in life. Or, conversely: A person can be protected if he or she has several compensating factors (=protective gene variants) at the same time. With the genes mentioned in Table 2.6, polygenic risk measures have been developed and applied (Belsky and Beaver 2011; Davies et al. 2020; Huang und Starr 2020; Starr et al. 2020; Zhang und Belsky 2020). As has already been done with the candidate genes, there are now the first meta-analyses for the polygenic risk measures. The matter has been more successful here than with the meta-analyses of individual candidate genes. For example, if we look at several genes that regulate the amount of the neurotransmitter dopamine in the brain, those traumatized persons with a low polygenic risk have a favorable development course (Bakermans-Kranenburg and van Ijzendoorn 2011). Certainly, it is more promising to combine several gene variants than to look at a single candidate gene. For this, those gene variants have to be examined in combination for which there is a biological plausibility. By this I mean the combination of gene variants in a cumulative risk factor, which contribute to a common biological function with a corresponding phenotype such as aggression (lots of noradrenaline) or depression (little noradrenaline or little serotonin) (Zhang und Belsky 2020). In addition to this approach, there is another way of investigation that is not initially directed at any biological plausibility, but which will be the most promising of all. By this I mean the hypothesis-free human genome-wide association studies. 2.5.4.4 Phase 4—Human Genome-Wide Association Studies While decoding the human genome in the 1990s, human genome-wide association studies were designed. In these studies, thousands of people with a certain disease on one side are compared with healthy control persons on the other side with regard to thousands of gene variants across the entire genome—hence the term “human genome-wide”. Here the researchers examined all gene variants of the two groups without a specific hypothesis, which was possible after the development of corresponding powerful techniques for the analysis of many genes. With these association studies, individual gene variations can be found completely without hypothesis, which are significantly associated with a disease. The first preliminary study of this kind dates back to 1994 in patients with psoriasis (Tomfohrde et al. 1994). Psychiatrists were very quick in this respect, and as early as 1995 an international group found the first risk genes for schizophrenia (Moises et al. 1995). Whether these first, non-hypothesis-based, human genome-wide studies were useful in the further course was examined 20 years later by means of meta-analyses, and I can take it in advance: Not all found gene variants were confirmed, but many were very useful. Further hypothesis-free gene search took place for the following diseases:

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inflammatory bowel diseases, diabetes mellitus, obesity, heart attack, macular degeneration, rheumatoid arthritis, prostate cancer, schizophrenia, depression and many more. Here, there were partly fantastic new findings, which brought us very many important insights into the pathogenesis and cause of the disease. In neuroscience, the focus was first on diseases of psychiatry (depression, schizophrenia, anxiety disorders and bipolar disorders) and neurology (Parkinson, Alzheimer, epilepsy) and less on behavior, disturbed behavior or stress sensitivity in the sense of orchids and dandelions by Thomas Boyce. The patients’ diseases from psychiatry and neurology were better definable, at least the doctors believed. The investigation of behavior is difficult because it depends on many influencing variables and diagnostic tests, which are not always uniform and clear. The definition of prostate cancer is much more clear. Therefore, it took a long time in this field of behavioral research for the first useful human genome-wide association studies on the sensitivity of children to appear. A first survey brought together childhood trauma and later depression. The study consisted of several parts. In a first step, typical risk variants for depression were defined in the context of a human genome-wide association study with more than 15,000 people. In a second step, on the basis of the found genetic variants, the researchers formed a polygenic risk score. In a third step, they found the following after the analysis. If an unfavorable polygenic risk score was present, those children with a traumatic experience in their young years had a much higher probability of later suffering from depression than those children with a favorable risk score and traumatic experiences. In other words, there are compensating factors (=favorable genetic variants) that make the occurrence of depression less likely despite a bad childhood experience (Peyrot et al. 2014; Colodro-Conde et al. 2018). These are the predicted sensitivity factors that are decisive for orchids and dandelions. Whether the polygenic risk score was oriented towards a biological plausibility was not important, because the approach was initially hypothesis-free. The genetic variants found in this way were often provided with a biological function by other working groups only in the course of further research work, and biological plausibility post hoc shows up. This is painstaking work that can take many years (e.g. Straub et al. 2018; Straub et al. 2021). In another genome-wide study, the authors examined 1026 identical twins (Keers et al. 2016). The twins had a different degree of anxiety (=phenotype). With the help of this phenotypic difference between the twins, a human genome-wide association study was carried out, which defined a polygenic risk score for anxiety. Now the authors examined a further group of 1406 children in a second step, in which they related the parental education, the newly found polygenic risk score and the emotional problems of the children. Here the polygenic risk score was able to make a prediction between unfavorable education and emotional problems. In a third approach, the same authors examined whether the polygenic risk score could predict whether cognitive behavioral therapy is effective in children with negative emotions. In fact, those children with a high risk score benefited most from the

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individual therapy. Those traumatized and at-risk children—the orchids—achieved the highest gain after an improvement in environmental conditions through individual therapy. The dandelions with a low risk score did not benefit and were not as emotionally affected (Keers et al. 2016). Fortunately, this work could be repeated with a corresponding study approach with a similar result by other authors (Lemery-Chalfant et al. 2018). At this point we now recognize the risk variants that make children sensitive like orchids or insensitive like dandelions. This is a wonderful discovery because we can diagnose and treat sensitive children to put them on a better path in life. It looks like those highly sensitive children would benefit most from the therapy methods. However, these therapy studies require further confirmation. In addition to the pure psychological/psychiatric meaning, candidate genes (phase 2), combined consideration of several candidate genes (phase 3) and combined genetic variants from genome-wide association studies (phase 4) can give us clues why the at-risk individuals have a more active immune system that can contribute to chronic inflammation (more on this later). In addition, the findings from the four phases of genetics can be used to better classify and plausibly approach epigenetic questions.

2.5.5 Favorable or Unfavorable Epigenetic Changes The term epigenetics I have already illuminated in explanation 1. If the scientist speaks of an epigenetic change, he means a subsequent modification of genes or gene-related sections of DNA or of DNA packaging proteins, without changing the sequence of DNA building blocks. Although biologists have known such epigenetic principles since the 1960s (McClintock 1961; Allfrey et al. 1964), the phenomenon only came into focus of the broader biomedical science from the 2000s onwards. Starting around 2010, studies with epigenetic content are now being published regularly. This environmentally induced modification of the reading of genes leads to an increase or inhibition of intracellular protein production, and this principle is by no means engraved in DNA. The image of the engraving is appropriate because after the production of the material (DNA like metals, stone or glass), subsequent changes (chemical groups like ornaments, writings and decorations) can be added. This subsequent influence on gene reading came into the focus of new research interests. The phenomenon helped to understand how environmental influences can cause long-term changes to genes and thus functions. The emphasis is here on longterm, because they can be passed on from generation to generation (more on this in the Sect. 2.7). Such a platform was necessary because people needed an explanation for why there are more than 200 different cell types in the body, even though all cells have the same set of genes. If all the cells have the same genetic starting point, why are there 200 different cell types? Shouldn’t they all look the same? No, because cells develop depending on their internal autonomous and external conditions—that is, through the “local environmental influences” in the neighborhood of

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the cells—in one direction or the other, namely from fertilization of the egg cell. This was already the topic of Hans Spemann (1869–1941) in his experiments with amphibians, when he was able to prove how tissue transplanted early in embryonic development behaved in a location-specific manner. The neighborhood influences create epigenetic changes that lead to the reading of a certain set of genes, but not to the simultaneous reading of all genes. In this way, cell diversity can arise. Epigenetic modification is the starting point for plasticity (malleability), which allows adaptation to environmental conditions. Others spoke of programming (Barker 1998), when it came to early influence in the uterus (embryonic and/or fetal), around birth (perinatal) or in childhood and adolescence. Today we recognize the importance of early years in the process of development of a living being, in which this programming is the origin of health and disease (developmental origin of health and disease, e.g. Barker 1998, 2007; Gabory et al. 2011; Rinaudo and Wang 2012; Breton 2013; Hanson and Gluckman 2014, 2015). I subscribe to this idea of early programming. It is taken up again in the Sect. 2.8. These long-term effective epigenetic influences are important for the malleability of the brain and the immune system. But which genes are epigenetically modified?

2.5.5.1 Phase A—The Candidate Genes are Epigenetically Modified Above, we had mentioned the candidate genes when we spoke of the different sensitivities of orchids and dandelions (Table 2.6). However, variations in the candidate genes were not well coupled with this sensitivity, although early studies in the 2000s suggested this connection (Caspi et al. 2003). Meta-analyses of many studies brought the exclusive consideration of individual candidate genes into difficulty, and therefore modern researchers turned to polygenic risk measures or whole-genome considerations (Phase 3 and 4). The friends of epigenetics went a similar way because they first included the candidate genes in their considerations. Indeed, most of the candidate genes in Table 2.6 were checked to see if there were epigenetic changes (Park et al. 2019). For this purpose, typically leukocytes or lymphocytes from blood or DNA samples from saliva were tested. In fact, the researchers identify epigenetic markers in these peripheral blood leukocytes, for example in the gene of the glucocorticoid receptor, the FKBP51, the serotonin transporter and the nerve growth factor BDNF, all factors from Table 2.6. For these genes, an increased methylation of susceptible DNA sections is observed (Park et al. 2019), which reduces the readability of the genes (methylation see explanation 1). Consider Table 2.6 again and you will recognize what the reduced or increased function means. The reduced function can be unfavorable and contribute to depression. Others showed demethylations at other sections of the same genes—that is, the removal of methyl groups (see explanation 1)—as a result of traumatic life circumstances, which can also have unfavorable effects (Klengel et al. 2013). Whether methylation or demethylation is important remains very vague for one or the other gene. Here, there are only

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relatively few basic research studies that show the way to the goal in a causal sense. With regard to the transfer of all these results to humans, there is a catch. If the telescope is aimed at depression or other psychopathological states in adulthood after previous childhood traumas, it is surprising when one looks at the conditions in white blood cells or in the DNA from saliva (Thompson et al. 2013; Park et al. 2019; Szyf 2019). We learned that epigenetic differences are relevant for the differentiation of cell types. Wouldn’t the doctors rather have to examine local material from brain areas that are directly related to the respective psychopathology? Difficult, if not impossible, because the researchers do not have easy access to brain material for ethical reasons. Here, studies on human brains can help, which were removed from deceased persons. Some groups have actually done this, but the number of cases is very small (Lutz et al. 2017). Furthermore, animal experiments can lead to success because tissue can be removed at will (Jensen Peña et al. 2012; Schraut et al. 2014; Wu et al. 2014; Massart et al. 2016; Cao-Lei et al. 2017). Due to the short time period since the start of epigenetic surveys, the number of studies on candidate genes is small. The first meta-analyses do exist, but we do not yet have a final picture of the epigenetic changes of the candidate genes. Certainly we need a comprehensive view of many genes, as is done in a polygenic approach (see phases 3 and 4 in the previous subchapter). In any case, the removal of DNA from leukocytes and saliva is problematic for this question. The study of leukocytes can lead us to another important clue, namely chronic immune activation (which will be reported below). The studies on children with trauma say the following for the moment: Instead of the favorable epigenetic changes, the unfavorable modifications are observed. Conversely, if a child is resistant to the methylations of the critical candidate genes, it has a compensating positive factor in terms of the subchapter heading. A child thus protected may be a dandelion.

2.5.5.2 Phase B—Polygenic Approaches in Epigenetics For this approach, the observers need, as in the human genome-wide association studies for gene variants, a human genome-wide investigation of the methylations of gene sections. Methylation was an important aspect of epigenetic change that leads to the inhibition of gene reading (explanation 1). In fact, corresponding tools have been developed with which the scientists can investigate the methylations of many gene sections on a large scale (Bibikova et al. 2006; Bibikova et al. 2011). The second important aspect of epigenetic regulation, acetylation (explanation 1), is, however, much less in focus because assignment to a defined gene are more difficult to obtain. In addition, the first studies already appeared in 2011, which applied the technique to a small number of abused children (Naumova et al. 2012; Yang et al. 2013; Cicchetti et al. 2016). However, the interpretability of these small surveys is still low. More recent studies were carried out on a maximum of 200–300 people, but unfortunately the value is still unclear because leukocytes were used as a source of DNA again. I summarize: In these human genome-wide methylation studies there are no really hard data so far.

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In addition, the other possibilities of epigenetic influence (e.g. acetylation, explanation 1) would have to be considered in parallel.

2.5.5.3 Summary—Epigenetics The first meta-analyses of candidate genes show positive relationships between methylation at certain gene loci on the one hand and childhood maltreatment on the other (Phase A). The current findings point to a promotion of circumstances that favor depression in adulthood. This research approach is relatively new, and we are all eagerly awaiting basic research that includes an adequate number of affected individuals and goes beyond mere associative considerations. Important methodological considerations include, for example, the analysis of the right cell material. In the end, epigenetics will shed new light on the connection between childhood trauma and later diseases in adulthood. Epigenetics offers explanations of how early childhood episodes stimulate long-term biological changes.

2.6 Child Disadvantages and Steeling Effects In the previous chapters, we met important compensating positive factors that protect the affected with early traumatic experiences from consequences. We wonder if these positive factors must be stimulated by adversity, if resilience must be induced, if epigenetically not only the bad, but also the good things are set in motion. Thus, some scientists assume a steeling effect induced by adverse childhood experiences. Others call such a form of induced insensitivity to adversity “stress vaccination”. The proponents of the theory speak of a kind of vaccination, in which an early administration of the unfavorable factor generates psychological resistance in later life. In case-reports, preferably in competitive sports, among creative artists and people with outstanding performance, early traumatic experiences are repeatedly brought together with a favorable course in later life (Joseph and Linley 2006; Seery et al. 2010a; Shrira et al. 2010; Cheng et al. 2015; Damian und Simonton 2015; Mittal et al. 2015; Sarkar et al. 2015; Standing et al. 2015; Simonton 2016; Sarkar und Fletcher 2017; Thomson und Jaque 2018). Steve Jobs, the founder of Apple, is a good example. Another impressive model is Édith Piaf, the very successful French chanson singer in the 1950s, etc. In recent studies, so-called bell-shaped curves have been found, which correspond to those in Fig. 2.4. A Swiss working group examined 270 older people with different numbers of adverse childhood experiences (Höltge et al. 2019). Approximately 8–9 unfavorable childhood experiences were associated with optimal quality of life and best possible mental health. Zero or few bad experiences are associated with lower quality of life and poorer mental health. On the other hand, too many early traumatic experiences are bad for both quality of life and mental health (right in Fig. 2.4) (Höltge et al. 2019). Here we enter the field of psychopathology, which we will discuss in more detail later in the

2.6  Child Disadvantages and Steeling Effects

b

Mental health

Individual quality of life

a

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Number of bad childhood experiences

Number of bad childhood experiences

Fig. 2.4   Steeling effect, stress vaccination. This schematic figure shows the relationship between the cumulative number of adverse childhood experiences on the one hand and quality of life (a) or mental health (b) on the other. The blue and red function resembles a bell-shaped curve (shape of a bell). The vertical line shows the mean number of adverse childhood experiences for the entire group of subjects. That is where the optimal range lies. In the literature, the average number of childhood traumatic experiences is not always 8–9, as in this example. Depending on the measuring method, depending on the trauma experiences queried, depending on the age of the examined and depending on the culture, the location of the optimal range is different. Elsewhere, I identified the number 4 as the critical unfavorable number when investigators used the Felitti questionnaire of Tab. 2.1. The information comes from Höltge et al. (2019)

book. These studies support the idea of stress vaccination, but the number of subjects is small. There it is again, the bell-shaped curve, which I had reported on extensively in my last book on memory (Straub 2020). A bell-shaped curve occurs when a variable represents a favorable response and is plotted as the Y coordinate, and higher values indicate ​​ a more favorable result (see Fig. 2.4). Inversely, U-curves arise when higher values on the Y-axis show an unfavorable result. Bell-shaped curves or U-curves always occur when there are optimum ranges, and optimum ranges are often the result of a balanced development during the course of evolution (Sect. 2.8). Further studies by other groups confirm the bell-shaped curve or the U-curve (Edge et al. 2009; Seery et al. 2010a, b; Howell and Sanchez 2011; Boyce 2016; Shakiba et al. 2020). In another impressive example, the steeling effect of previous traumatic experiences in childhood is shown. You may remember the tsunami of March 11, 2011 in the Fukushima region, which led to a nuclear disaster in the local nuclear power plant Fukushima-Daiichi and to the nuclear power plant shutdown promise of Chancellor Merkel in Germany. This tsunami, caused by the Tōhoku earthquake of magnitude 7,

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not only devastated the nuclear power plant, but also other regions of the Fukushima and Miyagi prefectures, for example the 2 million city of Iwanuma. The death rate was 2% of the population, and the devastation was enormous with a flooding rate of 48% of the total area. In the Tamaura district, 68% of the houses were completely or partially destroyed. Such events often provide an opportunity to study the stress response of the affected residents, which was done in Iwanuma with 580 participants over the age of 65 in a large-scale study (Inoue et al. 2019). Natural disasters can trigger post-traumatic stress disorder, and this was related to these old people’s unfavorable childhood experiences. The tsunami triggered post-traumatic stress in 56 people, 524 showed no such signs. Triggers for post-traumatic stress disorder were the destruction of the house, the loss of a relative or the death of people from the circle of friends. A total of 40% of the respondents had no traumatic childhood experiences, 39% remembered a negative episode, and 21% reported two or more events. The participants remembered things like economic hardship, the loss of a parent, the divorce of their parents, paternal violence against their mother, physical punishment of themselves, and emotional abuse (insults). Thus, similar to what we know from the ACE questionnaire from Table 2.1. If unfavorable childhood experiences are protective in the sense of steeling, those people without childhood experiences should suffer from post-traumatic stress disorder more often than those with early childhood trauma. This is exactly the result of the Japanese tsunami study, because only in participants without a childhood trauma did the devastation of the tsunami trigger a post-traumatic stress disorder (Inoue et al. 2019). In this study, no search was made for a bell-shaped or U-shaped relationship between the number of childhood adversities and post-traumatic stress disorder. Should children therefore be deliberately burdened for the purpose of steeling effects? Disgusting idea! However, this has happened again and again over the centuries in various cultures. The already reported example of the Masai in the subchapter Resilience shows in the same direction. However, we know a clear connection between childhood trauma and psychopathological sequelae such as depression, anxiety disorders, post-traumatic stress disorder, and many other physical problems such as cardiovascular diseases, diabetes mellitus, tooth problems, etc. How would we know in targeted steeling attempts of our children where to set the limit of adversity? The connection between childhood trauma and the occurrence of post-traumatic stress disorder after deployment in a crisis area has been investigated in soldiers. After a war deployment, people are more at risk if they experienced childhood trauma (Pratchett and Yehuda 2011). Where is the steeling effect here, the stress vaccination? Where is the bell-shaped curve here? Such steeling attempts or stress vaccinations are dangerous because you do not know which child you have in front of you. Finally, we must remember the remarks of Thomas Boyce, who described sensitive Orchids and robust Dandelions. The properties of the two types depend on genetic traits. In natural disasters, Dandelions may fairly well survive, while Orchids suffer. The discussion of “steeling by adversity” without considering the genetically/epigenetically

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determined sensitivity of those affected is one-sided, misleading and dangerous. It could, for example, incite researchers to expose all children to a program of moderate adversity without regard to their sensitivity, in order to vaccinate them against stress. We have had such programs in Germany before (Reichsarbeitsdienst, youth organizations in the National Socialism), but we certainly do not want them back. So what do we learn from this subchapter? The phenomenon of steeling or stress vaccination exists, but we by no means know how a researcher can implement this principle in a meaningful way with which child using which methods. For ethical and legal reasons, experiments on children using systematically applied adversity fortunately are prohibited anyway.

2.7 Transmission of Behavior from Generation to Generation Sometimes investigators find psychological abnormalities in grandparents, parents, children, etc. over several generations. They may be favorable and positive or unfavorable and negative, if you think, for example, of creativity and tolerance or addiction and psychopathology. Obviously, behavior is passed on from one generation to the next.

2.7.1 Genetic Transmission Remember the statement of Robert Plomin, who classified the degree of heritability of behavior at 50%. So it’s no wonder that there is a transmission of behavior. If on average 50% of behavior is passed on genetically to the next generation, we can infer in return an environmental share of also 50%. Plomin recognizes after many population-based studies, which have a high degree of validity, that these environmental influences are largely independent of the family (Plomin 2018). Who would have expected that? Plomin explains how children with the same family environment are different because they make decisive experiences outside the family (non-shared environment). Usually we think here of experiences elsewhere, in daycare centers, kindergarten, primary schools, secondary schools, peer groups, sports clubs, with friends and partners, in the job, etc. However, it has so far been difficult to define such factors outside the family well (Plomin 2018). Individual randomly appearing experiences set the course in one direction or the other. I can remember events of this kind that changed me a lot because they were nodes in my life path (e.g. explanation 4). Nodes are present when, at a time (node), there are at least two possible life paths and a backward movement is not possible. Plomin also says: “We would be just as similar to our parents and siblings (50% genetically determined) whether we grew up in our own family or were adopted by another genetically foreign family.” This is the case if both families have a normal—that is, average—form of education without severe childhood traumas. Plomin focuses on the totality of all children (therefore population-based).

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However, there are a few exceptions among the many behavior characteristics studied, where family is significant, namely in religiosity, political views, intelligence and school performance, where the shared environment in a family is only responsible for 10–20% and decreases significantly with age (Plomin 2018). For example, with intelligence and performance, the non-genetic familial influence disappears completely after the 20th year of life. For most of the behavior characteristics studied, the non-genetic family share is insignificant. Explanation 4: Randomly occurring events

Randomly occurring experiences from the environment sustainably influence behavior, as I once experienced. In December 1972, FC Freiburg had to play at home against Borussia Mönchengladbach in the soccer cup competition. You remember: Berti Vogts, Günther Netzer, Jupp Heynckes, Rainer Bonhof, Herbert Wimmer and Co. That was a big sensation for me, because FC Freiburg was only in the southern regional league and not significant nationwide. In order to be able to see this football game, I wanted to go to the ticket office, but unfortunately I fell so badly with the bicycle and got a kidney contusion. The urine was bloody—into the clinic. In the early 1970s, there were no ultrasound examinations, and so during one night I was monitored hourly by measuring the waist circumference on the surgical intensive care unit of the University Hospital Freiburg. If the waist circumference had increased by a certain percentage, the doctors would have operated immediately. Although this did not happen, I experienced a longer hospital stay with lasting effects: 1. I had to repeat the grade because of the long sick leave and the resulting poor performance. 2. This episode impressed me intensely, because it promoted the decision in my 13th year of life to become a doctor in order to be able to help in the same way. A lot depended on these decisions, because they led to a different life, the life of a doctor and later a scientist (there were other nodes for the direction of science). By the way: FC Freiburg won 3–1 against Mönchengladbach without me, lost 7–1 in the return leg, and Mönchengladbach was able to continue. That was not a node for the FC Freiburg. ◄

2.7.2 Epigenetic Transmission In addition to the purely genetically determined transmission we know another form of transmission. I have made an example of this with the sentences to David Barker (Barker et al. 1989). You may remember: Children with low birth weight have a significantly higher risk of later heart attack. Since newborns were already affected, Barker and his team were finally able to point to a possible problem in the uterus during pregnancy (Barker et al. 1989). The nutritional situation in the uterus sensitized people in old age to heart attacks, strokes, hypertension, age-related diabetes and for childhood infectious

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respiratory diseases (Barker et al. 1993). The “Barker phenomenon” clearly points to epigenetic changes in the child during the time in the uterus (explanation 1). Such epigenetic changes can be passed on from generation to generation. Various ways of passing from generation F0 to F1, F1 to F2, F2 to F3, etc. have been described, which are either called intergenerational (F0-F2) or transgenerational (from F3 onwards) (Fig. 2.5) (Heard and Martienssen 2014). The inheritance can only take place if the DNA of the germ cells undergoes an epigenetic change, because only then can the information be passed on to the next generation via either the oocyte or the sperm. Some called this process a re-programming of the germline, because the germ cells are influenced (Heard and Martienssen 2014). Practically, this often happens in plants, and so an epigenetic trait can be maintained over generations and hundreds of years (Cubas et al. 1999). With animals, it has rarely been observed over a longer period in the sense of transgenerational transmission in Fig. 2.5, for example with the nematode (C. elegans) (Heard and Martienssen 2014). If we can only currently surmise the situation with humans, intergenerational transmission as in the “Barker phenomenon” from the first section is relevant. Whether there is transgenerational transmission over several generations in humans is unlikely (Heard and Martienssen 2014), because after the fusion of the germ cells, a complete demethylation takes place—so to speak a “reset” (Heard and Martienssen 2014). If the methylations are important for epigenetic transmission, the reset is necessarily linked to the deletion of epigenetic markers. The bypassing of a reset has not been described in humans so far. You certainly remember Jean-Baptiste Lamarck (1744–1829), who at the end of the 18th century founded the lamarckism. He said: If the organism uses an organ frequently, it will be strengthened, developed and enlarged, whereas non-use leads to atrophy. According to Lamarck, this is the “inheritance of acquired traits”. They are acquired because they are used intentionally. Lamarck speculated how giraffes, in order to feed, intentionally stretched their necks to high leaves and, because of this desired process, got long necks over the course of evolutionary history. Darwin’s theory of evolution tells us something different: For random reasons (mutations in the genome), a giraffe got a longer neck, and because this was favorable for eating high leaves and for survival and reproduction, this long-necked giraffe was positively selected. The information for this feature was retained in the giraffe’s genome over the course of evolutionary history. This is the inheritance of a trait not caused by intentional action. After Darwin, Lamarckism was pushed back (exception in the Soviet Union in communist times under the Soviet agronomist Trofim Denissowitsch Lyssenko, because he taught how desired traits could be passed on to the next generation; this fit in with the planned economy in communism). With the information we have received in the last decades in the field of epigenetics, Lamarckism is experiencing a kind of rebirth. Lamarckism and Darwinism exist side by side. As Fig. 2.5 shows, a noxa can lead to an epigenetic modification of the DNA, and this change can be transmitted to the offspring generation. And as with the giraffes that want to reach the high leaves lamarckistically intentionally, this noxa could

50 Fig. 2.5   Inter- and transgenerational inheritance of epigenetic information. In generation F0, an epigenetic change can occur in the DNA of the germ cells of F0 and in the DNA of the germ cells of an unborn child F1 through an influence such as stress, toxins, nutrition, smoking, alcohol, etc. F1 then passes on this epigenetic change and becomes pregnant. Since the germ cells of F2 are already laid down in F1 during the pregnancy of F0 with F1, the epigenetic change in F1 is already taken over by F2. Up to this point, scientists speak of intergenerational inheritance of the trait.—From generation F3, scientists speak of a true transgenerational inheritance of the trait if F3 was not exposed to the above-mentioned influence at any time.—The offspring generation F2 does not pass the epigenetic change on to F3 in most cases. If this did happen, it is very often not permanent (left). Very rarely does a stable inheritance take place (middle), and occasionally the epigenetic trait is lost in further generations (right).—The order of the DNA building blocks is not changed by this influence. This is the special feature of the epigenetic change (explanation 1). (Information from: Heard and Martienssen 2014)

2  What is a Child’s Psychological Trauma? intergenerational DNA of the germ cell changed DNA of the germ cell changed

DNA of the germ cell changed

DNA of the germ cell changed

transgenerational

No transfer (frequent)

DNA of the germ cell changed

stable transmission Transfer & Loss (rare) (occasional) DNA of the germ cell Loss changed of DNA modification

be administered intentionally. If we look at the orange area of Fig. 2.5 in the lower part, Lamarck’s form of transmission is very rare and not stable over many generations, at least not in humans. Lamarckian inheritance is far less significant in animals and humans than Darwinian inheritance, but it exists in plants (Heard and Martienssen 2014). At the end of this subchapter, I would like to make an example of epigenetic transmission from generation to generation.

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2.7.2.1 The Dutch Hunger Winter—An Example of Intergenerational Transmission (F0 to F2) During the German occupation of the Netherlands in the Second World War, a severe famine occurred between October 1944 and the end of April 1945, which people in Holland called the Hongerwinter. A German blockade prevented the Dutch from receiving food and fuel from the southern and rural regions of the country from September 1944 onwards. Around 18,000 to 22,000 people lost their lives, and calorie intake fell to 1000 kcal/day. As expected, there were many pregnant mothers (F0 in Fig. 2.5) and affected fathers (F0) who were exposed to hunger during this critical period. Daughters (F1 in Fig. 2.5) and sons (F1) from this Hungerwinter birth cohort and their children (F2), the grandchildren of the starving mothers (F0) and fathers (F0), were subsequently studied in medical long-term studies up to the present day (Veenendaal et al. 2013). As a control group, daughters/sons (F1) and their children (F2) whose parents/grandparents (F0) were not affected by the Hongerwinter were used. After decades of scientific observation, the focus is now on the grandchildren, that is, the F2 generation according to Fig. 2.5. Affected grandchildren (F2) whose grandfathers had starved showed higher body weight and a higher body mass index (body weight in kg divided by the square of body height in m, unit: kg/m2) than control children. However, grandchildren whose grandmothers had starved did not show this difference (Veenendaal et al. 2013). At the time of the study in 2013, the grandchildren (F2) were on average 37 years old and showed no health problems such as hypertension, diabetes mellitus, hypercholesterolemia, asthma, allergic eczema or cardiovascular diseases, which may still come (the studies are ongoing). Similar studies were carried out in Sweden with the same results (Bygren et al. 2014). This is a true intergenerational transmission.

2.7.3 Transmission—without Genetic and Epigenetic Explanations Many authors in the field of psychology and sociology use the terms “intergenerational” and “transgenerational” incorrectly to describe the transmission of behavior (see Fig. 2.5), because they neither look at genetics nor epigenetics. For example, they describe mothers who themselves suffered from childhood adversities and now have toddlers who show conspicuous emotional behavioral reactions, as if this were passed on from generation to generation (Hipwell et al. 2019). It is unclear how the process of transmitting the conspicuous behavior from the mother to the child takes place. Other authors studied mothers who were traumatized in childhood, who were socially poorly integrated, had high anxiety, showed depressive symptoms, more fatigue, sleep disorders and more pain compared to a control group. Now the children of these mothers also showed more depressive symptoms at the age of 8–12 years. Here it is said that

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intergenerational transmission takes place, although neither genetics, epigenetics nor anything else was included (Dennis et al. 2019). Mothers who have experienced childhood trauma are often depressed, and this can intensify during pregnancy and shortly afterwards. For example, one study showed how negative emotionality and conspicuous behavior in children of traumatized mothers are closely linked to the mothers’ symptoms of depression (Bouvette-Turcot et al. 2020). Nothing is reported about genetics or epigenetics. Others showed that mothers who were exposed to adversities and harsh methods of upbringing repeated the harsh methods with their own children. This transmission of rough motherhood leads to a similar style of upbringing over generations (Lomanowska et al. 2017). The authors speculate about genetic and epigenetic influences, nothing of the sort was properly investigated. Many similar studies and review articles can be mentioned here (Bifulco et al. 2002; Galler and Rabinowitz 2014; Widom et al. 2015; Cowan et al. 2016; Bowers et al. 2018; Kane et al. 2018; Najman et al. 2018; Schoon und Melis 2019; Zipple et al. 2019). Traumatized mothers and fathers pass on negative elements to their children, but there are no reliable genetic or epigenetic findings. I am not saying that these data do not exist in these studies. But up to the time of discovery, the technical terms should be used correctly. Why don’t the authors write “transmission from generation to generation” more correctly?

2.8 An Evolutionary Medicine Perspective I had already reported in detail on biological evolution in my earlier books, and I do not want to deepen the theory here again (Straub 2018, 2020). The evolutionary psychology is a discipline that combines aspects of biological evolution and psychology. “Adaptation to the environment” and “reproductive success” are central in Darwinian terms.

2.8.1 Historical Development As early as Charles Darwin, he integrated aspects of biological evolution with behavior when he reported on “the evolutionary basis of emotional expression in mammals” (Darwin 1872; Snyder et al. 2010). He recognized some parallels in the forms of emotional expression between humans and animals, and he took this similarity as evidence of common ancestors. He considered behaviors such as anger, fear, surprise, disgust, happiness, and sadness. These early considerations were long forgotten, and it was not until the boom in Ethology (comparison of humans and animals) by Nobel laureates Niko Tinbergen, Konrad Lorenz, and Karl von Frisch that a new area emerged within psychology in

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the early 1970s, the “evolutionary psychology” (Ghiselin 1973; Wood-Gush 1963). Sometimes it takes a long time for something to break through. After that, there was a phase of pros and cons against evolutionary psychology because the idea of mind and body as separate entities still prevailed (Bunge 1979). The cons said: Mind and thus psychology are not influenced by evolutionary processes because evolution only affects the material part of the body (e.g. the DNA). Increasing progress in comparative anatomy and physiology in the 1980s found neural structures in humans and animals that were seen as a prerequisite for similar behavior (e.g. Kaas 1989). At the same time, behavioral genetics experienced a boom. Plomin and colleagues said: 50% of behavior is genetically determined (Plomin and Colledge 2001). Thus, any positively selected behavior received a stable genetic anchoring. At the same time, scientists developed animal models that led to problems in later life following previous traumatic adversities during early development. A good example is “maternal deprivation”, which we learned about from John Bowlby and is associated with attachment disorder and other consequences in adulthood. Animal experiments using maternal deprivation showed similar consequences in monkeys, rats, mice, and guinea pigs as studies in children after separation from caretakers. The similarities between animals and humans in terms of behavior and thus a common ancestry were obvious. Later, the theory of evolution was applied to psychiatric disorders such as anxiety disorders and others (Nesse 1990; Glover 2011). Anxiety was interpreted as an adaptive advantage that protects the individual or group in dangerous situations because the anxious warn and protect themselves in time. Anxiety is therefore basically normal, but excessive and recurring anxiety can make one sick. The expression of anxiety is, like all behavioral expressions, a continuous variable with a distribution with values of zero, little, medium, much, or very much (Fig. 2.6). Furthermore, evolutionary psychologists recognized many “adaptive advantages” of personality traits, for example in social exchange (in relation to extroversion and agreeableness), in the formation of coalitions (in relation to agreeableness), in altruistic behavior (in relation to conscientiousness and agreeableness), with regard to physical attractiveness (in relation to extroversion), the number of sexual partners (in relation to extroversion), the testing of social behavior (in relation to emotional instability and vulnerability; neuroticism) and the detection of fraudulent behavior (in relation to emotional instability and vulnerability; neuroticism) (Buss and Penke 2015). Adaptive advantages were positively selected, and so the adapted individual is better equipped for life. The first theories that brought biological evolution, early positive and negative childhood experiences and fertility/reproduction into direct connection date back to the early 1990s by Draper and Belsky (Draper and Belsky 1990; Belsky et al. 1991). The authors discussed the following: individuals from a protected childhood become sexually mature in later ages, have their first sexual intercourse later, form stable relationships, take less risks, develop a positive relationship with the opposite sex and take better care of their own children. Conversely, it is the case with children who have early traumatic

Fig. 2.6   The expression of anxiety is a continuous variable with a positively skewed distribution. On the x-axis, the anxiety variable is plotted. People can have little or much anxiety. On the y-axis, the number of people affected is plotted. For anxiety, a positively skewed distribution function typically results from surveys of people (red line). For other continuous behavioral variables, normal distributions (blue) and negatively skewed distributions (green) can result

2  What is a Child’s Psychological Trauma?

Number of people affected

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positive skew

0

little

normally distributed negative skew

medium

much

a great deal

Anxiety variable (points on a scale)

experiences, who mature sexually early, have many partners and do not live healthily (Belsky et al. 2010). Meanwhile, these relationships have been confirmed in many studies with animals and humans. If people experience adversity in childhood, it is adaptive in the sense of evolutionary medicine if the different body systems are set to a shorter life span. For example, after traumatic childhood experiences, girls experience early physical maturity and they have early sexual intercourse, as a recent large-scale meta-analysis found in 43 studies (Zhang et al. 2019). Intriguingly, this adaptive program transfers to decision-making processes, as people with previous adversity make decisions faster than people without this history (Knowles et al. 2019). The acceleration of life is reflected in an accelerated aging process (a subchapter in Chap. 3 Accelerated Aging). Today we think that only the protected variant has an adaptive advantage because these people are healthier and live longer. This does not have to be the case under other circumstances—for example in war situations, in countries with unstable conditions or in cultures with other orientations (e.g. Masai!). The adaptive advantage of children with negative and traumatic experiences is significant because they find their way around in a tough environment, have children in the same way, and do so earlier and more often. From a perspective of evolutionary medicine, they must reproduce successfully, and that’s all that counts. They are, so to speak, programmed for the adverse conditions and pass on these properties. These considerations were developed by Jay Belsky in the 1990s (Belsky 1997). If we look at the connection between childhood/adolescent stress experiences and later psychopathological or other physical ailments (see examples in Chap. 1), there are very strong relationships between the one and the other, as is the case in the above

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example of the protected and the lifestyle. With this knowledge, some authors have given positive and negative childhood experiences an evolutionary medicine significance since the mid-2000s (Ellis and Bjorklund 2005; Bakermans-Kranenburg and van Ijzendoorn 2007; Belsky et al. 2007; Belsky and Pluess 2009; Del Giudice et al. 2011; Glover 2011; Bakermans-Kranenburg and van Ijzendoorn 2015; Hanson and Gluckman 2015; Boyce 2016; Szepsenwol and Simpson 2019; Shakiba et al. 2020). If this connection between the early childhood situation and the later situation during life is so strong, then—according to the considerations of various groups—a sound theory must exist that can integrate these connections. So some others come to a similar conclusion as Draper and Belsky, and they developed it further (Ellis and Bjorklund 2005; Bakermans-Kranenburg and van Ijzendoorn 2007; Belsky et al. 2007; Belsky and Pluess 2009; Del Giudice et al. 2011; Glover 2011; Hostinar and Gunnar 2013; Bakermans-Kranenburg and van Ijzendoorn 2015; Hanson and Gluckman 2015; Boyce 2016; Szepsenwol and Simpson 2019; Shakiba et al. 2020). The model says roughly the following. In the course of evolution, mechanisms were positively selected to set switches in regulatory systems of the brain and in other parts of the body (e.g. immune system) during early development in utero, around birth, in early childhood up to puberty, which allow adaptation to later life situations. Put a little simpler: Harshly raised children then fit into a rough environment and gently raised children fit into a peaceful and supportive world. Everyone fits into their niche. This theory explains how possibilities for change were maintained during the course of evolution (positively selected), which still allow later modification of the individual after the fusion of the germ cells. This modification is plasticity (Belsky and Pluess 2009). When I speak of plasticity, I mean subsequent changes by epigenetic processes, where information is amplified or not read from the existing gene (explanation 1). Here the environment can have an influence, and this possibility of modification was positively selected during the course of evolution to allow for plasticity. Not reading means setting the switch to NULL (e.g. methylation = DNA reading prevented), and amplified reading means pushing the switch to ONE (e.g. demethylation). Possibly whole networks of genes are turned on or off. Otherwise we would not see the continuous changes in the observed variables as in Fig. 2.6, but a drastic ON or a clear OFF. This machinery serves during the extremely plastic development to better prepare individuals for their own future. This first consideration is now linked to the idea of Boyce and Belsky of the “different sensitivities” of the dandelions and orchids, and already a very impressive synthesis has arisen. How does this theory work out?

2.8.2 Childhood Trauma and Evolutionary Medicine—the Results Children from the same family can be quite different, like Thomas Boyce and his sister! Parents unconsciously set their children up for at least two different life plans, and

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that’s why the children in a family are often different (Dunn and Plomin 1990; Plomin 2018). Life plan 1 always results in promoted and cared for life and life plan 2 results in readiness for rough and combative environment (Boyce 2019). One of the children is often handled carefully, it is sensitive or delicate, an orchid, and the educators have to be gentle and supportive with this child in order to create something good. The other child is brought up rougher, does not receive the same care and gentleness, rather a strict upbringing, and yet everything goes well, a dandelion. How does all this work? On the one hand, children with their genetically determined 50% behavior programs create the conditions for this careful/supportive or rough/combative result because they, through their nature, trigger the respective supportive behavior patterns of the parents. Plomin calls this “nature of nurture” and he means by it the way the children understand, interpret, search for and actively shape their environment (nurture) influenced by genes (nature) (Plomin 2018). Children actively shape their environment and also their parents, and this action is genetically determined in the children. An orchid triggers something different than a dandelion. On the other hand, the environment changes the children through the setting of the epigenetic switches (explanation 1) (Boyce 2016, 2019). At the beginning, the genetic predisposition for an orchid or a dandelion is laid down, but only the corresponding environmental influences create the real orchid and the true dandelion. Genetic and epigenetic processes are responsible at the same time, according to the protagonists (Belsky and Pluess 2009; Boyce 2016, 2019). The children from the two different camps are themselves involved in this by shaping their environment—keyword “nodes of life” (Plomin 2018). Why do we need something like this? From an evolutionary medicine perspective, this parent-controlled difference is favorable because at least one child in a supportive and peaceful environment can often achieve high performance and be healthy (orchid) and because the other child can be successful and healthy in a rough but also normal world. In the respective niche, one and the other can develop and—what is evolutionarily central—survive and reproduce. However, adverse childhood experiences, as described in the Sect. 2.2, are often of a strong nature and go far beyond the aforementioned peaceful or harsh upbringing. Nevertheless, the theory should be applicable, whereby the situation may lead to a strong shift in the stress reaction. Figure 2.7 shows the relationship in the form of a U-shaped curve (Shakiba et al. 2020), which is the mirror image of the bell-shaped curve. A bellshaped curve is created when a favorable reaction is plotted on the Y-axis and higher values show a more favorable result (see Fig. 2.4). Conversely, U-curves arise when higher values on the Y-axis show an unfavorable result (Fig. 2.7, blue line). If I come to this U-curve on the X-axis from left to low childhood stress and from right to high childhood stress, the reactivity is high and the quality of life and mental or physical health are often endangered or poor. This is called maladaptive reaction because the normal, expected reaction ranges of the organism are exceeded with regard to various functions. We say: The answer is outside the reaction norm of Fig. 2.7. This happens much more easily with orchids because the niche is smaller.

Stress reactivity of the HPA axis and the sympathetic nervous system

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outside the reaction norm

high = unfavorable The niche of the dandelions is large, actually not a niche anymore, because they can get along anywhere. The niche of orchids is small, because they can only manage under favorable conditions.

low = favourable low

medium

reaction norm

high

family stress Fig. 2.7   Relationship between bad childhood experiences—here family stress—and stress reactivity. For stress reactivity of the hypothalamic-pituitary-adrenal axis (HPA axis) or the sympathetic nervous system on the Y-axis, I can enter the frequency of psychopathological and physical sequelae as equivalent. The small niche for orchids is yellow and the large area for dandelions is green. Orchids feel comfortable in the small yellow niche, dandelions in the large green area. If stress reactivity remains within a normal range, the reaction norm, this is favorable (gray area). High stress reactivity outside the reaction norm is unfavorable (red area). Schematic drawing according to the following literature: Ellis and Bjorklund 2005; Howell and Sanchez 2011; Schweizer et al. 2016; Shakiba et al. 2020

There is an evolutionary advantage on the left or right side of the U-curve in Fig. 2.7, because a high level of stress in children often means earlier reproduction (Belsky et al. 2015). This leads to the emergence of an individual in the next generation who, through the aforementioned epigenetic reset (text at Fig. 2.5—general demethylation) in the fertilized egg, has a new chance for a positive life plan without the epigenetic baggage of the parents.

2.8.3 Gender Differences—an Evolutionary Medicine Perspective With regard to, the reactions to prenatal stress episodes differ between boys/men and girls/women. Men have a more aggressive variant of psychopathology with rule violations, and they are more often affected by attention deficit and hyperactivity or autistic behaviors. Women, on the other hand, suffer more from anxiety disorders and depression (Glover and Hill 2012). Even in animal experiments, females show more anxiety reactions and depressive features than males. Males tend to show more learning and memory disorders. The stress reactivity increases in girls/women compared to boys/men if the birth weight—a sign of intrauterine stress—is low. In boys/men, an increased peripheral vascular resistance is observed, which can contribute to chronic hypertension (Glover and Hill 2012).

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Early intrauterine stress situations can lead to adaptive phenomena because, for example, in the case of malnutrition and growth retardation, the body switches on programs that lead to a rapid normalization of the situation after birth (Barker 2007; Hanson and Gluckman 2015; Barker 2018). This can contribute to a very rapid weight gain up to puberty. In this respect, these reactions can be seen as adaptive switch positions, i.e. plasticity, in order to counteract the growth retardation. Mechanisms for the emergence of plasticity have been preserved in the course of evolution (positively selected). Likewise, prenatal growth retardation can lead to more psychopathology such as depression or schizophrenia (Glover and Hill 2012). These reactions are similar to obesity, diabetes mellitus and cardiovascular diseases a maladaptive response to an actually adaptive regulation, which only has negative effects in a modern world of abundance and increased stimulus offers. Just maladaptation. From an evolutionary medicine perspective, increased aggressiveness and the increase in rule violations are beneficial for men in competition in order to have a large number of sexual partners and to increase reproductive success. For them, it makes sense if they show a low stress reactivity in this game, which can contribute to a lower behavioral inhibition (Glover and Hill 2012; Sutherland and Brunwasser 2018). In contrast, a program of increased attention to child-rearing is switched on in women, where risk-taking behavior is suppressed by anxiety (Glover and Hill 2012; Sutherland and Brunwasser 2018). A higher stress reactivity in women can contribute to an increased defensive reaction, as found, for example, in female rhesus monkeys (Maestripieri 2011).

2.9 To the Point • Since the World War II, Anglo-American protagonists from different disciplines developed an understanding of early traumatic events in childhood and chronic follow-up problems. • Questionnaires were created to find adverse childhood experiences. • Events can have an impact on the sensitive brain in different time windows. This can lead to functions of the organs being permanently changed in different ways in later life. The follow-up problems are discussed in the next chapter. • Bad childhood experiences are common (adverse childhood experiences). In a German study of students, about 25% of those surveyed had made four or more bad childhood experiences. • The balancing positive factors that counter childhood trauma include resilience (psychological resistance), benevolent childhood experiences occurring simultaneously, reduced sensitivity to impacts (Dandelions better than Orchids), and favorable genetic and epigenetic factors. Epigenetic mechanisms inhibit or promote gene reading in different cells in various ways.

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• Resilience (psychological resistance) is often present, very strongly developed, and based on fundamental protective mechanisms that were positively selected during evolution. • In terms of favorable genetic factors, scientists distinguish between variations in candidate genes, a combination of variations of different candidate genes, or hypothesis-free gene variants found in human genome-wide association studies. Favorable factors are the mirror image of the risk factors for late consequences that are more often investigated by scientists. • Regarding favorable epigenetic changes, the field of science is only at the beginning. • Some authors think that “steeling” can be favorable in childhood (stress vaccination). However, we do not know how an examiner can implement this principle in a meaningful way for which child with which methods. Ethical and legal considerations fortunately prohibit experiments on children using systematically imposed hardships. • To some extent, the effects of early traumatic experiences can be passed on to the next generation, and then the offspring generation suffers from similar consequences as the parental generation. The transfer can take place epigenetically over 1–2 generations. A long-term transfer over many generations is unlikely in humans because of a typical deletion of epigenetic markings (demethylation of the entire genome = reset). • The theory of evolution arrived earlier in the field of psychology than in medicine. During evolution, mechanisms were preserved to allow for switch positions in brain regulatory systems during early development in utero, around the time of birth, during early childhood up to puberty, that allow for adaptation to later life situations. This environment-changeable plasticity has been positively selected. Dandelions and orchids have their niches.

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Straub RH (2018) Altern, Müdigkeit und Entzündungen verstehen – Wenn Immunsystem und Gehirn um die Energie im Körper ringen. Springer, Berlin/Heidelberg Straub RH (2020) Drei Gedächtnisse für den Körper. Springer Nature, Berlin Strauss J, Barr CL, George CJ, King N, Shaikh S, Devlin B, Kovacs M, Kennedy JL (2004) Association study of brain-derived neurotrophic factor in adults with a history of childhood onset mood disorder. Am J Med Genet B Neuropsychiatr Genet 131B:16–19 Strøm IF, Thoresen S, Wentzel-Larsen T, Hjemdal OK, Lien L, Dyb G (2013) Exposure to life adversity in high school and later work participation: a longitudinal population-based study. J Adolesc 36:1143–1151 Stroud LR, McCallum M, Salisbury AL (2018) Impact of maternal prenatal smoking on fetal to infant neurobehavioral development. Dev Psychopathol 30:1087–1105 Sutherland S, Brunwasser SM (2018) Sex differences in vulnerability to prenatal stress: a review of the recent literature. Curr Psychiatry Rep 20:102 Szepsenwol O, Simpson JA (2019) Attachment within life history theory: an evolutionary perspective on individual differences in attachment. Curr Opin Psychol 25:65–70 Szyf M (2019) The epigenetics of perinatal stress. Dialogues Clin Neurosci 21:369–378 Teicher MH, Parigger A (2015) The ‚Maltreatment and Abuse Chronology of Exposure‘ (MACE) scale for the retrospective assessment of abuse and neglect during development. PLoS One 10:e0117423 Thapar A, Pine DS, Leckman JF, Scott S, Snowling MJ, Taylor E (2015) Rutter‘s child and adolescent psychiatry, 6th Edition, Wiley, Chichester/West Sussex Thompson TM, Sharfi D, Lee M, Yrigollen CM, Naumova OY, Grigorenko EL (2013) Comparison of whole-genome DNA methylation patterns in whole blood, saliva, and lymphoblastoid cell lines. Behav Genet 43:168–176 Thomson P, Jaque SV (2018) Childhood adversity and the creative experience in adult professional performing artists. Front Psychol 9:111 Tomfohrde J, Silverman A, Barnes R et al (1994) Gene for familial psoriasis susceptibility mapped to the distal end of human chromosome 17q. Science 264:1141–1145 Tonmyr L, Draca J, Crain J, Macmillan HL (2011) Measurement of emotional/psychological child maltreatment: a review. Child Abuse Negl 35:767–782 Turner HA, Finkelhor D, Hamby S, Henly M (2017) Victimization and adversity among children experiencing war-related parental absence or deployment in a nationally representative US sample. Child Abuse Negl 67:271–279 U.S. Department of Energy – Office of Science and Office of Biological and Environmental Research (2019) Human genome project information archive 1990–2003. https://web.ornl.gov/ sci/techresources/Human_Genome/index.shtml. Accessed 24 Oct 2020 van Dijken S (1998) John Bowlby: his early life: a biographical journey into the roots of attachment theory. Free Association Books, London/New York Veenendaal MV, Painter RC, de Rooij SR, Bossuyt PM, van der Post JA, Gluckman PD, Hanson MA, Roseboom TJ (2013) Transgenerational effects of prenatal exposure to the 1944–45 Dutch famine. BJOG 120:548–553 Ward IL (1972) Prenatal stress feminizes and demasculinizes the behavior of males. Science 175:82–84 Werker JF, Hensch TK (2015) Critical periods in speech perception: new directions. Annu Rev Psychol 66:173–196 Westen D (1998) The scientific legacy of Sigmund Freud: toward a psychodynamically informed psychological science. Psychol Bull 124:333–371

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Wickrama KK, O‘Neal CW, Lee TK, Wickrama T (2015) Early socioeconomic adversity, youth positive development, and young adults’ cardio-metabolic disease risk. Health Psychol 34:905–914 Widom CS, Czaja SJ, DuMont KA (2015) Intergenerational transmission of child abuse and neglect: real or detection bias? Science 347:1480–1485 Wiehn J, Hornberg C, Fischer F (2018) How adverse childhood experiences relate to single and multiple health risk behaviours in German public university students: a cross-sectional analysis. BMC Public Health 18:1005 Wong KK, Raine A, Venables P (2018) The effect of being left home alone at age 3 years on schizotypy and antisocial behavior at ages 17 and 23 years. J Psychiatr Res 105:103–112 Woo E (2005) Urie Bronfenbrenner, 88 – Co-founder of Head Start urged closer family ties Los Angeles, Los Angeles Times Wood-Gush DG (1963) Comparative psychology and ethology. Annu Rev Psychol 14:175–200 Wozniak JR, Riley EP, Charness ME (2019) Clinical presentation, diagnosis, and management of fetal alcohol spectrum disorder. Lancet Neurol 18:760–770 Wu Y, Patchev AV, Daniel G, Almeida OF, Spengler D (2014) Early-life stress reduces DNA methylation of the Pomc gene in male mice. Endocrinology 155:1751–1762 Yang BZ, Zhang H, Ge W, Weder N, Douglas-Palumberi H, Perepletchikova F, Gelernter J, Kaufman J (2013) Child abuse and epigenetic mechanisms of disease risk. Am J Prev Med 44:101–107 Zhang L, Zhang D, Sun Y (2019) Adverse childhood experiences and early pubertal timing among girls: a meta-analysis. Int J Environ Res Public Health 16:2887 Zhang X, Belsky J (2020) Three phases of Gene × Environment interaction research: theoretical assumptions underlying gene selection. Dev Psychopathol 3:1–12 Zipple MN, Archie EA, Tung J, Altmann J, Alberts SC (2019) Intergenerational effects of early adversity on survival in wild baboons. elife 8:e47433

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3.1 Many Places are Affected The resulting follow-up problems are manifold. They primarily affect the brain and, secondly, the periphery such as the heart, vessels, kidneys and urinary tract, genitals and fertility, lungs, teeth, stomach, intestine, bones and muscles, body weight, metabolism, growth and the immune system. The susceptibility to cancer is also significantly increased after previous traumatic experiences. This multimorbidity was illuminated in a large meta-analysis. This meta-analysis included a total of 96 articles, all of which used the ACE questionnaire by Vincent Felitti (Petruccelli et al. 2019), which we have learned about in Table 2.1 The risk of developing a subsequent problem thus increases with the number of early traumatic episodes. The highest risk is for the development of an alcohol problem, a depression with suicide or an anxiety disorder. With regard to the internal problems, the risk of overweight, a heart attack, a lung disease and for gastrointestinal disorders is highest. The increased activation of the immune system was not treated separately in the aforementioned meta-analysis. This is surprising because in 2019 this was actually a clear thing and because with 96 studies surely not all of them refrained from considering this follow-up problem. Therefore: For many people, the problem of inflammation or rather chronic inflammation is still not properly described in 2019. I will present this point at the end of the chapter in order to lead into the actual core of the book (Chap. 4). We have already heard of the “snowball effect” when additional traumas are added to an adverse childhood burden. Similarly, we can speak of a snowball effect with regard to the follow-up problems of alcoholism or nicotine abuse, for example, because they often lead to other follow-up problems such as heart attack, stroke, tumor, etc. Mental

© The Author(s), under exclusive license to Springer-Verlag GmbH, DE, part of Springer Nature 2023 R. H. Straub, Early Trauma as the Origin of Chronic Inflammation, https://doi.org/10.1007/978-3-662-66751-4_3

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and internal follow-up problems cannot be considered in isolation from each other, they promote each other and often lead to multimorbidity.

3.2 The Brain Probably Suffers the Most In the aforementioned Felitti study, patients who had four or more adverse stress experiences in their childhood had an increased risk of health problems such as alcoholism, drug use, depression, suicide, nicotine abuse, promiscuity and sexually transmitted diseases, physical inactivity and obesity by a factor of 2 to 12 depending on the follow-up problem (Felitti et al. 1998). The brain is thus without a doubt affected. The brain has always been in the focus of attention of most scientists, and consequently we have the most data on this.

3.2.1 Alcohol, Nicotine and Drugs Addictive behavior is a frequently described consequence of early traumatic experiences. Alcohol in particular was in the crosshairs of the researchers, for example of the Centers for Disease Control and Prevention in Atlanta, Georgia. A publication from 2018 summarizes the situation after questioning almost 70000 people: Both excessive binge drinking and other forms of drinking are more common in people after traumatic childhood experiences than in control subjects. Men and people with a higher education are more affected (Loudermilk et al. 2018). However, people do not ask about the dangerous side effects and the social consequences. If two negative elements such as alcohol abuse in the family and early traumatic experiences come together, the problem of dangerous alcoholism is particularly high (Sorocco et al. 2015). Soldiers of the US armed forces who were stationed in Iraq or Afghanistan as part of Operation Enduring Freedom from 2003 to 2006 showed alcohol problems and a risk-taking behavior if they had experienced trauma at a young age. Sexual abuse was a strong risk factor (Clarke-Walper et al. 2014). Similarly, we find a higher number of smokers—often in combination with alcohol abuse—in the group of traumatized people (Hsu and Kawachi 2019). Abused women compared to controls have more difficulty quitting smoking (Smith et al. 2016). Authors of a longitudinal study of women in Ukraine described how early childhood stress stimulates the onset of smoking in adolescence (Iakunchykova et al. 2015). In the large British Child Development Study, which began in 1958 and is still providing data, adult individuals with economic constraints in childhood showed a much higher willingness to smoke heavily (Bartley et al. 2012). Some scientists trace a cascading course that begins with trauma in childhood, leads to less self-control and thus leads to an addictive behavior (Otten et al. 2019), an idea that is supported by others (Sorocco et al. 2015). In addition, personality traits such as

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impulsivity (tendency to rash spontaneous actions with reduced self-control), sensation-seeking (strong desire for new experiences) and aggressive behavioral components drive addiction (Kim et al. 2018). This is quite the opposite of “executive control”, which we met in Table 2.4. Generally, men are more at risk of addiction after previous traumatic childhood experiences than women. If the number of negative experiences is very high (i.e. greater than 4 and more), the gender difference disappears. This is true for alcoholism and especially for drugs, where there is even a reversal of the problem and women are more addicted than men, as a study showed (Evans et al. 2017). The large American study on “alcohol dependence and related problems of addiction (NESARC)” started in 2001–2002 with a first wave of observation of more than 26,000 people to systematically uncover mental problems in the population. In this first wave of observation, no person was addicted to drugs, but this changed dramatically 3 years later, when 1145 people were addicted to drugs. With regard to the reasons for this change, the researchers found, among other things, early traumatic experiences (Harrington et al. 2011). I can continue this list indefinitely, the scientific literature is full of it. Things repeat themselves from different perspectives. Animal experiments show similar difficulties in mice, rats and monkeys (Pastor et al. 2017, 2018; Walker et al. 2018). They drink, smoke or become more drug-dependent if they are stressed before birth or in their early years. But what mechanisms are behind these clear phenomena?

3.2.1.1 Where in the Brain is the Problem? The regions for reward, motivation, well-being and motivational movement control are well known in the brain. Figure 3.1 shows these regions in detail by looking at the inside of a brain hemisphere. These regions are at the center of considerations when it comes to addiction, which can be triggered by adverse childhood experiences. A study on humans showed how the wakefulness-promoting drug amphetamine released significantly more dopamine from important reward centers (dorsST in Fig. 3.1) in those persons with previous early childhood trauma than in persons without trauma (Oswald et al. 2014). If dopamine is responsible for rewards, motivation, and well-being, the dopamine increase caused by amphetamine is a pleasantly experienced signal. This study showed exactly this positive feeling after amphetamine, and in people with adverse childhood experiences this feeling was significantly increased. This opens the door to addiction. In another consideration of humans, the authors carried out a stress test in which the test person had to calculate quickly, and not everyone is a quick mental calculator. During the calculation tasks, the calculation errors were immediately displayed, which corresponded to an additional unpleasant negative stimulus. In persons without early trauma, the dopamine release from the reward center did not change during the stress test (dorsST in Fig. 3.1). However, dopamine release was significantly reduced in those persons with adversities in childhood. When these people were stressed, they had to feel the

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top SNpc

occipital frontal

VTA

Brainstem

Fig. 3.1   Dopamine pathways of the reward system. We look from the midline of the brain at one hemisphere. The brown-red pathways of the neurotransmitter dopamine originate in two important regions in the midbrain, namely in the VTA (ventral tegmental area) and in the SNpc (substantia nigra pars compacta). From there, these pathways reach four different regions: 1) The long arrows lead into the cortex (mesocortical pathway; for motivation, cognition and emotional response), 2) a short arrow leads to the nucleus accumbens (NAc, reward, motivation, well-being), 3) three arrows lead to the dorsal striatum (dorsST, motivational movement control), and 4) three arrows lead to the yellow nuclei in the brainstem (serotonergic area, noradrenergic area; relevant in depression, etc.). The cauliflower-like structure on the lower right is the cerebellum (movement control)

opposite of reward. Low dopamine release means sparse reward, low motivation, and little well-being. So these people get the positive stimulus elsewhere, for example through drugs like amphetamines. The platform for addiction is thus created. In explanation 1 and in the Chap. 2 I pointed to epigenetic changes that can be engraved by early traumatic experiences. Such engraving of DNA was observed in animal models with young rats when they were separated from their mother for a longer period of time (maternal deprivation). They saw epigenetic changes in an important reward center in the brain, the nucleus accumbens (lat. accumbere = to lie down) (Fig. 3.1). Rats with these changes took more amphetamines, the wakefulness-promoting drug (Lewis et al. 2016). In a similar way, another team of scientists demonstrated in rats a preference for nicotine after early trauma. This preference of the animals was accompanied by an increased number of a receptor for dopamine in the Nucleus accumbens (here: D2, one of 5 different dopamine receptors) (Fig. 3.1). Since dopamine is a reward neurotransmitter, it has a stronger effect on the reward center due to the higher number of these receptors (Said et al. 2015). Nicotine therefore stimulates dopamine effects that make you happy, and the animals loved to reward themselves repeatedly. Similar findings were found in other regions of the reward system (Brenhouse et al. 2013; Hausknecht et al. 2013).

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Finally, in the animal experiment after stress in the uterus, the researchers found a reduction in the formation of synapses in the nucleus accumbens (Fig. 3.1) and in the hippocampus, which is responsible for memory, among other things (Martínez-Téllez et al. 2009). Both findings contribute to disturbed reward behavior. In summary, we recognize manifold changes on a functional and morphological level that create a platform for addiction. Early childhood trauma leads to a more sensitive reward system, and this functions differently under stressful conditions. Stress means punishment, bad feeling and by no means motivation, which can only be compensated by drugs. These mechanisms create the starting point for addictive behavior in traumatized people.

3.2.2 Depression Stressful events can already affect the future mother before fertilization of an egg, which can lead to depression during pregnancy. If more than 4 childhood traumas were present in the future mother’s childhood, the risk of pregnancy depression is significantly increased. The risk of depression is additionally increased if social support is lacking or the relationship with the partner is strained (Wajid et al. 2020). Traumatic life situations can already have an impact on mother and child in the womb. An example would be war experiences, which represent a particularly drastic example with a clear beginning and end, making cause and effect better definable. Israel is a country with a long tradition in psychology and psychiatry, and so, for example, Israeli scientists were interested in these questions around war events (Kleinhaus et al. 2013). Since its existence in 1948, the state of Israel has constantly been confronted with internal and external conflicts. In addition to the early independence war, the so-called Six-Day War in 1967 and the Yom Kippur War in 1973 were the most impressive episodes in Israeli history, because there the neighbors threatened with violent war words, “to throw the state of Israel into the sea”. Imagine the mothers whose husbands were drafted into the wars while their unborn children were growing up in their womb (Israel always had a large reserve army and many husbands were affected). The Six-Day War began on June 5, 1967, and during the first two days, West Jerusalem was heavily bombarded (Kleinhaus et al. 2013). In the following days after the Israeli mobilization, no further evacuations and food shortages were to be expected because the war was over within a short time. So there was a clear beginning and end of the stressful constellation. The unborn children of the mothers living in West Jerusalem were observed over the next 35 years. The children confronted with the war in the first third of pregnancy showed a three- to fourfold higher risk of being treated for depression in the follow-up period (they were compared with a control group with non-stressed pregnancies). The children from the other thirds of pregnancy were not affected (Kleinhaus et al. 2013). Consequently, the

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first third of pregnancy is critical because that is where an important window of brain development lies (time window see Sect. 2.3). Sometimes children are evacuated from crisis areas without the accompaniment of their parents. Do you remember how President Trump treated the children from Guatemala at the Mexican-American border? He put them in cages—unspeakable! My protagonist Prof. Michael Rutter was displaced to the USA with his sister during the Second World War, without experiencing any additional Trump-like hardships. Evacuation is a severe trauma for children, and all too often it is the starting point for depressive development, which can lead to an open depression or anxiety disorders during adolescence or adulthood. Even the children of displaced people suffer from similar problems in the next generation. This is exactly what Finnish scientists had in mind when they questioned the second generation (F1) of the girls displaced during the Second World War (F0). They found in the second generation (F1) under 45955 affected women a doubled risk of a psychiatric illness and almost a fivefold increased risk of depression (Santavirta et al. 2018). Here the term “intergenerational” is appropriate because the influence of the F0 generation is directly passed on to the F1 generation (Fig. 2.5). In Scandinavia, large population-based studies are often conducted. Such a study took place in Denmark, involving almost one million people born in Denmark between 1980 and 1998. The scientists examined, among other things, early traumatic experiences in the age group 0 to 15 years. The risk of depression in adulthood increased significantly with the number of negative experiences (snowball effect). The risk was particularly high for those people for whom the family structure had broken down between the ages of 0 and 4. Similarly, the risk was increased in people who, between the ages of 10 and 14, grew up outside the family due to adverse domestic conditions (Dahl et al. 2017). In addition, it should be reported that if this latter group of adolescents grew up under private conditions with another family and not in a public institution, they were more effectively protected from depression (Kessler et al. 2008). A meta-analysis from 2012 brought together 16 publications with a total of 23544 participants. The authors find a clear connection between childhood trauma and later episodic or chronic depression. In addition, these affected people have a lower chance of benefiting from antidepressant therapy (Nanni et al. 2012). For older people, the symptoms of depression typically decrease around the time of retirement (Airagnes et al. 2016), because occupational stress factors are eliminated, new meaningful activities are added, or a better ability to regulate mood during uninterrupted aging is present. However, it was long unknown whether early traumatic experiences in childhood affect this improvement in depressive mood. This question was examined in 2016 on almost 10,000 employees of the French national gas and electricity company. For men and women with a high number of childhood adversities, there was little or no improvement in chronic depression around the time of retirement. The more adversities there were, the less protective the effect of the

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beginning retirement was (Airagnes et al. 2016). The influence of childhood adversities therefore extends far into the future. In addition, people with depression are at risk of committing suicide in later life (suicide) (Wan et al. 2019; O‘Neill and O‘Connor 2020). The risk of a suicide attempt increases by a factor of 2.5 to 3.5 (Angelakis et al. 2019). The more complex the situation of child abuse, the higher the risk of suicide (Goldney 1981; Dube et al. 2001; Björkenstam et al. 2017a; Angelakis et al. 2019). If you need help as a reader, I refer here to very good offers on the Internet—take the step in time (for Germany: German Society for Suicide Prevention 2021).

3.2.2.1 Where is the Problem in the Brain? In Fig. 3.2 important regions are shown which exhibit abnormalities in functional magnetic resonance imaging after childhood trauma and subsequent depression. The amygdala is morphologically changed, becoming smaller on both sides after the trauma (Favaro et al. 2015; Luby et al. 2019; Gray et al. 2020; Nogovitsyn et al. 2020). Similarly, the region of the ACC is smaller, a region for emotional control and evaluation, especially after social stimuli (Fig. 3.2) (Carballedo et al. 2012; Jensen et al. 2015; Kuhn et al. 2016; Bromis et al. 2018; Luby et al. 2019; Gray et al. 2020). Furthermore, the ACC no longer takes on its typical important role as a neuronal hub (Cisler et al. top

occipital

frontal frontal brain regions

Uncinate fasciculus

Amygdala Hippocampus Brainstem

HPA axis cortisol Fig. 3.2   Brain areas involved in depression. We look at a hemisphere from the midline. The green areas become smaller after childhood trauma and subsequent depression. The tract between the amygdala and the hippocampus as well as the frontal lobe in the front part of the brain is shown by red lines (uncinate fasciculus). This tract can be disturbed and the inhibitory function of the frontal lobe on the amygdala and hippocampus may be absent. Important areas in the frontal lobe are the ventral and dorsal medial prefrontal cortex. Abbreviations: ACC, anterior cingulate gyrus (emotional control and evaluation); NAc, nucleus accumbens (reward center)

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2013). In addition, the important memory region of the hippocampus decreases in size (Rao et al. 2010; Carballedo et al. 2012; Frodl et al. 2014; Calem et al. 2017; Bromis et al. 2018; Humphreys et al. 2019; Luby et al. 2019). In the animal model, reductions in the branching of nerve cells or cell loss can be clearly seen in these regions (Brunson et al. 2001, 2005; Danielewicz and Hess 2014; Lajud and Torner 2015). Cell loss corresponds to a situation with insufficient nerve development and increased breakdown. Finally, some areas in the frontal lobe are smaller (Carballedo et al. 2012). In animal experiments, a special function of nerve cell groups, long-term potentiation, can also be studied. I discussed it in a previous book as an indicator of memory function (Straub 2020). During the investigation of long-term potentiation, nerve cell groups in the hippocampus are electrically stimulated, and a resulting voltage change in the nerve cells an be observed. If the investigator caries out this electrical stimulation over several days, one notices an increase in the voltage change in the nerve cells. I wrote at the time: “As if by magic, the voltage change” increases in the multiply stimulated nerve cells, and this is a sign of memory formation (Straub 2020). This longterm potentiation was studied in animals in the hippocampus after previous stress during pregnancy or stress after birth. These animals later showed a reduction in long-term potentiation as an indication of reduced memory formation (Yeh et al. 2012; Grigoryan and Segal 2013). When an experimenter offers emotionally stimulating faces to the test person during the stay in the tube of the magnetic resonance tomograph, various regions in the brain react differently. In people with early childhood trauma before puberty and later depression, the amygdala reaction was weakened, while later traumatic effects after puberty resulted in an increased reaction (Zhu et al. 2019). Others showed an increased reaction of the amygdala to sad faces, indicating an overactivity of the limbic system (Suzuki et al. 2014). In parallel, an increased reaction of the ACC is observed, which is responsible for the evaluation of the faces (Suzuki et al. 2014; Peters et al. 2019). When children and adolescents grow up, the observer sees a clear increase in activity in the reward center, the nucleus accumbens (Fig. 3.1). If an early childhood trauma preceded and a depression is present, this maturation process is attenuated, and significantly lower activity is observed in this nucleus (Goff et al. 2013). This change means a smaller reward experience for the depressive. The hook-shaped nerve fiber bundle, the uncinate fasciculus (uncinate, lat. hookshaped) (Fig. 3.2) is noticeably changed. This fasciculus is a central connecting tract in the limbic system, which connects the amygdala and the hippocampus on the one hand with the frontal lobe on the other. After early childhood trauma with later depression, the function of this important tract is disturbed, which impairs the tasks of the limbic system and disturbs emotional reactions (Kircanski et al. 2019). Similarly, the second major limbic tract, the fornix, which is not shown in Fig. 3.2, is also disturbed (Frodl et al. 2012). A critical point is the HPA axis. This axis is often overactive in depression and therefore too much CRH is produced in the brain and too much cortisol is produced in the

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periphery (van Bodegom et al. 2017). We will come back to this topic in more detail later (Chap. 4, Sect. 4.2.3). We therefore clearly recognize changes in the morphological structure of the brain and in functional aspects. The regions can be very well defined by means of functional magnetic resonance imaging. Often parts of the limbic system (amygdala, hippocampus, ACC, uncinate fasciculus, fornix), the memory system (hippocampus, ACC) and the reward system (nucleus accumbens) are affected. It changes the processing and storage of emotional stimuli, and depressive and anxious reactions are more often observed.

3.2.3 Anxiety Disorders Anxiety is a normal thing if we go through the pitch-dark forest at night, stand on a high rock without security, climb a high tree, drive too fast with the car, jump out of an airplane for the first time, etc. Anxiety has a protective function because it protects us from the dangers of everyday life. For some people, however, anxiety is more pronounced and for some it even takes on an exaggerated form. We speak of anxiety disorders. Although the sight of a snake like the ringed snake is not exactly a feeling of comfort, after a relatively short assessment of the situation, the first fear has turned into curiosity and amazement. Some people, however, react phobically to snakes, and then there is an anxiety disorder from the field of phobias. Other phobic reactions can occur on a large square, in confined spaces, in front of objects, in front of animals (e.g. snake, spider, wasp) or other situations. A phobia is an excessive fear reaction to defined triggers. In contrast, there are other anxiety disorders such as panic disorders (sudden anxiety attacks lasting a few minutes without focus on object or situation), generalized anxiety disorder (diffuse anxiety about everyday events lasting at least 6 months), and anxiety disorders that are coupled with depression. Anxiety disorders are often associated with physical symptoms of the fight-or-flight response (sweating, heart palpitations, trembling, dry mouth, etc.), and they typically impair the lives of those affected. An anxiety disorder can intensify in a vicious circle and lead to social withdrawal. The connection between childhood trauma and anxiety disorders in adulthood was summarized in a meta-analysis (Carr et al. 2013). Furthermore, more than 100,000 people in Sweden were included in a large population-based study in which childhood traumas were systematically recorded. In total, 42% of the people had at least one severe trauma in childhood (the most common being the parents’ divorce). People with childhood trauma had more psychiatric disorders than control persons, most often anxiety disorders. If several adversities occurred at the same time, the risk of an anxiety disorder increased by a factor of 2 (Björkenstam et al. 2016). In a large British longitudinal study of a group of people born in 1958 (Child Development Study), the researchers found that more than 9000 people had anxiety

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disorders as adults at the age of 45 years. This anxiety disorder was associated with a smaller social network and interpersonal relationship problems (Ford et al. 2011). Others showed the connection between early traumatic experiences and social phobia, in which the affected persons were afraid of situations in which they were the center of attention (DeWit et al. 2005). The traumas can have an effect during pregnancy, as is the case, for example, with stressed pregnant women (Phillips et al. 2005). One thing the publications on anxiety pointed out was that more women than men were affected (Wanner et al. 2012). In 2013, there was a severe earthquake of magnitude 6.6 in Sichuan Province, China (sometimes called Ya’an), and the situation lasted for about 2 days with aftershocks. A total of 196 people died, 24 were missing, and 11826 were injured (968 seriously). Three years after the earthquake, Chinese scientists conducted a study of 6132 children and adolescents aged 9 to 18 years. Children/adolescents were more likely to be affected by excessive fear if they were exposed to the earthquake, left alone, poor, or experienced hostility and harassment from the peer group, and women were more affected than men (Tang et al. 2020). In animal models with mice and rats, something similar to anxiety can be quite well determined by behavioral studies. The expert speaks more of a defensive behavior because animals take a defensive position. Obviously, early stressful life experiences lead to increased defensive behavior in these animals (Fride et al. 1986; Wang et al. 2012; Wilson et al. 2013; Rau et al. 2015). With animals, the observer can also look into brain regions, and this has been done, for example, with regard to the amygdala, the hippocampus (memory region) and various frontal brain regions (Kraszpulski et al. 2006; Eiland and McEwen 2012; Laloux et al. 2012; Rau et al. 2015). In rats, the memory of fear is less erasable (Green et al. 2011), and female animals are more affected than male animals (Bowman et al. 2004). If you ask at this point where all this takes place in the brain, I can again refer to Fig. 3.2, because that is where the most important regions are basically shown. In humans, these are the amygdala, the hippocampus, the frontal brain region and the ACC (Williams et al. 2009; Kuhn et al. 2016; Lange et al. 2019; Murthy and Gould 2020). The amygdala is central here, which after a trauma shows inadequate increased activity (Kraaijenvanger et al. 2020). The increased activity arises from the disturbed connection between the amygdala and frontal brain parts via the impaired uncinate fasciculus (Fig. 3.2) and the fornix (Graham et al. 2015; Scheinost et al. 2017; Kaiser et al. 2018; Herzberg and Gunnar 2020). In animals, these regions are similarly affected (Murthy and Gould 2020). The appearance of similar regions as in depression shows us the close connection between anxiety disorder and depression. Part of the connection between important areas such as the amygdala and hippocampus and the ACC is disturbed (Kim et al. 2019), and the nerve activity is changed in the respective regions. In the animal model, the observer sees how density of neuronal synapses decreases in these regions (Lemaire et al. 2000; Brunson et al. 2005; Yang et al. 2006; Derks et al. 2016).

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3.2.4 Personality and Childhood Trauma A person’s personality is usually constant over a long period of time. We know five distinct personality traits (Explanation 5). Personality disorders are “extreme manifestations of a personality with inflexible, rigid and inappropriate personality traits that impair the quality of life of the affected person and lead to suffering and/or frequent conflicts with the environment” (Professional associations and societies for psychiatry; child and adolescent psychiatry; psychotherapy; psychosomatics; neurology and neurology from Germany and Switzerland 2021). Explanation 5 Personality—The Big Five

In the so-called Five Factor Model five essential factors for a personality with weak compared to strong expression are observed: 1. Openness to experience (“conservative, cautious” compared to “inventive, curious”) 2. Conscientiousness (“carefree, negligent” compared to “effective, organized”) 3. Extraversion (“reticent, reserved” compared to “sociable”) 4. Agreeableness (“competitive, antagonistic” compared to “cooperative, friendly”) 5. Neuroticism (“emotional, vulnerable” compared to “self-confident, calm”) In alternative models, “honesty-humility” is sometimes considered as a sixth factor that is included in “agreeableness” under the Big Five. These description factors are very stable, independent of each other and existent in different cultural circles, and they can change slightly during aging (towards less openness, with more conscientiousness and agreeableness). The heritability of personality traits is very high at 50%. Only 40–45% are determined by environmental influences (Nettle 2009). ◄ Adverse childhood experiences influence these stable personality traits by exacerbating or bringing them out more. In a large Australian study, the authors found a clear relationship between early trauma and a higher degree of neuroticism, a negative mood, a stronger loss of self-control, and pronounced anti-social behavior, regardless of age or gender (Rosenman and Rodgers 2006). In addition, we often see personality disorders in people with previous trauma, for example narcissistic personality disorders with drastic emotional behavior and those with anti-social or eccentric behavior. Abuse and neglect in early years promote the exacerbation of personality traits up to personality disorders, as shown by large population-based studies (Afifi et al. 2011). In a Finnish study over 30 years, the following was observed: A higher number of personality disorders is present in people aged 30 if the mothers experienced subjective stress during pregnancy. The higher the perceived stress, the more often personality

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disorders occurred. The result is therefore significant because this analysis controlled for the influence of important confounding factors such as maternal and paternal mental illness, nicotine exposure, and pregnancy depression (Brannigan et al. 2020). A similar English study found a relationship between stress during pregnancy and personality disorder (Winsper et al. 2012). In a similar way, a Swedish longitudinal study from the Stockholm area often finds a personality disorder in young adulthood if the children were exposed to a higher number of adverse childhood experiences. At the same time, the school performance of these people was lower than that of normal controls (Björkenstam et al. 2017b). A Swiss study confirmed the relationship between trauma and personality disorders (Winsper et al. 2012). Thus, the special thing is a sharper shaping of the personality, which can develop into a real personality disorder.

3.2.5 More Psycho- and Neuropathology Above, only the most common problems were described extensively. In this book, there is also not enough space to describe all psychopathological consequences in detail. This is left to the specialized literature (Thapar et al. 2015). Therefore, in a short table, further psycho- and neuropathological consequences are summarized briefly and the important literature is demonstrated (Table 3.1). If the trauma expert observes children after adversities over a very long period of time, the psychopathological disorders remain—they do not weaken very much (Clark et al. 2010). Furthermore, bad childhood experiences can lead to an increased rejection of antipsychotic drugs by those affected, which can fuel the disease process (Ajnakina et al. 2018). However, trauma experiences in childhood and adolescence are not solely responsible for the onset of psychopathology. There are other factors in the sense of “double hits”. Such double hits can be events in childhood and later in adolescence (e.g. drugs or new traumas and stress experiences) (Peh et al. 2019). We will come back to the double hits in several places in the book. The development of psychoses is assumed to be caused by trauma-induced neuronal developmental disorders, in which there are structural and functional brain disorders that we have already learned about in the previous chapters. A dopaminergic dysregulation, atrophy of brain areas (e.g. amygdala, frontal lobe), damage to the hippocampus and hyperactivity of the HPA axis as in depression are of importance (Longden and Read 2016). Furthermore, the observer often sees different response patterns in women and men. I have already dealt with this in the Sect. 2.8.3. So women show accelerated sexual maturity more often, with central nervous system effects playing an important role (Bath 2020). Men, on the other hand, have delayed sexual maturity. Female animals have an early-maturing development in terms of emotional stimuli and fear learning. The amygdala undergoes faster maturation, whereas in male animals

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Table 3.1  Further psycho- and neuropathological follow-up problems after early traumatic experiences outside of addiction, depression and anxiety disorders Psycho- and Neuropathology

Literature

Schizophrenia

(Wicks et al. 2005; Matheson et al. 2013; Schroeder et al. 2016; Sideli et al. 2020)

Paranoid psychoses

(Sideli et al. 2020)

Bipolar Disorders (manic-depressive)

(Palmier-Claus et al. 2016; Post et al. 2016)

Autism Spectrum Disorder

(Kinney et al. 2008; Berg et al. 2016)

Attention Deficit-/Hyperactivity Disorder (ADHD)

(Zhu et al. 2015; Østergaard et al. 2016; Björkenstam et al. 2018; MacKinnon et al. 2018); in animals (Bock et al. 2017)

Adjustment Disorder (Reaction to Stressful Life Events)

(Shaw et al. 1994; Kiff et al. 2012)

Attachment disorder

(Shaw and Vondra 1993; van Dijken 1998; Opendak et al. 2017; Perry et al. 2017; Venta 2020)

Disorder of the executive function This includes self-control, emotion regulation, planning ability, working memory, and conscious attention control.

(Richards and Wadsworth 2004; Laplante et al. 2008; Hackman et al. 2010; Hostinar et al. 2012; Schwabe et al. 2012; Li et al. 2015; Mittal et al. 2015; Lambert et al. 2017; Sheridan et al. 2017; Chen et al. 2019; Goodman et al. 2019; Lovallo et al. 2019)

Disorder of social behavior (conduct disorder), (Beck and Shaw 2005; Provençal et al. 2015; MacKinnon et al. 2018) aggression Disorder regarding the parental role

(Barrett 2009)

Dementia (Alzheimer’s disease)

(Persson und Skoog 1996; Norton et al. 2011; Ravona-Springer et al. 2012; Pesonen et al. 2013; Donley et al. 2018; Lemche 2018; Tani et al. 2020)

Fatigue (chronic fatigue)

(Cho et al. 2012; Crawley et al. 2012; Bower et al. 2014)

Epilepsy

(Edwards et al. 2002; Jones et al. 2014; van Campen et al. 2014); in animals (Ali et al. 2013; Dubé et al. 2015)

Motor disorders and reduced muscle strength

(Buitelaar et al. 2003; Cheval et al. 2019); in animals (Schneider et al. 1999)

Sexual orientation; men become more feminine and women become more masculine; faster sexual development in women, slowed sexual development in men

(Ellis and Cole-Harding 2001; Hines et al. 2002; McLaughlin et al. 2012; Suglia et al. 2020); in animals (Ward 1972, 1984; Bowman et al. 2004; Meek et al. 2006; Morgan and Bale 2011; Popova et al. 2011)

Sleep disorders and pain

Its own subchapter below and in the introduction

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accelerated development of the hippocampus and amygdala can be seen (Bath 2020). In general, there is accelerated maturation of the limbic system and delayed development of cortical areas in both sexes (Bath 2020). Women are characterized by increased depression and anxiety, whereas men are more likely to suffer from autistic disorders, attention deficit/hyperactivity and aggressive behavior (see 2.8.3) (Wainwright and Surtees 2002; Davis and Pfaff 2014).

3.2.6 More Sleep Disorders as a Result of Previous Trauma I mentioned the topic of sleeping in a introductory text in the first chapter, and I ask again: How can I sleep while my bed is burning? Children from families with lower incomes go to bed late (on average at 10:36 p.m.) and have a high variability of sleep time of plus/minus 3.68 h. The parents have hardly any knowledge of official recommendations on the topic of sleep in children, and 65% of the parents slept with their children in one bed (Ordway et al. 2020). Other authors see the same connection between the financial situation of the family and the sleep problems (El-Sheikh et al. 2015). Childhood adversities often lead to problems falling asleep and other forms of sleep deterioration in teenagers later (April-Sanders et al. 2020). The more childhood traumas there were, the stronger the sleep problem in later life (Sullivan et al. 2019; Sheehan et al. 2020). If the investigator asks women of middle age about the quality of sleep, he often recognizes in those with childhood adversities a short sleep duration, a longer time to fall asleep, frequent nocturnal awakenings and more often short daytime sleep (2019). Others observed in adults with previous bad childhood experiences numerous nightmares, sleepwalking and sleep spindles. The latter are typically observed in electroencephalography in the deep sleep phases of the eye movement-free sleep (Non-REM-sleep) (Nielsen et al. 2019). Here is the principle of the “double hit,” because bad sleep often appears when there have been previous adverse childhood experiences and another trauma situation arises later in life. This was observed in students who were just starting their studies at the university and had experienced emotional neglect in their childhood (2018). Thomas Boyce conducted an important study on children. He showed how children with adverse childhood experiences showed different sleep behavior depending on the activation capacity of the sympathetic nervous system. For this purpose, he offered four slightly stress-inducing events in quick succession and tested the reaction of the sympathetic nervous system. If children with trauma had a weak sympathetic nervous system response, they had more sleep problems than those with a good sympathetic nervous system response. He interpreted the weakened sympathetic nervous system response as a dulling to the stress-inducing stimuli as a sign of a severe disorder (Alkon et al. 2017). Finally, two large epidemiological studies are to be mentioned, in which 22000 and almost 10000 people were interviewed. In both studies, the risk of a sleep disorder was

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dependent on the number of adverse childhood experiences: the more traumas, the worse the sleep (Wang et al. 2016; Sullivan et al. 2019).

3.2.6.1 Where in the brain is the problem? Previously, we suspected the cause of insomnia (falling asleep and sleeping through the night) in people affected mainly in the brain centers responsible for the circadian rhythm and regular sleep/wakefulness (Van Someren 2021). According to newer concepts, these brain areas are not involved alone (Van Someren 2021), but rather those areas that we already learned about in the context of depression in Fig. 3.2. These new considerations came about after the influence of stressors on sleep behavior was examined more closely (Van Someren 2021). Stressors lead to short-term and long-term overexcitability in some brain centers (e.g. amygdala, Locus coeruleus). Doctors distinguish between different sleep phases, and one phase is called REM sleep, in which we move our eyes rapidly back and forth (Rapid Eye Movement). During the REM sleep phase, we have a high plasticity for the formation of synapses, which is why this interval is important for the development of memory (Van Someren 2021). In this phase, the topmost noradrenaline area (the locus coeruleus from Fig. 3.3) must be switched off, because noradrenaline otherwise interferes with the formation of synapses. A reasonable REM sleep is absolutely essential in order to protect the brain at least in these intervals from an excess of noradrenaline (Van Someren 2021). Stressors can disrupt this shutdown of the locus coeruleus, and restless or fragmented sleep is the result. People react very differently to stressors. Some can still sleep great and process stress during sleep. Others, however, experience restless sleep, which can be dangerous because recovery is lacking and because memory formation is disturbed. Here, too, genetic factors are important (Van Someren 2021). This is typically associated with an activation of the HPA axis (Van Someren 2021). This increased readiness to release hormones of the HPA axis—for example, CRH from the hypothalamus and cortisol from the adrenal gland—we have already encountered in depression. This phenomenon is associated with increased responsiveness and lack of nocturnal shutdown of the amygdala (Amygdala) and the locus coeruleus (Van Someren 2021). The amygdala and locus coeruleus are controlled and braked by the frontal lobe and ACC (Fig. 3.2). Since the frontal lobe and ACC and others perceive their function of control poorly, the brake of the amygdala and the locus coeruleus is lacking. Somehow it looks as if the affected people are constantly in a state of increased vigilance, and so these responsible regions are typically changed after childhood traumas. The affected person has, so to speak, learned to be constantly attentive. He is more sensitive to negative information and he becomes “hyperaroused”. However, we cannot be constantly wide awake because this is extremely exhausting—energy-consuming. Finally, repeated negative events can stabilize this misalignment in the long term.

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3.2.7 More Pain after Childhood Adversities In the introductory chapter, it was already reported about pain in newborns. There it was pointed out that early pain situations can have long-term consequences: fibromyalgia, migraine, chronic pelvic pain, irritable bowel syndrome and chronic urethral and bladder pain, which can all occur more frequently after early traumatic experiences. The connection between childhood adversities and chronic pain has been known for quite some time (Davis et al. 2005). Furthermore, the connection between the number of hardships and the severity of functional limitations caused by pain was described (Nelson et al. 2018; Groenewald et al. 2020). In a large epidemiological study of more than 6000 adolescents, a connection was shown between back pain, neck pain and headache on the one hand and previous experiences of violence on the other. The risk of these chronic pain problems was increased by 2–2.5 times in those affected. At the same time, these people had mental disorders that partly explained the pain (McLaughlin et al. 2016). Some scientists speak of an increased pain sensitivity, which is caused by central nervous system factors. Our brain has excellent possibilities to block pain from the body periphery, so to speak to block the inputs. Central to the suppression of pain are mechanisms in the brainstem and in the spinal cord. The inhibition takes place through central areas of the brain, among other things through descending pain-inhibiting pathways (Middlebrook et al. 2021) (blue path in Fig. 3.3). Although there is no perfect test to investigate these functions, various possibilities of testing have been proposed (Middlebrook et al. 2021). In one type of examination, increased pain sensitivity is tested as a reduced pain threshold to various stimuli. Descending pathways can also amplify the pain inputs, which gives the brain a controlled possibility of amplified pain perception (blue path in Fig. 3.3). After the experience of childhood trauma, doctors found increased pain sensitivity more often in those affected (e.g. (Tesarz et al. 2016; You and Meagher 2016, 2018; Atlas et al. 2018)). Since pain receptors are always slightly stimulated in the periphery, lower pain thresholds easily switch on pain perception. The person affected experiences the normally subliminal stimuli as painful or different. A mild touch of the skin maybe perceived as a burn. A slight pressure on a bone protrusion is noticed as pressure pain, etc. So patients with fibromyalgia often experienced childhood adversities (Low and Schweinhardt 2012; Jones 2016). Harmless-looking pressure stimuli are perceived by those affected as painful—this is the nature of neuropathy. There are several animal models—mostly on rodents—in which exactly this type of chronic, centrally mediated pain hypersensitivity can be investigated (e.g. (Alvarez et al. 2013; Prusator and Greenwood-Van Meerveld 2016)). Early traumatic experiences are coupled with increased pain sensitivity. In the animal experiment on the rat with previous separation experience (maternal deprivation), those animals with high estrogen levels had more pain than animals with low levels (Moloney et al. 2016), which speaks for the

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top postcentral gyrus conscious pain processing

frontal

insular cortex

occipital Cingulum

medial prefrontal cortex

medial

ACC

NAc

thalamus

PAG Amygdala Hippocampus

HPA axis cortisol

Raphe

LC

sympathetic noradrenaline

descending pathway

ascending pathways report pain

Fig. 3.3   Central nervous components of pain processing. We look from the midline of the brain at one hemisphere. The green and blue areas are significantly involved in pain processing (there are more areas involved, but not shown because of complexity). The red track from the periphery reports the pain via the thalamus to the cortex (postcentral gyrus), where we become aware of the pain and where it is assigned to a location. The blue descending pathway picks up information in the frontal lobe, anterior cingulate gyrus (ACC), nucleus accumbens (NAc), periaqueductal gray (PAG) and in the raphe nuclei (serotonin) and forwards it to the spinal cord in order to inhibit or increase pain inputs there (blue line). The insular cortex, the amygdala, hippocampus, LC (locus coeruleus = topmost noradrenaline center) and HPA axis are interconnected with all regions (not shown). This activates the topmost centers of hormones and the sympathetic nervous system during pain. At the same time, emotions arise in the limbic system (amygdala) and a memory of the pain in the hippocampus. The frontal lobe is responsible for the evaluation of the pain. Further aspects are illustrated in Fig. 3.1. Abbreviations: LC, locus coeruleus (noradrenaline center); NAc, nucleus accumbens (reward center); PAG, periaqueductal gray

influence of biological sex. Estrogens can increase the feeling of pain, and that affects women more than men (Straub 2007). A special brain area is the nucleus accumbens (NAc), which we have learned about in the reward system (Fig. 3.1). Why does the reward system have something to do with pain? The answer is: The occurrence of pain is experienced as punishment and the alleviation of pain as a reward. Sounds trivial, is well researched, and endogenous opioids are of great importance for this positive feeling (Navratilova et al. 2015). So if we are rewarded (opposite: punished), we learn more easily to avoid the action leading to pain

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and to carry out the right measure to combat pain, because a reward memory is created (opposite: a punishment memory). The inputs for these pains can also come from the gastrointestinal tract or from the regions of the bladder and genital organs (red line in Fig. 3.3). This can result in stomach pain, irritable bowel syndrome or chronic urethral and bladder complaints (Miranda 2009; O’Mahony et al. 2009). The insular cortex is primarily responsible for the conscious perception of visceral pain from the abdomen (Fig. 3.3 and explanation 6). Explanation 6 Perception of the inner world—the insular cortex

You feel the sunshine, a bird tweet, a pleasant smell of spring, the taste of tiramisu, a tingling on your foot from a fly. Usually, these perceptions are related to the five senses: sight, hearing, smell, taste and touch. In addition, we feel whether our body is in balance and we recognize the position of our body or the position of our movable parts of the body; in short, you perceive the outside world. If we pay attention, we also perceive things from the inside of the body. So we feel our heartbeat, the filling of the stomach, the stretching of the intestine and the tension of the bladder wall. If the blood pressure rises, we notice a feeling of pressure in the chest or neck area. For these individual sensations, we have specific receptors (receptors on nerve fibers; Nobel Prize in Medicine 2021) in different body areas that send information to the brain. Therefore, there are regions in the brain that tell us something about things from the outside world and the inside world. Things from the inside world are perceived in a special region, the insular cortex (Fig. 3.3), and they can be very versatile. For example, we feel the accumulation of metabolic products (lactate in the tissue), cell contents (when cells are destroyed), parasites (via the hormone histamine), infectious agents (e.g. bacterial components), cytokines (immune cell messengers) and hormones. We usually don’t have clear concepts for this and rather vague feelings that we can only connect with difficulty to a location in the body. While things from the outside world can be named very well (postcentral gyrus in Fig. 3.3), they can only be felt and described badly for the inside world. To give clear names to the consciously perceived things of the inside world, we need quite a bit of training and experience. A beautiful example of this is the start of a cold. The day before, we notice strange restlessness that is suddenly replaced by a bad feeling. Even before the mucous membranes in the nose and throat swell and hurt, we then have a feeling of “being affected”, “being weak”, “lack of motivation” and sometimes “being numb”. Instinctively, we switch from high activity to a low level. Friends of home remedies now consciously use those small helpers such as tea, warm beer, herbs and others in a prophylactic way. ◄ Intensified pain does not only result from a reduced inhibition of pain input, but is also caused by expectations, which in turn can be based on an anxious or depressive mood.

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Expectations can, in fact, influence the way pain is experienced (Atlas and alʼAbsi 2018). Furthermore, attention to pain can be increased by childhood trauma (Lane et al. 2018). Finally, sleep is of great importance because sleep disorders increase pain sensitivity (Mathur et al. 2018). Pain, in turn, leads to sleep disorders, and thus a vicious circle can develop.

3.2.8 Summary Many brain regions in Fig. 3.3 play an important role in the previous descriptions of central nervous locations for addiction, anxiety, depression and sleep disorders (Fig. 3.1 and 3.2). Since these regions described earlier are closely related to early trauma, the connection between pain—especially pain sensitivity—and childhood adversity is explained. The medial prefrontal cortex and the anterior cingulate gyrus (ACC) are inhibited and/or reduced in size and there is a dopamine dysregulation in the nucleus accumbens and elsewhere (Rauschecker et al. 2015), which severely impairs the descending inhibitory pathway (Fig. 3.3). These regions influence the evaluation of pain, the memory of pain, the expectation of pain, the emotions associated with pain, and the “Gain Control”, which is what the doctor means by the control of peripheral pain inputs (Rauschecker et al. 2015). The embedding of pain processing in the brain regions discussed is schematically shown in Fig. 3.4. The elements of Fig. 3.4 are often connected to each other, that is, they influence each other in inhibitory or stimulatory ways. You can see this, for example, in the magenta connection lines between insular cortex, amygdala and locus coeruleus with the output of the central sympathetic nervous system, the caudal and rostral ventrolateral medulla (in the medulla oblongata, shortly C/RVLM in Fig. 3.4). These connections will be picked up again later in the book. Without much effort, I can imagine the normally functioning brain in a balanced situation: The weighing scale in the middle of Fig. 3.4 shows a horizontal position. Damages either by too much influence on one side of the balance (too many synapses, too many cells, over-activation, too strong connection between regions, enlarged brain regions) or too little influence (loss of synapses, cell death, under-activation, weak connection between regions, shrinking of brain areas) deflect the scale in the wrong direction, which leads to follow-up problems like addiction, anxiety, depression, chronic pain, sleep disorders and other neuro- and psychopathologies. The long-term programmed change after childhood adversities deflects the scale—so to speak reprograms its basic setting—and thus leads to neuro- and psychopathological follow-up problems, especially when further events occur, which deflect the scale in the same direction. The memory is programmed in a wrong way. These central nervous follow-up problems can cause plenty of difficulties also in the body periphery.

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Evaluation Memory Consciousness

Emotional processing of pain

Insular cortex Emotion social role memory ex. control

Frontal brain: medial prefrontal cortex

Place of pain perception

Post central brain

Hippocampus

ACC: anterior cingulate gyrus Reward

Nucleus accumbens

Locus coeruelus [reticular formation]

balance

NTS (N. Vagus) C/RVLM

Hypothalamus Pituitary HPA axis Cortisol

Fear, emotion memory

Amygdala

PAG Thalamus Ascending pathways report pain

Descending pathways inhibit or increase pain input

Memory Central noradrenaline Sympathetic noradrenaline

Ascending pathways report pain from the chest and abdominal area, among others

Fig. 3.4   Important brain regions for the consequences of early trauma. This figure schematically summarizes the elements from Fig. 3.1, 3.2 and 3.3 and others. Due to the complexity of the situation, this figure must be interpreted as greatly simplified. Descriptions are given in the text. Abbreviations: ACC; anterior cingulate gyrus; C/RVLM; caudal (C) and rostral (R) ventrolateral medulla (in the medulla oblongata); ex. control, executive control (self-control, emotion regulation, planning ability, working memory, and conscious attention control); HPA axis, hypothalamus-pituitary-adrenal axis; NTS, nucleus tractus solitarii (inputs from the chest and abdomen); PAG, periaqueductal gray (periaqueductal gray)

3.3 The Body Periphery Suffers as Well With regard to the body periphery, I would like to focus on body weight first, because it is often the starting point for follow-up problems when it is in the range of a BodyMass-Index of 30 kg/m2 or more (explanation 7). Diabetes mellitus of the aging person is then much more common. On the other hand, follow-up problems such as hypertension, cardiovascular diseases, stroke, osteoarthritis of large joints (knee, hip, etc.) and tumors occur more frequently. These people are more susceptible to viral diseases like COVID19 (Mahamat-Saleh et al. 2021). If obesity is combined with an addiction problem—for example smoking—the negative effect is amplified and the risk for the consequences goes up. We recognize the snowball effect again. This is why I treat heart attacks and other cardiovascular events, lung diseases, gastrointestinal diseases, and age-related problems, and finally address the epidemiological link between early trauma and activation of the immune system. The next main chapter explains why chronic immune activation can occur.

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Explanation 7 Obesity—the Body Mass Index

The doctor speaks of obesity from a body mass index of 30 kg/m2 (body mass index = weight in kg, divided by height in m squared). People are called normal weight if the body mass index is between 18.5 and 25 kg/m2. There is overweight between 25 and 30 kg/m2. The body mass index is only an approximate measure because it does not take into account the body composition, that is, whether muscle or fat tissue. It is favorable to have a lot of muscle and unfavorable to have a lot of fat tissue. People with a high body mass index can be quite healthy if the body weight in kilograms is essentially determined by the muscles. To better assess this situation, the doctor would have to examine the body composition using bioimpedance analysis or magnetic resonance imaging. ◄

3.3.1 High Body Weight The topic obesity has already occupied me in my two previous books, and the considerations led to a comprehensive table, which I reproduce here and now add more points. Elements or consequences of early childhood stress were already mentioned in this table. These include food shortages for the child in the womb (Barker phenomenon, see 2.1), the reward behavior with the possibility of developing an addiction (see Sect. 3.2.1), the lack of self-control as a result of trauma (impairment of executive function, Table 2.4) and the socioeconomic status, which—nowadays widely recognized—is an adverse experience according to Urie Bronfenbrenner (2.1.1). An example of an extensive study of children with low socioeconomic status and a developmental course with high Body-Mass-Index can be found in Bae et al., who interviewed over 11,000 people over a period of 13 years (Bae et al. 2014). This work is confirmed by other researchers (e.g. Wickrama et al. 2014). This table must now be extended to include additional early traumatic experiences after further study. The increased body weight is certainly not determined solely by the early traumatic experiences, but is often based on a combination including the genetic disposition (the 25% from Table 3.2) (Beach et al. 2020). Early childhood adversities, on the other hand, are not associated with the opposite—that is, underweight—as a study of over 105,000 students in the USA showed (Davis et al. 2019). If mothers experience objective hardships when the children are about 5 years old, this affects the children’s body weight at the age of 11 years. If the mothers were highly stressed, the child’s obesity risk was 2.3 times higher (Hope et al. 2019). Here we see the important influence of the mothers again, which extends even into the time of the pregnancy. For example, American-New Zealand scientists were able to identify in more than 5800 pregnant women with objective risk factors such as smoking, older age, status as a single parent, low educational level, economic constraints, unemployment, living in a

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Table 3.2  Concepts for explaining obesity Name

Meaning

Calories*

In relation to body size and body weight, too many calories are consumed and too few are used.

Physical activity*

Physical activity is too low. Too few calories are burned.

Wrong calories*

Wrong calories—namely carbohydrate calories— instead of protein or fat calories induce obesity more, because more insulin is released (the storage hormone No. 1). This theory is now being questioned again because newer comparative studies did not confirm the concept.

Genetics*

About 25% of obesity is due to genetic factors. However, the 97 known genetic factors only explain 2.7% of all cases of obesity. This means: The combination of genetic factors with each other and the combination of genetic factors with environmental factors are not yet understood.

Epigenetics

Barker phenomenon*

Food shortages for the child in the womb lead to faster weight gain in childhood. The weight once acquired is maintained.

Fat mother, fat child*

A luxury situation in the womb leads to obese children who are obese in adulthood.

Anatomical requirements*

The number of fat cells is determined after birth and in early childhood and remains the same throughout life. The amount of brown, energy-consuming and heat-generating fat tissue is adjustable. Most obese people have little brown fat tissue.

Chemical environmental factors

Factors such as polyfluorinated chemicals and Bisphenol A have been suspected because they act on body’s own hormone receptors. The matter is not clarified, but important and exciting.

Smoking*

Smoking reduces body weight and quitting smoking increases body weight. Nicotine can slow down food intake, and smoking shifts the microbiome to lower food utilization.

Disruption of the gut-fat-brain axis*

The success of bariatric surgery (obesity surgery) points to important connections between the gut and brain that depend on the storage state in the fat tissue. Leptin is the prototype of the connecting hormones. Here, the so-called microbiome can have an additional influence, because an obesity-promoting microbiome can break down energy carriers and increase the utilization of nutrients. Smoking disrupts this. (continued)

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Table 3.2   (continued)

Name

Meaning

Pro-inflammatory situation in the fat tissue*

Obesity is associated with more inflammation in the fat tissue and this mild inflammation prevents the adequate release of fatty acids from the fat tissue. Pretty sure the inhibition of sympathetic influence in the fat tissue is important. Since the sympathetic nervous system promotes fat release, its inhibition is obesity-promoting.

Behavior

Reward*

Food is considered a reward. The reward memory plays an important role. Similar to addiction, this is more pronounced in the obese.

Self-control*

Lack of self-control and impulsiveness towards food cues lead to increased food intake. This is associated with increased sensitivity and emotionality towards food cues. Change of executive functions (Table 2.4).

Overcompensation*

In stressful life circumstances, too many calories are consumed that exceed the expenses through the stress. Here alcohol has a meaning (verified in men).

Cool types*

In stress-inducing life circumstances, the stress axes are only slightly activated in relaxed people. Somehow they stay cool. This way, the stored energy reserves cannot be accessed.

Ignorance*

The calories consumed in excess are not recognized and ignored. The lack of self-control leads to high calorie intake. The corresponding episodic memory for the relationship between food stimulus and “obesity problem” does not work properly.

Socioeconomic status

A lower socioeconomic status is associated with a higher rate of obesity. Quite certainly, cheap, readily available, heavily marketed, calorie-dense foods with quickly digestible energetic substrates are important (keywords: snacks, junk food, etc.).

Early traumatic experiences

The events mentioned here are those in Table 2.1 and 2.2.

*Already mentioned in previous books. Table from (Straub 2020).

social housing, welfare recipient, and high population density in the apartment how their children developed a higher body weight after 2 and especially after 5 years. These risk factors determined 17% of the variation in the Body-Mass-Index (Explanation 7) or, in other words, 17% of the causes of child obesity were explained by this stressful environment (Farewell et al. 2018). This is a very high value when you compare it with the 2.7% that results from the 97 known genetic obesity factors (Table 3.2).

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Iowa is a US state that is regularly hit by devastating flood disasters, even though the state is not located by the sea but in the middle of the continent (Iowa Flood Center 2021). The floods occur as a result of a unique river system between the Mississippi in the east and the Missouri in the west in a densely populated country with wide, relatively flat river valleys. The homepage of the Iowa Flood Centers impressively shows the extent of flood disasters. In June 2008, there was a devastating flood, and the authors of a study included 217 pregnant women who were affected by the floods. They recorded objective measures of adversity and subjective measures of perceived stress, and they noted the time during the pregnancy (i.e. first, middle, or last trimester). If the mothers were burdened during the first trimester of pregnancy, the extent of the burden predicted a higher increase in the body-mass-index of the child at 2.5 and 4 years (Dancause et al. 2015). Regardless of the flood-related burden, the body-mass-index of the mother or maternal nicotine abuse predicted the body weight of the children at both assessment points. This sounds like a double hit, because pre-existing burden (maternal factors) and prenatal trauma have to be present at the same time to have an effect. In a follow-up study, the authors found cognitive problems and language difficulties in the children if the mothers were burdened during pregnancy (Laplante et al. 2018). Very similar results can be found in many studies: stress in the uterus or in early childhood leads to later adiposity (Thomas et al. 2008; Entringer et al. 2010; Davis et al. 2014; Tanenbaum et al. 2017; Wickrama et al. 2017; Robson et al. 2020), and the early influence during pregnancy is more problematic than at later stages of pregnancy (Li et al. 2010; Spencer 2013; Dancause et al. 2015). The children are thus set on life courses that lead to a much higher weight level if we compare them with people without previous adversity (Fig. 3.5). Furthermore, they develop the metabolic syndrome with the four cardinal signs of obesity, hypertension, insulin resistance (insensitivity to insulin in muscle, fat tissue and liver) and disturbed lipid metabolism (Delpierre et al. 2016). These factors are the platform for the development of diabetes mellitus in susceptible individuals (Campbell et al. 2018; Amemiya et al. 2019; Lown et al. 2019; Salas et al. 2019). When I write “susceptible”, this points to a second or even third factor that must also be present (in the sense of the double hit). This could, for example, be a genetic variant that promotes diabetes mellitus in old age. Similarly, a second traumatic experience in adulthood can stimulate this development (Farr et al. 2015). Women with previous childhood trauma are more likely to develop gestational diabetes (Schoenaker et al. 2019). Early traumatic situations lead to similar problems in animals. In this respect, obesity is well studied there—for example, as a result of separation from the mother (maternal deprivation). The animals develop similar to humans a metabolic syndrome (Eller et al. 2020). Other researchers looked at prenatal influences and saw how stress in the mother during pregnancy leads to increased body weight in the offspring (Mueller and Bale 2006). The offspring also showed altered eating behavior, which contributed to weight gain (Lesage et al. 2004).

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34 The BMI development line passes through various percentiles to always higher values.

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Age (years) Fig. 3.5   Life courses of the Body-Mass-Index for boys (similar for girls). Three lines for normal, overweight and obese boys are shown. Furthermore, the red line shows an example of how the development from an initially normal level over the years leads to an obese level (thick red line). The figure shows a case with rapid weight development in an exemplary manner. The data for the normal line, the overweight line and the obesity line come from the “Contributions to Health Reporting of the Federal Republic of Germany” of the Robert Koch Institute from the year 2013, which are published there as a table (Robert Koch Institute 2013)

When we ask about the causes of increased weight development, the items in Table 3.2 come into consideration, and some factors stand out. Eating behavior changes greatly (Table 3.2 under the heading “Behavior”). With regard to the genetic predisposition, variants are involved that mainly have tasks in the central nervous system, which also points to causes in the brain, such as eating behavior and similar. So I could have dealt with obesity in the previous Sect. 3.2 because there are a large number of influencing brain factors.

3.3.1.1 Fat-Making Eating Behavior People who have experienced previous traumatic events often have a fattening eating behavior. In stressful life circumstances, too many calories are consumed (overcompensation; Hitze et al. 2010), the wrong calories are consumed in the form of high-calorie snacks (type chocolate bar) (Spencer 2013), the consumed calories are not perceived as problematic and ignored, and in the absence of self-control, fattening foods are preferred (summarized in: Straub 2018, 2020). Food can be considered a reward, and similar to an addiction to alcohol, cigarettes or drugs, the eater rewards himself, and he switches on similar brain areas that we have learned about in the other addictions (Spencer 2013) (Fig. 3.1).

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A study found the phenomenon of “eating without hunger” in traumatized children, which typically takes place after the regular meal—that is, in between two regular meals. Likewise, the children show increased food intake when they are anxious, and anxiety can be a consequence of child adversity (Sect. 3.2.3). The problem can increase with the age of the affected children (Miller et al. 2018). Other researchers demonstrated the susceptibility to so-called external stimuli such as the smell and sight of food, as you experience them when you pass by a beautiful display of a grocery store (van Dammen et al. 2019). The external stimuli are added to the internal, bodily stimuli and increase the intake of highly palatable snacks outside of regular meals. Some called this behavior “Junk Food Self Medication” (Hemmingsson 2018). All of these things are coupled with an inactive sedentary lifestyle (Wickrama et al. 2017). More recent studies show a positive effect of lifestyle change. In a longitudinal study, the authors showed in almost 110 women with a Body Mass Index of 29 kg/m2 and more, in comparison to a control group, how those who were exposed to early traumatic situations benefited particularly and had a 3.6 kg/m2 lower Body Mass Index after six years (van Dammen et al. 2021). Furthermore, bad childhood experiences are often associated with severe eating disorders such as binge eating or addiction to eating (Schmidt et al. 1993; Vartanian et al. 2014; Su et al. 2016; Quilliot et al. 2019; Stojek et al. 2019), but not all researchers were able to identify this relationship (Björkenstam et al. 2016). The eating disorders often occur together with other addictions (Hodson et al. 2006). Experiments with animals can help to characterise the affected areas in the brain more closely, because animals under stress-filled conditions prefer junk food (Machado et al. 2013). The neurotransmitters of the reward system such as dopamine and serotonin appear more frequently in the considerations (de Souza et al. 2020; Tavares et al. 2020). Finally, the HPA axis from Fig. 3.2 plays an important role (Spencer 2013). All of these neurotransmitters and hormone systems target the regulation of eating in the hypothalamus, where we have a feeding center and a satiety center, both of which are involved in food intake (Spencer 2013). The feeding center prevails over the satiety center. The scale is deflected in the wrong direction. If the deflection is chronically fixed, that is, the basic setting is in an unbalanced position, the correction will be difficult.

3.3.2 Heart Attack and Co. The evacuation of children to rural areas in war is a problem because this separation and the fear for the parents represent a severe trauma. This took place in several places during the Second World War. I have mentioned the fate of Michael Rutter (Sect. 2.1.3) and his sister (Michael Rutter, psychiatrist, 1933–2021). In Finland, as a result of the wars with the Soviet Union during the Second World War, there was an evacuation of children to other locations. After this, Finnish researchers included a very large number of children born between 1934 and 1944 in their considerations (Eriksson et al. 2014).

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Of the people enclosed, 1781 people were evacuated to Sweden and Denmark. The children were between 2.5 months and 10.6 years old at the time of separation, and the duration of separation was between 18 days and 8 years. A comprehensive follow-up study was carried out between 2001 and 2004. In this study, the typical mental disorders such as depression and cognitive dysfunction were examined in addition to physical problems such as reduced athletic performance, hypertension and high cardiovascular risk (Eriksson et al. 2014). The rate of cardiovascular diseases and mortality was higher in evacuated children than in children of the control group. If the children were young, they were more often affected, and a long separation led to more problems. The risk of a cardiovascular event was 2 times higher than in controls (Eriksson et al. 2014). In terms of a dose-response effect, the risk of a heart attack depended on the number of childhood adversities (Gilbert et al. 2015; Chou and Koenen 2019; Pierce et al. 2020). Interestingly, the principle of double hit comes into play again here, as it is precisely the combined stress of early traumatic experiences plus adverse life experiences in adulthood that increases the risk of cardiovascular events (Halonen et al. 2015). As early as the 2000s, New Zealand researchers pointed to another connection. They showed the importance of socioeconomic status, which under unfavorable conditions increases the risk of cardiovascular diseases (Poulton et al. 2002; O‘Rand and HamilLuker 2005). Part of this may be due to higher blood pressure, which has been observed again and again in these affected people and in other children/adolescents who have been traumatized (Lehman et al. 2009; Stein et al. 2010; McIntyre et al. 2012; Su et al. 2015; Wickrama et al. 2015; Appleton et al. 2017; Murphy et al. 2017; Jakubowski et al. 2018). The increased blood pressure response occurs more often in men than in women (Schreier et al. 2019). Early traumatic experiences are also more often associated with kidney diseases up to kidney failure (Ozieh et al. 2020; Weldegiorgis et al. 2020). Poor kidney function can promote hypertension. Animals showed a higher blood pressure reaction to stress if they were exposed to early traumatic experiences (Igosheva et al. 2007; Loria et al. 2010a, b, 2013; Alastalo et al. 2013a). The animals showed an increased reaction of the adrenal gland with the release of larger amounts of cortisol, the stress hormone, and the circadian rhythm of heart rate was disturbed (Mastorci et al. 2009). About the metabolic syndrome and diabetes mellitus as the cause of cardiovascular problems, I have already spoken in the preceding chapter (e.g. Delpierre et al. 2016; Burgueno et al. 2020). The special activation of the sympathetic nervous system, which can lead to high blood pressure through fluid retention and vasoconstriction, is mentioned below (Sect. 3.3.5). A disturbed lipid metabolism, oxidative stress, physical inactivity and a generally accelerated aging process are also discussed in the Sect. 3.3.5. Furthermore, there is the increased general inflammatory state, which additionally stimulates the inflammation-related arteriosclerosis of large and small vessels. I will address it more specifically in the next main chapter.

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Finally, the American Heart Association has recognized the fact of “early traumatic experiences leading to more heart attacks” and has begun to pay more attention to these findings (Suglia et al. 2018).

3.3.3 Chronic Lung Diseases We start with one of the largest studies on the subject, which was conducted in the USA. Here, the researchers examined the relationships between early traumatic experiences on the one hand and chronic obstructive lung disease or asthma on the other. The authors included more than 100,000 people in their analysis and were able to determine how smoking partly explained the aforementioned link to chronic obstructive lung disease and asthma. In other words, the addiction, namely nicotine abuse, preceded or accompanied the lung problems. The more hardships were endured, the more often chronic obstructive lung disease and asthma occurred (Waehrer et al. 2020) (Fig. 3.6). This large study confirmed an earlier study from Sweden (Hjern et al. 1999). But first let’s come to the stressful life situations during pregnancy. While in the above study by Waehrer and colleagues smoking still contributed as a risk factor to explain, it is different in the following situation. Japanese mothers with a stressful pregnancy had more children with asthma. In particular, maternal irritation and anger were predictive factors for asthma. 10% of the women smoked, but it had no effect on the results (Kawamoto et al. 2020). The development of asthma could be significantly attenuated by breastfeeding the infant if only one trauma was present. If the child had two or more traumas, breastfeeding was no longer effective (Abarca et al. 2019). If mothers were more heavily burdened during pregnancy and had experienced five or more stress-inducing episodes, their children showed objectively measurable signs of asthma at the age of seven, and boys were more affected than girls (Lee et al. 2017a). The stronger burden on boys compared to girls was described by others (Bose et al. 2017; Rosa et al. 2018). At the same time, a European working group carried out a meta-analysis and brought together 30 studies on prenatal stress. The stressful burden of the mother and thus of the child in the third trimester of pregnancy was more often associated with allergic rhinitis, asthma and atopic dermatitis. Especially the previous loss of one’s own child or of the partner were severe stress experiences that affected the lung problems of the later born child (Flanigan et al. 2018), and these stressors were confirmed by others (Khashan et al. 2012; Liu et al. 2015). And there we have it again, the double hit! If there was a traumatic burden on the mother during pregnancy and at the same time a high nitrate load acted on mother and child, the risk of asthma in the offspring was significantly higher, and it affected boys in particular. The time window of the effect was in two ranges, between the 7th and 19th week of pregnancy and the 33rd and 40th week (Bose et al. 2017). The combination of traffic-related air pollution and stressful life situations during pregnancy and childhood

Percentage of persons in relation to all persons included (%)

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Number of childhood traumatic experiences Fig. 3.6   Dose-response relationship between stress level and lung disease. 109628 people were included, and they developed asthma and chronic obstructive lung disease (COPD) spontaneously or in dependence on the number of hardships. The number of early traumas was closely associated with smoking. In all cases, a dose-response relationship is shown. The data come from the large epidemiological study by Waehrer et al. and are given there in numerical form (Waehrer et al. 2020)

asthma was examined in meta-analysis and confirmed (Exley et al. 2015). So the environment plays a role in programming that ultimately leads to asthma in the child. Stress episodes are not only relevant during pregnancy, as they also act during childhood and adolescence (Waehrer et al. 2020 or Bhan et al. 2014). In a study from Norway, the connection between early traumatic experiences and asthma or chronic obstructive pulmonary disease was confirmed, whereby the influences of the parents’ smoking and the parents’ asthma were taken into account and controlled or removed statistically (Sheikh 2018). Others recognized a connection between childhood adversities and the onset of asthma in adulthood (Scott et al. 2008). If adolescents had not yet developed asthma by the age of 16, previous stressful experiences promoted the development of asthma, even though nicotine abuse was taken into account and controlled or removed statistically (Oren et al. 2017). Experiences of violence in adolescence also promote the development of asthma, as described in a study of more than 6000 adolescents (McLaughlin et al. 2016). Animal models showed in the same way the connection between stress-inducing situations and later lung problems (Nogueira et al. 1999; Pincus-Knackstedt et al. 2006;

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Vig et al. 2010; Ouchi et al. 2018; Zazara et al. 2018). The increased inflammation in the lungs was particularly in focus. In humans, mild inflammation is relevant in the same way as in animal models with regard to the connection between traumatic experiences and later asthma (Packard et al. 2011). This finally leads us to the possible causes of asthma and chronic obstructive lung disease. In addition to inflammatory components, genetic factors, gender, smoking, the shift of stress axes, a changed microbiome on the body surfaces and in the respiratory tract and chemical stressors from the environment are important (Rosa et al. 2018). These things are particularly shown in the next main chapter.

3.3.4 The Stomach Aches and the Stool Consistency Bothers Every field in medicine treats people with a higher pain sensitivity. While this is the case for rheumatologists and orthopedic surgeons with patients with fibromyalgia, for urologists it is patients with chronic pain in the pelvic area or at the bladder/urinary tract (Schrepf et al. 2018), for gastroenterologists it is patients with irritable bowel syndrome and for dermatologists those with lipomatosis dolorosa (painful fatty tissue deposits on the abdomen, knee, elbow and buttocks). About 50% of patients visiting a gastroenterological specialist suffer from irritable bowel syndrome. After excluding serious problems—such as bowel or stomach cancer, chronic inflammatory bowel diseases, liver, biliary and pancreatic diseases, food allergies, disorders of food absorption, bacterial overgrowth, motility disorders of the digestive tract, autoimmune diseases and others—often only the diagnosis of irritable bowel syndrome remains, which is largely harmless, but still unpleasant (Drossman 2016). There is an irritable bowel syndrome if recurrent abdominal pain has existed for at least once a week over the last three months and at the same time problems of defecation, stool frequency and stool consistency are present. These things can be accompanied by flatulence. Detailed examinations and differentiations from other aspects of functional gastrointestinal disorders are left to the specialists (Drossman 2016). At the last meeting of the experts on functional gastrointestinal disorders in Rome in 2014, the biopsychosocial model was extended and the importance of stress in early life was discussed (Drossman 2016). In any case, there is a clear connection between early traumatic experiences and irritable bowel syndrome, as I already mentioned in the introductory Chap. 1 (Berens et al. 2020). Others reported increased air swallowing in patients after previous stress exposure in childhood and adolescence (Rajindrajith et al. 2018). These things affect the quality of life of the patients (Biggs et al. 2004). The more adversity there is, the more intense the irritable bowel problem (Park et al. 2016). Furthermore, the irritable bowel syndrome is associated with depression and increased anxiety , because the affected people suffer more frequently from both (Lee et al. 2017b). Women are more affected than men,

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and women have more pain, for which during the reproductive years estrogens can be responsible (Straub 2007). Higher pain sensitivity in irritable bowel syndrome has been studied in humans and is closely related to depression and increased anxiety (Elsenbruch et al. 2010a). Furthermore, these patients show a more extensive reaction in central areas of emotion regulation, as determined by functional magnetic resonance imaging (Elsenbruch et al. 2010b). Furthermore, altered connections between various brain regions are present, and this may be a central nervous cause of the high pain sensitivity (Icenhour et al. 2017). An accompanying inflammation, wherever it may come from, exacerbates the higher pain sensitivity and abdominal pain (Benson et al. 2012). It can, for example, be due to a higher permeability of the intestinal wall to bacteria, as has been shown in irritable bowel syndrome (Witt et al. 2019). Animal experiments also make the increased visceral pain sensitivity very clear (O’Mahony et al. 2009, 2017; Chaloner and Greenwood-Van Meerveld 2013; Pohl et al. 2015, 2017; Holschneider et al. 2016; Prusator and Greenwood-Van Meerveld 2017; Wong et al. 2019). The amygdala is important because changes can be found there that are associated with the increased sensitivity (Prusator and Greenwood-Van Meerveld 2017). Furthermore, early-stressed animals have increased inflammation when an additional inflammatory stimulus in the form of a double hit occurs (Veenema et al. 2008). Another observation in animals after prenatal stress is the later change in the composition of the gut bacteria (Bailey et al. 2004; Golubeva et al. 2015; Gur et al. 2019). A criterion for a poor bacterial composition is the reduced diversity of the various types of bacteria (Moussaoui et al. 2017). Furthermore, there are more pathogenic and less regulatory gut bacteria, as a study of stressed mothers and children showed (Zijlmans et al. 2015) and animal experiments suggest (O‘Mahony et al. 2017). Fig. 3.7 summarizes the situation. Furthermore, the composition of the bacteria in the intestine affects the brain in return. For example, the quality of sleep can be influenced by different bacterial compositions (Sen et al. 2021). At the same time, poor sleep affects the bacterial composition of the intestine in return (Sen et al. 2021). The information between the gut lumen and the brain is conveyed via afferent nerves of the vagus nerve, via inflammatory mediators from the gut wall via the bloodstream and via microbial metabolites that are recognized by nerve fibers (Sen et al. 2021). A microbial-induced disturbance of the circadian rhythm can be one of the causes of sleep disorders (Sen et al. 2021).

3.3.5 And When We Get Old? Then other things are added or intensify. In my book about aging, the dramatic experience of the menopause of women and the andropause of men over the age of 50 is reported. From this point on, the energy consumption changes impressively (Straub 2018). The energy consumption for physical activities decreases continuously and

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Psychosocial factors Life stress Personality Psychology (anxiety, depression) Coping / Cognition / Resilience Physical activity Social support

Physiology Gastrointestinal movement Pain sensitivity Modified bacteria Nutrition Inflammation Intestinal wall permeability

Functional gastrointestinal disorders e.g. irritable bowel syndrome etc. Symptoms Severity Behavior

Fig. 3.7   Biopsychosocial model for functional gastrointestinal disorders. The model is based on the summary by Drossman (Drossman 2016). The elements of the so-called bidirectional gut-brain axis are schematically incorporated into this figure. Psychologists use the term coping to refer to the coping strategy in dealing with stressful experiences

parallel to this, fat mass increases steadily (Speakman and Westerterp 2010). Under these conditions, we should not be surprised that the Body-Mass-Index (explanation 7) increases and follow-up problems develop. Above I wrote: “In addition, they [the traumatized] develop the metabolic syndrome with the four cardinal signs of obesity, hypertension, insulin resistance (insensitivity to insulin in muscle, fat tissue and liver) and disturbed lipid metabolism.” Animals also develop a similar disease pattern after stressful life experiences (Eller et al. 2020). Regardless of trauma, the metabolic syndrome is a problem of older age. It is accompanied by an increased activation of the sympathetic nervous system, while the activity of the HPA axis remains roughly the same (Straub et al. 2001). However, the hormones of the sympathetic nervous system (adrenaline, noradrenaline) and the HPA axis (cortisol) are relatively higher than many other hormones (for example, sex hormones). Higher

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sympathetic activity can contribute to hypertension, and high blood pressure has been linked to early trauma (Alastalo et al. 2013b). In addition, high blood levels of the hormones of the sympathetic nervous system (adrenaline, noradrenaline) and the HPA axis (cortisol) promote insulin resistance, in which insulin does not work sufficiently at the target cells of the liver, muscle and fat tissue. During insulin resistance, the blood levels of glucose and free fatty acids are increased because they are not taken up into the target tissue, and this contributes to follow-up problems. For example, susceptible people can develop age-related diabetes. In addition, the general inflammatory situation and oxidative stress increase slightly with age, additional reasons for a deterioration of the situation. As people age, adversities from their younger years worsen the situation. In addition to obesity, traumas also cause depression and anxiety disorders, sleep disorders and increased pain, all of which can also increase with age. In my book on aging, I explained how these things can rob energy as single, double, and triple hits, which can be especially problematic because this energy is missing for the desired activities of daily life (Straub 2018). These activities include desired physical and mental work. When these hits are combined with early trauma, the problems in old age are clearly visible. For example, the Finnish study of children sent to other locations during the war years showed that those individuals with hardships had poorer physical condition and poorer functioning brains (von Bonsdorff et al. 2019). The researchers again see a dose-response effect, because those with more hardships showed the physical and mental deterioration more pronouncedly (Alastalo et al. 2013b). The affected persons had a higher frailty (Haapanen et al. 2018) and their physical abilities were reduced (Anderson et al. 2017). If symptoms of depression are added, the process of frailty is exacerbated and aging is accelerated (Shrira and Litwin 2014).

3.3.5.1 Accelerated Aging When we talk about accelerated aging, the length of telomeres is often used as a measure of cell aging. What is that? The telomeres consist of repeating units of DNA at the end of chromosomes (Fig. 3.8). If these repeating pieces become smaller over the course of cell life, this is an indication of cell aging. Since almost all cells in all organisms age, the shortened telomeres are a widely accepted phenomenon of cell aging (Epel et al. 2004). The enzyme telomerase ensures the extension of telomeres and thus works against the cellular aging process (Fig. 3.8). If the molecular biologist artificially introduces telomerase into an otherwise telomerase-poor cell, the lifespan can be increased (Jaskelioff et al. 2011). But let’s get back to the topic of this book. The acceleration of the aging process after early traumatic experiences was an important topic in the last two decades, and the length of telomeres was taken into account for this (Blackburn and Epel 2012). If stress experiences occur already during pregnancy, the telomeres are shortened in young adults (Entringer et al. 2011). The more adversities occurred in early childhood, the shorter the telomeres were in adolescence (Shalev et al. 2013; Puterman et al. 2016) and in later life

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Fig. 3.8   The telomere and the telomerase. On the left, the chromosome is shown in black, at the end of which are the pink caps of the telomeres. Schematically, DNA (genetic material) is now shown in the telomere area (the pink area). The resolution increases from left to right until the individual letters (A, C, G, T) of the genetic code become visible on the right. The telomere consists of always the same DNA sections, i.e. the sequence of the genetic code in the telomere repeats itself constantly. On the right is the blue telomerase, which extends the end of the telomere. In this way, the total length of the telomere remains as constant as possible. The telomerase attaches DNA pieces that correspond exactly to the repeating code of the telomere

stages (Surtees et al. 2011; Savolainen et al. 2014; Mayer et al. 2019). These findings were confirmed in animals (Schneper et al. 2016). The researchers typically looked at the telomeres in the leukocytes present in the blood, and thus essentially take a look at the aging of the immune cells. In addition to the telomeres, the focus is on many other places where this accelerated aging is recognized. Girls reach the menarche earlier and are thus more fertile earlier (Belsky and Shalev 2016; Zhang et al. 2019). With functional magnetic resonance imaging, an acceleration of brain maturation was observed (Herzberg and Gunnar 2020; Miller et al. 2020). Electrical derivations of the brain on the skull surface (electroencephalography) show the finding of accelerated aging in a technically different way (Hassan et al. 2020). The consideration of epigenetic markers in blood cells is aimed at the same phenomenon of faster aging (Fiorito et al. 2017; Austin et al. 2018; Lawn et al. 2018; Pepper et al. 2018; Ridout et al. 2018; Sumner et al. 2019). Especially the DNA changes were related to tumor diseases, and so the question arises of the higher frequency of cancer in old age in people after early traumas.

3.3.5.2 Cancer Disease If I subsume cancer under the age-related diseases, it is due to the increased probability of occurrence in old age. In addition, most tumors are based on acquired genetic cell changes that are common in old age.

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Similar to work on depression and obesity, the groundbreaking work on cancer by Vincent J. Felitti and a group of scientists from the Centers for Disease Control and Prevention in Atlanta, USA, found that compared to controls, those with six or more childhood adversities had three times the risk of lung cancer. When the tumor was diagnosed, the individuals with childhood adversities were, on average, 13 years younger than those without adversities. So they experienced the cancer much earlier and had a shorter life expectancy. Increased smoking among the traumatized individuals also contributed to the stimulation of tumors (Brown et al. 2010). According to a large British study that reported on a birth cohort from 1958 (Child Development Study), those with two or more childhood adversities had twice the risk of cancer before the age of 50. This result persisted after important known cancer risk factors such as smoking, alcohol, and obesity were included and controlled for in the analysis (Kelly-Irving et al. 2013). Both studies from the USA and England suggest premature aging because the tumors occur earlier. In a comparative study between Finland and Japan, childhood adversities in Japan and especially poverty were associated with an increased risk of cancer (Amemiya et al. 2019). When the researchers looked at typical cancer risk factors such as smoking, alcohol, cancer-causing agents from the environment, chronic inflammation, obesity, etc., these cancer-causing risk factors were significantly more common in people with previous trauma, especially for smoking, alcohol, and obesity (Ports et al. 2019). In another large American study of 67,011 people, there was a relationship between childhood adversities and cancer risk with a maximum increase in the risk factor of 1.35 (which is not so much). In this study, smoking, alcohol, and obesity had a measurable impact on the aforementioned relationship (Waehrer et al. 2020). When we now think of possible causes of the greater frequency of cancer, in addition to smoking and alcohol, the immune system must be important. Why? In recent years, we have recognized how important the immune system is for the body’s own and continuous cancer fighting, which we do not experience consciously. This is shown to us by the new therapies with the so-called checkpoint inhibitors. Immunological checkpoints are central and important switches in immune cells that can inhibit the respective immune cell in its activity (Fig. 3.9). The inhibition of this inhibition by means of checkpoint drugs activates the tumor-fighting immune cells and represents an important cancer therapy. For the discovery of the first checkpoints and the checkpoint inhibition, James P. Allison, USA, and Tasuku Honjo, Japan, were awarded the Nobel Prize in Medicine for 2018. Therapies that block checkpoint number 10 in Fig. 3.9 can fight tumors and trigger autoimmune reactions at the same time. These works clearly show the special role of the immune system in the development of cancer. If tumors now depend on the good function of the immune system, a disorder of the immune system or a inhibition of the same is more often associated with the development of tumors. Similar questions were asked by the trauma researchers, and so they examined important immune cells that are involved in tumor defense.

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3  Consequences of Early Traumatic Experiences Uptake of the tumor material in the tumor area

Nucleus

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Presentation of tumor antigen and activation of T cells

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Fig. 3.9   Role of immunological checkpoints. Go through the figure from top to bottom using the numbers. 1) First, a phagocyte recognizes a piece of tumor with a green receptor while wandering in the tumor tissue. 2) Then the green receptor and the tumor piece are taken up and stored in a vesicle. 3) Now the tumor pieces are digested and 4) deposited on a red receptor. 5) This receptor with the small tumor piece migrates to the surface of the cell and 6) is presented to the environment there. Now the prepared cell migrates along the lymphatics into the lymph nodes. 7) There, the phagocyte—now called an antigen-presenting cell—presents this tumor piece to an immunological T cell via the red receptor, which randomly recognizes the tumor piece in the blue T cell receptor. 8) Additional receptors on the cell surface of both cells are involved in this process (dotted red and blue line). These additional receptors are called checkpoints because only if the two receptors match, the T cell is activated or inhibited. 9) If the T cell is activated, it begins to multiply identically. It migrates back into the tumor tissue and meets tumor cells that present the same tumor piece on their surface. 10) Then the checkpoints become important again. If they are inhibitory checkpoints, the tumor can inhibit the activation of the T cells and the deadly contents of the T cells cannot be released (11, red vesicles). If the experimenter blocks the checkpoint at 10) by means of suitable drugs, the T cell is activated and releases the contents that are deadly for tumor cells

In addition to the T-cells and antigen-presenting cells mentioned in Fig. 3.9, other important cells are so-called “natural killer cells”. If the investigator offers tumor material to the killer cells in the experiment similar as in Fig. 3.9, they react approximately like T-cells, in that they secrete deadly substances for tumor cells. However, killer cells related to T-cells must first be activated. This activation is inhibited by stress factors such as cortisol (HPA axis) and noradrenaline (sympathetic nervous system). In patients with breast cancer, those women with previous childhood trauma more often showed poor quality of life after tumor diagnosis, more fatigue and depressive symptoms, and the activity of “natural killer cells” was reduced compared to a control group without stressors (Witek Janusek et al. 2013). Such factors can be relevant for the body’s own control of the tumor. Another indication of a possible involvement of the immune system is the consideration of antibodies against herpesviruses. The blood concentration of antibodies is high when the body cannot control the herpesviruses and they are constantly present in the body (Fagundes et al. 2013). This chronic reaction is recognizable by the serum concentration of the antibodies, and this does not speak for the quality of the immunological fight against the viruses by T-cells and their partners, the B-cells. Since the same T-cells are important for cancer defense, a reduced function of these immune cells gives an indirect indication of the lack of body’s own immunological cancer defense. In a study of patients with breast cancer, a higher concentration of antibodies against herpesviruses was now found in those women with childhood trauma compared to the control group without adversity (Fagundes et al. 2013). The affected women had more depressive symptoms and poorer sleep quality, both of which impair the HPA axis and/or the sympathetic nervous system. These data speak for a reduced T-cell/B-cell function, which can partly explain tumor development. These relationships point to the involvement of the immune system, which can be either suppressed or activated nonspecifically. The suppression refers more to the T-cells

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and killer cells, which play a protective role in viral infections and tumors. The unspecific activation refers more to the B-cells and to the elements of the innate immune system, which has important tasks in the acute bacterial, fungal and parasitic defense on the surfaces of the body.

3.4 And Finally the Immune System is Activated First indications of a connection between early childhood stress or socio-economic adversity on the one hand and an increased inflammatory response on the other hand were made in the CARDIA study (CARDIA = Coronary Artery Risk Development in Young Adults) (Taylor et al. 2006). This study appeared eight years after the epidemiological study by Vincent J. Felitti (Sect. 2.1.5), which showed the follow-up problems after childhood stress (Felitti et al. 1998). In this CARDIA study, people in the USA were systematically examined from the mid-1980s to investigate the risk of coronary heart disease in young white and black people. 3248 people aged 32 to 47 years were re-examined 15 years after the study began and the C-reactive protein was determined in the serum. In addition, the researchers had complete data sets of these people describing the socio-economic status in childhood and childhood adversity (Taylor et al. 2006). The factors of childhood stress had a direct effect on C-reactive protein and an indirect effect on this inflammation marker via body weight. Children with traumatic experiences showed disturbances in psychosocial coping, which was positively associated with serum concentration of C-reactive protein. They were also overweight and this was also associated with a higher C-reactive protein (Taylor et al. 2006). However, it should be said right away: The C-reactive protein was within the normal range in almost all people at less than 5.0 mg/l and the mean was 1.76 mg/l, because the investigators excluded people with a serum value greater than 10 mg/l (it was assumed that an immunological/ infectious disease was present). This epidemiological study was preceded by studies in animals that showed a relationship between prenatal stress and increased inflammation in later life (Klein and Rager 1995; Vanbesien-Mailliot et al. 2007). Other experiments in animals showed clear immunological changes in adulthood, which can be better described as inhibited or altered immune response (Kay et al. 1998; Chisari et al. 2001; Coe et al. 2002; Llorente et al. 2002; Tuchscherer et al. 2002; Fonseca et al. 2005). Further work followed describing the connection between early traumatic events or socio-economic status and higher inflammation in humans (Danese et al. 2007; Carpenter et al. 2010; Slopen et al. 2010, 2015; Kiecolt-Glaser et al. 2011; Packard et al. 2011; Cole et al. 2012; Pace et al. 2012; Hartwell et al. 2013; Witek Janusek et al. 2013; Ehrlich et al. 2016; Elwenspoek et al. 2017; Janusek et al. 2017; Finy und Christian 2018; Pinto Pereira et al. 2019; Rasmussen et al. 2019; Dieckmann et al. 2020; Kuhlman et al. 2020; Kuzminskaite et al. 2020; Lacey et al. 2020). A later longitudinal

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study showed a clear connection between early childhood trauma and later increased levels of C-reactive protein (Slopen et al. 2013). Extensive meta-analyses summarized the situation: There is a positive connection between childhood adversities and slightly increased inflammation later in life. Factors such as body weight, concurrent depression, smoking and others have an additional influence (Slopen et al. 2012; Tursich et al. 2014; Baumeister et al. 2016; Muscatell et al. 2020). Do people with early adversities have higher inflammation later in life because they had more stress experiences in adulthood? One study looked at this question specifically and came to the following conclusion. Childhood trauma and stress-inducing episodes occurring shortly before the study slightly increased inflammation (Hostinar et al. 2015). If both factors were present at the same time in the form of a double hit, inflammation was higher than with just one factor alone. This theory of the double hit was confirmed independently by other authors (Lin et al. 2016). At this point, we ask how high the serum values of C-reactive protein or the often also measured cytokine interleukin-6 actually rise. In fact, the increase in these two inflammation values, as it results from the many studies mentioned, is not high. For C-reactive protein, serum values up to a maximum of 10 mg/l and for interleukin-6 a maximum of 10 pg/ml are achieved. Compared to a real autoimmune disease, these are relatively low values (there for C-reactive protein: 100–200 mg/l and for IL-6: 100–1000 pg/ml), and the lower serum values correspond approximately to a situation with a well-treated chronic inflammatory disease. I take up this point of the possibly mild inflammation in Chap. 5 in more detail.

3.4.1 Early Trauma and Autoimmunity C-reactive protein and IL-6 discussed in the former subchapter are rather markers of the innate immune system. With regard to the acquired immune system, the important question arose as to whether autoimmune diseases also occur more frequently after childhood traumas. First major publications date back to the 1970s, when a group of clinical scientists in Rochester, New York, investigated links between early childhood stress and juvenile idiopathic arthritis (the form of arthritis in children) (Henoch et al. 1978). Rochester in New York began at that time under Bob Ader, Nicolas Cohen and David Felten to become the first center for psychoneuroimmunological research (Ader 2007). Although the modern classification of childhood arthritis and a questionnaire in the style of the Felitti questionnaire (Table 2.1 or 2.2) were still missing at that time, the clinical picture and the suffering of the children were well known, and so the researchers included 88 girls and boys with arthritis and almost 3000 control persons in their considerations. A total of 28% of children with arthritis had a “broken family structure” due to divorce, single parenting, or death of a parent, and in the comparison group only 11% of children had a similar fate (Henoch et al. 1978). In addition, 9% of the children in the arthritis group had been adopted before the onset of the disease, and in the control group

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it was only 3%. Both findings differed at a high statistical level (Henoch et al. 1978). Further studies with similar statements followed afterwards (summarized until 2000 in: Herrmann et al. 2000). In 2013, these findings were confirmed in almost 700 children and about 1000 control persons: the risk of a childhood form of arthritis increased by a factor of 2 to almost 7 (depending on the type of joint inflammation and the type of childhood experience) if traumatic situations preceded (Neufeld et al. 2013). The longitudinal epidemiological study on the adult form of arthritis only came onto the market in 2004, which examined a connection between childhood or adolescent trauma and arthritis in adulthood in more than 9000 Canadians (Kopec and Sayre 2004). The authors relied on the Felitti questionnaire (Table 2.1), which must have been known to them. People with arthritis more often had traumatic experiences in their younger years, for example a longer hospital stay or episodes that were very anxiety-provoking (Kopec and Sayre 2004). However, the authors did not explain which form of arthritis was involved, and since there are very different types with more or less inflammation, these data are incomplete. For this question, similar epidemiological studies had to be carried out, since only they could definitely uncover the connection. Here the Canadian work from the year 2004 took on a pioneer role. So a groundbreaking report appeared in 2009 by Shanta Dube from the Centers for Disease Control and Prevention(CDC) in Atlanta, Georgia, which I mentioned in Chap. 1. She used the data from Vincent J. Felitti and Robert Anda from the late 1990s on more than 15,000 people (Dube et al. 2009), and she used the Felitti-ACE questionnaire from Table 2.1. If two, three or more childhood traumas were present, the risk of a chronic autoimmune disease was increased (Dube et al. 2009). These findings were confirmed in a German study of patients with rheumatoid arthritis, where the risk increased by a factor of 2.0 to 2.6 (Spitzer et al. 2013). Even for the much less inflammatory osteoarthritis, researchers found a link between early adversities and the onset of the disease (Fuller-Thomson et al. 2009). Another autoimmune disease is systemic lupus erythematosus (SLE for short), which is characterized by a colorful picture of disease manifestations, including kidney inflammation, vasculitis, brain involvement, joint inflammation, blood cell depletion, and other things. In the large American study of 67,516 nurses that began in 1989, 94 women had SLE in 2015, and for those with physical and emotional abuse, the risk for SLE was 2.6 times higher (Feldman et al. 2019). The work on SLE patients was recently confirmed in a group of black women in the USA (Cozier et al. 2020). In the autoimmune disease of multiple sclerosis, which affects the central nervous system, this link between childhood stress experiences and disease could also be observed (Spitzer et al. 2012). For psoriasis, confirmatory data are available in a small group of patients (Crosta et al. 2018). In patients with autoimmune type-1 diabetes mellitus, in which the insulin-producing pancreatic cells are destroyed by autoimmune inflammation, the link was confirmed by means of an epidemiological study in a very large cohort (Bengtsson et al. 2021).

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These studies suggest a possible transition from an increased inflammatory state to a chronic inflammatory disease that manifests as a chronic autoimmune disease. In the next chapter, I try to explain which mechanisms in particular can contribute to this development of chronic immune activation.

3.5 To the Point • Early traumatic experiences primarily affect the brain. Nevertheless, they have an effect on the periphery of the body and can cause various long-term problems there. • The number of early experiences is directly linked to the severity of the problem. • In the foreground are: alcohol and drug abuse, smoking, depression with/without suicide, anxiety disorder, sleep disorder, increased pain, obesity, heart attack, lung disease (e.g. asthma), gastrointestinal disorders (e.g. irritable bowel syndrome) and chronic inflammation. • With regard to the resulting problems of the brain, I spoke specifically about the mechanisms of addiction, depression, anxiety, sleep disorder and increased pain sensitivity, and I briefly touched on personality changes. • In Table 3.1 further psycho- and neuropathological sequelae are reported. These include schizophrenia, paranoid psychosis, bipolar disorder, autism spectrum disorder, dementia, fatigue, epilepsy and changed sexual orientation. • Sleep problems and increased pain are treated separately; both are more common in previous trauma. There is an increased sensitivity to pain. The central nervous system components of pain processing are discussed. • The interaction of the different brain regions is presented in an integrated approach, and the image of the weighing scale is used to represent a horizontal pointer on the scale as a normal situation. Childhood adversities can permanently change the programming of the weighing scale. A trauma memory with a disturbed position of the pointer of the weighing scale arises. • The disturbed position of the weighing scale affects the function of the HPA axis, the sympathetic nervous system, the parasympathetic nervous system, the descending inhibitory and facilitatory pain pathways (and thus the perception of pain), among other things, in the periphery. • With regard to the resulting problems in the periphery, I am dealing with a high body weight (and disturbed eating behavior), heart attack, asthma and chronic obstructive lung disease, irritable bowel syndrome, accelerated aging and the higher probability of cancer. • Last, the presence and extent of the slightly increased inflammation are illuminated. Various autoimmune diseases are more common after early traumatic events. These include the childhood form of arthritis (juvenile idiopathic arthritis), rheumatoid arthritis of adults, systemic lupus erythematosus (SLE), multiple sclerosis, psoriasis and autoimmune type-1-diabetes mellitus. Why this is so is explained in more detail in the following text.

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Ward IL (1972) Prenatal stress feminizes and demasculinizes the behavior of males. Science 175:82–84 Ward IL (1984) The prenatal stress syndrome: current status. Psychoneuroendocrinology 9:3–11 Weldegiorgis M, Smith M, Herrington WG, Bankhead C, Woodward M (2020) Socioeconomic disadvantage and the risk of advanced chronic kidney disease: results from a cohort study with 1.4 million participants. Nephrol Dial Transplant 35:1562–1570 Wickrama KA, Kwon JA, Oshri A, Lee TK (2014) Early socioeconomic adversity and young adult physical illness: the role of body mass index and depressive symptoms. J Adolesc Health 55:556–563 Wickrama KAS, Bae D, O’Neal CW (2017) Explaining the association between early adversity and young adults’ diabetes outcomes: physiological, psychological, and behavioral mechanisms. J Youth Adolesc 46:2407–2420 Wickrama KK, O‘Neal CW, Lee TK, Wickrama T (2015) Early socioeconomic adversity, youth positive development, and young adults’ cardio-metabolic disease risk. Health Psychol 34:905–914 Wicks S, Hjern A, Gunnell D, Lewis G, Dalman C (2005) Social adversity in childhood and the risk of developing psychosis: a national cohort study. Am J Psychiatry 162:1652–1657 Williams LM, Gatt JM, Schofield PR, Olivieri G, Peduto A, Gordon E (2009) ‚Negativity bias‘ in risk for depression and anxiety: brain-body fear circuitry correlates, 5-HTT-LPR and early life stress. NeuroImage 47:804–814 Wilson CA, Vazdarjanova A, Terry AV Jr (2013) Exposure to variable prenatal stress in rats: effects on anxiety-related behaviors, innate and contextual fear, and fear extinction. Behav Brain Res 238:279–288 Winsper C, Zanarini M, Wolke D (2012) Prospective study of family adversity and maladaptive parenting in childhood and borderline personality disorder symptoms in a non-clinical population at 11 years. Psychol Med 42:2405–2420 Witek Janusek L, Tell D, Albuquerque K, Mathews HL (2013) Childhood adversity increases vulnerability for behavioral symptoms and immune dysregulation in women with breast cancer. Brain Behav Immun 30(Suppl):S149–S162 Witt ST, Bednarska O, Keita ÅV et al (2019) Interactions between gut permeability and brain structure and function in health and irritable bowel syndrome. Neuroimage Clin 21:101602 Wong HLX, Qin HY, Tsang SW et al (2019) Early life stress disrupts intestinal homeostasis via NGF-TrkA signaling. Nat Commun 10:1745 Yang J, Han H, Cao J, Li L, Xu L (2006) Prenatal stress modifies hippocampal synaptic plasticity and spatial learning in young rat offspring. Hippocampus 16:431–436 Yeh CM, Huang CC, Hsu KS (2012) Prenatal stress alters hippocampal synaptic plasticity in young rat offspring through preventing the proteolytic conversion of pro-brain-derived neurotrophic factor (BDNF) to mature BDNF. J Physiol 590:991–1010 You DS, Meagher MW (2016) Childhood adversity and pain sensitization. Psychosom Med 78:1084–1093 You DS, Meagher MW (2018) Childhood adversity and pain facilitation. Psychosom Med 80:869–879 Zazara DE, Perani CV, Solano ME, Arck PC (2018) Prenatal stress challenge impairs fetal lung development and asthma severity sex-specifically in mice. J Reprod Immunol 125:100–105 Zhang L, Zhang D, Sun Y (2019) Adverse childhood experiences and early pubertal timing among girls: a meta-analysis. Int J Environ Res Public Health 16:2887

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Chronic Immune System Activation

4.1 Egoistic Brain and Egoistic Immune System are Fourfold Interconnected Brain and immune system are basically egoistic and each reacts according to the respective stimulus without consulting the other in order to eliminate the problem or the disturbing stimulus. A brain-specific stimulus is, for example, noise or psychological stress (e.g. an attack situation). An immune system-specific stimulus is an infectious agent or an allergen. I have reported extensively on the egoism of the two organ systems, which is expressed above all in the egoistically controlled self-allocation of energy (Straub 2018). The egoism refers to the, hierarchically considered, dominant position vis-à-vis other body systems in the egoistic regulation of all downstream organs and the enforcement of the energy self-allocation (Straub 2018). Nevertheless, there is a certain mutual influence of brain and immune system, which becomes apparent through the tone or “ambiance” of the other system preceding a stress response (more on this later in Sect. 4.2.1 and in Sect. 4.2.3.2 etc.). After early traumatic experiences, the disturbing psychological stimulus primarily affects the brain, and depending on the time window (Sect. 2.3) and type of stimulus, different brain regions are more or less severely affected, which is summarized in Fig. 3.4. Time windows are very important because different areas of the brain develop at different speeds (Fareri and Tottenham 2016). Adversities lead to a changed maturation of the brain and to structural and functional changes in different brain regions (McEwen et al. 2016), and these changes act back into the periphery in order to influence the immune system there. But how do these things now reach the periphery towards the immune system? For this purpose, so-called “connectors” are needed, as I once called them for simplicity when assessing a Collaborative Research Center of the German Research Foundation in Lübeck. © The Author(s), under exclusive license to Springer-Verlag GmbH, DE, part of Springer Nature 2023 R. H. Straub, Early Trauma as the Origin of Chronic Inflammation, https://doi.org/10.1007/978-3-662-66751-4_4

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There are at least four different connectors. Direct connectors (No. 1) with the direction “brain → immune system” are typically hormonal systems such as the HPA axis or the sex hormone axis, neurotransmitters of the nervous system extending from the brain to the periphery (they are called efferent: sympathetic nervous system, parasympathetic nervous system and the pain-regulating system emanating from the brain). In addition, direct connectors with the direction “immune system → brain” should be mentioned, such as circulating cytokines, circulating activated immune cells, hormones and neurotransmitters from immune cells and nerves extending from the periphery to the brain (they are called afferent: sensory nervous system and other afferent nerve tracts, especially in the vagus nerve). Furthermore, we know indirect connectors stimulated by the brain or immune system via other organ systems (No. 2), which release factors that can influence either the brain or the immune system (explanation 8). Explanation 8 Indirect connectors via other systems that influence brain and immune system

Although brain and immune system have their own connectors that have a direct influence on the other selfish organ system, there are indirect factors induced by the brain and the immune system in other organs that play the role of a connector of the two selfish organs. An example are the fatty acids, the basic components of all fats. Fatty acids are stored in the fat tissue, but can be released from the fat tissue under the influence of the brain or the immune system. Neither brain nor immune system can release fatty acids as a messenger substance from their own stocks in a quantitatively comparable way, but both—brain and immune system—can release the fatty acids from the fat tissue by messenger substances. These fatty acids can influence the brain and the immune system. In this way, fatty acids are indirect connectors via other systems (here the fat tissue system) that influence brain and immune system (Straub 2020a, b). ◄ Furthermore, there are connectors that are located in the environment of the individual and can be called extra-corporeal connectors of brain and immune system (No. 3) (explanation 9). Explanation 9 Extracorporeal connectors that influence the brain and immune system

These are factors that are changed by the brain or the immune system in the environment and that have an impact on the other selfish system. For example, the brain decides whether you want to smoke cigarettes, that is, whether you need cigarettes and smoking as “reward factors”. Smoking has an effect on the immune system via the respiratory tract, mostly in an activating and unfavorable way (for example in autoimmune diseases). Smoking is such an extracorporeal connector between brain and immune system.

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On the other hand, the immune system can influence the brain through extracorporeal connectors. The immune systems of different people can deal with a pathogen in different ways. As an example, the leprosy pathogen is mentioned here, which is quickly and effectively fought by one immune system, but poorly by the other. In the case of insufficient attack by the immune system, leprosy is not well controlled and it leads to long-term illness and death. This has, among other things, chronic socio-economic and family follow-up reactions during the often long-term illness of the affected person, which in turn have an impact on the brain. All of this is spared to the person with the effective immune system because he does not get leprosy. ◄ Then there are connectors from the field of genetics and epigenetics. A platform for this connection are genetic or epigenetic predispositions that, for example, lead to an unfavorable and disease-causing brain change after an early trauma. You will remember genetic and epigenetic elements in Sect. 2.5, where such conditions were mentioned. Let’s assume there is a defined genetic or epigenetic factor that directly worsens the follow-up problems after early adversities in the brain at nerve cell assemblies, and let’s assume that the same factor directly favors chronic immune system activation, then there is a connection between trauma sequelae and chronic immune system activation. Here we can speak of a pleiotropic connector (No. 4). I use the word “pleiotropic” here because it is used for this purpose in genetics. What is it? A gene with the fictitious name X that causes different things in two separate places in the body is called pleiotropic by geneticists (gr. pleíōn, engl. more; gr. tropein, engl. change). In other words, through a variant of gene X, more than one thing is changed in different places in the body. If the variant of gene X causes psychiatric consequences after trauma and at the same time stimulates chronic activation of the immune system, psychiatric problems and chronic inflammatory diseases can occur at the same time, even though the brain and immune system do not influence each other. I call such links “pleiotropic connectors” (No. 4). In the case of earlier trauma experiences, these four connectors create the link from the damaged brain to the immune system and vice versa. These four connectors must form the platform for chronic immune system activation (Fig. 4.1 gives a first overview). Basically, I am discussing the direction “brain → immune system” because this is how the problem of chronic immune system activation can be explained. Before we deal in detail with the four connectors and the associated examples of immune activation, we must briefly clarify how the brain stimulates the direct and indirect connectors.

4.1.1 Areas in the Brain that Stimulate Direct and Indirect Connectors Remember the strong connection between the amygdala and the output of the central sympathetic nervous system (the magenta colored lines in Fig. 3.4). These connections are shown in more detail in Fig. 4.2. However, this representation only scratches the

138 Abb. 4.1   The four connectors. 1. Direct connectors are messenger substances that are released by the brain or immune system and influence the other selfish system. 2. Indirect connectors come from subsystems (not brain or immune system) and are either released by the influence of the brain or immune system to manipulate the other selfish system (brain or immune system). 3. Extracorporeal connectors are located in the environment of the individual. The brain or immune system can control the exposure to these connectors, and so the other system is influenced because of the consequences of the exposure. 4. Pleiotropic connectors are of genetic or epigenetic nature, for example, promoting unfavorable brain changes and causing unfavorable changes in the immune system at the same time. The changes in the brain and immune system do not have to be mediated by direct or indirect links between the two organs. The parallel changes lead to unfavorable consequences in one and the other system

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Genetics Epigenetics pleiotropic No.4 connectors

selfish brain

Environment

D I R E C T No.1 C

No.3

extracorporeal connectors

O N N E C T O R S

Fatty tissue Muscle tissue Intestine Skin Lung No.2 Mouth amongst others indirect connectors

selfish immune system pleiotropic connectors No.4

Genetics Epigenetics

surface of the true complexity of the relationships, but it shows manifold possibilities to transfer central nervous derangement from Fig. 3.4 into the periphery via three main pathways. In the example of Fig. 4.2 this can lead to changes in the blood concentration of cortisol, noradrenaline and adrenaline as well as the local tissue concentration of substance P (which are shown at the bottom of Fig. 4.2). In addition to the main pathways, there are also bystander pathways, for example the sex hormone axis, which I will also address. However, the feedback of hormones and neurotransmitters to the brain is not given in Fig. 4.2, such as how cortisol directly influences various brain regions in order to generally counteract too high cortisol blood concentration. There are similar negative feedback possibilities for the sympathetic nervous system, and this function is mainly performed by neuronal links. Such feedbacks can be defective or no longer function properly under chronic illness. Cortisol, noradrenaline, adrenaline and substance P can now directly influence immune processes (more on this in the next chapters), and so we can identify them as

4.1  Egoistic Brain and Egoistic Immune System are Fourfold Linked Insular cortex

Post central gyrus

Frontal brain: medial prefrontal cortex

Amygdala Hippocampus

ACC. Anterior cingulate gyrus

Locus coeruleus (reticular formation)

Nucleus accumbens

NTS (N. Vagus) C/RVLM

Hypothalamus PAG

Thalamus

Ascending pathways report pain from the chest and abdominal area, among others

Spinal cord segment Hypothalamus (PVN)

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Ascending pathways report pain

Descending pathways inhibt pain input

Inter mediolateral nuclei in the spinal cord

CRH

Pituitary

ACTH

Dorsal root ganglion

Pain - nerve fiber

Sympathetic chain ganglia Sympathetic nerve fiber Adrenal medulla

Adrenal cortex Cortisol

Substance P

Noradrenaline

Adrenaline

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Fig. 4.2   The brain activates pathways into the periphery. The red lines show connections between different brain regions and the top center of the hypothalamic-pituitary-adrenal axis (HPA axis). These can be inhibitory or activating pathways. In any case, it becomes clear how present the connections are between critical regions of Fig. 3.4 and the HPA axis. Similarly, there are manifold connections between different brain regions and the top centers of the sympathetic nervous system (brown lines: locus coeruleus and C/RVLM, hypothalamus and C/RVLM). There are inhibitory and facilitatory influences. The blue lines show important connections between pain centers, amygdala, and peripheral pain fibers. Thus, it becomes clear how a disturbed balance of the brain regions mentioned in Fig. 3.4 can easily be transferred to hormonal and neuronal pathways in the periphery. This is only a small but nonetheless important selection of possibilities. Abbreviations: ACC; anterior cingulate gyrus; ACTH, corticotropin (other name: adrenocorticotropic hormone); C/RVLM; caudal (C) and rostral (R) ventrolateral medulla (in the medulla oblongata); CRH; corticotropin-releasing hormone; NTS, nucleus tractus solitarii (inputs from the thoracic and abdominal cavities via, for example, the vagus nerve); PAG, periaqueductal gray; PVN; nucleus in the hypothalamus (periventricular nucleus: top center for the HPA axis and sympathetic nervous system). The figure was created using information from the literature (Veinante et al. 2013; Bulloch and Daly 2014; Barman and Yates 2017; Contreras et al. 2017; Mendiguren et al. 2018; Herman et al. 2020)

direct connectors in the sense of Fig. 4.1. These direct connectors must be at least partially responsible for chronic immune system activation as a result of early adversity. Cortisol, noradrenaline, adrenaline and substance P influence other systems, for example adipose tissue, by promoting the release of fatty acids. In this way, they acquire a function in the release of indirect connectors such as fatty acids (explanation 8). These indirect connectors can then influence the immune system. The roles of individual connectors in the problem of chronic immune system activation will now be presented in the following text. Chronic immune system activation is the core issue of this book for me as a clinical immunologist and rheumatologist, which is why the reverse link from the immune system to the brain is not discussed here. This reverse connection can induce further problems that can exacerbate the consequences of trauma. A vicious circle can develop. The order of presentation is arbitrary, and I start with the direct connectors, followed by the indirect and extracorporeal connectors, and then the genetic pleiotropic connectors (“pleiotropic” see Fig. 4.1).

4.2 Direct Connectors Chronically Activate the Immune System (No. 1) The brain and immune system influence each other, which is ensured by the tone of the other system. The brain largely determines the tone of the sympathetic and parasympathetic nervous system, the HPA axis, the efferent pain system and the sex hormone axis in the sense of Fig. 4.2. This tuning is usually expressed in people with previous trauma experiences in a higher concentration of noradrenaline/adrenaline, cortisol and a hypersensitivity of the pain system (substance P), and a suppression of sex hormones and the parasympathetic nervous system (vagus nerve). This is due to the long-term adjustments of many centers in the brain, for example, the more active regions of the amygdala, the locus coeruleus, the caudal (C) and rostral

▶

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(R) ventrolateral medulla in the medulla oblongata (C/RVLM) and other regions shown in Fig. 4.2. Other regions are less active (hypofunction), such as the medial prefrontal cortex in the frontal lobe, the anterior cingulate gyrus and the hippocampus, including the connecting tracts to the aforementioned more active areas. In other words, since the latter inhibit the former, the former become overactive. Eus van Someren, a scientist at the Netherlands Institute for Neuroscience in Amsterdam, has compared this brain situation after early trauma with the state of increased and constant arousal in a recently published review article on sleep disorders (Van Someren 2021). I wrote earlier: “He [the person affected by the trauma] is more sensitive to negative information and he becomes ‘hyperaroused’. (…) Finally, repeated negative events can stabilize this misalignment in the long term.” A “memory of the unfavorable inclination” of the weighing scale shown in Fig. 3.4 is formed. The deflection of the balance remains in the long term because the highly plastic brain can be changed so easily in fetal years, childhood and adolescence. What we feel as a benefit in these young years, when memory can be easily shaped, is a negative factor after trauma experiences because a chronic trauma memory is created. What do the changes in central nervous tone mean for the immunological periphery?

4.2.1 The Sympathetic Nervous System I’m talking about a very extensive nerve fiber system that reaches into almost all organs and tissues, and also the adrenal gland (more precisely, the inner part of the adrenal gland, called the adrenal medulla). With regard to the nerve fibers, the main transmitter is noradrenaline, followed by so-called co-transmitters such as neuropeptide Y. At low concentrations, noradrenaline primarily binds to the α-adrenergic receptor (2 types: α1, α2) and at high concentrations to the β-adrenergic receptor (3 types: β1, β2, β3). Here we see a different affinity between the neurotransmitter and the two different receptors: look at Fig. 4.3. Adrenaline from the adrenal gland behaves in the opposite way, because it has a higher affinity for the β-adrenergic receptor. The concentration of noradrenaline in tissue is dependent on the presence of corresponding sympathetic nerve fibers. If the number of sympathetic nerve fibers is low, the concentration is correspondingly low. In addition to noradrenaline, other neurotransmitters are present in the nerve ending. The best known of these is neuropeptide Y. In contrast to noradrenaline, it is produced in the cell body of the nerve cell and it is transported along the fiber to the sympathetic nerve ending (Fried et al. 1985; Lundberg et al. 1989). This cell body can be very far from the actual site of action, and it can take a long time for neuropeptide Y to arrive at the scene. In the sense of a co-transmitter, neuropeptide Y supports the effect of noradrenaline essentially via the β-adrenergic receptor, because it is not secreted at low activity of the nerve fiber (low firing rate, when alpha-adrenergic signaling prevails) (Rudehill et al. 1987; Lundberg et al. 1989).

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Concentration of noradrenaline adrenergic

pro-inflammatory

adrenergic

often anti-inflammatory (exception: antibody formation, B-cell, allergic reaction, leukocyte migration, leukocyte production in bone marrow, energy supply for active immune cells)

Fig. 4.3   The affinity of noradrenaline for its receptors and the consequences for inflammation. Noradrenaline has a higher affinity for alpha-adrenergic receptors than for beta-adrenergic receptors. So you need a small concentration of noradrenaline to achieve binding to alpha-adrenergic receptors. For binding of noradrenaline to the beta-adrenergic receptor, you need large amounts of the neurotransmitter. In the synaptic cleft around the sympathetic nerve ending, there is usually a basal concentration of about 10−7 mol/l (in the blood 10−9 mol/l). With strong stimulation, the concentration rises to about 10−6 mol/l, with weak stimulation it decreases to 10−8 mol/l. With alpha-adrenergic action, the observer often sees a pro-inflammatory constellation (Bierhaus et al. 2003; Miksa et al. 2009; Grisanti et al. 2011; Lu et al. 2014; Liu et al. 2020; Straub et al. 2020). This is the opposite with regard to the beta-adrenergic side (important exceptions are mentioned in the figure)

At normal firing rates on the nerve axon of 3–5 Hz, noradrenaline is mainly released, which acts via α-adrenergic receptors. At higher firing rates of 5–10 Hz and more, neuropeptide Y is additionally secreted. Noradrenaline thus acts on β-adrenergic receptors and neuropeptide Y supports it via Y receptors. The nerve ending can become impoverished in neuropeptide Y if the firing rate was high for some time, because the supply of neuropeptide Y can no longer keep up. With β-adrenergic effects, an inhibition of immune reactions is often observed (exceptions see Fig. 4.3), with α-adrenergic signaling almost always a pro-inflammatory situation appears. When we talk about the consequences of earlier traumatic experiences, there are several possible sympathetic responses that can be observed as a consequence. The basal or resting tone of the sympathetic nervous system can be increased, normal, or reduced. In the same way, the response to an actual stressor can be increased, normal, or reduced. In a large overview article from 2020, Holochwost and colleagues show how, after early trauma, an increased resting tone and a reduced sympathetic response to a stimulus are usually observed (Holochwost et al. 2021). However, this is not always the case, as, especially in the situation of a physically related, stress-inducing stimulus, excessive reactions have been observed (for example, in Rinnewitz et al. 2018). I will first present the importance of sympathetic tone, as it has a clear influence on inflammatory situations and inflammatory diseases.

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4.2.1.1 Hans Selye and the Pro-inflammatory Response of the Sympathetic Nervous System Hans Selye, who was born in Vienna at the turn of the century (1907), grew up in a Hungarian family of surgeons and began studying medicine at the age of 17 at Charles University in Prague. Selye made his doctorate in medicine there, then a doctorate in organic chemistry, then he moved to the USA to Johns Hopkins University, only to work long-term in biochemistry at McGill University in Montreal (Tan and Yip 2018). Selye is the “father of modern stress research”. He discovered why different forms of stress—toxins—caused similar physical symptoms such as reduced body temperature, loss of appetite, weight loss, feeling of illness, enlargement of the adrenal gland, stomach ulcers, shrinking of the thymus and lymph organs and other things. He called this disorder of the internal milieu (after Claude Bernard, 1813–1878) or homeostasis (after Walter Cannon, 1871–1945) the “general adaptation syndrome”, which has three phases: 1. Alarm reaction, 2. Resistance and 3. Exhaustion (up to death). This reaction is accompanied and promoted by a strong activation of the sympathetic nervous system and the HPA axis. The activation of the sympathetic nervous system was mostly understood here as a supporter or activator of the immune system. In the spirit of the fight-or-flight reactions, the sympathetic nervous system stimulates, in addition to the heart, circulation, lungs and muscles, the immune system. Hans Selye recognized early on how the B-cell-driven immune response is promoted by the sympathetic nervous system and, thus, leads to the formation of antibodies, which he called the “serological response” (Selye 1946). By the way, the immunologists at that time had no idea of the multitude of different immune cells or immune cell messenger substances (cytokines, etc.). From these first considerations to the early 1980s, the sympathetic nervous system was therefore largely regarded as a promoter of the immune system. With the advent of immune cell cultures, the T-cellular immune response in addition to the B-cellular antibody response, the consideration of individual adrenergic receptors and their stimulators and inhibitors, as well as the ability to easily measure immunological messenger substances such as cytokines, the picture changed, however. From the mid-1980s to around 2000, the sympathetic nervous system was considered an inhibitor of the immune response. Today we know the complexity of the sympathetic influence on the immune system quite well and have an insight into the possibilities of the sympathetic nervous system to increase and inhibit (Fig. 4.4). 4.2.1.2 The Tone of the Sympathetic Nervous System Promotes Inflammation First, we consider the influence of the entire sympathetic nervous system without going into individual fractions of this nervous system. Because if we turn off this nervous system by chemical-pharmacological methods, we do not exactly know where we have put our hand. We therefore do not see whether this or that subfraction of the sympathetic nerve fibers is responsible for the observed effect on the bone marrow, lymph node,

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4  Chronic Immune System Activation pro-inflammatory acute inflammation

chronic chronic and acute inflammation inflammation

Selye Today

anti-inflammatory

View of "serological" B cell responses Allergy and anaphylactic reactions

View on T cells & subtypes B cells and subtypes Macrophages Dendritic cells Natural killer cells Neutrophils Cytokines, antibodies, etc. etc.

Fig. 4.4   The effect of the sympathetic nervous system on inflammation. In the past (between 1945 and 1985), the sympathetic nervous system was considered pro-inflammatory, then for a while until around 2000 quite anti-inflammatory. As always, the truth lies somewhere in between. Today it is pro-inflammatory in some immune reactions and anti-inflammatory in others. With anaphylactic, the doctor means an allergic immediate reaction within seconds to minutes, for which the patient, for example, must be observed by the doctor for a few minutes after a COVID-19 vaccination

spleen, intestine, heart, lung, etc. This approach seems valuable to me because the generally high tone of the sympathetic nervous system after early traumatic situations is more general than organ-specific in nature. However, we do not know exactly, since an organ-specific measurement of the activity of sympathetic nerve fibers in humans and animals is lacking in a comparative approach. Scientists are sometimes forced to carry out animal experiments when new drugs are being tested, as the new preparations have to be tried out on animals first. Studies of this kind are carried out, for example, on mice and rats with chronic arthritis, which closely resembles the human arthritis in young people and adults. Experimentally, the researcher can trigger the autoimmune disease of chronic arthritis in mice and rats with a strong immune stimulus and the simultaneous administration of an autoantigen localized in the joint (Trentham et al. 1977). After immunization, the autoantigen is recognized by the patrol of immune cells in the joint area and attacked permanently; a chronic arthritis, an experimental autoimmune disease in the joint, develops. In this form of chronic autoimmune disease, the researcher can very well see the importance of the tone of the sympathetic nervous system. If, for example, he blocks the sympathetic nervous system before immunization/vaccination with the autoantigen, that is, if he drastically reduces the tone of the sympathetic nervous system, a much milder form of arthritis develops or it does not develop at all (Härle et al. 2005). Similar experiments by other groups confirmed this fact, and it is irrelevant how the arthritis was

4.2  Direct Connectors Chronically Activate the Immune System (No. 1)

with intact sympathetic nervous system

Joint swelling

Abb. 4.5   The blockade of the sympathetic nervous system inhibits the development of arthritis. Arthritis is triggered at time zero. A few days earlier, the sympathetic nervous system was blocked. If there is a blockade of the sympathetic nervous system, the joint inflammation is significantly less than in the presence of an intact sympathetic nervous system. Figure schematically according to data from Ebbinghaus et al. (2012)

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with blockade of the sympathetic nervous system

Observation time Triggering arthritis

triggered: Reducing the sympathetic tone before triggering arthritis significantly reduces the disease (Fig. 4.5) (Levine et al. 1986a; Basbaum and Levine 1991; Aloe et al. 1992; Lorton et al. 1999; Härle et al. 2008; Ebbinghaus et al. 2012, 2017; Schaible und Straub 2014; Klatt et al. 2016). This can be an interesting drug approach. In this example, we recognize the importance of the preceding tone of the sympathetic nervous system in triggering chronic joint inflammation. Several mechanisms are relevant that scientists gradually recognized (Schaible and Straub 2014). A key mechanism is the migration of leukocytes, which is supported by the sympathetic nervous system (Schedlowski et al. 1996). The migration of leukocytes, such as T lymphocytes or B lymphocytes, is very important in arthritis because only in this way can the antigen be recognized and attacked in the joint area or in the lymph node. So the sympathetic nervous system supports the exit of leukocytes from the involved and activated lymph nodes and from the spleen, and blockade of the sympathetic nervous system reduces the exit of these leukocytes and thus reduces joint inflammation (Klatt et al. 2016). Other researchers confirm the supportive effect of the sympathetic nervous system on the exit of leukocytes from lymphoid organs (Katayama et al. 2006; Wohleb et al. 2014; McKim et al. 2016; Ao et al. 2020). Interestingly, the leukocytes that have entered the bloodstream can go to the brain and trigger anxiety reactions (Wohleb et al. 2014; McKim et al. 2016). Currently, we already have a rough idea of the ​​ scene of the action, the subfraction of the sympathetic nervous system in lymph nodes, spleen and bone marrow. Others found β-adrenergic increased production of monocytes and granulocytes in the bone marrow. This led to an increased transition of activated cells from the bone marrow into the blood, and these cells show a particular conserved inflammatory character (Powell et al. 2013). The increased production of bone marrow precursor cells of

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monocytes and granulocytes was confirmed by others (Heidt et al. 2014). Migration and production of leukocyte precursor cells are thus supported by the sympathetic nervous system. At this point we can also ask whether the sympathetic tone has any significance in other inflammatory diseases. If the experimenter removes the sympathetic influence in a parasitic infection, the infection worsens and the individuals die sooner. This finding speaks for the immunosupportive effect of the sympathetic nervous system and indirectly shows how the higher sympathetic tone elicits a stronger immune response (Roggero et al. 2016). A similar finding is seen by the researcher after the reduction of sympathetic tone in acute staphylococcal infection of the abdomen, because there the existing low sympathetic tone leads to a reduced immune response and a greater spread of the bacteria (Straub et al. 2005). The sympathetic nervous system helps in some infection situations, but not in all. In a model of acute liver inflammation, the sympathetic nervous system supports a higher inflammatory state in the liver and systemically in the blood (Lin et al. 2015). In the case of chemically induced acute colitis, an increased sympathetic tone is unfavorable because it promotes inflammation (Straub et al. 2008). A group of researchers found out how the local removal of sympathetic influence on the heart reduced inflammation in the heart tissue after a heart attack (Ziegler et al. 2018). This finding was associated with better heart function (Zanoni et al. 2017). Even on the gingival tissue the sympathetic influence is mainly proinflammatory in nature (Breivik et al. 2005; Haug and Heyeraas 2006). If the doctor removes the sympathetic influence on the kidney in humans by destroying the sympathetic renal nerves, the general inflammatory state in the blood is reduced after 3 and 6 months (Zaldivia et al. 2017). If the examiner stops the sympathetic influence on the head by surgical interruption of the sympathetic nerve on both sides, the fever response to the peripheral administration of bacterial components is significantly reduced (Romeo et al. 2009). The increased sympathetic tone therefore contributes to a fever reaction. Furthermore, sympathetic tone promotes the inflammatory immediate reaction triggered by traumatic blood loss (Xu et al. 2015). The sympathetic tone also stimulates pain caused by different stimuli (Levine et al. 1986b; Kinnman and Levine 1995; Chen et al. 2010; Xie et al. 2016). This also applies to abdominal pain, such as bloating (Kalmari et al. 2001). In this way, sympathetic tone stimulates the pro-inflammatory effects mediated by the pain system (α-adrenergic, see Fig. 4.3). If the experimenter reduces the tone of the sympathetic nervous system in chronic sleep disorders, the inflammation caused by the sleep disorder is attenuated (Mishra et al. 2020). On the one hand, we can see here the increase in sympathetic activity caused by sleep disorders and, on the other hand, the downstream sympathetic-dependent inflammation.

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These global pro-inflammatory reactions make it clear how sympathetic tone directly affects inflammation. The sympathetic nervous system is a direct connector in the sense of chronic immune system activation. But now I have to pour cold water on the matter because the sympathetic nervous system sometimes has anti-inflammatory properties. This picture, which contradicts the concept of chronic immune system activation, will be discussed in the next subchapter.

4.2.1.3 The Tone of the Sympathetic Nervous System Inhibits Inflammation Sometimes the observer can see an anti-inflammatory effect instead of a pro-inflammatory effect of the sympathetic nervous system in the same disease. That sounds pretty paradoxical, but can sometimes be resolved quite well. We have conducted studies with chronic inflammatory diseases: The sympathetic tone supported the acute inflammation in arthritis and colitis, but the chronic inflammation was inhibited (Härle et al. 2005; Straub et al. 2008). This may be due to different disease mechanisms that are switched on at different stages of arthritis or colitis. The effect of the sympathetic nervous system depends on several factors, which are briefly mentioned in Table 4.1. Some studies have supported the idea of the immunosuppressive effect of sympathetic tone (De Luigi et al. 1998; Lorton et al. 1999; Rice et al. 2002; Straub et al. 2005, 2008; Pongratz et al. 2012; Willemze et al. 2018). The attentive observer begins to wonder why there can be such differences, why the sympathetic nervous system can thus cause such dual mechanisms. These considerations could fill an entire book, but here I can only give a short explanation in order not to exceed the scope of this work. A detailed discussion of some important factors mentioned in Table 4.1 is given in the further text of the subchapter. Important are various adaptation reactions that strongly change the effect of the anti-inflammatory β-adrenergic receptor. 4.2.1.4 The Sympathetic Nervous System Promotes Inflammation Through Various Adaptation Reactions Some rearrangement reactions that can result from an early traumatic experience and are proinflammatory in nature are already shown in Table 4.1. Therefore, it is worth discussing a few of them in more detail, and I will start with the co-transmitter neuropeptide Y. Increased prolonged stimulation of the sympathetic nerve fiber can lead to depletion of neuropeptide Y at the sympathetic nerve ending. Since neuropeptide Y normally supports the β-adrenergic side as a co-transmitter at high firing rates of the nerves, the loss of neuropeptide Y is associated with a lower effect through the β-adrenergic receptor. The proinflammatory α-adrenergic effect prevails (Fig. 4.6). For example, if there is a high resting tone after early traumatic experiences, the nerve ending will increasingly become depleted of neuropeptide Y. This has not been investigated so far, but this scenario is plausible. In the brain, however, neuropeptide Y is a neurotransmitter that has been associated with the development of resilience (2.5.1) (Nahvi and Sabban 2020).

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Table 4.1  Factors that determine the pro- or anti-inflammatory effect of the sympathetic nervous system (Pongratz and Straub 2013; Schaible and Straub 2014) Factors Immune stimulus and associated immune response to a particular disease After all, not all types of diseases are always associated with the same immune reaction under the same disease name. For example, there are at least two types of rheumatoid arthritis, one started by B cells and the other by T cells (T helper type 1 or T helper type 17). The end result is always joint inflammation, which the doctor does not see the hidden immune reactions behind. Since sympathetic neurotransmitters have different effects on these different cell types, it can sometimes lead to stimulation and sometimes to inhibition. Nothing is fixed, because the relevant cell type can change over the course of a disease. This is not only the case with rheumatoid arthritis, but also with other autoimmune diseases The importance of migration of immune cells promoted by the sympathetic nervous system. The sympathetic nervous system promotes migration The meaning of energy provided that can be important for immune reactions. The sympathetic nervous system provides energy-rich substrates such as glucose and free fatty acids The additional cell types involved in addition to the immune cells are important because they react differently to sympathetic neurotransmitters (e.g. vascular endothelial or smooth muscle cell versus epithelial cell, etc.) The on and off of the sympathetic nervous system in relation to the triggering of the chronic immune reaction (vaccination/immunization). In the acute phase, the sympathetic nervous system is proinflammatory, in the chronic phase it is anti-inflammatory The possible function of other neurotransmitters of the sympathetic nerve ending, such as neuropeptide Y, which has its own effect on immune cells and other cells. With long-term stimulation of the sympathetic nerve fiber, the nerve ending becomes depleted of neuropeptide Y, and then this influence is lost. This can be the case, for example, with a strong sympathetic response. This reduces the effect via β-adrenergic receptors (see Fig. 4.3) The concentration and type of sympathetic neurotransmitter (low concentrations act via α-adrenergic receptors that is pro-inflammatory, and high concentrations act via β-adrenergic receptors anti-inflammatory, Fig. 4.3) The variability of the presence of sympathetic nerve fibers in the tissue (low density, effect via proinflammatory α-adrenergic receptors; high density, effect via β-adrenergic receptors) The variability of the presence of adrenergic receptors on the surface of involved cells, especially immune cells (that is, whether there are many or few α- or β-adrenergic receptors) The variability of signal transduction from the adrenergic receptor into the respective cell. This can vary greatly

Furthermore, the sympathetic stress response to an acute stimulus has the following significance. After early trauma experiences, the sympathetic stress response was often described as being reduced (in the case of psychosocial stress, Holochwost et al. 2021), but in the case of physical stimuli, there are excessive sympathetic reactions (Rinnewitz et al. 2018). Unfortunately, these physical stimuli have been little studied in patients with early trauma, but it would be worth undertaking.

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Neuropeptide Y

Bacteria wall component

normal tone

one time high tone

low tone underreaction

NPY supports -action

anti-inflammatory pro-inflammatory

permanently high tone overshooting NPY Support of -activity is missing pro-inflammatory

Fig. 4.6   Proinflammatory reactions in case of excessive sympathetic activity. Normally, at low sympathetic activity, there is a balanced ratio of α- and β-adrenergic effects on stimulated TNF secretion (leftmost field, bottom). With a onetime higher tone, the β-adrenergic side prevails, which is supported by neuropeptide Y (NPY), and there is a TNF inhibition (2nd field from left, bottom). With low tone or low sympathetic reaction, the α-adrenergic side prevails, and there is an increase in TNF (3rd field from left, bottom). If there is a high sympathetic tone at rest or regular excessive sympathetic reactions, the nerve terminal may become depleted of NPY, and NPY can no longer support the β-adrenergic side. So the α-adrenergic side prevails with an increase in TNF. The α- and β-adrenergic modulation of TNF was investigated by Spengler and colleagues (Spengler et al. 1990, 1994)

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If the patients suffer from anxiety disorders, depression, weight gain, sleep disorders, metabolic syndrome, alcohol abuse and nicotine abuse, they often have the status of the physically untrained, and here the doctor typically expects excessive sympathetic responses after physical stress exposure (Carter and Ray 2015; an example of an anxiety disorder in Coupland et al. 2003). Untrained individuals have a continuously higher sympathetic tone, which could be eliminated through training (Carter and Ray 2015). In the case of excessive stress responses, the firing rates at the sympathetic nerves are significantly increased, and so the parallel influence of neuropeptide Y is lost (Fig. 4.6). The α-adrenergic proinflammatory side may predominate because the neuropeptide Y-related help for the β-adrenergic receptor is lost (Fig. 4.6). If additional pro-inflammatory factors are added to those affected by early traumatic adversity—as we discuss in this book—the balance of anti- and pro-inflammatory can further shift in a pro-inflammatory direction. There is a very good explanation for this based on the β-adrenergic receptor. Interestingly, in inflammatory conditions, the β-adrenergic receptor on immune cells is subject to a switch with a different outcome. Contrary to the inhibitory effects on the secretion of the highly pro-inflammatory TNF shown in Fig. 4.6, the β-adrenergic receptor is switched so that it has an α-adrenergic effect that increases TNF secretion Fig. 4.7. The α-adrenergic effect supports the inflammatory side because signal transduction into the cell occurs differently here. The switching processes inside the cell are partly understood (Daaka et al. 1997; Baillie et al. 2003; Lorton et al. 2013; Jenei-Lanzl et al. 2015b; Zhang et al. 2018). A psychological stress reaction can, via this switch, induce an important pro-inflammatory intracellular signalling factor—NFkappaB (Bierhaus et al. 2003). In addition, inflammation can lead to a depletion of tetrahydrobiopterin, an important cofactor in the biosynthesis of noradrenaline (Werner et al. 1993, 2011). An inflammatory-induced vicious circle can stabilize and aggravate the condition. Another variant that causes a β- to α-adrenergic proinflammatory switch is a loss of sympathetic nerve fibers in an inflammatory area. Two possibilities can cause nerve fiber loss. If there is inflammation in a tissue, activated macrophages and other cells can produce substances that cause an active repulsion of sympathetic nerve fibers from the inflammatory area (so-called semaphorins) (Miller et al. 2004; Straub et al. 2008; Fassold et al. 2009; Koeck et al. 2009; Stangl et al. 2015). In the second case, a tissue loses its sympathetic nerve fibers when it grows and enlarges and when the adequate ingrowth of sympathetic nerve fibers fails, as we can observe in intestinal polyps (Graf et al. 2012). In both cases—with active repulsion and with staying away in growing tissue— the area becomes impoverished in sympathetic nerve fibers (Straub et al. 2008; Koeck et al. 2009; Graf et al. 2012; Pongratz and Straub 2013; Schaible and Straub 2014). This causes the concentrations of noradrenaline to slip into the low to very low range, and there are α-adrenergic proinflammatory effects of noradrenaline. At the same time, pain fibers grow more strongly into the inflamed area and create an imbalance of

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Noradrenaline

Bacteria wall component

SWITCH

TNF normal tone

one time high tone

low tone underreaction

anti-inflammatory pro-inflammatory

permanently high tone overshooting

pro-inflammatory because of SWITCH

Fig. 4.7   Pro-inflammatory reactions with altered signal transduction. Normally, in the absence of inflammation and at rest there is a balanced ratio of α- and β-adrenergic effects (i.e. no influence on TNF, far left, bottom). With a onetime increase in tone, the anti-inflammatory side predominates (2nd from left, bottom). With inflammatory stimulation of the cell, there is a switch (SWITCH) in which the β-adrenergic receptor becomes pro-inflammatory via α-adrenergic signal pathways. With low tone or weak sympathetic response, the α-adrenergic side predominates, resulting in an increase in TNF (3rd from left, bottom). With a permanently increased tone or with excessive sympathetic response and existing SWITCH, the α-adrenergic side predominates with a significant increase in TNF (far right, bottom)

proinflammatory substance P to anti-inflammatory noradrenaline (Pongratz and Straub 2013, 2014). The situation is illustrated in Fig. 4.8. In a constellation with predominantly α-adrenergic action, noradrenaline supports pain processing in the local area (Levine et al. 1986b; Kinnman and Levine 1995; Aley et al. 1996; Chen et al. 2010; Xie et al. 2016), which promotes the release of inflammatory substance P. Thus, the proinflammatory effect depends on the number of pain nerve fibers present in the tissue. This number is variable and typically increases significantly with inflammation (Straub et al. 2008; Pongratz and Straub 2013). Another important phenomenon directly at the inflamed site is the production of sympathetic neurotransmitters by immune cells. This allows them to intervene in local processes in an unprecedented way (Mousa et al. 2004; Capellino et al. 2010, 2012;

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healthy situation ratio 1:1 sympathetic nerve fibres (noradrenaline, neuropeptide Y)

pain nerve fibres (substance P)

Tissue alteration due to inflammation

inflammatory situation ratio 1:9 sympathetic nerve fibres (noradrenaline, neuropeptide Y)

pain nerve fibres (substance P)

Tissue

Fig. 4.8   Proinflammatory reactions after reduced sympathetic innervation. There is tissue without (above) and with inflammation (below) inflammation. Without inflammation, there is a balance of sympathetic and pain nerve fibers (ratio 1:1). In this situation, the concentration of the neurotransmitter noradrenaline can be high and there can be an anti-inflammatory β-adrenergic effect. With inflammation, sympathetic nerve fibers decrease (repulsion), and proinflammatory pain fibers with substance P predominate (ratio 1:9). Now the noradrenaline concentration is low, and only a proinflammatory α-adrenergic effect can occur

Jenei-Lanzl et al. 2015a). Here we still know little, but it looks as if the concentration of the neurotransmitters released from these immune cells is not enough to inhibit inflammation. Nevertheless, the β-adrenergic effect of the released noradrenaline is very small. Prominent examples from Table 4.1 were presented in more detail above. Finally, we ask the general question: Is the sympathetic nervous system now pro- or anti-inflammatory? According to Fig. 4.4 I was a convinced supporter of the immunosuppressive effect of the sympathetic nervous system from around 1990 to 2005. The verdict resulted from studies of isolated cells or tissue with β-adrenergic stimulants, where the cells came from a healthy human or animal. We took the immunological target cells for the observation from a healthy environment and stimulated them only briefly with an infectious stimulus (bacterial components). In these “healthy situations” onetime given noradrenaline acted via β-adrenergic receptors to inhibit proinflammatory cytokines such as TNF (for example Kees et al. 2003). This situation changes very much in stress and disease situations

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(Dhabhar 2014; Pongratz and Straub 2014), because here there are long-term adaptation reactions in the tissue and in the target cells (Figs. 4.6, 4.7 and 4.8). In addition, we recognized the proinflammatory importance of the α-adrenergic effect on various immune cells (Bierhaus et al. 2003; Miksa et al. 2009; Grisanti et al. 2011; Lu et al. 2014; Liu et al. 2020; Straub et al. 2020). By now, the pro-inflammatory effect of the sympathetic nervous system prevails for me for the aforementioned reasons (Figs. 4.6, 4.7 and 4.8 and Table 4.1). The most important aspects—are above all—the strongly altered signal conduction through the receptor (SWITCH in Fig. 4.7) and the nerve fiber loss in inflammation and proliferative tissue growth (Fig. 4.8). Therefore, you should not be surprised why a change in sympathetic activity contributes to a generally increased inflammatory condition, regardless of whether there is an over- or underreaction. After all, sympathetic nerve fibers are everywhere (exception: placenta, where they are prevented from growing in by the aforementioned repulsion factors, as my good acquaintance Monika Brauer and her team in Montevideo, Uruguay, were able to show [Marzioni et al. 2004; Brauer 2008; Richeri et al. 2011]). This makes the role of the sympathetic nervous system as a direct connector obvious in order to promote chronic immune system activation in various places.

4.2.2 The Parasympathetic nervous system When I speak of the parasympathetic nervous system, I am essentially referring to the vagus nerve, which has been studied primarily. The sacral autonomic nerves that were previously assigned to the parasympathetic nervous system are not parasympathetic, but sympathetic nerve fibers (Espinosa-Medina et al. 2016). In cases with a high sympathetic tone, we expect a low parasympathetic tone because the two systems antagonize each other, and this fact has been common knowledge in medicine for decades (e.g. Genovely and Pfeifer 1988). If an early traumatic experience leads to a increased sympathetic tone or to excessive sympathetic responses, we expect a low parasympathetic tone or an excessive inhibition of parasympathetic responses as a consequence. Using a respiratory sinus arrhythmia test (i.e. sinusoidal fluctuations in heart rate in relation to deep breathing), the examiner can approximately determine the parasympathetic tone. If the respiratory fluctuation is strong, the parasympathetic tone is high (Genovely and Pfeifer 1988). Conversely, the respiratory fluctuation becomes very small when only the sympathetic nervous system has an influence (Genovely and Pfeifer 1988). When considering various adverse experiences in young years, researchers found, with the help of this method, a low parasympathetic tone or a reduced reaction to stress (Miskovic et al. 2009; Oosterman et al. 2010; Shenk et al. 2010; Skowron et al. 2011; Gray et al. 2017; Lunkenheimer et al. 2018). Significantly fewer publications show no reaction or an increased tone (summarized in Holochwost et al. 2021). This altered vagal situation can have some effects on the immune system.

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Kevin Tracey is a descendant of a Sicilian father and an Irish mother who studied medicine in Boston. He was trained as a neurosurgeon in New York and soon moved to the prestigious Feinstein Institute in New York. After a few years of scientific work, he became president and CEO there, after publishing important publications (Borovikova et al. 2000; Wang et al. 2003). The important observation of the vagal inhibition of inflammation is due to Kevin Tracey and his group. Although he always emphasizes in his work how mainly the vagus nerve plays the anti-inflammatory role in the inflammatory reflex, he neglects the anti-inflammatory effects of the sympathetic nervous system when it acts under acute “healthy conditions” (see above). Nevertheless, I recognize how Kevin Tracey gave the vagus nerve this new and important anti-inflammatory meaning. His group examined the acute effect of electrical vagus nerve stimulation on the release of TNF induced by bacterial components in live animals (Borovikova et al. 2000). This acute effect of vagus nerve stimulation was only given if the spleen was present in the body. If the researchers cut the vagus nerve in animals, they had a higher TNF level in the blood, which spoke for the inhibitory effect of the parasympathetic tone. Many groups confirmed the anti-inflammatory effects of the vagus nerve in model diseases such as arthritis (Levine et al. 2014), chronic inflammatory bowel disease (Meregnani et al. 2011), postoperative intestinal ileus (de Jonge et al. 2005), acute renal artery occlusion and reperfusion (Inoue et al. 2016) etc. The essential effects were mediated by the important neurotransmitter of the vagus nerve, the acetylcholine, and a special acetylcholine receptor (name: α7nAChR) (Wang et al. 2003). The work around the vagus nerve caused some criticism in professional circles because anti-inflammatory effects were observed throughout. The attentive observer does not expect such a large number of acetylcholine receptors (at least 20 different) to have uniform anti- or pro-inflammatory effects, but a mixed picture, as we saw with the adrenergic receptor and noradrenaline. I don’t want to go into this here, because an anti-inflammatory role of the vagus nerve is pretty clear. With this information we can now briefly summarize: Since the parasympathetic tone and the parasympathetic reaction to early trauma and later stressful second reactions are often reduced in the face of a high sympathetic tone, there is a clear pro-inflammatory constellation. We recognize another important direct connector in acetylcholine and in the vagus nerve.

4.2.3 The HPA Axis Before we steer towards inflammation, I would like to briefly introduce the HPA axis here first, even though this partly already took place in Fig. 4.2. The corresponding feedback regulations are shown in Fig. 4.9. Cortisol production in the adrenal cortex is influenced by the brain and also by peripheral factors. Figure 4.9 likewise shows the effect of cortisol inside the cell and the intracellular negative feedback via a protein called FKBP51.

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other brain regions see Fig. 4.2 Cortisol

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Hippocampus

Cortisol

Hypothalamus (PVN)

Cortisol

CRH

Cortisol

Pituitary

ACTH

Adrenal cortex intravascular

Cortisol

intravascular

Cortisol Glucocorticoid receptor

Cortisol

Immune cell or any other cell in the body

Cort

FKBP51

isol

Inhibition or stimulation of gene reading

Nucleus

FKBP51 blocks the glucocorticoid receptor

FKBP51

for example stimulation of FKBP51

Fig. 4.9   The HPA axis with feedback loops. The stimulus for the activation of the hypothalamus comes from various brain regions, as schematically illustrated in Fig. 4.2 and as shown in the upper left of the image. More specifically, this is the paraventricular nucleus (PVN). There, corticotropin releasing hormone (CRH) is produced, and this leads in the pituitary to the production of adrenocorticotropic hormone (ACTH). ACTH stimulates the adrenal cortex to produce cortisol, which has a negative (with bars at the end of the line) or positive (with an arrow at the end of the line) effect. The effect on the memory center of the hippocampus is positive, and the hippocampus in turn inhibits the hypothalamus. Cortisol also affects other brain regions. Cortisol enters cells quite unhindered and exerts its effect there when it binds to the intracellular glucocorticoid receptor (brown square U-shape) and enters the cell nucleus with it to reach the DNA. The complex binds to the DNA and causes the stimulation of factors (e.g. FKBP51) or the inhibition of factors (e.g. TNF, not shown). FKBP51 blocks the glucocorticoid receptor and can thus reduce the effect of cortisol in the cell (local intracellular, negative feedback)

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The effect of cortisol in the cell can inhibit and increase gene reading of various factors. For example, cortisol inhibits the new formation of TNF and other proinflammatory cytokines. In contrast, it increases the generation of other factors, such as the anti-inflammatory cytokine IL-10 or FKBP51, which is shown in Fig. 4.9. FKBP51 blocks the glucocorticoid receptor in the cell, so that this cannot bind free cortisol. FKBP51 thus inhibits the glucocorticoid effect in the sense of a negative feedback within the cell.

4.2.3.1 What is the Tone and Stress Reactivity in Previous Early Traumas In the systematic review by Holochwost et al. from 2021, the effects of earlier adverse experiences on the later investigated tone of the HPA axis and the later acute stress reaction are summarized from many studies (Holochwost et al. 2021). Of a total of 37 studies published by different authors, 19 describe a tonic overactivity of the HPA axis, 5 an underactivity, and 7 publications find no effects. In other words: Most observers find a tonic overactivity of the HPA axis, and that fits very well with findings in depression, a common consequence of earlier traumatic experiences (Rothe et al. 2020). There the situation is clear, because depression is associated with a higher tone of the HPA axis and with glucocorticoid resistance (newer overview in Rothe et al. 2020). Glucocorticoid resistance means nothing other than the lack of effect of cortisol via its glucocorticoid receptor (Fig. 4.9), because we see no hormone deficiency, but a reduction in efficacy at high concentrations of cortisol in the blood (Rohleder et al. 2003a). In terms of reactivity to stress, we experience the opposite of increased tone, as there is a decrease in HPA axis activity after a typical psychosocial stressor, similar to what we see with the sympathetic nervous system. Holochwost found 11 studies in total that documented the decrease in activity, and 6 out of 23 studies showed overactivity. As with the sympathetic nervous system, physical stress such as the cold water stress test can trigger overactivity (Rinnewitz et al. 2018). Only one out of 23 studies showed no reaction of the HPA axis at all (Holochwost et al. 2021). In summary, I find that most studies report an increased baseline tone and a reduced acute stress reaction of the HPA axis. However, tonic overactivity is not always present, and we do not know the reasons for this with certainty. Let me remind you again of Thomas Boyce. In one study, he found an inverse U-shaped relationship between early stress-inducing experiences and later cortisol response. For people with high or low levels of stress, the cortisol stress response was high. For people with a moderate level of stress in childhood, the later cortisol stress response was smaller (Shakiba et al. 2020). Such considerations can explain the discrepancy in the cortisol stress response. Further explanations for sometimes high and sometimes low stress responses are provided by studies that examine the timing of the trauma in relation to the time of puberty. These studies show that people with a trauma before or at the beginning of puberty have a high tone and a reduced stress response—and those after puberty have a lower stress tone and a high stress response (King et al. 2017; DePasquale et al. 2019; Gunnar et al. 2019; Khoury et al. 2019). Here, sex hormones can play an important role, as

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their influence on the HPA axis is well known (Kirschbaum et al. 1996; Rohleder et al. 2003b). The sex hormones are discussed in the Sect. 4.2.6 The tone of the sex hormone axis. Further investigations to clarify the differences in HPA responses point to the type of trauma, whether physical abuse, sexual abuse, emotional abuse, physical or emotional neglect, etc. Depending on the situation, there is a high or low tone or a low or high stress reactivity of the HPA axis (Essex et al. 2011; Kuhlman et al. 2015; Laceulle et al. 2017; Khoury et al. 2019). In Chap. 5 I make a further suggestion based on energy consumption how this discrepancy of the high and low response patterns of the HPA axis can be explained. In summary, after traumas, usually a higher tone of the HPA axis and a reduced stress response are found. In this respect, the findings are very similar to those in the studies of the sympathetic nervous system.

4.2.3.2 The Increased Tone of the HPA Axis Increases Inflammation First indications of an immunostimulatory effect of preceding increased cortisol levels were found in humans in a simple-looking experiment (Barber et al. 1993). The researchers gave volunteers a defined amount of bacterial components intravenously over 5 min to simulate an inflammatory situation. By the way, this is a good experimental idea because after stress bacteria can cross from the intestinal lumen into the body (see Sect. 4.3.5 The permeability of the gut is pro-inflammatory below), where bacterial components occur more frequently. Components of bacteria trigger an immediate inflammation reaction, which the researcher detects by measuring proinflammatory cytokines such as TNF and IL-6 in the blood (Barber et al. 1993). Surprisingly, this inflammation reaction was significantly increased in subjects to whom the investigators had infused a larger amount of cortisol intravenously 12 hours or 6 days earlier. We can call this pre-infusion of cortisol the “cortisol-priming”. If subjects received cortisol at the same time as components of bacteria, the inflammation reaction was strongly suppressed. Figure 4.10 summarizes the findings for TNF. The data for C-reactive protein, serum IL-6, and soluble TNF receptor in serum look very similar to those in Fig. 4.10, and the working group confirmed these findings in further studies two years later (Barber et al. 1995). In the discussion of the publications, the authors recognize the danger of the preceding high cortisol levels as a possible cause of overshooting inflammatory responses. Even if this constellation does not exactly correspond to what we call a high tone of the HPA axis, these studies provide first indications of a pro-inflammatory effect of hypercortisolemia. These work from the mid-1990s were later confirmed by other researchers in an independent manner (Yeager et al. 2009), and they confirm earlier work on rats (Renz et al. 1992). In a more recent study in humans, the scientists confirm the cortisol-priming on the acute inflammatory reaction subsequently triggered by bacterial components. They show an enhancing effect on pro-inflammatory factors after a 12-hour preceding cortisol

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Serum TNF (pg/ml)

LPS + Cortisol 6 days ago

LPS + cortisol 12 hours ago

LPS LPS + cortisol simultaneously

Time (min) Fig. 4.10   Cortisol tone and increased inflammation. If the researcher gives bacterial components (LPS, lipopolysaccharides) intravenously, he can trigger an inflammation reaction in humans (red curve). If he gives the LPS at the same time as the cortisol (black line), the TNF production is completely inhibited (34 pg/ml is the detection limit of the measurement procedure). If the researcher had infused cortisol either 12 hours (light violet) or 6 days (dark violet) before the LPS, the inflammation reaction was strongly increased. Thus, hypercortisolism, in other words an increased HPA-axis tone, can contribute to an increased inflammation reaction. The experiments were carried out by Barber et al. The figure summarizes results from the study group in graphical form using tabular data of the original publication (Barber et al. 1993)

infusion that produced cortisol levels comparable to a strong stress response (Kamisoglu et al. 2014). In this work, they demonstrated the increased migration of leukocytes—especially neutrophilic granulocytes (short: neutrophils)—already before and especially after administration of the bacterial components (Kamisoglu et al. 2014). These findings in humans confirm a supportive effect of glucocorticoids on leukocyte migration, as observed in animals. The migration of leukocytes such as granulocytes and monocytes stimulated by cortisol in humans leads to an increased presence of these cells in inflammatory regions. This is due to an increase in cytokines that are important for the directed movement into the inflammatory area (called: chemokines) (Yeager et al. 2016). A preceding cortisol-priming thus promotes increased migration and presence in the inflammatory area, which can fuel the inflammation. If the researcher looks at immune cells in a culture dish, the three-day treatment with low-dose cortisol compared to a situation without cortisol leads to a significantly higher

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release of TNF, IL-6 and other pro-inflammatory factors when now stimulated with bacterial components after the cortisol-priming. Ergo, this cortisol-priming exists in the culture dish to make the cells more pro-inflammatory (Chae 2021). If the experimenter gives rats corticosteroids in the drinking water (increased tone) for 14 days and now obtains their macrophages from the lungs, the macrophages of the animals respond with cortisol priming to additional administration of bacterial components with a significantly stronger TNF response, which is about 8- to 10-times stronger than in animals without corticosteroids (Renz et al. 1992). Further studies on immune cells in culture also show stimulating effects of cortisol on pro-inflammatory factors from B cells, T cells, macrophages or mixed blood leukocytes (Cooper et al. 1981; Wiegers et al. 1995; Broug-Holub and Kraal 1996; Wiegers et al. 2000; Lim et al. 2007). Corticosteroids induce a special form of T cell (T helper type 2 cell), which can play a role in allergies and autoimmune diseases (Ramírez et al. 1996; DeKruyff et al. 1998; Franchimont et al. 2002; de Castro Kroner et al. 2018; Shimba and Ikuta 2020; Taves and Ashwell 2021). At this point, the experienced reader begins to wonder why corticosteroids like cortisol can be pro-inflammatory instead of anti-inflammatory. Obviously, the anti-inflammatory effect at high concentrations of corticosteroids is a clear matter, and this is supported by the success of acute therapy with corticosteroids (Buttgereit et al. 2011). So what makes cortisol pro-inflammatory? On the one hand, the pro-inflammatory effect of corticosteroids has something to do with the time of action, because with cortisol priming the tone of the corticosteroids must be increased before the immunostimulus is given. An increase in cortisol that arrives at the same time as the bacterial components—that is, cortisol simultaneity—inhibits inflammation. With cortisol priming, it is as if the immune cells are prepared for the immunostimulus that arrives later. On the other hand, the lack of effect of glucocorticoids may be due to the concentration of this hormone. For the anti-inflammatory effect, high concentrations of about and greater than 10−7 mol/l are required. With regard to the effect on macrophages, a low concentration of glucocorticoids in the dose range of 10−10 to 10−8 mol/l is even stimulating (in the blood the doctor normally observes 10−7 mol/l) (Giles et al. 2001; Lim et al. 2007; Zhou et al. 2010). And finally we can ask ourselves the following question: What happens if the receptor for the anti-inflammatory cortisol is not produced in sufficient quantities or if the movement of cortisol together with its receptor is prevented from entering the cell nucleus (cf. Fig. 4.9)? Does this happen after early traumatic experiences?

4.2.3.3 Glucocorticoid Receptor Resistance Increases Inflammation General high glucocorticoid levels—regardless of their nature—lead to reduced sensitivity of their own receptor: a high HPA-axis tone, with multiple high stress reactions or after administration of glucocorticoids leads to glucocorticoid receptor resistance. This is textbook knowledge. The reduced sensitivity is due to a real deficiency of the receptor molecule and an increase in the receptor blocker FKBP51 (cf. Fig. 4.9).

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Immune response

If FKBP51 is increased, the binding of cortisol to the glucocorticoid receptor is inhibited and the movement of the glucocorticoid receptor into the cell nucleus is prevented. Glucocorticoids such as cortisol can then not exert their effects. But what about the glucocorticoid receptor after early traumatic experiences? In systematic studies of the facts in leukocytes, researchers found the following. After early traumatic experiences, the amount of the glucocorticoid receptor is significantly reduced, which is mediated by epigenetic processes (Explanation 1). This finding could be confirmed in 89% of all studies conducted on human material (Turecki and Meaney 2016). Another systematic review confirms the facts (Holmes Jr. et al. 2019). The glucocorticoid receptor mechanism is disrupted in white blood cells, and this means that at higher glucocorticoid levels in the blood or tissue, the effect is reduced. So the range of action of the glucocorticoids is shifted to higher concentrations (red line in Fig. 4.11). In the Sect. 2.5.5 I wrote how the researchers often use leukocytes to detect the evidence of methylation of important gene sections. I doubted this approach because the things that were changed should be in the center of attention, namely the brain. For the consideration of immunological processes, however, the analysis of leukocytes is extremely valuable because these cells trigger inflammation. Another problem of glucocorticoid resistance is the insensitivity to cortisol in various places in the brain, because the same resistance is relevant there. Although it has not been epigenetically examined in the brain, the clinical findings speak in favor of a glucocorticoid resistance in the hypothalamus and in the pituitary gland. Therefore, the negative feedback of Fig. 4.9 is weakened and the production of cortisol remains high (Rothe et al. 2020). However, not all regions in the brain are resistant to cortisol. Some regions

Immunostimulation

Immunosuppression

therapeutical range

Cortisol concentration in blood (mol/l)

Fig. 4.11   Anti-inflammatory and pro-inflammatory range of action of cortisol. The usual range of action of cortisol is adequately represented by the black line. If we observe pro-inflammatory reactions of cortisol, the concentration is 10−8 mol/l or less. By glucocorticoid resistance, the dose-response curve is shifted to the right to higher values, as schematically represented by the red curve. Now the researcher suddenly observes at concentrations of 10−7 to 10−8 mol/l pro-inflammatory immunostimulatory effects of cortisol. Any form of desensitization of the receptor leads to a higher inflammatory effect of cortisol

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are sensitive and therefore suffer particularly from high concentrations of this hormone (Rothe et al. 2020). This situation exacerbates the central nervous system problems such as depression and anxiety disorders (Sect. in 3.2), and the inclination of the pointer on the weighing scale from Fig. 3.4 is stabilized and amplified. What are the other reasons for the lack of effect of cortisol in addition to glucocorticoid resistance? After early traumatic situations, an intracellular increase of the FKBP51 protein was found on the basis of epigenetic influences (significance: see Fig. 4.9). An increase in FKBP51 activity has an pro-inflammatory constellation as a result (Zannas et al. 2019), and here direct effects of FKBP51 on inflammatory factors and additionally a glucocorticoid resistance are relevant. Furthermore, genetic effects can come into play with FKBP51, because certain genetic changes of the FKBP51 gene are associated with diseases such as depression (Wang et al. 2018). For the sympathetic nervous system, I wrote: “If additional inflammatory factors are added to those affected by early traumatic adversity (…), the balance of anti- and pro-inflammatory can further shift in the pro-inflammatory direction.” We can use the same sentence when considering the HPA axis, because additional inflammatory activation increases glucocorticoid resistance (Pace et al. 2007; Quax et al. 2013). The black curve in Fig. 4.11 moves to the right due to inflammation. Here, a vicious circle can easily develop if an increased inflammatory state has once begun, promotes glucocorticoid resistance and further increases the inflammatory state, which in turn promotes glucocorticoid resistance, and so on.

4.2.3.4 An Increased Breakdown of Cortisol Increases Inflammation Another way to reduce the effect of cortisol in tissue is an increased breakdown of cortisol by a cortisol-degrading enzyme (it is called 11β-Hydroxysteroid Dehydrogenase Type 2). Researchers have shown the possibility of why this enzyme is increased in placental tissue of prenatally traumatized newborns. They observed a reduced methylation of the gene for this enzyme (means increased production, see Explanation 1), the cortisol-degrading enzyme was more present and local cortisol levels were low (Appleton et al. 2013). In the animal experiment with prenatal stress, there was also an increased concentration of the enzyme in the placenta (Lucassen et al. 2009). On the other hand, the loss or reduced function of this enzyme during pregnancy in the child leads to higher cortisol levels and various consequences such as low birth weight, lifelong increased cortisol levels, high blood pressure and cardiovascular consequences (Seckl and Holmes 2007; Yehuda et al. 2009). Since immune cells also have this enzyme and promote cortisol breakdown there, it can easily lead to an increased inflammatory state due to the lower cortisol levels (Schmidt and Straub 2015). 4.2.3.5 Cortisol Mobilizes Important Elements of Inflammation The stress hormone cortisol is an important factor for the migration of leukocytes. People who are stressed and come to the emergency room for some reason often have very high leukocyte counts in their blood. The treating physician then often thinks of an

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infection, as in this case typically many leukocytes swim in the blood. This does not necessarily have to be the case, as the stress reaction alone with high cortisol values ​​already causes an increase in leukocyte counts. We had already discussed the matter along with the sympathetic nervous system, as noradrenaline has the same effect. Here we see again how cortisol and noradrenaline do the same thing. Furthermore, cortisol like noradrenaline is important for the provision of energy-rich substrates from energy stores, for example free fatty acids or glucose (Straub 2018). Without these energy-rich substrates, the immune system cannot work because immune reactions are very energy-consuming. We see the importance of cortisol for energy provision when the pituitary is defective for reasons of illness. If the doctor injects bacteria components into such persons with weak pituitary function, the provision reaction of free fatty acids is clearly lower than in healthy control persons (Bach et al. 2016). In contrast, people with increased HPA axis activity—that is, the opposite of weak pituitary function—permanently make more energy-rich substrates such as glucose, free fatty acids and triglycerides available in the blood, and this situation can drive the inflammatory reaction.

4.2.3.6 Summary of the HPA Axis and Inflammation All of the mentioned aspects can, with increased tone of the HPA axis instead of the usually expected anti-inflammatory effect of cortisol, cause a pro-inflammatory situation. Let’s also imagine how cortisol repeatedly drops in phases that trigger stress— this has been described as reduced stress response or stress reaction. Repeated drops in bood cortisol would further exacerbate the existing problem of the lack of cortisol-induced immunosuppression if stressful life circumstances occur. This is especially true for psychosocial stressors (Holochwost et al. 2021), whereas with physical stressors—or with sports—high glucocorticoid levels are to be expected and therefore an inhibition of inflammation can be expected. So far, we have only talked about the constellation of permanently increased HPAaxis tone and reduced stress reactivity. But what about the low HPA-axis tone and increased stress reactivity that have been observed in a few studies? Does this constellation have an inflammation-promoting effect? The logic of the matter is shown in Fig. 4.12. Basically, this latter constellation has not been studied often, which is why corresponding data is lacking. I can imagine how a low HPA-axis tone and intermittent high stress reactions can neither properly inhibit inflammation nor properly increase it (Fig. 4.12). Here, a stalemate exists, which can quickly be diverted in the wrong direction towards higher glucocorticoid resistance in the presence of additional inflammation, and that means reduced glucocorticoid effects and increased inflammation. Thus, the HPA axis behaves similarly to the sympathetic nervous system with cortisol, an anti-inflammatory hormone, because stress reactions interfere with the anti-inflammatory effects of the two systems. The altered function of the receptors of cortisol and noradrenaline is decisive. In this constellation, there is the danger of the vicious circle illustrated in Fig. 4.13. The early traumatic episode triggers the stress reaction leading to an altered glucocorticoid receptor, an altered adrenergic receptor system and

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Immune cell or any other cell in the body

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FKBP51 blocks the glucocorticoid receptor

Inhibition or stimulation of gene reading

Nucleus

for example stimulation of FKBP51

with early traumatic experiences normal tone normal stress response

high tone low stress reaction

low tone high stress response

Glucocorticoid receptor

Cortisol effect good

Cortisol effect very weak

Cortisol effect weak-good

Inflammation

Inflammation

Inflammation

Fig. 4.12   Summary of the HPA axis and inflammation. In this figure, the normal situation is shown in the lower left, in which the cortisol concentration in the blood, the number of glucocorticoid receptors and the natural cortisol blocker FKBP51 are normal. In the presence of inflammation and with adequate cortisol levels, inflammation is well suppressed.—In the middle, the constellation with increased HPA-axis tone and low stress reaction is shown. The glucocorticoid receptor is reduced by the increased tone and the previous trauma, and at the same time FKBP51 is intracellularly increased due to the trauma (epigentic reasons): too little receptor and too much receptor blocker. Here, the cortisol effect is weak, which contributes to the increased inflammation.—The opposite reaction of the HPA axis, which has been documented in a few studies, is shown in the lower right. There, although the HPA-axis tone is low—and so the glucocorticoid receptor may indeed be higher than in the middle—, the number of molecules of the glucocorticoid receptor is not as high as in the normal situation (left) due to the previous trauma. At the same time, the number of FKBP51 molecules is higher than in the normal situation due to the previous trauma. The inflammation is probably not properly suppressed, but otherwise not increased (arrow up and down, the stalemate)

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late disease problem

5. aggravated glucocorticoid receptor resistance, aggravated switching of the adrenergic receptor towards α 3. enhanced α-adrenergic effects of noradrenaline

5. increase in inflammation

2. increase in inflammation 4. increase in inflammation

1. methylations: Glucocorticoid receptor low, FKBP51 increased, cortisol effect on immune system reduced

early trauma

Fig. 4.13   Vicious circle of stress reactions and inflammation

consequently to inflammation, which further exacerbates the unfavorable situation. This makes the importance of cortisol and the HPA axis as a direct connector apparent in order to promote chronic immune system activation at various sites.

4.2.4 Disruption of the Circadian Rhythm You know in healthy people the ups and downs of hormone levels in the blood during the day. So the body’s own cortisol in the blood at 7 am is maximally high and at midnight very low. But at midnight, melatonin and prolactin are maximally high and in the morning both hormones are minimal. We recognize different hormones that behave totally contrary to each other like cortisol and prolactin and totally in phase like melatonin and prolactin. This is not a random whim of nature! It is a deliberate desynchronization and synchronization, because in this way the hormones can act separately or at the same time. Why does man need something like this? In synchronization, two hormones can act synergistically or additively, following the motto “Together we are stronger”. With desynchronization, hormones often have opposite effects and can act separately. Synchronization applies to melatonin and prolactin because they both have a pro-inflammatory component that they develop together in the early hours of the night to promote a special form of nocturnal immune response (Lange et al. 2006; Lange et al. 2011). Cortisol would prevent this, which is why this hormone is minimal at midnight. From these different rhythms, diseases such as morning stiffness

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of the hands and feet in certain rheumatic diseases (Straub and Cutolo 2007; Buttgereit et al. 2008) can now be explained. Synchronized partners in this sense are cortisol and noradrenaline, because both reach their maximum in the early morning hours. The partnership of the two hormones is often evidenced by a mutual reinforcement of effects. The two signal paths help each other in the cell by prolonging and amplifying each other’s effects (Oikarinen et al. 1984; Gruol et al. 1986; Nakada et al. 1987; Dong et al. 1989; DiBattista et al. 1991; Korn et al. 1998; Eickelberg et al. 1999; Schmidt et al. 2001). Throughout the body, they promote each other by cortisol stimulating the production of noradrenaline (Brion et al. 1978; Schubert et al. 1980) and vice versa noradrenaline stimulating the production of cortisol (EhrhartBornstein et al. 1998). The synchronization of cortisol and noradrenaline is crucial for the daily morning to afternoon immunosuppression (Straub and Cutolo 2007). So the morning symptoms in patients with rheumatic and other inflammatory diseases get better throughout the morning and afternoon because these two hormones inhibit inflammation (Straub and Cutolo 2007; Buttgereit et al. 2008). Only in the night hours up to the early morning do the inflammatory symptoms increase again due to the lack of these two hormones while nocturnal secretion of pro-inflammatory hormones such as melatonin and prolactin takes place. These considerations have already led to the development of new anti-inflammatory glucocorticoids that are specifically released at 2 a.m. to inhibit the morning rise in inflammation (Buttgereit et al. 2008; Buttgereit et al. 2013). If the circadian rhythm of these two hormones is disturbed, a reduced anti-inflammatory effect is expected.

4.2.4.1 Circadian Rhythm After Early Traumatic Experiences First considerations in the direction of disturbed circadian rhythm in children with previous trauma came up in the early 1990s when observers noticed disturbed sleep-wake rhythms (Glod 1992). In rats after prenatal stress, other investigators observed phase shifts in glucocorticoid secretion and higher levels throughout the day in the late 1990s (Koehl et al. 1997, 1999; Mastorci et al. 2009). First work on circadian rhythm disorders in adults and children with early traumatic experiences appeared around 2010 (Gonzalez et al. 2009; Saridjan et al. 2010). By looking at several measurements from waking up to falling asleep, which are typically captured in saliva samples, the doctor can recognize increases, decreases, and flat curves—that is, disturbances of the normal secretion—of the HPA axis hormone cortisol. The situation with early traumatic experiences was summarized by Holochwost and colleagues in 2021 (Holochwost et al. 2021). Of 10 studies, 8 reported an increase in rhythmic cortisol levels, which was accompanied by a visibly flatter circadian rhythm. “The system doesn’t swing right anymore. Keyword: flat and high!” Only two of the 10 studies showed a decrease in the cortisol day curve (Holochwost et al. 2021). Unfortunately, there are no studies in which cortisol and noradrenaline or another measure of the sympathetic nervous system such as neuropeptide Y (Fig. 4.6) were measured together. Such findings could provide information about synchronization or

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phase shifts of the two hormones. Disruptions of synchronization disturb a common anti-inflammatory effect (Straub et al. 2002; Meyer-Hermann et al. 2009). So it is only logical that we describe the observed changes in the sympathetic nervous system and HPA axis—especially the flat circadian rhythm—in the presence of disturbed receptor mechanisms as a proinflammatory signal that is stimulated by the shift of the adrenergic receptor system (Figs. 4.6, 4.7 and 4.8) and the glucocorticoid receptor system (Fig. 4.12). This again shows the role of the sympathetic nervous system and the HPA axis as direct connectors and how they promote chronic immune system activation by a disturbance of the circadian rhythm.

4.2.5 Tone of the Pain Pathways Painful stimuli reach the dorsal root ganglion in the periphery via sensory nociceptive nerve fibers and are received in the dorsal horn of the spinal cord, once switched to the opposite side and travel up the spinal cord to regions in the brainstem and midbrain, from where they are forwarded to the cerebral cortex (Fig. 4.14). Painful stimuli can be heat, cold, mechanical stimuli, acidic pH, immunological messenger substances such as cytokines, the chili extract capsaicin, bacterial components, etc. Figure 4.14 shows a selection of the possible pain stimuli that can act on the nerve ending. Typically, with pain there is also sensitization of the pain pathway at different levels. Sensitization means that, in the long term, the readiness to forward pain stimuli from the periphery to the brain is increased. The sensory nerve fiber is often of afferent nature (i.e. periphery → brain), but it also has a strong efferent aspect (brain → periphery, Fig. 4.14, pink pathway). With this efferent side, the sensory nerve fiber exerts a constant tone by ensuring a constant release of neurotransmitters into the area of the nerve ending. These neurotransmitters can contribute significantly to the local inflammatory situation. They are the key molecules of “neurogenic inflammation” (Basbaum et al. 2009). The central neurotransmitter is substance P, a peptide with 11 amino acids, a neuropeptide. This constant tone is influenced on the one hand by pain stimuli themselves, that is, the afferent side, and on the other hand by descending tracts from the brain (blue elements in Fig. 4.14) (e.g. (Willis Jr. 1988; Sandkühler 1996; Heinricher et al. 2009; Bannister and Dickenson 2017; Lockwood and Dickenson 2020)). We had already addressed these aspects of the blue descending tracts in Fig. 3.3. With the help of the blue nerve tract from Fig. 4.14, the brain takes a significant influence on things in the periphery through its effect at the level of the spinal cord cross-section. Do not imagine this to be simple, because this regulation depends on many factors and cells in the spinal cord (Xanthos and Sandkühler 2014). In this respect, the sensory nerve fiber is an afferent or efferent element for pain experience or inflammation regulation. The first clear indications of the pro-inflammatory importance of these pain fibers in a chronic inflammatory disease (arthritis) came from Kathleen A. Sluka from the University of Iowa (the work originates from the time at the University of Galveston,

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Frontal brain: medial prefrontal cortex

ACC

NAc

DOPAMINE

thalamic nuclei

PAG Raphe

SEROTONIN

LC

NORADRENALINE

Pain nerve pathway in the spinal cord

descending spinal pathways Dorsal root ganglion

Spinal cord cross section

Outputs Histamine Prostaglandine

sensitive nerve ending

Bacterial wall components

Noradrenaline α-adrenergic cytokine Substance P, CGRP Glutamate, Galanin

Heat, cold mechanical stimuli Capsaicin (chili)

Muscle and sympathetic ganglia

acidic pH

Growth factors

Substance P, CGRP Glutamate, Galanin

Inflammation

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Fig. 4.14   Pain pathways and inflammation. Red pathways are afferent and come from the nerve ending via the dorsal root ganglion to the spinal cord cross-section, to the pain pathways and so to the thalamus and the cerebral cortex. The red factors around the nerve ending can stimulate the pain fiber and trigger a pain stimulus that becomes conscious in the cerebral cortex. The same pain fiber can be activated in an efferent way (pink), and the nerve ending releases various neurotransmitters in the tissue (pink). These neurotransmitters can stimulate inflammation (pink). The red and pink pain system can be directly inhibited and excited by the descending blue system. The relevant neurotransmitters for the blue pathways are shown in green and capitals. Compare Fig. 3.3. Abbreviations: ACC, anterior cingulate gyrus; CGRP; calcitonin gene-regulated peptide; LC, locus coeruleus; NAc, nucleus accumbens (reward center); PAG, periaqueductal gray; raphe; raphe nuclei (serotonin)

Texas). She recognized the efferent path to the inflamed joint because she was able to suppress the inflammation in the periphery of the joint directly in the spinal cord cross-section from Fig. 4.14 by means of certain inhibitors of a selected neurotransmitter (Sluka and Westlund 1993). The manipulation of the nerve cells at spinal cord level changes the inflammation in the periphery. This work has been confirmed by many authors in a similar way with a view to different aspects of inflammation (for example Lin et al. 1999, 2007; Dong et al. 2002; Pertovaara and Koivisto 2011; Riol-Blanco et al. 2014). Another proof of the importance of efferent pain fibers was published by two groups of workers at approximately the same time. In the human chronic inflammatory disease of rheumatoid arthritis, the rheumatologist successfully uses so-called TNF inhibitors, which inhibit the pro-inflammatory TNF and thus reduce joint inflammation. Since TNF has an inflammation-promoting function in the spinal cord section of Fig. 4.14, the inhibition of TNF at spinal cord level may influence peripheral inflammation in the joint. This is also what the working group of Hans-Georg Schaible at the University of Jena and the working group of Gary Firestein at the University of San Diego thought. Both observed how inhibition of TNF at spinal cord level reduced peripheral joint inflammation (Boyle et al. 2006; Boettger et al. 2010). In order to create a clear effect, the researchers needed much less of the inhibitor when injecting into the spinal cord than when administered subcutaneously or intravenously (Boettger et al. 2010). Hans-Georg Schaible and his working group were also able to work out the importance of peripheral cytokines, where above all TNF, IL-1β, IL-6 and IL-17 strongly stimulate the nerve ending, which can intensify the inflammatory process (Schaible 2014). If now the brain can vary the tone of the blue descending nerve tract, it can influence peripheral inflammation via the sensory nerve ending of Fig. 4.14 in a very direct way. The brain thus defines the amount of peripherally released pro-inflammatory neurotransmitters, for example substance P. Substance P thus activates almost every type of innate and adaptive immune response (Suvas 2017). Substance P dilates the blood vessels, the blood flow is slowed down and leukocytes can more easily leave the bloodstream and enter the tissue. Substance P is a chemoattractant for leukocytes of all kinds and thus helps with the migration and accumulation of leukocytes in the tissue. This list is very long and there is no doubt about the pro-inflammatory importance of this neurotransmitter (Straub 2000).

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With the known information from the Sect. 3.2.7 we recognize the increased pain sensitivity in people after early traumas (Low and Schweinhardt 2012; Jones 2016; Tesarz et al. 2016; You and Meagher 2016; Burke et al. 2017; Atlas and alʼAbsi 2018; You and Meagher 2018), and animal models with maternal deprivation confirm this (Alvarez et al. 2013; Prusator and Greenwood-Van Meerveld 2016a). There, early traumatic experiences are coupled with increased pain sensitivity, which can be explained by altered function of the blue descending nerve pathway from Fig. 4.14. These changes lead to an increased tone of the pain pathways and to an enhanced release of substance P and other neurotransmitters into the tissue. Thus, the pain system becomes a direct connector between brain and immune system in the periphery.

4.2.6 Tone of the Sex Hormone Axis The sex hormones estrogen (female), progesterone (female) and testosterone (male) have a strong influence on the immune system and inflammation. Table 4.2 gives an overview of the most important aspects of this influence. Normally, this is little considered in the world Table 4.2  Sex hormones influence the immune system and inflammation Hormone

Influence

17β-estradiol in ovulation concentration and pregnancy

Inhibit T helper 1 and T helper 17 T cell immunity Inhibit macrophages, dendritic cells, neutrophilic granulocytes, microglia, fibroblasts via the proinflammatory factor NFkappaB Support regulatory T cells and T helper type 2 T cell immunity (B cell help) Support B cells and antibody production

17β-estradiol in menopausal concentration

Support T-cell immunity and macrophages as well as B-cells and antibody production

Progesterone

Inhibits macrophages and neutrophilic granulocytes Inhibits natural killer cells, T helper 1 and T helper 17 T-cell immunity and interferons Supports T helper 2 T-cell immunity (B-cell help), B cells and antibody formation

Testosterone

Support the formation of neutrophilic granulocytes in the bone marrow and regulatory T-cells Inhibits monocytes and macrophages and their proinflammatory cytokines TNF, IL-1β and IL-6 Inhibits mast cells and IL-33 Inhibits B cells and antibody production, as well as T helper 1 T cell immunity, interferon γ and IL-12

Information from review articles (Straub 2007; Cutolo and Straub 2020)

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of childhood adversity research, although we recognize great differences in the susceptibility of women compared to men with regard to the occurrence of autoimmune diseases and painful diseases such as fibromyalgia etc. So the often mentioned rheumatoid arthritis is 3 times more common in women than in men, as is multiple sclerosis, and systemic lupus erythematosus is 9 times more common in women than in men (Whitacre 2001). On the other hand, if we see on the intensive care unit four people with sepsis, then, three are men and one is a woman, which speaks for the better immune system of the woman. Women are generally and especially during pregnancy and afterwards during breastfeeding more susceptible to infection. The stronger immune response in women compared to men was positively selected during evolution for these reasons. During pregnancy, B cells with their antibody production are primarily responsible for the immune response to infectious agents. T cells and killer cells are particularly inhibited in the placenta. If we look more closely at Table 4.2, we can see the inhibitory effect of all sex hormones on so-called T helper type 1 and T helper type 17 T cell immunity, which are relevant to many chronic inflammatory diseases. In addition, all sex hormones inhibit monocytes and macrophages, which are crucial to innate immunity. Estrogens lose their inhibitory effect at low concentrations, as they prevail after menopause. Then they can even stimulate chronic inflammatory diseases on the basis of T helper type 1 and T helper type 17 T cell immunity and support chronic inflammatory diseases after menopause (Straub 2007). At one point, estrogens/progesterone differ from testosterone in that they promote B-cell and antibody production. Here, estrogens/progesterone support the B-cells, and testosterone inhibits the B-cells. This is a fundamental contrast between female and male sex hormones. This is particularly important in those chronic inflammatory diseases that are primarily triggered by B-cells and antibody production (Straub 2007). These chronic inflammatory diseases primarily occur in the reproductive phase of women. But how are early traumatic experiences linked to these sex hormones? To discuss this, we need to address two questions: • How does trauma in early life affect the world of sex hormones? • How does the increased HPA-axis with cortisol affect sex hormones?

4.2.6.1 Influence of Early Trauma on the World of Sex Hormones In general, women and men may react differently to early trauma because women and men go through different brain development, have different time windows for the influence of trauma, receive different attention and education, and on the basis of the different sex chromosomes—genetically independent of sex hormones—produce different functions in the brain, etc. (Bath 2020). These factors may intervene at important points in the brain and therefore have consequences for the chronic inflammation situation (Bath 2020). In this book, I am concerned with the peripheral role of sex hormones, whose importance for the immune system is quite clear.

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Many studies confirm an earlier maturity (menarche) in girls after previous traumas (Kim and Smith 1998; Mendle et al. 2011; Bleil et al. 2013; Amir et al. 2016; Magnus et al. 2018; Zhang et al. 2019; Suglia et al. 2020). Girls with previous adversities have earlier first sex and are often pregnant at a younger age (Anderson 2015). Consequently, they already have high estrogen levels at an early age and experience menopause at a limited ovarian reserve of oocytes at an earlier age—before the 40th birthday or around the age of 40 (Vélez et al. 2010; Magnus et al. 2018). This speaks for an increased effect of estrogens and progesterone in young years and parallel for an early decline of this hormone activity after an early menopause. Similar observations have been made in female guinea pigs and there the progesterone levels are higher in stressed animals compared to control animals in the young years (Schöpper et al. 2012). After maturity, however, the estrogen levels are lower in stressed animals (at higher cortisol serum values) (Kapoor and Matthews 2008; Ordyan et al. 2013; Del Cerro et al. 2015). Women who were traumatized at an early age and are now 40+ years old show methylations in the regulatory DNA section (promoter) of the estrogen receptor gene (Explanation 1), and thus the function of the estrogen receptor and the effect of estrogens are reduced in leukocytes. The extent of the methylations in this section correlates with the number of adversities in the young years (Fiacco et al. 2019). At the same time, the ratio of saliva estrogen to saliva cortisol is significantly lower in those with adversities compared to those without (Fiacco et al. 2019). This may be due to an earlier menopause in people with 40+ years, to generally increased glucocorticoids or to both. In men, however, there is rather a delayed maturity (Suglia et al. 2020), which can also be observed in animals after early trauma (Anderson et al. 1985; Kerchner et al. 1995; Kaiser et al. 2003; Morgan and Bale 2011; Pérez-Laso et al. 2013; Ashworth et al. 2016; Hernández-Arteaga et al. 2016; Davis et al. 2020). In animal experiments, this delayed development can be reversed by administration of testosterone (Pereira et al. 2006; Kapoor and Matthews 2011). In stressed male animals, androgen levels are lowered and estrogen levels increased (Kapoor and Matthews 2011; Eck et al. 2020). This gives us the following picture for women and men: Women experience sexual maturity earlier and have higher levels of estrogen and progesterone at that time, which fall sharply over the course of life, especially after early menopause, and the estrogen/ progesterone effect is lost soon. Men, on the other hand, have a generally lower supply of the strongly anti-inflammatory testosterone. With this interim result, we ask ourselves another question and summarize afterwards. If the tone of the HPA axis is often increased after early trauma (Sect. 4.2.3), does this heightened HPA axis activity takes direct influence on the sex hormones?

4.2.6.2 HPA Axis and Sex Hormones Remember the increased tone of the HPA Axis after early traumas! The HPA axis has an inhibitory effect on the sex hormone axis (Kalantaridou et al. 2010; Tsigos et al. 2021). For example, the hormone with the highest hierarchy in the HPA axis, called

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corticotropin-releasing hormone (CRH), inhibits the neighboring gonadotropin-releasing hormone (GnRH), which is the hormone with the highest hierarchy in the sex hormone axis. Cortisol from the adrenal gland can inhibit at all levels of the sex hormone axis (Tsigos et al. 2021). The GnRH is secreted in pulsatile waves, which is very important for reproductive function, and cortisol can suppress these waves (Tsigos et al. 2021). Under various chronic stress conditions, the function of the sex hormone axis in women and men is severely impaired, and this can lead to amenorrhea in women and lack of libido and reduced fertility in men (Kyrou and Tsigos 2008; Valsamakis et al. 2019). Cortisol and other hormones of the HPA axis are directly involved in this phenomenon. If inflammation is added and, for example, IL-6 is produced to a greater extent, this IL-6 can suppress the production of sex hormones within hours (Tsigos et al. 1999). In summary, cortisol has an inhibitory effect on the gonads and sex hormones and can therefore turn off the anti-inflammatory effects of these hormones (Table 4.2). Since the activity of the HPA Axis is often increased after early traumatic experiences, a high cortisol tone is more likely in a large proportion of those affected (Sect. 4.2.3). If cortisol has a lower or no immunosuppressive effect (Sect. 4.2.3), the inflammatory situation is additionally aggravated by the shutdown of the sex hormones. This can open doors for those chronic inflammatory diseases that occur after menopause or andropause.

4.2.6.3 Differential Effects of Sex Hormones on Inflammation The influence of sex hormones on various elements of the immune system is shown in Table 4.2. The influence is not uniformly inhibiting or stimulating, but quite differentiated. This results in a different susceptibility of men and women to autoimmune diseases and other chronic inflammations, which are controlled by different components of the immune system. With the development of so-called biologics, which can specifically shut down individual components of the immune response (therapies with neutralizing inhibitors), we gradually recognize different subtypes of autoimmune diseases. So the same disease may appear the same from the outside—for example, rheumatoid arthritis in the fingers and toes—but a different immune response may be found behind it. For example, the doctor can very specifically inhibit T cells by an anti-T cell therapy, but this can only help a smaller part of the affected people very well. The rate of complete suppression of the immune response in rheumatoid arthritis, depending on other circumstances such as concomitant medication, etc., is between 10 and 40% (Lutt 2009). So 10–40% of people with rheumatoid arthritis benefit very well from this therapy. So 10–40% of patients have a T cell-dependent chronic inflammation, and in 60–90% of patients the disease is based on another immunological process. Now let’s look at the targeted therapy to shut down the B cells, the picture looks similar. This allows us to recognize different disease subtypes that, from the outside—phenotypically—produce a very similar disease picture with comparable symptoms. These different subtypes show why female sex hormones can act differently and therefore why the appearance or disappearance of hormones can promote or inhibit

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different subtypes of the same disease at different times in life. With this knowledge, we now look at Fig. 4.15. An inflammatory influence is added in women because estrogens stimulate many different aspects of pain pathways (review article by Straub 2007). The result is an increased sensitization, which leads to increased input signals into the spinal cord (2007). In addition, central nervous aspects of pain processing in the brain are stimulated by estrogens (2007). Heightened pain pocessing leads to an increased release of the proinflammatory substance P at the nerve ending in peripheral tissue (Sect. 4.2.5 Tone of the Pain Pathways). Looking on the effects of estrogens, we are not surprised that typical diseases of early traumatized people such as fibromyalgia, migraine, pelvic pain, irritable bowel syndrome and urethral and bladder pain are more common in women than in men (e.g. Chaloner and Greenwood-Van Meerveld 2013). The estrogens sensitize nociceptive pathways.

Women

Traumas

early B-cell driven immune response increases high estrogens high progesterone

childhood

low estrogens low progesterone additional inhibition by HPA axis

reproductive years early menarche

Men

early T-cell driven immune response increases

postmenopausal early menopause

various immune responses increased

Traumas

low testosterone

very low testosterone additional inhibition by HPA axis

childhood

reproductive years late puberty

posttestosterone andropause

Fig. 4.15   Trauma, sex hormones and chronic immune system activation. Women with early high estrogen/progesterone levels as a result of early childhood adversity would stimulate the B-cell-dependent diseases in the reproductive age. If there is a drop in estrogen/progesterone after early menopause, the T-cell-dependent chronic immune diseases are intensified. The latter mechanism is aggravated by high activity of the HPA axis with high cortisol, because cortisol inhibits the sex hormone axis. In men after early trauma, the generally lower tone of testosterone would mean stimulation of chronic inflammation at all stages of life, and the problem increases especially after andropause. Parallel increased cortisol levels further aggravate the situation when cortisol inhibits the sex hormone axis and when they are no longer anti-inflammatory in usual concentrations (Sect. 4.2.3)

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This makes the function of sex hormones as direct connectors obvious, because both the increased appearance (with estrogens/progesterone promote B-cell immunity and pain) and the shutdown (with estrogens/progesterone after premature menopause and testosterone) can promote chronic inflammation by different immune reactions at different times of life. In this Sect. 4.2 “Direct connectors chronically activate the immune system (No. 1)” we learned about the most important connectors that can promote an inflammatory situation in a direct, brain-influenced way. Part of the anti-inflammatory system has become pro-inflammatory by receptor switching processes (sympathetic nervous system, HPA axis). Other direct connectors could be mentioned here, such as growth hormone and especially thyroid hormones, but I do not want to exceed the scope of the book.

4.3 Indirect Connectors Activate the Immune System Chronically (No. 2) 4.3.1 Adipose Tissue is Pro-inflammatory I had already mentioned the topic of obesity under Sect. 3.3.1 in the context of trauma sequelae and cited the epidemiological studies. The connection between early traumatic episodes and later higher body weight is undisputed (e.g. Thomas et al. 2008; Entringer et al. 2010; Bae et al. 2014; Davis et al. 2014; Wickrama et al. 2014; Tanenbaum et al. 2017; Wickrama et al. 2017; Farewell et al. 2018; Robson et al. 2020). The starting point is clear. But what does this have to do with higher inflammation and with the indirect connector from the chapter heading? The brain is significantly involved in weight gain. In Table 3.2 and in Chap. “Fatmaking Eating Behavior”, I spoke about the brain-related causes of high body weight. I focused on fat-making eating behavior in the sense of reward, just like with alcohol, nicotine and drugs (overview in Spencer 2013). The HPA axis plays an important role in overeating behavior. After childhood adversities, the HPA axis is activated. If a stress reaction is triggered, the top hormone of the HPA axis, corticotropin-releasing hormone (CRH), rises and cortisol from the adrenal gland increases gradually over 15-30 minutes, which stimulates appetite (Spencer 2013). A chronic increase in cortisol chronically stimulates appetite; the relationships are well explained in a review article (Spencer 2013). Perhaps you can already imagine how the brain uses the adipose tissue to chronically stimulate inflammation. The famous publication from 1993 by Gökhan Hotamisligil in Spiegelman’s laboratory at Harvard Medical School in Boston brought attention to inflammatory factors in adipose tissue (Hotamisligil et al. 1993), more specifically: to TNF. Other authors were the first to investigate the influence of weight loss on TNF levels in adipose tissue, as they observed significantly lower TNF levels in adipose tissue after a decrease in body weight (Kern et al. 1995). In the early 1990s, an increasing awareness developed for a

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possible increased inflammatory state in adipose tissue. Later, other cytokines were added, for example IL-6 (Mohamed-Ali et al. 1997). These investigations were further stimulated because researchers in the field of cardiovascular research discovered inflammatory aspects in the atherosclerotic vessel wall (Kern et al. 1995). Since arteriosclerosis was in turn associated with a higher body weight, a connection was made between vessel wall and adipose tissue inflammation. Since IL-6 was recognized as the trigger of the acute phase inflammatory reaction in the liver (Andus et al. 1988), the focus was on the universally measurable acute phase C-reactive protein. As always, various scientific groups came from different directions over time to take C-reactive protein as an indicator of the connection between adipose tissue and inflammation (Deehan et al. 1994; Wolfe 1997; Maugeri et al. 1998; Hak et al. 1999; Visser et al. 1999; Yudkin et al. 1999). In 2000, the matter was clear, but the causative cell in adipose tissue was unknown. Although macrophages in adipose tissue were already detected in rats after a fish oil diet at the end of the 1970s (Danse and Verschuren 1978), this finding ended up in the veterinary pathology drawer for years. In the early 1980s, others discovered the ability of adipose tissue cells to produce colony-stimulating factor (CSF) from bone marrow, which is relevant for the survival of monocytes and macrophages in adipose tissue (Lanotte et al. 1982). The detection of specific immune cells took a long time because first the corresponding methods for the detection of different types of immune cells had to be discovered. Macrophages have been associated with spontaneous or experimentally induced necrosis in adipose tissue (Friedman and Winkelmann 1989), but were not recognized as spontaneous settlers in adipose tissue. Although factors from macrophages influenced lipolysis and insulin resistance in adipose tissue (e.g. Ogawa et al. 1989), the colonization of adipose tissue by macrophages was unknown for a long time after the initial description by Danse and Verschuren (Danse and Verschuren 1978). The Spiegelman laboratory in Harvard discovered additional immune factors in adipose tissue that spoke for the presence of macrophages without finding them in these endeavors (White et al. 1992). Finally, various groups discovered lymphoid tissue in abdominal fat—so-called milk spots—and there they were, the macrophages and lymphocytes, who felt comfortable in the adipose tissue (Dullens et al. 1993; Pond and Mattacks 1995). However, these studies were limited to the special case of lymphoid tissue in abdominal adipose tissue. Then migration factors were found in fat cells that favor the accumulation of macrophages in this tissue (Hirokawa et al. 1997). More and more researchers recognized many inflammatory factors from adipose tissue. Finally, the real breakthrough came in 2003 when two groups described the accumulation of macrophages in adipose tissue in the same prestigious journal (Weisberg et al. 2003; Xu et al. 2003). Unfortunately, neither of them mentioned the 25-year-old original work from veterinary pathology from 1978, where the situation was already visible (Danse and Verschuren 1978). I summarize (Fig. 4.16): After early traumatic situations, the brain contributes significantly to the increase in fat tissue (obesity), and the enlargement of fat tissue is associated

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with an inflammatory activity in fat tissue (Schäffler and Schölmerich 2010; Choi et al. 2013). The main players in fat tissue are macrophages and fat cells themselves. The inflammation in fat tissue is transferred to the rest of the body because inflammatory factors in the blood are increased (C-reactive protein). Many authors see this as a way in which obesity can act back on the brain to be involved in depression (Ambrósio et al. 2018). Finally, the brain can still act on fat tissue in other ways, for example by sending hormones from the HPA axis (cortisol) and the sympathetic nervous system (noradrenaline). Both systems can activate lipolysis—the breakdown of stored fatty acids—and insulin resistance (see next section), or they can prevent the uptake of fatty acids and glucose from the bloodstream into the fat cell (summarized in Straub 2020b). If the brain releases fatty acids in this way, they can have a pro-inflammatory effect, especially in the case of saturated fatty acids (summarized in Straub 2020b). Here is the dilemma. People affected by early trauma take in too many bad foods high in saturated fatty acids over a long period of time. In Chap. “Fat-Making Eating Behavior”, I called it Junk Food Self Medication. These fatty acids are typically stored in fat tissue, and the release of these fatty acids stimulated by the brain leads to a proinflammatory constellation (Straub 2020b). We have a kind of memory for bad fatty acids in fat tissue when we have previously taken them in (Straub 2020b). Furthermore, people who have experienced trauma and obesity have lower blood levels of good HDL cholesterol and higher blood levels of bad LDL cholesterol and triglycerides, which we recognize as additional factors in a proinflammatory constellation (Reid et al. 2018; Cubbin et al. 2019; Péterfalvi et al. 2019). This makes obvious the function of the brain and its downstream assistants—the HPA axis and the sympathetic nervous system—as well as the fat tissue indirect connectors, because they promote inflammation in fat tissue and induce fat tissue factors such as TNF, IL-6, free fatty acids and others to promote chronic immune system activation in various places (Fig. 4.16). This also includes sympathetic overactivity and resistance to insulin, that is, the lack of effect of insulin in fat tissue and elsewhere.

4.3.2 The Insulin from the Pancreas Promotes Inflammation The constellation of high inflammation in fat tissue and simultaneous activation of the HPA axis and the sympathetic nervous system is a strong causal platform for the development of insulin resistance, that is, the reduced effectiveness of insulin due to changes in signal transduction through the insulin receptor into the cell. Each individual factor can cause insulin resistance, and in combination they are particularly unpleasant. So various disorders of the central nervous system (e.g. stress, pain, depression, schizophrenia) and many inflammatory diseases are associated with insulin resistance (compiled in Straub 2014). Therefore, it should not surprise us if people with previous trauma in young years develop insulin resistance with increased body weight, increased sympathetic activity

4.3  Indirect Connectors Activate the Immune System Chronically (No. 2) Fig. 4.16   The importance of fat tissue as an indirect connector. Factors from the brain use fat tissue to stimulate chronic inflammation. Lipolysis serves to release fatty acids. Insulin resistance (next section) serves to prevent the uptake of fatty acids/glucose into the fat cell. Both circulate more in the bloodstream. Both contribute to the increase in inflammation in addition to the local macrophages and lymphocytes. Typical mediators are cytokines such as TNF, IL-6 and free fatty acids themselves

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selfish brain fattening diet smoking excessive alcohol high cortisol high nor-/adrenaline low physical activity

lipolysis insulin resistance

much fat tissue indirect connector fat cells themselves macrophages in adipose tissue lymphocytes in adipose tissue TNF, IL-6, free fatty acids, etc.

mediators

chronic inflammation

and increased HPA axis activity (Vargas et al. 2016; Suarez et al. 2017; Campbell et al. 2018; Reid et al. 2018; Fuller-Rowell et al. 2019; Robakis et al. 2019; Stojek et al. 2019). Similar findings of insulin resistance can be seen in animal experiments with early trauma (Lesage et al. 2004; Kaufman et al. 2007; Brunton et al. 2013; Ruiz et al. 2018; Eller et al. 2020; van Niekerk et al. 2020; Zardooz et al. 2021). The ineffectiveness of insulin is caused by the hormones, neurotransmitters and cytokines directly at the insulin receptor (compiled in Straub 2014, 2018). You remember the selfishness of the brain and the immune system (Sect. 4.1). Both use insulin resistance in different ways—brain: hormones/neurotransmitters, immune system: cytokines—because insulin resistance means reduced uptake of fatty acids and glucose in fat cells, muscle cells and liver cells. Thus, higher levels of glucose and fatty acids circulate in the blood, and in crisis situations the brain and immune system can access these circulating energy-rich substrates. So what’s the problem with insulin resistance? Higher blood levels of glucose and fatty acids stimulate the pancreas to further produce insulin. Inevitably, insulin resistance leads to hyperinsulinemia; that is, more insulin circulates in the flowing blood. Here we have the indirect influence of the brain, because the brain indirectly increases insulin resistance and insulin levels in the blood through the HPA axis (cortisol) and the sympathetic nervous system (noradrenaline, adrenaline) as well as through increased inflammation in fat tissue (Fig. 4.17). The direct influence of the brain on the parasympathetic nervous system of the vagus nerve

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higher inflammatory activity in the abdominal adipose tissue

genetic aspects

physical inactivity

immobility increase in fat tissue

insulin resistance insulin glucose free fatty acids

activation of the HPA axis and the sympathetic nervous system (cortisol, nor-/adrenaline)

overeating increase in fat tissue

microbiome

malnutrition with high-calorie snacks with spikes in circulating glucose and fatty acids

Fig. 4.17   Development of insulin resistance and hyperinsulinemia. The described factors influence insulin resistance and hyperinsulinemia. Those that are determined by the brain are marked in red. Insulin, glucose and free fatty acids are increased in the blood and contribute to inflammation. We will discuss the microbiome, the sum of all microorganisms that live on the skin or mucous membranes of an individual (nose, mouth, gastrointestinal tract, urogenital, respiratory tract, etc.), below

increases insulin secretion, and this influence is lost when the parasympathetic nervous system is inhibited. Insulin, glucose and free fatty acids can be proinflammatory factors at high concentrations (Frauwirth and Thompson 2004; Calder et al. 2007; Maciver et al. 2008; Ieronymaki et al. 2019; van Niekerk et al. 2021). Insulin is an important element for immune cell survival and growth (van Niekerk et al. 2021). Therefore, insulin is important for macrophage function (Ieronymaki et al. 2019). Insulin can have anti-inflammatory effects to some extent, but especially in combination with higher blood values of glucose and free fatty acids and parallel inflammation processes, the picture can change. The dual role of insulin can be reversed into a proinflammatory direction by intracellular switching reactions (van Niekerk et al. 2020). Furthermore, insulin can contribute to improved conduction and sensitization of pain nerve fibers (Lázár et al. 2020). Here, those sensory nerve fibers are particularly favored by

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the presence of insulin, which possess the chili receptor (capsaicin, TRPV1) (Lázár et al. 2020). The increased activation of pain nerve fibers can in turn set off an inflammatory reaction because substance P is released locally (see Sect. 4.2.5 Tone of the Pain Pathways). Thus, the role of the brain, the HPA axis, and the sympathetic nervous system becomes visible, because they indirectly promote high blood levels of insulin from the pancreas, glucose from the liver, and free fatty acids from the adipose tissue (indirect connectors), and all contribute to chronic immune system activation.

4.3.3 Reduced Physical Activity—Anti-inflammatory Factors are Missing Early trauma has a significant impact on physical activity, muscle strength, and physical dexterity (Cooper et al. 2010; Birnie et al. 2011; Murray et al. 2013; Anderson et al. 2017; Cosco et al. 2018; Allen et al. 2019; Cheval et al. 2019; Hwang et al. 2019; Maunder et al. 2019), all of which an be reduced in those affected. We also see such relationships in animal experiments (Eller et al. 2020). In a comprehensive review of the literature, the authors found increased muscle mass in people with favorable socio-economic conditions, which was particularly relevant in countries with high income levels. The opposite picture emerged in middle-income countries (Bridger Staatz et al. 2021). In monkeys with trauma in young years, important functional parameters of the performance of the heart are lower than in controls (Coplan et al. 2018). In traumatized people, little muscle mass and muscle strength go hand in hand with increased adipose tissue. This constellation was called the “sarcopenic obesity”, in which the muscle mass is low (that is, sarcopenic) and at the same time a high body mass index is present (fat instead of muscle) (Stenholm et al. 2008). What does this sarcopenic obesity mean for the inflammatory situation? The role of adiposity has already been reported (Fig. 4.16). We have to talk about the muscle here, because if muscular work is anti-inflammatory, the loss of muscular work is pro-inflammatory. I am referring here mainly to work by Bente Pedersen from the Center of Physical Activity Research at the University of Copenhagen. In the 1990s, the scientists postulated a “Work Factor”, which is released into the blood during muscular work and affects many other organs. At the beginning of the 2000s, Pedersen and her group found the first Work Factor in IL-6 (Steensberg et al. 2000). IL-6 was considered mixed pro- or anti-inflammatory at that time, no one knew for sure. A little later, rheumatologists from Japan recognized the pro-inflammatory importance of high tissue concentrations of IL-6 in the treatment of rheumatic patients, as the neutralizing therapy with antibodies against IL-6 had very good anti-inflammatory effects (Mihara et al. 2005). Bente Pedersen was not deterred by these new findings and propagated IL-6 as an anti-inflammatory factor (Pedersen and Fischer 2007). Finally, various investigators recognized other factors that are released from the muscle into the blood, and the endocrine function of the muscle took shape (Pedersen 2013). The scientists

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called these new factors “myokines”, similar to the new factors of white adipose tissue “adipokines” and those of brown adipose tissue “batokines” (brown adipose tissue). Of these myokines, IL-6 was anti-inflammatory in that it could inhibit TNF from macrophages and also stimulate the anti-inflammatory cytokine IL-10 and the neutralizer of the pro-inflammatory IL-1 (IL-1 receptor antagonist). Its anti-inflammatory role in the body depends on the duration of its presence and the level, as short IL-6 peaks are favorable but prolonged increased IL-6 concentrations are unfavorable (Severinsen and Pedersen 2020). In rheumatic diseases, the long-term presence of IL-6 has a pro-inflammatory meaning. In addition, the anti-inflammatory role of physical exercise was gradually recognized (Benatti and Pedersen 2015), as well as the protective effect of sport with respect to the natural aging of the immune system (Duggal et al. 2019). These anti-inflammatory and protective effects of physical exercise are multifaceted and involve many organs of the body (for example, by inhibiting white and promoting brown adipose tissue). In addition, a direct anti-inflammatory component of muscle factors is recognized (Severinsen and Pedersen 2020). In this way, the brain is responsible for the reduced physical activity after early trauma, and this lack of muscular work indirectly induces a higher level of inflammation. We recognize in the muscle and its myokines another indirect connector.

4.3.4 Microbiome and Inflammation Nobel laureate Joshua Lederberg (1925–2008) was a molecular biologist and geneticist and participated in the Human Genome Project of the 1990s. He coined the term microbiome because he recognized the involvement of the multitude of bacteria in human metabolism and suspected that this might influence the body. Lederberg saw in the coexistence of humans and microbiome a symbiosis that can be disturbed in case of disease. Lederberg’s statements were the starting point for the more extensive microbiome studies with the motto: “What else do we have to genetically investigate?” The microbiome is the sum of all microorganisms that live on the skin or mucous membranes of an individual (nose, mouth, gastrointestinal tract, urogenital, respiratory tract, etc.). This includes bacteria, fungi, parasites, viruses and bacteriophages, and one thing is quite certain: Most people live peacefully with their microbiome. In the intestine and other places, bacteria perform many helpful tasks, so we cannot do without them (e.g. metabolic tasks). In this sense, it is a symbiosis. Since scientists have been refining the so-called high-throughput sequencing of DNA since 2000, many researchers have begun to include the microbiome in their genetic considerations. They take samples of the microbiome from different body sites and analyze the genetic material of the microbes. From the found sequences, the researchers can infer the presence and amount of different bacterial strains. The vast majority of the microbiome is made up of the bacterial species Bacteroides (Bacteroides and Prevotella) and Firmicutes (Ruminococcus, Lactobacillus and Clostridium).

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In the last 10 years, this microbiome has increasingly been associated with chronic inflammatory diseases (van den Munckhof et al. 2018; Salem et al. 2019; Dalmády et al. 2020; Aldars-García et al. 2021). While causal relationships are clearly visible in animal experiments on mice and rats, because experimenters can transfer very defined bacterial strains to an otherwise germ-free animal (called monoassociation), the situation is not yet clear in humans. The proponents of a bidirectional relationship between the microbiome in the intestine and changes in the brain rely on animal experiments on mice. So far, we have only found a few causal links between microbiomes and diseases. The shining exception is antibiotic-induced pseudomembranous colitis, a severe acute disease caused by infection with the bacterium Clostridium difficile, because in this case the transfer of gut bacteria from healthy donors really helps. In this particular case, the dysbiosis caused by antibiotics is cured in 80–90% of cases by microbiome therapy, because the diversity of bacteria increases sharply (Brandt 2015). There are only small effects in the therapy of colitis ulcerosa with probiotics or synbiotics (probiotics + bacterium-promoting additive), because here the diversity of bacteria in the intestine is directly supported (Kaur et al. 2020; Zhang et al. 2021). But what about all the non-gut-related diseases? At the moment it is open whether a certain microbiome causes or worsens a disease (causality) or whether, on the other hand, a special microbiome is a consequence of a certain disease situation (correlation). One thing is relatively certain: A high diversity of bacterial strains is healthy (e.g. Brandt 2015; Shi et al. 2016; Gavriilaki et al. 2020). However, findings in stressed animals, in which the microbiome was examined before and after stress, indicate that the change of the microbiome can be a consenquence rather than a cause. Such studies have been carried out on rodents. For example, Mike Bailey from Columbus, Ohio, observed how repeated aggression stress (social disruption) reduced this bacterial diversity. Furthermore, there were differences in groups of bacteria between stressed and non-stressed animals (Bailey et al. 2011). Other researchers support these findings in rodents (Tannock and Savage 1974; Golubeva et al. 2015; Bharwani et al. 2016; El Aidy et al. 2017; Moussaoui et al. 2017; Gur et al. 2019). Prenatal stress can already change the composition of bacteria in the intestine in monkeys after birth (Bailey et al. 2004). Thus, early trauma has an effect on the composition of gut bacteria. In animal experiments, connections from the microbiome to the brain have been established, which contributed to the designation microbiome-gut-brain axis. Such contacts can contribute to pathological changes in the body. For example, John Cryan’s research group from Cork, Ireland, was able to show a stronger stress response of the HPA axis in germ-free mice compared to control animals (Clarke et al. 2013). This work confirmed earlier work by a Japanese research group led by Sudo and colleagues (Sudo et al. 2004). Here, the authors saw how the administration of certain bacterial strains normalized the stress response of the HPA axis.

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Similarly, the activity of the sympathetic nervous system is related to the colonization of germs in the gut. Germ-free mice have increased activity of sympathetic nerve fibers (Muller et al. 2020). This increased sympathetic activity can be reduced by colonization with germs. In this respect, the sympathetic nervous system behaves similarly to the HPA axis, which often show synchronous behavior (see Sect. 4.2.4). In these experiments, a connection was found between the short-chain fatty acids produced by bacteria and the activation of sympathetic nerve fibers (Muller et al. 2020). In addition, anxiety reactions in animals with separation experiences are stimulated by the presence of germs in the gut. Animals without germs show a significantly reduced anxiety reaction (De Palma et al. 2015). These experiments show the influence of the microbiome on different levels of the brain. However, we only recognize this in mice because the germ influence can be controlled very well experimentally (monoassociation). There is a huge difference between germ-free and normal germ diversity, which makes a significant difference in animal experiments compared to the situation in humans. When we look at humans, we can only speak of slightly different microbiomes, which never comes close to the drastic contrast between germ-free and normal germ diversity. However, there can be indirect influencers—that is, via the microbiome—on the immune system. This is suggested by studies on a large number of newborns with a high diabetes risk. In these children, the early administration of probiotics already in the first month of life led to a lower risk of developing an autoimmune reaction against the insulin-producing cells in the pancreas nine years after birth (Uusitalo et al. 2016). Wow! A recent small randomized, unblinded study in healthy people over 10 weeks showed the slightly anti-inflammatory importance of a diet with fermented foods (e.g. yogurt, cottage cheese, kimchi vegetables, sauerkraut, kombucha tea, kefir, buttermilk, kvass, vegetable drinks, etc.) (Wastyk et al. 2021). Here we see a direct influence of therapeutically given bacteria on the immune system. However, the number of studies is still small. Finally, there are the first small studies in humans, which compared to controls observe a different microbiome in those with early traumatic experiences (Hantsoo et al. 2019; Callaghan et al. 2020; Flannery et al. 2020; Hantsoo and Zemel 2021; Reid et al. 2021). Now we can formulate the following hypotheses: 1) After early trauma, the microbiome changes through the sustainable influence of the HPA axis and the sympathetic nervous system, 2) the change in the microbiome affects the immune system in return. 3) This influence creates chronic immune system activation. At this point, I warn all readers against premature conclusions. Let’s wait for the well-designed study in humans.

4.3.5 The Permeability of the Gut is Pro-inflammatory Stressed individuals have a “leaky” intestinal wall, which allows bacteria to enter the body and thus stimulate the intestinal immune system. The penetration of particularly

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infectious intestinal bacteria across the barrier of the intestinal mucosa has been known in animals and humans for a long time. Doctors have examined this in the context of typhus infection by Salmonella species, as these bacteria enter the body (Orskov and Moltke 1928; Sprinz et al. 1966). Now, stressful conditions like shock situations or pain reactions (heat, cold) can promote translocation of harmless bacteria from the intestine into the tissue (Deitch and Bridges 1987; Berg 1999). Furthermore, psychological stress situations increase the permeability for intestinal bacteria (Bailey et al. 2006; Reber et al. 2011). High glucocorticoids of the HPA axis are important for this (Meddings and Swain 2000; Reber et al. 2011). In addition, the sympathetic nervous system is relevant, because its deactivation reduces bacterial translocation through the leaky intestinal wall, but the effect may be different for different bacterial strains (Straub et al. 2005; Worlicek et al. 2010). Thus, both main stress axes favor the permeability of the intestinal wall. This bacterial translocation occurs in humans under stressful life situations, such as after major surgery (Woodcock et al. 2000; Ono et al. 2005; Nishigaki et al. 2014; Schietroma et al. 2015). Extreme sport experiences like an ultra-marathon reduce the imperviousness of the intestinal wall (Gill et al. 2015). In this way, the brain can increase the permeability of the intestinal mucosa, bacteria can enter the interior of the body and activate the immune system in lymph nodes or elsewhere. It is not difficult to imagine how the permanent deflection of the weighing scale from Fig. 3.4 activates the HPA axis and the sympathetic nervous system, which influence the intestinal imperviousness and finally a continuous immune activation. In this case, the intestine, bacteria and the permeability of the intestinal mucosa are the indirect connectors.

4.3.6 The Skin Itches Chronically and is Inflamed The neurodermatitis or atopic dermatitis is the most common chronic inflammatory skin disease worldwide. The prevalence is between 15 and 20%. It is characterized by intense pruritus, a relapsing-remitting course with free intervals and systemic inflammation. The pruritus leads to sleep problems, concentration problems, social stigmatization, reduced quality of life of those affected, work absenteeism, reduced productivity at school, at university or in working life (summarized in Thijs et al. 2015; Weidinger et al. 2018). The systemic inflammation becomes apparent when considering biomarkers of atopic dermatitis, because there are increased numbers of eosinophilic granulocytes, raised immunoglobulins of the IgE type, and some increased cytokines and chemokines in the blood (Thijs et al. 2015; Sinikumpu et al. 2018; Weidinger et al. 2018; Daniluk et al. 2019). Nevertheless, atopic dermatitis typically does not belong to the highly inflammatory skin diseases, and I therefore rather speak of low inflammation. However, in rare cases, the extent of the disease can affect up to 90% of the skin, and then the systemic signs of inflammation are clearly increased.

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The development of atopic dermatitis is based on genetic factors with a relatively high heritability, on dysfunction of the epidermal barrier, on a high susceptibility to skin germs (especially Staphylococcus aureus), on intradermal inflammation with a T helper type 2 T cell immunity (IL-4, IL-13, IL-31, IL-33; in addition, IL-17 and IL-22) and an increased irritation of the skin showing up as pruritus, which is conveyed to the brain via special pruritus-conducting sensory nerve fibers (Weidinger et al. 2018). With regard to pruritus, the doctors recognized the neurotransmitter histamine in addition to other factors (IL-4, IL-13, IL-31, endothelin-1 and TSLP [thymic stromal lymphopoetin]), which can bind to the pruritus-conducting sensory nerve fibers via specific receptors (Weidinger et al. 2018). At the same time, there is an increased ingrowth of these nerve fibers into the affected skin regions (Haas et al. 2010). This increased innervation is another important platform for an inflammation that is mediated by the neurotransmitters of these sensory nerve fibers (substance P and others) (Lönndahl et al. 2019). Stress and anxiety exacerbate atopic dermatitis and itching, which has been shown many times (overview in Sanders and Akiyama 2018). In addition, in recent years, the connection between early traumatic life situations and atopic dermatitis has been confirmed in population-based studies (Andersson et al. 2016; Chang et al. 2016; McKenzie and Silverberg 2020; van der Leek et al. 2020). We thus recognize the influence of the brain on local skin inflammation and itching, and itching exacerbates the problem in a vicious circle. All findings point to the skin as a platform for an indirect connector between the brain and a chronically activated immune system.

4.4 Environmental Factors Chronically Activate the Immune System (No. 3) We are talking here about extra-corporeal connectors, in which early trauma stimulates exposure to an environmental factor more often, an environmental factor that in turn triggers chronic immune system activation.

4.4.1 Where There’s Smoke, There’s Fire In Sect. 3.2.1 under alcohol, nicotine and drugs, I presented the common follow-up problem of smoking. Early adversity leads to a significant increase in smoking in young and old age (Iakunchykova et al. 2015; Smith et al. 2016; Hsu and Kawachi 2019). Smoking is experienced as a reward (text around Fig. 3.1) and smoking changes important centers in the brain, similar as a psychopharmaceutical can do (Jacobsen et al. 2004; Newhouse et al. 2011). Not only people with early trauma smoke, but also patients with psychiatric illnesses, especially schizophrenia. They treat themselves in a special way with smoking (psychopharmaceutical).

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Table 4.3  Smoking and chronic inflammatory disease Chronic inflammatory disease is promoted

Literature

Rheumatoid arthritis

(Jiang und Alfredsson 2020; Prisco et al. 2020; Qian et al. 2020; Jansen et al. 2021; Safy-Khan et al. 2021)

Psoriasis vulgaris (psoriasis)

(Zhou et al. 2020)

Psoriasis-Arthritis (psoriasis with arthritic joints)

(Dalmády et al. 2020)

Multiple Sclerosis (autoimmunity in the brain or spinal cord)

(Nishanth et al. 2020)

Periodontitis

(Dalmády et al. 2020)

Systemic Lupus Erythematosus (multiple autoimmunity)

(Costenbader et al. 2004)

Thyroid Autoimmunity (Morbus Basedow)

(Köhling et al. 2017)

Primary biliary cirrhosis (gallbladder ­autoimmune disease)

(Howel et al. 2000)

Morbus Crohn (not in colitis ulcerosa!)

(Berkowitz et al. 2018)

Smoking is thus stimulated by the brain and has a peripheral importance independently of direct or indirect connectors, because it acts especially in the mouth, nose, throat, lungs and gastrointestinal tract. Smoking is clearly associated with chronic inflammatory diseases (Table 4.3). How can smoking have this influence on these diseases? Smoking can, for example, disturb the bacterial composition on inner and outer body surfaces, the microbiome (Gui et al. 2021). The change in microbiome is associated with chronic inflammatory diseases (van den Munckhof et al. 2018; Salem et al. 2019; Dalmády et al. 2020; Aldars-García et al. 2021). Smoking, among other things, stimulates a certain mouth bacterium called Porphyromonas gingivalis (short P. gingivalis), which is significantly involved in gingivitis. This mouth bacterium has an interesting enzyme called PAD (Peptidylarginine Deaminase), which converts proteins with the amino acid arginine into proteins with the amino acid citrulline (Fig. 4.18). While arginine is a typical amino acid of the human proteome, citrulline is not a typical amino acid. This can be dangerous because citrulline proteins can be recognized by the immune system as foreign. The disturbance of the immune system, which leads to an incorrect recognition of the citrulline proteins, is actually a cause of the most common chronic inflammatory rheumatic disease, rheumatoid arthritis (Hochberg et al. 2015; Manoil et al. 2021) and the arthritis associated with psoriasis (psoriatic arthritis) (Dalmády et al. 2020). The one with the wrong arginine, namely citrulline, is also discussed as a possible cause in other chronic inflammatory diseases such as juvenile autoimmune diabetes mellitus (Yang et al. 2021), multiple sclerosis (Gudmann et al. 2015) and ankylosing spondylitis (Gudmann et al. 2015).

186 Fig. 4.18   Smoking stimulates a bacterium that causes inflammation. Smoking stimulates Porphyromonas gingivalis and this bacterium can convert arginine proteins into citrulline proteins because it has peptidylarginine deaminase (PAD). This creates a foreign protein (the blue part is foreign). This process is called citrullination. This foreign part is attacked by the immune system and corresponding antibodies are produced (the pink Y-structure), which recognize and bind the antigen. Once an immune memory is established, there is a permanent production of corresponding autoimmune antibodies that can lead to an inflammatory reaction

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Smoking

arginine bacterium: P. gingivalis

peptidylarginine deaminase autoimmune antibodies

such changes are recognized as foreign by the immune system

citrulline

Inflammation In addition, smoking stimulates a type of T cell that is often involved in chronic inflammatory diseases, namely the T helper type 17 T cell (Donate et al. 2021). Smoking is associated with activation of lymphocytes and thrombocytes as well as increased inflammation values in the blood (IL-6, C-reactive protein, fibrinogen) (Huan et al. 2016). Smoking can lead to epigenetic changes in leukocytes that persist after smoking cessation for years (Joehanes et al. 2016). Smoking induces oxidative stress, which in medicine is meant to be an increase in dangerous and pro-inflammatory free radicals compared to anti-inflammatory radical scavengers (Jansen et al. 2021). Oxidative stress arises as a result of previous adversities (Horn et al. 2019), and so additive or synergistic effects can occur here. Smoking is primarily responsible for structural lung changes, such as chronic obstructive lung disease, which in turn, similar to atherosclerosis, entails a pro-inflammatory situation. A nice overview of the topic of smoking and chronic inflammation is provided by a work from the teaching hospital of Harvard University (Costenbader and Karlson 2006). I can therefore summarize: Where there is smoke, there is fire; in other words: it ignites. Inflammation and lung cancer are more common after long-term smoking. Since

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unfortunate people with a difficult childhood or youth smoke much more often, we experience here with smoking the typical example of an extra-corporeal connector between brain and immune system.

4.4.2 Where Fine Particles are Flying, It Gets Uncomfortable Particles floating in the air are called dusts, and depending on the particle size, the occupational physician speaks of coarse and fine dust. Dusts can contain pollutants that adversely affect human health if no protective masks are worn. During the Corona pandemic, many people learned to wear protective masks, and that was important. I myself now put on the mask more easily when I am exposed to an increased amount of dust (household and gardening work). Nothing is so stupid (Corona pandemic) not to be good for anything (mask use). In the quarry, in construction, in mining, in dealing with sand (sandblasting, etc.), and everywhere where stones are mechanically processed, such fine rock dusts can arise, to give an example of particles floating in the air. Fine dusts are particularly relevant for chronic inflammatory diseases because they can penetrate deep into the lungs via the trachea and bronchi. The classic examples in medicine are chronic bronchitis and the dust lung or silicosis, both of which are associated with the development of lung cancer and have pro-inflammatory significance (Poinen-Rughooputh et al. 2016). In the foreground are the quartz fine particles, which the chemist calls crystalline silicon dioxide (SiO2) (silica). These silica dusts pack a punch. People with silica exposure are more likely to suffer from the chronic inflammatory joint disease of rheumatoid arthritis, as studies of a very large number of patients showed (Prisco et al. 2020). These people are more likely to have other chronic inflammatory autoimmune diseases, such as systemic sclerosis, systemic lupus erythematosus and vasculitis (ANCA-positive vasculitis and glomerulonephritis) (Miller et al. 2012). The intruded fine particles can locally stimulate the innate inflammatory system in the lung. The activation of, for example, macrophages takes place via surface receptors that can normally detect infectious dangers (toll-like receptors and others) (Fig. 4.19) (Anaya et al. 2016; Anaya et al. 2018). This permanent stimulation causes a cascade-like immune activation in susceptible individuals, which can lead to an autoimmune disease. Decisive is the loss of the actually existing immunological tolerance towards own proteins (Anaya et al. 2016, 2018). Partly, the transformation of proteins is of importance, as we have discussed them in Fig. 4.18. In this respect, smoking at the same time is unfavorable. What does it have to do with childhood adversities and where are the connectors? Early experiences of stress often lead to a lower level of education and less upward mobility (Pesonen et al. 2011; Heinonen et al. 2013). This connection was very clear in the large Finnish study of children separated from their parents during World War II. If the fathers were employed in manual occupations, children with separation experiences

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lung phagocytes

Inflammasome

5 6

IL-1β TNF IFN-γ IL-17

4

Nucleus 3 Phagolysosome Phagosome

2

1

acute: inflammation 7

Silica (300–1000 nm)

late: fibrosis Fig. 4.19   Silica crystals cause inflammatory reaction and scarring fibrosis. 1) At the beginning is the uptake of a silica crystal in a phagocyte of the lung, which is mediated by receptors on the cell surface. 2) The crystals are stored in an intermediate stage in a phagosome. 3) Phagosome and lysosome fuse to the phagolysosome. 4) The presence of the silica crystals make the phagolysosome unstable, and parts can escape into the cell interior. 5) The released elements now stimulate the inflammasome, and there is activation of interleukin-1β (IL-1β). 6) More cytokines are stimulated (TNF: tumor necrosis factor, IFN-γ: interferon gamma and IL-17: interleukin-17). 7) There is an acute inflammation, which manifests itself as bronchitis and can later be converted into scarring fibrosis

showed no upward mobility, but rather a downward trend (Pesonen et al. 2011). Social position is clearly linked to early traumatic experiences in a bidirectional way. There is a connection between socio-economic disadvantages in childhood and adolescence and school education and training, occupational choice and annual income (Romito et al. 2003; Anand et al. 2019). Those occupations in the quarry, construction, mining or handling of sand with direct exposure to silica dust are heavy manual occupations that are not taken up by everyone and are found in lower positions on a comparative salary list (Federal Employment Agency 2020). Socio-economic disadvantages are passed on, which is especially true if early experiences of stress are also present (Pesonen et al. 2011). So the start of working life can be accompanied by an imbalance in important health-impairing circumstances (e.g. more or less dust). In this example—and I can list other airborne substances such as solvents, pesticides, smoke from welding, agricultural dusts, fertilizers, cleaning solution aerosols, coal dusts, soot, irritating gases (CO, NO, NO2, NOx, O3) etc. (Miller et al. 2012; Prisco et al. 2020; Adami et al. 2021)—it becomes clear how an extra-corporeal connector can arise here between early traumatic experiences, social position, occupational work and exposure to

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particulate matter and chronic immune system activation. The matter is aggravated by smoking cigarettes at the same time. The problem can only be prevented by consistent protection—for example, a functional mask—and giving up smoking. Of course, the employers and employees involved must play their part responsibly. The above-mentioned connectors also make it clear why school and vocational training and the achievements resulting therefrom can be closely linked to the occurrence of chronic inflammatory diseases, as a large genetic-epidemiological study recently showed for rheumatoid arthritis (Jiang and Alfredsson 2020). There it becomes visible how a favorable effect (absence of autoimmune disease) is less linked to training than to favorable risk behavior (avoiding risks, e.g. dust, smoking and drugs). Avoiding risks is an educational or training issue.

4.4.3 Asthma Asthma belongs in this subchapter of the extra-corporeal connectors, if the exposure to environmental factors is increased by early traumas and these environmental factors trigger asthma, which in turn leads to increased immune activation. When we talk about the environment, we are thinking here of asthma with allergens (nearly 90% of all asthma forms). Asthma also fits into Sect. 4.3 Indirect connectors activate the immune system chronically (No. 2), when factors from the brain trigger non-allergic asthma and the downstream lung involvement leads to chronic immune system activation. So there would be an indirect connections through the lungs, leading to a chronic inflammatory situation. I will deal with both forms here.

4.4.3.1 Environmental Factors (Extra-corporeal Connectors, 90% of All Forms) Typical stimuli for the development of asthma are allergens of all kinds of pollen and grain dust, house dust mites, mold spores, animal hair, bird feathers and droppings, certain foods (e.g. nuts), chemicals (such as chlorine, varnishes or disinfectants) and others. The question arises as to whether someone with early traumas comes into contact with these allergens more often. An intensive search in common literature databases yielded only 3 hits for the combination of “various early traumatic experiences” plus “allergen” out of a total of more than 40,000 hits for “various early traumatic experiences”. However, the 3 hits did not contribute to understanding the discussed connection. So there must be other environmental factors for allergic asthma that need to be considered. Table 4.4 shows the most common points for triggering asthma attacks. The elements of Table 4.4 are in part closely related to early traumatic experiences—for example smoking, fine dust, psychological stress and possibly painkillers and respiratory infections. If we look only at smoking and psychological stress, we do not need to

190 Table 4.4  The following factors can trigger an asthma attack independently of the type of asthma

4  Chronic Immune System Activation Physical or sports activity (triggers exercise-induced asthma) Respiratory infections Certain medications (for example, some painkillers) Cigarette smoke and exhaust fumes Fine dust Strong smells (salmiac) Cold ambient air Fog and wind Psychological stress Stress, social position, economic situation From: (Novartis Pharma GmbH 2021)

research whether these things occur more frequently in people with early adversities. We can say: These environmental factors for the triggering of asthma occur more often. Regardless of the basis of asthma, there are environmental factors that are more common in people with early severe stress experiences and promote asthma and can trigger an attack. In addition, prenatal stress situations, which mainly come from the mother, are particularly asthmogenic when additional environmental factors such as gases and dusts are also present (Bose et al. 2017; Rancière et al. 2017; Lee et al. 2018). Finally, socio-economic background and school education play a role, as asthma is more common in children/adolescents with a low social position and with less education (Sternthal et al. 2011; Altman et al. 2021; Schyllert et al. 2021). Now, we have to clarify whether asthma causes chronic immune system activation (in the subchapter after the next one).

4.4.3.2 The Brain Promotes Non-allergic Asthma (Indirect Connector, 10% of All Forms) Among some possibilities of central nervous system influence on the lungs, I would like to highlight the direct influence through sensory nerve fibers that run with the vagus nerve into the lungs, the best-studied way. These nerve fibers have proinflammatory neuropeptides such as substance P and calcitonin gene-regulated peptide that can create an inflammatory environment locally (Camp et al. 2021). Patients with asthma are hypersensitive to substance P, substance P induces bronchoconstriction, substance P increases local mucus production, facilitates cholinergic innervation of bronchi (narrowing) and promotes plasma leakage from vessels (swelling) (Camp et al. 2021). Substance P can activate mast cells and the local immune system (Sect. 4.2.5 Tone of Pain Pathways). In addition, early trauma often results in increased pain sensitivity (see Sect. 3.2.7 More Pain after Childhood Adversities). This hypersensitivity is partly the product of poorer inhibition of descending pain pathways from the brain (Figs. 3.3, 4.14, and Sect. 4.2.5 Tone of Pain Pathways). Diseases such as fibromyalgia, chronic pelvic pain

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syndrome or irritable bowel syndrome indicate this. Is this hypersensitivity regulated by the brain involved in non-allergic asthma? Allergy researchers are asking the same question for the non-allergic problems in the nose (Tai and Baraniuk 2002; Baraniuk and Zheng 2010; Singh and Bernstein 2014; López-Requena et al. 2017). This question of hypersensitivity in non-allergic asthma has been raised several times and doctors have developed a test for this purpose (Millqvist et al. 1998; Pullerits et al. 2014). Today, many people recognize the phenomenon of hypersensitivity. Patients with positive test results in the lungs also report more pain from mechanical stimuli on the skin and have lower pain thresholds (Heba et al. 2020). The same people show conspicuous changes in brain networks that are responsive and altered after early trauma (Heba et al. 2020). Furthermore, people with asthma and positive test results have a worse course of environmental allergic asthma (Kanemitsu et al. 2020). The brain can control the readiness to cough and asthma, and the brain is involved in the triggering of non-allergic asthma. At least it can worsen the situation in allergic asthma, as the mentioned study with positive hypersensitivity test shows (Kanemitsu et al. 2020). The brain can negatively influence the situation in asthma. Does asthma actually cause inflammation?

4.4.3.3 Asthma Makes Chronic Inflammation Whether asthma is a chronic inflammatory disease is beyond doubt when looking at lung tissue. However, the inflammation remains largely local and does not lead to large systemic inflammatory reactions. On the allergic side, processes take place in which so-called T helper cells type 2 (a certain subtype of T cells) play a major role—similar to atopic dermatitis (Sect. 4.3.6). These T helper cells type 2 create a favorable starting point for the production of antibodies directed against the allergens that are produced by B cells/plasma cells. These antibodies of type IgE continue the inflammatory process when allergens arrive in the lungs by stimulating other cells, such as mast cells, eosinophilic granulocytes and bronchial muscle cells. A local cytokine cocktail of IL-4, IL-5, IL-13, etc. rounds off the inflammatory process. All reactions lead to an acute inflammation of the lung mucosa, which can lead to a change in the lung framework structure over years and to a chronic obstructive lung disease (Fanta 2009; Rosa et al. 2018; Chau-Etchepare et al. 2019; Hammad und Lambrecht 2021). In non-allergic asthma, however, macrophages and so-called ILC type 2 (innate lympoid cells type 2) are involved in the inflammatory reaction, which activate eosinophilic granulocytes and bronchial muscle cells. On this non-allergic side, there is a colorful cytokine cocktail of IL-5, IL-9, IL-13, IL-15, IL-33, etc., which, in addition to prostaglandins, stimulates the inflammatory process (Chau-Etchepare et al. 2019; Hammad and Lambrecht 2021). Similarly to allergic asthma, chronic activation leads to a remodeling of the lung. Although asthma causes a relatively low systemic inflammation, the treating physician notices a very slight inflammatory reaction of the whole organism on the basis of the C-reactive protein in serum (Oh et al. 2020; Abdo et al. 2021; Zhu et al. 2021).

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At this point, we therefore recognize how asthma is associated with a mild inflammatory process, to be more precise: with a mild chronic immune system activation. Now we ask whether asthma has a relationship to real autoimmune diseases, or whether asthma is even a risk factor for an autoimmune disease. In fact, patients with asthma more often have rheumatoid arthritis, as a meta-analysis showed (Charoenngam et al. 2020). How asthma is causally related to autoimmune diseases is unclear. I summarize: After early traumatic experiences, the brain can favor the triggering of asthma either through extra-corporeal connectors (higher exposure to triggers) or through indirect linking (pain nerve fibers, hypersensitivity, substance P) and thus contribute to chronic immune system activation. In this respect, the asthma-triggering environmental factors are extra-corporeal connectors between the brain and the immune system.

4.4.4 Infections are Extra-corporeal Connectors We have already discussed the links between smoking and periodontal disease. You will remember the bacterium Porphyromonas gingivalis, which is associated with the development of autoimmune diseases (Fig. 4.18). Smoking was the extra-corporeal connector. The relationship between early traumatic experiences and poor oral health has been described several times (Poulton et al. 2002; Bright et al. 2015; Crouch et al. 2019; Ford et al. 2020). The lack of dental care and the missed preventive examination were of great importance (Crouch et al. 2019), so that periodontal infections can spread. In the group of New Zealand children (Explanation 3), which has been followed up over a long period of time since the early 1970s, a clear connection was found between socio-economic status and periodontal diseases such as periodontitis and tooth decay (Poulton et al. 2002). In the foreword of the editor, a connection to infection is mentioned (Power 2002). This study was confirmed more recently: The lower the socio-economic position, the more pronounced the periodontal diseases were (Schuch et al. 2019). So the socio-economic position of the parents/the affected persons is the trauma and at the same time the extra-corporeal connector, which determines the bacterial composition and thus promotes infection and chronic inflammation. Furthermore, Roswith Roth from the Helmholtz center in Munich and many international colleagues from the TEDDY study group were able to observe a clear connection between negative life situations in childhood and a higher rate of infection episodes of the respiratory tract (Roth et al. 2019). Since in this phase of life immunological tolerance and immunological aggression are learned, there is a danger of educational errors of the immune system (Rook 2012; Murdaca et al. 2021; von Mutius 2021). So negative effects in youth and adulthood can become important and lead to a kind of “misalignment” of the immune system. There is a special relationship to infection by sexually transmitted diseases. Why is this relevant in early trauma? In people after early traumatic experiences, conspicuous

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sexual behavior can be observed (Dillard et al. 2019), girls enter puberty earlier (Belsky and Shalev 2016; Zhang et al. 2019; Suglia et al. 2020), they are younger and less experienced at first intercourse (Sansone et al. 2009), human trafficking for the purpose of sexual exploitation is more common (Naramore et al. 2017; Reid et al. 2019b), sexual behavior is risky (Naramore et al. 2017; Kidman et al. 2018; Alley et al. 2021), and drug use with injections is more common. These risk factors increase the number of infections. Although the connection between infectious diseases on the one hand and the occurrence of chronic inflammatory autoimmune diseases on the other is not often causally proven, there is a clear causal relationship for one or the other pathogen. For example, the chain of infection with the Epstein-Barr virus (EBV) and multiple sclerosis is quite obvious (Ascherio and Munger 2010; Jakhmola et al. 2021; Yuan et al. 2021). Since the EBV infection or infectious mononucleosis is called kissing disease, the reference to the awakening sexuality in adolescents is illustrated. If this happens more often and earlier, as can happen after early trauma, the risk of EBV infection is higher. The EBV infection can remain in the body without symptoms for a longer period of time, and then those affected constantly produce antibodies against the virus. The constantly increased antibody level in the blood speaks for a continuous unresolved infection (Fagundes et al. 2013). These antibody levels are increased in people after early traumas, and this speaks for the difficulty of finally defeating the pathogen (Fagundes et al. 2013; Slopen et al. 2013; Yazawa et al. 2019). More often there is a latent virus infection that is reactivated during stress situations (Schmeer et al. 2019). A study showed the connection between socio-economic situation and the occurrence of high EBV antibody levels. People with a lower socio-economic status had higher EBV antibody concentrations in their blood (Slopen et al. 2013). Furthermore, the cytomegalovirus is more active in people with previous traumatic experiences in childhood and adolescence, and increased antibody concentrations can be seen in the blood (Fagundes et al. 2013; Elwenspoek et al. 2017; Reid et al. 2019a). The continuous infection with cytomegalovirus has been linked to the aging of the immune system and misguided immune activation (Fülöp et al. 2013; Weltevrede et al. 2016). Early traumas are associated with a stronger reactivation of herpesviruses—cold sores— (Shirtcliff et al. 2009). Another human pathogenic virus is HTLV-1 (Human T-cell Lymphotropic Virus type 1), which is transmitted through sexual contact. HTLV-1 is associated with all sorts of diseases and often an immune activation is visible (Schierhout et al. 2020). Apparently it is causally related to chronic inflammatory diseases, for example Sjögren’s syndrome, chronic bronchitis, asthma, rheumatoid arthritis and other forms of arthritis (Schierhout et al. 2020). To be up to date, we can look at the coronavirus pandemic of recent years and see a connection here between trauma and chronic inflammation. According to a study from Switzerland, people in lower socio-economic positions test themselves less for COVID19, but they are more often COVID-19-positive (Riou et al. 2021). A similar study from

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Norway showed that, among immigrants who are socio-economically disadvantaged (close living quarters, low income, little education), there are more frequent COVID-19 illnesses. Furthermore, the mortality rate from COVID-19 is higher among migrants than among non-migrants (Vanthomme et al. 2021). And being a migrant is, per se, a traumatic experience for children and adolescents (Fazel et al. 2012; Kosidou et al. 2012; Das-Munshi et al. 2014; Vossoughi et al. 2018; Chen et al. 2019). If early childhood/adolescent trauma preceded, the trust in the official COVID-19 recommendations is significantly reduced. These people wear less mouth and nose protection and do not comply with the distance recommendations. They more often than non-affected people refuse the proposed vaccinations. The key to understanding the conspicuous situation is the lack of trust of early traumatized people in the official advisers (Bellis et al. 2022). But how is it related to chronic inflammation? Children with COVID-19 more often get a so-called multisystemic inflammatory reaction, which affects the skin, the mucous membranes (mouth, stomach-intestine, urogenital, lung), the coronary vessels, the heart muscle, the joints and the brain (Chen et al. 2021). Typical are fever and lymph node swelling. This inflammatory disease has a lot in common with a disease that has been known since 1967 as Kawasaki-Syndrom after the Japanese Tomisaku Kawasaki. Ultimately, it is an acute-chronic inflammation of medium-sized vessels, and problems can persist in the long term if the coronary vessels are affected (Hochberg et al. 2015). In addition, many of the above-mentioned axes are shifted in the Long-COVID-Syndrome, so that chronic immune system activation can result from this. Liver inflammation caused by the Hepatitis C Virus, which is also transmitted sexually or via injections, is another example of a chronic infection. If more risky sexual behavior leads to a chronic hepatitis C infection, this can result in a state of permanent immunoactivation (Younossi et al. 2016). Hepatitis C complications such as cryoglobulinemia (antibodies that form large complexes at low temperatures and induce inflammation), chronic kidney disease, type 2 diabetes mellitus, lymphoma, Sjögren’s syndrome, and arthritis (similar to rheumatoid arthritis) are accompanied by permanent immunoactivation. Patients often suffer from depression and chronic fatigue (Younossi et al. 2016). Even prenatal stress for the child or stress events for the expectant mother influence the later occurrence of infections in newborns (Nielsen et al. 2011). At this point, the doctor would have mentioned sexually transmitted diseases such as syphilis, gonorrhea, and other bacterial diseases without hesitation 100 years ago. These diseases are no longer considered chronic inflammatory diseases in at least Western countries because they are well treatable and therefore only of short duration. The situation for infections as extra-corporeal connectors is summarized in Fig. 4.20. In all these examples, we can see how preceding adversities in childhood and adolescence—for example, socio-economic position and other trauma experiences—increase the risk of dangerous, often sexually transmitted infections and favor the persistence of infection. In this way, risk factors from the environment are more easily accepted in those affected by traumatic situations in young life stages, and there can be an increased

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Traumas

Brain No.3 Smoking - Porphyromonas gingivalis - Gum infection - Chronic inflammation and immune activation Early and frequent sexual experiences - Chronic viral diseases (EBV, CMV, hepatitis viruses, HTLV-1, coronavirus, etc.) - Chronic inflammation and immune activation Lack of trust in medical advisors - more frequent infections (e.g. COVID-19) - chronic inflammation and immune activation Drugs - chronic viral diseases (HIV, hepatitis viruses, HTLV-1, etc.) chronic inflammation and immune activation

Immune system Fig. 4.20   Traumata induce chronic infections. Abbreviations: CMV, cytomegalovirus; COVID-19, coronavirus disease of 2019; EBV, Epstein-Barr virus; HIV, human immunodeficiency virus; HTLV-1, human T-cell lymphotropic virus type 1

chronic immune system activation. The combination of several latent virus infections is more inflammatory than the presence of a single virus. Here, the acquired infection acts as an extra-corporeal connector between the brain and the immune system.

4.4.5 Risk Behavior We have already learned about risk behavior in the context of infections. I am reminded of sexually transmitted diseases. Risk behavior is also evident in increased alcohol consumption, nicotine abuse, and drug use, as Vincent Felitti showed in his famous first epidemiological study (Felitti et al. 1998). Risk behavior is also evident in overeating, resulting in higher body weight and reduced physical activity as triggers of chronic immune system activation. We recognize risk behavior as externalizing behavior, for example as attention deficit hyperactivity disorder and changes in social behavior. Symptoms such as attention

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problems, increased activity, impulsivity, oppositional-defiant (disobedience) and aggressive behavior are typical. In the long term, there is an increased risk of dropping out of school prematurely, early parenthood, job problems, marital problems, violence, delinquency, etc. (Thapar et al. 2015). The risk of self-injury and other types of injuries is increased (Jokela et al. 2009; Meza et al. 2021). Risk behavior is also evident in an increased rate of injuries, such as head and brain injuries and others (Rowe et al. 2004; Guinn et al. 2019). When more serious injuries occur, such as with non-suicidal self-injury (Nock et al. 2006), we recognize the danger of chronic immune system activation. When there are severe injuries such as burns (Piazza-Waggoner et al. 2005; Fritz and Butz 2007), there is long-term activation of the immune system (Rendon and Choudhry 2012). In this behavior defined by the brain and the injury situation with repercussions on the body, we recognize extra-corporeal connectors between the brain and the immune system.

4.5 Gene Mutations as Pleiotropic Connectors (No. 4) In this chapter, I present a few genetic factors that have separate meanings in the brain and in the immune system. In the brain, on the one hand, they promote unfavorable processes that can lead to behavioral problems or psychiatric diseases. On the other hand, they promote chronic immune system activation in the periphery. I call them pleiotropic connectors, because they do not have direct material effects on each other because of the separate place of action. Figure 4.21 illustrates the importance of pleiotropic connectors. Today, the scientist can retrieve the pleiotropic connectors from databases on the Internet, and to do it two things must be present at the same time (Tenesa et al. 2019; Watanabe 2019; Watanabe et al. 2019; National Center for Biotechnology Information 2021). The database must first be fed with studies on genetic variants that are relevant to various chronic inflammatory diseases or autoimmune diseases. I had already discussed these studies under Phase 4—Human genome-wide association studies in Chap.  2. Secondly, the database must be linked to genetic variants (also called single nucleotide polymorphisms, short SNPs) that are relevant to a particular behavior or psychiatric illness. The researchers call them phenome-wide association studies because they focus on the visible phenotype—the character traits. With information from both databases, one can bring together chronic inflammatory disease and behavior/psychiatric illness by simultaneously focussing on a genetic variant. This type of study was carried out for the pleiotropic connectors mentioned in this subchapter. I will discuss the search in more detail in a moment. This chapter could overwhelm some readers due to the complexity of the descriptions of the found genetic variants, because it is about tiny details in the brain and in the immune system. The author does not intend to overwhelm, which is why I will not present the genetic variants found in the databases in detail. You must accept the mentioned

4.5  Gene Mutations as Pleiotropic Connectors (No. 4)

Early trauma

197

Change in Gen X

selfish brain Smoking Alcohol abuse Drugs Depression Fear Schizophrenia Neurocism amongst others no material connecon, but pleiotropic connecon

Change in Gen X

chronic inflammation Chronic Immune Acvaon Chronic Inflammatory disease Fig. 4.21   Pleiotropic gene variants. Upper part of the figure: A gene with the fictitious name X leads to the production of a factor that performs a certain function in the brain. A variant of the gene X is associated with psychiatric problems. If this variant of the gene meets with early traumatic experiences, the manifestation of the psychiatric problem can worsen.—Lower part of the figure: The same variant of the fictitious gene X, which favors central nervous trauma sequelae in the brain, has a stimulating function in the immune system, causing chronic immune system activation. The gene has two different tasks at the two different locations—in the brain and in the immune system—it is pleiotropic (Greek pleíōn, Engl. more; Greek tropein, Engl. change), because more than one thing is changed by the gene. If the variant of the gene causes chronic immune system activation, psychiatric problems and chronic inflammation can occur at the same time, although the brain does not directly influence the immune system.— Here, no material connection is needed to bring both things together at the same time. The pleiotropic connection is sufficient to stimulate both at the same time

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genetic variants without prejudice. This is relatively easy to do because even the geneticists in the human genome-wide studies accept the found genetic variants that are related to a disease or behavior in the same way without prejudice. In Chap. 2 I wrote: “The genetic variants found in this way [without prejudice] were often provided with a biological function by other working groups only in the course of further research work, and biological plausibility post hoc shows up. This is painstaking work that can take many years (e.g. Straub et al. 2018, 2021).” The methods of human genome-wide and phenomenon-wide search for gene variants associated with disease or behavior are free of hypotheses and prejudices. If the statistics are correct, the researchers find gene variants that act as pleiotropic connectors. The following search was carried out using known databases (Tenesa et al. 2019; Watanabe 2019; Watanabe et al. 2019; National Center for Biotechnology Information 2021).

4.5.1 The Search in the Gene Databases Leads to Pleiotropic Connectors I focused on known chronic inflammatory diseases, as listed in the first column of Table 4.5. For each of the diseases mentioned, a few to many gene variants were found in the human genome-wide studies that are statistically highly significantly associated with the disease. These gene variants, which the geneticists call SNPs (Single Nucleotide Polymorphism, pronounced: snips), were given abbreviations that begin with the letters “rs” for “reference SNP” (see column SNPs in Table 4.5). For different diseases, there are different amounts of SNPs that act as genetic risk factors. In the case of the chronic inflammatory joint disease of rheumatoid arthritis, geneticists have found more than 100 relevant SNPs (Okada et al. 2014). In the human genome, therefore, more than 100 risk-associated gene variants are known that are directly related to this particular chronic joint inflammation. However, the presence of a SNP does not necessarily lead to the development of the disease, as a single risk-associated gene variant cannot trigger the disease on its own. If a person has several risk-associated SNPs in the genome, the likelihood of developing the disease increases. Now the expert can enter the name of a found SNP, which starts with “rs” and ends with a number (see column SNP in Table 4.5), into a second database that contains information about psychiatric diseases, behavioral aspects and many other characteristics. This second database came about through human genome-wide and phenomenon-wide studies. After entering the SNP, those psychiatric diseases, behavioral aspects and other characteristics that are also significantly associated with the entered SNP are now mentioned (column “Meaning in the Brain” in Table 4.5). Of the more than 100 relevant SNPs for rheumatoid arthritis, few are associated with psychiatric diseases, behavioral aspects and other characteristics. Mostly it is a futile search for pleiotropic connectors, but occasionally the lucky one hits a bull’s eye.

4.5  Gene Mutations as Pleiotropic Connectors (No. 4)

199

Table 4.5  Pleiotropic connectors in pleiotropic genes. Abbreviations: SNP, single nucleotide poly­ morphism (gene variant) Chronic inflammatory situation

Name of the Gene SNP

Meaning in the periphery

Meaning in the Literature brain

RASGRP1

Proinflammatory factor

*(Molineros Depression, Schizophrenia et al. 2019)

CD40

Proinflammatory factor, B-cell

Depression, Neuroticism

*

rs34695944 REL

Many proinflammatory functions in immune cells (partner of the proinflammatory factor NFkappaB)

Alcohol abuse

*

rs2736337

BLK

B-cell function, proin- Neuroticism flammatory factor

rs702873

REL

Many proinflammatory functions in immune cells (partner of the proinflammatory factor NFkappaB)

Alcohol abuse

*(Strange et al. 2010)

rs240993

TRAF3IP2

Proinflammatory factor, activates NFkappaB

Smoking, cannabis

*(Strange

et al. 2010) *(Hsieh

Rheumatoid rs8032939 arthritis rs4239702

Psoriasis

*

Crohn’s disease

rs6062496

TNFRSF6B

Immunomodulatory factor

Smoking

und Lin 2017)

Thyroiditis

rs2856698

HLA-DQB1

Proinflammatory factor; antigen presentation

Schizophrenia

*

rs8043085

RASGRP1

Proinflammatory factor

*(Molineros Depression, Schizophrenia et al. 2019)

rs7097397

WDFY4

T-cell supporting Depression factor, immunomodulatory factor

et al. 2021a, b)

rs2736337

BLK

B-cell function, proin- Neuroticism flammatory factor

*

rs5743618

TLR1

Proinflammatory factor

Alcohol abuse

*

rs773125

SUOX

Immunomodulatory factor

Smoking, high *(Luck et al. body weight 2020)

Systemic lupus erythematosus

Asthma

*(Li

(continued)

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4  Chronic Immune System Activation

Table 4.5   (continued)

Chronic inflammatory situation

Name of the Gene SNP

Chronic rs7733088 obstructive lung disease

HTR4

Meaning in the periphery

Meaning in the Literature brain

Immunomodulatory factor, histamine receptor 4

Neuroticism

*

*(Tenesa

et al. 2019; Watanabe 2019; Watanabe et al. 2019; National Center for Biotechnology Information 2021). For neuroticism see Explanation 5

In a further step, the researcher asks himself in which gene the found SNP is present. For this he needs another database, which is provided by the National Institute of Health in Bethesda, USA (National Center for Biotechnology Information 2021). There he finds the corresponding gene, which is of course responsible for a protein in the cell—he says: encodes for a protein (see column “Gene” in Table 4.5). Now he can check in another database of the National Institute of Health to what extent the protein is a key protein for inflammation, and thus on the one hand he receives the significance in the context of chronic immune system activation (see column “Meaning in the Periphery” in Table 4.5). On the other hand, the corresponding SNP is closely associated with a psychiatric disease or unfavorable behavior (column “Meaning in the Brain” in Table 4.5). In further studies, the researcher can work out why this SNP and the corresponding gene in the brain have such a risk-related significance. I did not do this in Table 4.5 because I was mainly interested in the chronic inflammatory situation and less in the function in the brain. From Table 4.5 you can see a whole range of gene variants that are significantly associated with the chronic inflammatory situation on the one hand and with the psychiatric problem on the other. In most cases, I can assess the significance for the immune system as an immunologist and judge the chronic stimulation situation. Why these factors have a risk-related significance in the brain at the same time is not well researched, but nevertheless highly relevant because it shows the pleiotropic connection. So if I have a gene variant—a SNP—from Table 4.5 that is relevant to chronic activation of the immune system and even plays a role in triggering a chronic inflammatory disease, and at the same time is associated with a psychiatric problem, this pleiotropic connector can exacerbate the psychiatric problem in people after previous early traumas on the one hand and stimulate the immune system on the other. This connection between brain and immune system is possible without direct, indirect or extra-corporeal material connectors. In recent years, however, more and more statistical studies have been appearing that, like in Table 4.5, bring together chronic inflammatory diseases and psychiatric problems or features of brain function (for the interested: they are called Mendelian Randomisation Studies). For example, one study linked the gene variants for rheumatoid

4.6 Summary

201

Table 4.6  Pleiotropic connectors from other genetic studies Causative factor (closely linked Inflammatory follow-up to early trauma experiences) problems

Literature

Lower intelligence

Rheumatoid arthritis

(Jones et al. 2019; Huang et al. 2021)

Smoking

Rheumatoid arthritis

(Qian et al. 2020)

Depression

Chronic inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis

(Luo et al. 2021)

High body mass index

Psoriasis

(Budu-Aggrey et al. 2019)

Smoking

Asthma

(Skaaby et al. 2017)

Studies with the technique of Mendelian Randomisation

arthritis with the gene variants for intelligence. Here the researchers found a highly significant link between the risk variants for rheumatoid arthritis and the risk variants for lower intelligence (Huang et al. 2021). Attention, in this analysis the researchers did not look at the actual outbreak of rheumatoid arthritis or at the actual intelligence, but only at the genetic risk of the two things coming together. Other researchers confirmed the connection (Jones et al. 2019). Such studies speak in favor of a pleiotropic connection in the sense of this chapter, since reduced intelligence is a risk factor for subsequent problems of early traumatic experiences and at the same time is closely related to the chronic inflammatory disease. These studies with the designation Mendelian Randomisation have a causal character that necessarily results from the epidemiological statistical approach. However, these studies do not make any statements about the involved gene variants, as I was able to do in Table 4.5 after days of searching. The approaches are different, but nevertheless prove the existence of pleiotropic connectors. Table 4.6 summarises the studies on Mendelian Randomisation.

4.6 Summary In people with early adversity, it became apparent that, as with all four connectors, there are several good reasons for stimulating and maintaining chronic immune system activation. With the direct connectors, often significant adjustment reactions occur after early trauma. I bring to mind the normally anti-inflammatory but after switching the pro-inflammatory signal transduction through adrenergic receptors (noradrenaline, adrenaline) and through the glucocorticoid receptor (cortisol). The circadian desynchronization of the sympathetic system and the HPA axis, the increased tone of the pain pathways (substance P) and the change in the sex hormone axis exacerbate the process.

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The inflammation is accompanied and additionally stimulated by indirect connectors such as weight gain, insulin resistance, hyperinsulinemia, lack of physical activity and stress-related increased intestinal permeability with changes in the microbiome. Extracorporeal connectors such as smoking, fine particles and increased risk-taking with infection exacerbate the situation. If certain genetic variants are present that favor trauma sequelae in the brain and inflammation by the immune system, there are further reasons for escalation. From this list, the observer can easily see the possibility of the formation of a vicious circle, as it was already shown in Fig. 4.13, since the increase in inflammation further promotes the switching reactions that negatively feedback on the brain, the pain system and on psychological-psychiatric aspects. Important are weight gain and the lack of physical activity (sarcopenic obesity), since both increasingly stimulate unfavorable sequelae. We do not get a high body weight from one day to the next. For this we need some years, as I know from my own experience. In addition, accelerated cellular aging, as discussed in Sect. 3.3.5 (Entringer et al. 2012; Belsky and Shalev 2016), exacerbates the situation. Faster cell aging increases oxidative stress, reduces the regenerative capacity of various tissues and increases the risk of malignant transformation. Special importance is attached to other stress situations occurring during life, since accumulation is unfavorable, as Bruce McEwen mentioned in the theory of allostatic overload (McEwen 1998). However, we cannot attribute the resulting problems of overload solely to events in the brain, since during accumulation the periphery increasingly changes, as I wanted to emphasize in this book. Inflammation and pain act back on the brain, overload is promoted by unfavorable peripheral sources, and so vicious circles can arise (see Dantzer et al. 2014; Nusslock and Miller 2016; Danese and Lewis 2017). In any case, the arrival of more than one severe stress experience during life is, so to speak, an important platform for stabilizing the imbalance acquired in young years (the out-of-balance weighing scale in Fig. 3.4) and thus of brain changes on the one hand and inflammation on the other (Lupien et al. 2009; McLaughlin et al. 2010; Gustafsson et al. 2012; Daskalakis et al. 2013; Woodward et al. 2013; Loria et al. 2014; Oldehinkel et al. 2014; Dich et al. 2015; Farr et al. 2015; Halonen et al. 2015; Bandoli et al. 2017; Loeb et al. 2018; Mayer et al. 2019). Similar cumulative findings have been demonstrated in animals with early traumas and stress situations later in life (Stewart et al. 2004; Pinheiro et al. 2012; Diz-Chaves et al. 2013; Prusator and Greenwood-Van Meerveld 2016b; Zardooz et al. 2021). We have now reached a point in this book where I can put down the pen or turn off the computer because the most important psychoneuroimmunological points on the way to chronic immune system activation have been discussed. I don’t want to make it that easy for myself, because in the two previous books of this Springer trilogy I discussed important aspects of energy regulation (Straub 2018, 2020a), and so energy will be the concluding topic of this book. Here you will be surprised.

4.7  To the Point

203

4.7 To the Point • Four connectors link the selfish brain with the selfish immune system. These connectors must be responsible for chronic immune system activation. • Connectors No. 1 are direct linking factors such as hormones and neurotransmitters of the brain-initiated stress pathways that have a direct effect on the immune system. • The sympathetic nervous system promotes inflammation. Important shift reactions that change the effect of sympathetic neurotransmitters are of great importance. • The parasympathetic nervous system is underactive and therefore cannot exercise the normal anti-inflammatory function. The brain causes the lower activity of this efferent nervous system. • The HPA axis can stimulate inflammation, with the preceding tone before an immune stimulus contributing to this. Important shift reactions prevent the anti-inflammatory cortisol effect. • The disturbance of the circadian rhythm is a consequence of earlier traumatic experiences. The desynchronization of cortisol and noradrenaline is the pro-inflammatory consequence. • An increased tone of the pain pathways promotes inflammation by the increased release of substance P and other neurotransmitters from the peripheral nerve ending. The increased sensitization of pain pathways is mainly involved in this. • The sex hormone axis is suppressed after trauma, and the lack of sex hormones has a pro-inflammatory meaning for many immune reactions in men and women. Estrogens have a dual meaning, as they inhibit T cells and macrophages, but promote B celldriven immunity, and the latter can stimulate an early B cell-mediated autoimmune disease with an early menarche. • Connectors No. 2 are indirect linking elements that are stimulated by the brain and exert an effect in another organ system to indirectly activate the immune system. • The brain is responsible for a high body weight and, thus, causes an inflammatory reaction in the adipose tissue. At the same time, the brain stimulates the release of free fatty acids, which can have a pro-inflammatory effect (especially if the eater has consumed pro-inflammatory, saturated fatty acids days, weeks, and months before; Junk Food Self Medication). • The brain stimulates insulin resistance, which prevents the uptake of free fatty acids and glucose in the adipose tissue, in the liver and in the muscle, which has a pro-inflammatory effect. The simultaneously increased blood levels of insulin can be proinflammatory. Insulin stimulates pain sensitization and promotes the proliferation of leukocytes. • The brain determines the extent of physical/athletic activity, which is often low after early trauma. Since anti-inflammatory factors are produced in the muscle, the low muscle mass and the low activity are coupled with a proinflammatory constellation.

204

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• The brain can provoke a “leakage” of the intestinal wall via an increased activity of the HPA axis and the sympathetic nervous system, which has a proinflammatory effect because bacterial components activate the immune system inside the body. It is called bacterial translocation. • The brain exacerbates itching and pain in atopic dermatitis and can thus act on the immune system in a proinflammatory way. • Connectors No. 3 are extra-corporeal factors from the environment, which are stimulated by the brain and act back on the immune system in a stimulatory way. • Early traumatic experiences increase the willingness to smoke and exposure to dusts, both of which have a proinflammatory effect. • The brain promotes asthma and asthma stimulates inflammation. In this respect, there is an extra-corporeal (higher exposure to extra-corporeal triggers) and an indirect connector (without allergens: pain nerve fibers, hypersensitivity, substance P) between the brain and the immune system. • The brain is responsible for a higher level of infection (e.g. higher sexual risk behavior), which contributes to chronic infections and chronic immune system activation. • Connectors No. 4 are pleiotropic genes, whose gene variants (SNPs, snips) on the one hand have an unfavorable effect on the brain in terms of worsening trauma sequelae and on the other hand promote immune stimulation independently of this. These can also be epigenetic changes to pleiotropic genes that were not discussed in the book.

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Energy, Early Traumatic Experiences and Chronic Immune System Activation

This chapter contains hypothetical aspects that the reader must already know before reading in order to be able to critically engage with them. But what is a book without testable hypotheses at the end? Such considerations lead into the future, to the next experiments, to observations and to the description of true complexity. Therefore, consider the conclusion from this perspective. You have been warned. Your valuable energy will not be wasted. The importance of energy questions was already clear in several places in the previous chapters. So we know: As a result of earlier traumatic experiences, there is often a high body weight (stored energy in the form of fatty acids; Barker et al. 1989), disturbed fattening eating behavior (Table 3.2, e.g. too many calories consumed, eating without hunger, Junk Food Self Medication), insulin resistance (lack of storage of energy-rich substrates in muscles, fat tissue and liver), cortisol changes (usually increased, releases energy-rich substrates into the bloodstream), changes in the sympathetic nervous system (usually increased, releases energy-rich substrates into the bloodstream), lowered sex hormones (muscle growth blocked, insulin resistance promoted), etc. All of the above points are signs of altered energy regulation in the body after early adversities. We see the same things during aging and in chronic inflammatory diseases, even if they are well treated (Straub 2018). This parallel occurrence of similar phenomena in different diseases, pathological conditions, as a result of trauma and during aging speaks for a general principle, and this prompts us to take a look at the energy regulation from a bird’s eye perspective (Straub 2018). Psychologists and psychiatrists have long recognized the importance of energy questions in stress-inducing situations (e.g. in allostatic overload: McEwen 1998; Danese and McEwen 2012), but there is no true experimental application of this theoretical knowledge in early traumatic experiences—I have found nothing in the literature. The knowledge, however, is important in order to better explain different reactions of the stress axes—for © The Author(s), under exclusive license to Springer-Verlag GmbH, DE, part of Springer Nature 2023 R. H. Straub, Early Trauma as the Origin of Chronic Inflammation, https://doi.org/10.1007/978-3-662-66751-4_5

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example, high versus low cortisol or high versus low sympathetic activity. Since these discrepant patterns – of too much and too little hormone activity – influence immunological reactions, we are interested in clarification. I want to make a proposal that includes energy questions. Furthermore, I describe the connection between energy and chronic immunoactivation after early traumatic experiences, which results in an astonishing finding.

5.1 Brain and Immune System Define Energy Expenditure In earlier texts, I made the selfish role of brain and immune system clear with regard to energy allocation in the body (Straub 2017, 2018). There, the two selfish organs were described in detail, and their function was briefly mentioned in this book in Sect. 4.1. What makes them so special? These two organ systems can regulate energy distribution in the body with their respective means and, in addition, shut down the other system (the brain shuts down the immune system; the immune system shuts down the brain). These means of energy self-allocation by brain and immune system are summarized in Table 5.1. The respective factors of energy self-allocation were positively selected during evolution because these two systems are the hierarchically highest authorities to sense immediate dangers. In other words: The brain and the immune system quickly recognize the dangers, they have the corresponding sensors, they have the methods of adequate response and they set the energy allocation for the rest of the body (Table 5.2). Most of the available energy regulated above the basal metabolic rate goes to the brain and immune system depending on the type of dangers. The brain and muscles must be considered together in terms of energy consumption because they form a psychomotor unit. These topics were presented in detail in the previous book and are not repeated here (Straub 2018). In energy allocation, both organ systems stimulate a higher amount of circulating energy-rich substrates in the bloodstream, as they both dictate and dominate the release of stored energy in the form of fatty acids from fat tissue, of glucose from muscle and from liver/kidney, and of amino acids from muscle (some amino acids go into the formation of glucose in the liver and kidneys = gluconeogenesis). If increased amounts of energy-rich substrates circulate in the bloodstream, they are available to the two egoists and other organs when they do not need insulin for the uptake of energetic substrates (because of parallel insulin resistance: fat tissue, muscles and liver cannot take up energy with insulin resistance) (Straub 2014a). As a rule, always one egoistic system dominates. If several dangers come together, which require the brain and immune system to act at the same time, the danger of overload is much greater. The energy shortages then increase dramatically, which can develop into a life-threatening overall situation (e.g. intensive care unit/stress PLUS infection). I see another important point in energy regulation in how the egoistic organs can stimulate each other in a certain way. I called this stimulation “mutual immediate help” in my

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Table 5.1  Means of energy self-allocation by brain and immune system The means of the brain

The means of the immune system

The sympathetic nervous system with adrenaline and noradrenaline stimulates glycogenolysis, gluconeogenesis and lipolysis and thus increases the free energy substrates in the blood, at the same time it induces insulin resistance.

Cytokines such as TNF, IL-1β and IL-6 induce insulin resistance, gluconeogenesis (IL-6) and lipolysis and thus increase the free energy substrates in the blood

The HPA axis with cortisol stimulates glycogenolysis, gluconeogenesis, lipolysis and muscle breakdown (amino acids for gluconeogenesis) and thus increases the free energy substrates in the blood, at the same time cortisol induces insulin resistance.

Danger Signals = Toll-like receptor agonists induce insulin resistance, gluconeogenesis and lipolysis and thus increase the free energy substrates in the blood.

Growth hormone from the pituitary gland stimulates glycogenolysis, gluconeogenesis and lipolysis and thus increases the free energy substrates in the blood, at the same time growth hormone promotes insulin resistance.

Cytokines increase the production of cortisol in the liver and thus contribute to glycogenolysis, gluconeogenesis, lipolysis and muscle breakdown (amino acids for gluconeogenesis). The free energy substrates in the blood increase, at the same time it makes insulin resistance.

The thyroid hormone axis supports the sympathetic nervous system, promotes muscle breakdown and at the same time induces insulin resistance.

Immune cells can produce cortisol and thus contribute to glycogenolysis, gluconeogenesis, lipolysis and muscle breakdown (amino acids for gluconeogenesis). The free energy substrates in the blood increase, at the same time it makes insulin resistance.

The sympathetic renin-angiotensin-aldosterone system makes glycogenolysis and gluconeogenesis and thus increases the free energy substrates in the blood, while at the same time inducing insulin resistance.

Immune cells produce adrenaline and noradrenaline, and these hormones make glycogenolysis, gluconeogenesis and lipolysis and thus increase the free energy substrates in the blood, while at the same time inducing insulin resistance.

Inhibition of the parasympathetic nervous system and of digestive functions that would be relevant for the storage of energy substrates in the body.

Immune cells convert inactive thyroid hormones into active ones. This supports the sympathetic nervous system, promotes muscle breakdown and at the same time insulin resistance. This increases the free energy substrates in the blood.

Inhibition of the sex hormone axis: no muscle growth (energy storage in muscle blocked), no insulin help (the hormones promote insulin action)

Immune cells produce growth hormone, which makes glycogenolysis, gluconeogenesis and lipolysis and thus increases the free energy substrates in the blood, while at the same time inducing insulin resistance.

From: Straub (2014a, b)

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Table 5.2  Dangers and sensory functions of the brain and immune system Dangers

Immediate response

Response system

Predator

Fight or flight

Brain, SNS, HPA axis

Wounding and bleeding

Blood clotting and Blood pressure stabilization

Blood clotting system Brain with SNS, HPA axis and the SNS-dependent renin-angiotensin-aldosterone system

Later: Replacement of the cellular elements of the blood system

SNS stimulates leukocyte production in the bone marrow

Foraging behavior

Brain, SNS, HPA axis Brain, SNS, HPA axis

Hunger Thirst

Water search

Cold

Warming up and searching for warm Brain, SNS, HPA axis places

Heat

Sweating and searching for cooler places

Brain, SNS

Infection

Immune reaction, inflammatory reaction

Immune system

Injury and infection

Immune reaction, inflammatory reaction

Immune system

Abbreviations: SNS, sympathetic nervous system; HPA axis, hypothalamic-pituitary-adrenal axis

previous book (Straub 2018). This immediate help manifests itself in two different ways, which are shown in Fig. 5.1. On the one hand, the brain can induce a typical factor of the immune system—in the example of Fig. 5.1 it's IL-6—and thus provide a kind of immediate help for the immune system. On the other hand, cytokines of the immune system can activate the stress axes of the brain, more precisely: the hypothalamus, the pituitary gland and the upper sympathetic centers, and thus provide immediate help for the brain. In terms of energy regulation, the goal is ultimately to provide energy-rich substrates such as glucose and free fatty acids, which the respective activated selfish organs—the brain or immune system— remove from the bloodstream. This mutual immediate help is only active in the first hours up to a maximum of 1–2 days after the recognition of the respective trigger, before the organ-specific mechanisms of Table 5.1 increasingly take over. This takeover serves to enforce the respective own goals in the context of energy self-allocation. Brain and immune system are selfish! Since the current energy consumption and the expected future energy consumption were/are fundamental parameters in our evolutionary history—because every single reaction only works in the presence of energy (e.g. in the form of ATP; Fig. 5.2)—the availability of energy dictates almost every reaction in the body. During the long evolutionary process, the presence of energy and its conservation were/are a powerful selection factor.

5.1  Brain and Immune System Define Energy Expenditure

237 acvated immune system

acvated brain various cytokines e.g. IL-6

sympathec nervous system brown fat

lymph nodes

IL-6

IL-6 free fay acids liver

IL-6

adrenal gland corsol adrenaline

corsol adrenaline

gluconeogenesis insulin resistance energy-rich substrates (glucose, fay acids)

Fig. 5.1   Mutual immediate help of brain and immune system. The blue or blue-red paths show the immediate help of the brain for the immune system. At the end of the blue path, for example, IL-6 (demonstrates immunoactivation) intervenes in energy regulation. The red and blue-red paths show the immediate help of the activated immune system for the brain (demonstrates stress axis activation, a brain function). At the end of the red path are cortisol and adrenaline, which intervene in energy regulation. IL-6, cortisol and adrenaline are just examples (there are other factors). The activation of IL-6 from brown fat tissue was described by Qing et al. (Qing et al. 2020). At the end, energy-rich substrates (at the very bottom) can circulate in the bloodstream and are then taken up by the active organ—brain or immune system

If there is no energy, reactions cannot take place. Reactions also include our behavior, which was developed in the context of energy issues during evolution. With this premise, I say: The energy consumption and regulation are of central importance in traumatic experiences in young years. Unfortunately, the scientists who studied people with early traumatic experiences have not yet carried out any specific energy investigations. At least I couldn’t find anything tangible in the known databases, even though we can exactly determine the basal

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5  Energy, Early Traumatic Experiences and Chronic Immunization 166 amino acids for interferon-γ mkytsyilaf qlcivlgslg cycqdpyvke aenlkkyfna ghsdvadngt lflgilknwk eesdrkimqs qivsfyfklf knfkddqsiq ksvetikedm nvkffnsnkk krddfekltn ysvtdlnvqr kaiheliqvm aelspaaktg krkrsqmlfr grrasq

5 ATP molecules for an amino acid bond or 825 ATP molecules for one molecule of INTERFERON-

Interferon-γ

Fig. 5.2   The tiniest reaction in our body requires a lot of energy. The cytokine interferon-γ consists of 166 amino acids (National Center for Biotechnology Information 2021), and the cell needs 5 ATP molecules to produce an amino acid bond (Princiotta et al. 2003). ATP is the energy currency in the cell (Straub 2018). For the production of one molecule of interferon-γ, the cell needs about 825 ATP molecules

metabolic rate (basic requirement in absolute rest) and the total energy requirements of the human being with two very good methods. For the interested readers, these methods will be described briefly. The basal metabolic rate is determined by indirect calorimetry, and with the doubly labeled water technique the total energy consumption is derived (hydrogen and oxygen in water are labeled with different isotopes). With the help of activity and fitness trackers, the proportion of energy consumption for physical activity is recorded. All three methods provide exact statements about different forms of energy consumption. With the doubly labeled water technique the researchers can even make a statement about the total consumption over several weeks, without disturbing the test person in their everyday life. The latter method is particularly suitable as a safe and non-invasive method, which is why it is often used in human and veterinary medicine.

5.2 The Trauma Reaction can Use a Lot and a Little Energy Thinking now in the context of this book of early traumatic experiences, we must interpret those severe traumatic life events of Table 2.1 and 2.2 as dangers that are recognized by the brain. Thus, we can easily insert an additional line into Table 5.2 which contains the following points. In the first column we put under “Dangers” the trauma, the “immediate response” is the trauma reaction and the “response system” is the brain with its downstream helpers such as the sympathetic nervous system, the HPA axis, the pain pathways, etc. With the immune system this initial trauma reaction has little to do,

5.3  Is there a Trauma and Energy Provision Memory?

239

although every stress reaction triggers a small inflammatory reaction in the sense of ‘mutual immediate help’ (Fig. 5.1). The thing is dominated by the brain, since it has the essential sensory function in trauma situations. In terms of energy, the trauma reaction is either energy-consuming, energy-saving or without effect on energy consumption. Here you wonder when I mention “energy-saving or without effect on energy consumption” at all. Do you not automatically think of high energy consumption when these dangers act? Not always! In addition to flight and fight, which really consume a lot of energy, reactions to dangers can be opposite reactions that we know in the animal kingdom as freezing. This “freezing of activity” is an essential survival program for reptiles, since they, unlike mammals or birds, do not have energy stores and cannot maintain their body temperature constant. They rely on immobility and excellent mimicry to save energy and not be discovered in nature. In humans, we know both reactions after traumas, the classical type of the traumatic reaction with high energy expenditure (fight/flight) and the alternative type with freezing, an inability to act and a distance to one’s own body (van der Kolk 2014; Straub 2020). The first reaction is an energy-consuming reaction, the second reaction is not (however, we do not know for sure because it was not measured). From this I hypothesize: Trauma reactions can require a lot or a little energy.

5.3 Is there a Trauma and Energy Provision Memory? Here I say clearly YES. If we measure the energy consumption and the reaction of the stress axes in a child, adolescent or young adult during the impact of the trauma, we can assess the provisioning reaction of the energy-rich substrates. So one affected person may respond with high energy expenditure and another with energy protection. I foresee how the type of trauma exerts a significant influence on the specific energy consumption. Personal characteristics may also be relevant because they are also related to energy issues. We do not know this at the moment because it has not been measured. If a memory of the trauma is formed that permanently deflects the pointer of the weighing scale in Fig. 3.4 (memory of the trauma), we expect, in view of the absolutely central importance of energy expenditure, a combined trauma and energy provision memory. The hypothesis is: This memory and thus the energy provision reaction can cause long-term changes in tone over a long period of time, or this memory of acute recation can be recalled in the event of further traumas in the sense of double or multiple hits. The long-term incorrect deflection (tone: too much/too little) and the acute recall (acute reaction: too much/too little) each influence, according to the original long-term programming in young years, the subsequent reactions of energy provision and energy consumption (too much/too little) in a later stress episode. The hypothesis is: It is programmed whether a lot of energy or little energy is provided, and accordingly the

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responses of the systems involved in Table 5.2 and the means for this from Table 5.1 are stored. The reactions of the stress axes with cortisol or noradrenaline/adrenaline can therefore be very different, since strong reactions are associated with high energy expenditure and weak reactions with low energy consumption. This approach can help us to clarify why there may be discrepant response patterns with too much or too little of these hormones. Studies in this direction are worthwhile.

5.4 Energy and Chronic Immune System Activation Now we return to the core messages in this book to link chronic immune activation and energy together. Chap. 4 has shown how early traumatic experiences can influence the inflammatory situation in the long term. We are no longer surprised when those affected have increased inflammation values stimulated by the four connectors. What is decisive for energy regulation in the body are other questions that are: How high are these inflammation values really? Do people with early adversities need a special energy provision memory to provide the necessary energy for the activated immune system? Is the immune system therefore the superordinate system that dominates the energy provision reaction? Does the brain then play no role in energy provision?

5.4.1 How High is Inflammation in People with Early Traumatic Experiences Really? One of the first studies in people with early traumatic experiences and the popular C-reactive protein was carried out by Andrea Danese from King’s College in London together with Avshalom Caspi from the Explanation 3 (Danese et al. 2007). Those affected with early trauma experiences had about 2.5 times as much C-reactive protein as people without trauma. Sounds like a clear case, right? However, the average values of the C-reactive protein in the serum were in the relatively low range of 1.5 mg/l in the control group and 4.0 mg/l in the traumatized. People with values over 10 mg/l were excluded because the researchers here suspected a “proper inflammation” (Danese et al. 2007). Since the normal range of C-reactive protein is up to about 5.0 mg/l (Thomas 2020), there is obviously no proper inflammation here as a result of early trauma. Is the same true for IL-6, which induces C-reactive protein in the liver (Andus et al. 1988)? With the help of a meta-analysis, which processed the relevant literature up to 2016 (Baumeister et al. 2016), Table 5.3 was compiled. For this purpose, those studies with a sample size of over 100 people were used from the meta-analysis, which determined the important inflammatory parameter IL-6. The use of serum IL-6 is valuable because it leads to a few more logical conclusions about the level of inflammation and energy consumption. Unfortunately, serum IL-6

5.4  Energy and Chronic Immune System Activation

241

Table 5.3  Serum IL-6 in controls and people with early adversities (n in parentheses gives the number of all investigated people in the respective study) Controls

People with trauma

Literature

1.11 pg/ml (n=702)

1.34 pg/ml

(Bertone-Johnson et al. 2012)

< 2.09 pg/ml (n=756)

≥ 2.09 pg/ml

(Carroll et al. 2013)

3.80 pg/ml

(Gouin et al. 2012)

2.50 pg/ml (n=132)

3.02 pg/ml

(Kiecolt-Glaser et al. 2011)

1.80 pg/ml (n=482)

2.40 pg/ml

(Rooks et al. 2012)

Mean: 1.98 pg/ml

Mean: 2.53 pg/ml

Difference statistically significant, but biologically very questionable

2.40 pg/ml (n=130)

For comparison, healthy normal people 1.00 (in 20-year-olds) to 2.50 pg/ml (in 70-year-olds)

(Straub et al. 1998)

v­ alues were not given in pg/ml in all studies, which I believe is not good because it prevents the entire assessment of the severity of the inflammation. The serum IL-6 values do go into the statistical analysis here and there, but no one knows if they are outside the normal range (only the authors know it). In the compilation of Table 5.3 the serum value of IL-6 is hardly increased in the early traumatized people and is only minimally above the serum value of old people from our own study with carefully selected normal controls (Straub et al. 1998). The level of inflammation is therefore very low or non-existent. Let us now compare this situation from Table 5.3 with other states and diseases, in which the investigators used the same methods of IL-6 determination as in the studies of Table 5.3. Accordingly, the traumatized persons of Table 5.3 are slightly above the healthy normal persons and near the stressed old persons who had to move from their home environment to a nursing home in later life (Lutgendorf et al. 1999). Persons with obesity show slightly higher values than the resettled persons in old age (Fig. 5.3). Even if we take the measurement value for patients with obesity as the target variable because obesity is a common complication in traumatized persons (Sect. 3.3.1), this serum concentration of IL-6 is surprisingly low, because it only causes a small change in energy expenditure. This relationship is shown in the next subchapter.

5.4.2 How High is Energy Expenditure at Different Levels of Inflammation? Here I repeat a few aspects of the previous book (Straub 2018), because they are central to the following consideration. At that time I wrote:

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Serum level of interleukin-6 (pg/ml) (logarithmic scale)

Sepsis, maximum

Sepsis, baseline

Sepsis, 2nd week after therapy Sepsis, 3rd week after therapy rheumatoid arthritis, 2nd study before therapy rheumatoid arthritis, 1st study before therapy rheumatoid arthritis, well treated Obesity / care for Alzheimer patients aged people moved to a nursing home 70 years old, healthy 20 years young, healthy

Fig. 5.3   Serum levels of interleukin-6 (IL-6) in different states. A logarithmic scale was used for the Y-axis, which is often used in exponential growth. The green color indicates the normal situation. With higher inflammation, the color changes to red, indicating a more severe inflammation situation. For rheumatoid arthritis, two examples of the serum IL-6 value before therapy are given, because this disease can start more or less severely (some patients have serum values up to 200 pg/ml). The maximum in sepsis occurred in one patient. The other data on sepsis are mean values of very many patients. Obesity is diagnosed by a body mass index of 30 kg/m2 (BMI = weight in kg, divided by height in m squared). (Mod. after Straub 2018)

In a much-cited study of healthy people, a team at the American National Institutes of Health in Washington was able to show (Tsigos et al. 1997), how the administration of IL-6 by means of injection under the skin increased the levels of the same IL-6 in the blood and how this led to an increased expenditure of energy of the whole body (Fig. 5.4). If the experimenter increased the levels of IL-6 from the usual 1 pg/ml to 7 pg/ml, the expenditure of energy increased by 250 kJ (60 kcal) per day (Fig. 5.4). If a patient with rheumatic disease is well treated, the level of IL-6 is 10 pg/ml. In the experiment with healthy people, the increase from the usual 1 pg/ml to 10 pg/ml led to an increase in energy expenditure of 300 kJ (72 kcal) per day. (…) Quite different is the case with the high levels of IL-6 from 1000–3000 pg/ml in Fig. 5.4, which lead to an increase in energy expenditure of 2500 kJ (600 kcal) per day.

A simulated inflammation situation with IL-6 thus results in higher energy expenditure. If we look at our low IL-6 values from Table 5.3 and compare them with the data in Fig. 5.4, we would not expect higher energy consumption in traumatized people. In other words: An energy provision memory with activated stress axes is not necessary to provide energy for the immune system with this low inflammation.

243

Increase in energy consumption per day in kJ (kcal)

5.4  Energy and Chronic Immune System Activation

Serum level of interleukin-6 (pg/ml) (logarithmic scale) Fig. 5.4   Energy expenditure per day. In the subjects studied, the cytokine interleukin-6 was injected with a syringe under the skin. After a short time, the blood level of interleukin-6 increased (black dots). At the same time, the increase in energy expenditure over the normal basal metabolic rate was measured. For example, 500 kJ on the Y-axis means an increase in energy expenditure of 500 kJ, which is due to the injection of interleukin-6 and the associated increase in inflammation. Numbers in brackets are given in kcal. The blue curve and the black measurement points show the relationship between serum levels of IL-6 and increase in energy expenditure. With increasing levels of interleukin-6 on the X-axis, the energy expenditure on the Y-axis increases. With an increase in the blood level to 3.5 pg/ml (green lines), the energy expenditure increases by 170 kJ (40 kcal) per day. With an increase in the level to 7 pg/ ml (red lines), the energy expenditure increases accordingly by 250 kJ per day. With an increase in the level to 100 pg/ml (black dashed lines), the energy expenditure increases by about 1200 kJ per day. Data according to Tsigos et al. (1997)

5.4.3 The Quintessence For me, therefore, the mild inflammation is a pure accompanying phenomenon of earlier traumatic experiences and not responsible for many of the so-called sequelae. Mild inflammation is an accompanying phenomenon in the sense of “mutual immediate help”, which ultimately only serves the stressed brain to provide a higher amount of energy-rich substrates for the psychomotor unit (brain-muscles). The problem of the so-called systemic inflammation, which we can easily measure in the blood, is, in my opinion, clearly overestimated by many scientists, since this so-called inflammation hardly changes the

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energy expenditure. If one thing hardly changes energy expenditure, it plays hardly any role in the whole system, because energy is a central control variable. Nevertheless, there is an energy provision memory after trauma, in which the reactions of the stress axes are stored accordingly in order to provide the right amount of energy for the brain’s response reaction in case of need. However, the provision of energy does not serve the largely calm immune system but only the activated brain. In my previous book and in a publication I have already pointed out the following (Straub 2017, 2018): In addition to the possibly mild chronic immune activation, there are manifold other elements that trigger increased energy expenditure. The problems mentioned in Table 5.4 and other trauma-related problems of the brain or the psychomotor unit (brain-muscles) described in this book have a much greater impact on energy consumption than the mild chronic immune system activation. Thus, I give the mild chronic immune system activation a low importance when discussing energy aspects. The central nervous system problems after trauma are much more important for the question of energy consumption, for the energy provision memory and for the reaction of the stress axes than the mild inflammation. The latter hardly needs extra energy above the basic requirement. Since the increased energy consumption for the unwanted side effects mentioned in Table 5.4 limits the energy availability for desired physical and mental activities, these side reactions become a decisive factor for premature aging, early illness, frailty and early death (Straub 2017). The non-inflammatory side effects decisively influence these unwanted energy expenditures of Table 5.4. Most of it takes place in the brain, the immune system is the spectator—at most the small first-aid kit. The immune system is not the pervasive system that dominates the energy provision reaction. This role is played by the brain. Allow me a final remark from the clinical immunologist on the increasingly occurring autoimmune diseases after early traumatic experiences (see Sect. 3.4). If the immune

Table 5.4  Percentage of additional energy expenditure stimulated by the brain Situation*

Additional energy expenditure

Acute pain (electric shocks to the abdominal wall)

up to 69% more

Chronic pain

up to 15% more

Psychological stress (activates psychomotor unit)

up to 30% more

Anxiety/fear

up to 10% more

Sleep disorders

up to 30% more

Chronic smoldering infections (stimulated by risky behavior)

up to 10% more

Chronic smoking (more than 6 cigarettes/day)

up to 15% more

*The individual situations cannot be considered independently of each other, since pain can be associated with sleep disorders or anxiety with psychological stress, for example. Therefore, you cannot add up the percentage figures to calculate the total increase in additional energy expenditure. Data from Straub (2017)

5.5  To the Point

245

system hardly deviates from the normal situation, why are there more autoimmune diseases? In addition to the known genetic factors, other elements must be significant here: for example smoking, drugs, chemicals (occupation!), floating fine particles such as silica dusts, the wrong microbiome, pathogens (especially viruses), junk food and the false free fatty acids (not the hardly measurable cytokines from the adipose tissue), lack of physical and mental activity, etc. These create the platform for the development of autoimmune diseases next to the genetic predispositions (e.g. for rheumatoid arthritis; Okada et al. 2014). Chronic mild immune system activation is not a platform that bears all the weight for the development of autoimmune diseases. I am sometimes asked why I do not give therapy recommendations in the books. The pathophysiological relationships are more important to me, especially the importance of the connectors, whose function I highlighted. From here, the interested reader can derive the therapy recommendations. Is it not a greater Aha experience when the reader comes to the right conclusions on the basis of his on reading of the book? At the end of the previous paragraph, it was clear what we have to avoid. If you have read the book carefully, you know what to avoid and what to stimulate.

5.5 To the Point • The availability of energy is central to the evolutionary process for chemical, biochemical and biological reactions. The availability of energy is a powerful force in natural selection. • If there is no energy, reactions do not take place, not even behavioral reactions, as behavior developed on the basis of the presence of energy during evolution. • The brain and immune system selfishly define the distribution of energy and use their own practical means to act independently of each other. • A trauma reaction can consume a lot (fight/flight) or a little (freezing) energy. In addition to the trauma memory, an energy provision memory is created. • This memory can cause long-term changes in the tone of the stress axes or, in the event of re-occurring trauma, it can define the acute reaction of the stress axes during double or multiple hits. • This approach can help us to clarify why there are discrepant patterns of response of the stress axes with too much or too little of hormones and neurotransmitters. • Surprisingly, early traumatic experiences only slightly increase the inflammatory situation (C-reactive protein, IL-6) later in life. This minimal increase in inflammation only marginally changes energy expenditure. • Therefore, the increased energy expenditure must be explained by mechanisms outside the immune system. Only the selfish brain can be responsible for increased energy expenditure after early adversities.

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5  Energy, Early Traumatic Experiences and Chronic Immunization

• Increased energy expenditure is caused by pain, psychological stress, anxiety, sleep problems (remember itchiness, etc.), possibly smoldering unnoticed infections (cytomegalovirus in immunocompromised people after risky behavior), chronic smoking, drugs, and other things. • These energy expenditures are not desired by the affected person because they rob the body of the necessary energy for physical and mental activity. The lack of physical and mental activity is the decisive risk factor for premature aging, early illness, frailty and early death. Most of this takes place in the brain, the immune system is the spectator and at most an “immediate helper”.

References Andus T, Geiger T, Hirano T, Kishimoto T, Heinrich PC (1988) Action of recombinant human interleukin 6, interleukin 1 beta and tumor necrosis factor alpha on the mRNA induction of acute-phase proteins. Eur J Immunol 18:739–746 Barker DJ, Winter PD, Osmond C, Margetts B, Simmonds SJ (1989) Weight in infancy and death from ischaemic heart disease. Lancet 2:577–580 Baumeister D, Akhtar R, Ciufolini S, Pariante CM, Mondelli V (2016) Childhood trauma and adulthood inflammation: a meta-analysis of peripheral C-reactive protein, interleukin-6 and tumour necrosis factor-α. Mol Psychiatry 21:642–649 Bertone-Johnson ER, Whitcomb BW, Missmer SA, Karlson EW, Rich-Edwards JW (2012) Inflammation and early-life abuse in women. Am J Prev Med 43:611–620 Carroll JE, Gruenewald TL, Taylor SE, Janicki-Deverts D, Matthews KA, Seeman TE (2013) Childhood abuse, parental warmth, and adult multisystem biological risk in the Coronary Artery Risk Development in Young Adults study. Proc Natl Acad Sci U S A 110:17149–17153 Danese A, McEwen BS (2012) Adverse childhood experiences, allostasis, allostatic load, and age-related disease. Physiol Behav 106:29–39 Danese A, Pariante CM, Caspi A, Taylor A, Poulton R (2007) Childhood maltreatment predicts adult inflammation in a life-course study. Proc Natl Acad Sci U S A 104:1319–1324 Gouin JP, Glaser R, Malarkey WB, Beversdorf D, Kiecolt-Glaser JK (2012) Childhood abuse and inflammatory responses to daily stressors. Ann Behav Med 44:287–292 Kiecolt-Glaser JK, Gouin JP, Weng NP, Malarkey WB, Beversdorf DQ, Glaser R (2011) Childhood adversity heightens the impact of later-life caregiving stress on telomere length and inflammation. Psychosom Med 73:16–22 Lutgendorf SK, Garand L, Buckwalter KC, Reimer TT, Hong SY, Lubaroff DM (1999) Life stress, mood disturbance, and elevated interleukin-6 in healthy older women. J Gerontol A Biol Sci Med Sci 54:M434–M439 McEwen BS (1998) Protective and damaging effects of stress mediators. N Engl J Med 338:171–179 National Center for Biotechnology Information. Domains & Structures Database. from https:// www.ncbi.nlm.nih.gov/guide/domains-structures/. Accessed 11 Jan 2021 Okada Y, Wu D, Trynka G et al (2014) Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 506:376–381 Princiotta MF, Finzi D, Qian SB, Gibbs J, Schuchmann S, Buttgereit F, Bennink JR, Yewdell JW (2003) Quantitating protein synthesis, degradation, and endogenous antigen processing. Immunity 18:343–54

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Qing H, Desrouleaux R, Israni-Winger K, Mineur YS, Fogelman N, Zhang C, Rashed S, Palm NW, Sinha R, Picciotto MR, Perry RJ, Wang A (2020) Origin and Function of Stress-Induced IL-6 in Murine Models. Cell 182:372–387 Rooks C, Veledar E, Goldberg J, Bremner JD, Vaccarino V (2012) Early trauma and inflammation: role of familial factors in a study of twins. Psychosom Med 74:146–152 Straub RH (2014a) Insulin resistance, selfish brain, and selfish immune system: an evolutionarily positively selected program used in chronic inflammatory diseases. Arthritis Res Ther 16(Suppl 2):S4 Straub RH (2014b) Interaction of the endocrine system with inflammation: a function of energy and volume regulation. Arthritis Res Ther 16:203 Straub RH (2017) The brain and immune system prompt energy shortage in chronic inflammation and ageing. Nat Rev Rheumatol 13:743–751 Straub RH (2018) Altern, Müdigkeit und Entzündungen verstehen – Wenn Immunsystem und Gehirn um die Energie im Körper ringen. Springer, Berlin/Heidelberg Straub RH (2020) Drei Gedächtnisse für den Körper. Springer Nature, Berlin Straub RH, Konecna L, Hrach S, Rothe G, Kreutz M, Schölmerich J, Falk W, Lang B (1998) Serum dehydroepiandrosterone (DHEA) and DHEA sulfate are negatively correlated with serum interleukin-6 (IL-6), and DHEA inhibits IL-6 secretion from mononuclear cells in man in vitro: possible link between endocrinosenescence and immunosenescence. J Clin Endocrinol Metab 83:2012–2017 Thomas L. Labor und Diagnose 2020 – Internet version. at 27.11.2021 from https://www. labor-und-diagnose-2020.de/ Tsigos C, Papanicolaou DA, Defensor R, Mitsiadis CS, Kyrou I, Chrousos GP (1997) Dose effects of recombinant human interleukin-6 on pituitary hormone secretion and energy expenditure. Neuroendocrinology 66:54–62 van der Kolk B (2014) The body keeps the score – mind, brain and body in transformation of trauma. Penguin Random House, New York

Glossary

Adaptive  When a trait is positively selected during evolutionary history due to its good adaption to the environment, the trait is then said to be adaptive. Adipokines  Factors produced by fat tissue that have hormone-like or cytokine-like effects in other parts of the body and in fat tissue. Adolescence  Adolescence is the period from late childhood (11th year of life) through puberty to full adulthood (21st year of life), Fig. 1.1. Adrenal gland, cortex and medulla The adrenal glands are glands that sit on both sides of the kidneys like caps. They each have the size of an apricot, and they produce various hormones that are released into the bloodstream. Anatomists distinguish between the adrenal cortex, from which cortisol and androgens originate. In the adrenal cortex, a important hormone for blood pressure regulation is also produced. In addition, the anatomist distinguishes the adrenal medulla, which is surrounded by the cortex (similar to the apricot kernel by the apricot flesh). Adrenaline is produced in the adrenal medulla. Adrenaline is the stress hormone number 1. The brain is the supreme master of the adrenal gland, which activates the adrenal cortex hormonally via the pituitary gland and the adrenal medulla via the sympathetic nervous system. Adrenal cortex and adrenal medulla belong to the stress system. Age-related diabetes  See diabetes mellitus type 2. ACC  anterior cingulate gyrus, responsible for emotional control, evaluation, emotions, social role, memory and executive function. Amygdala  The amygdala is a core area that is connected to many different areas of the brain. There, remembered emotional aspects are processed. In particular, the amygdala is responsible for fear and valuation of fear. The amygdala is the starting point of immediate reactions to danger with an increase in the activity of the HPA axis, the sympathetic nervous system and respiration. After early traumatic experiences, the amygdala experiences inadequate increased activity and responsiveness. Andropause  Andropause describes the menopause of man (gr. andrós, man). It occurs a little later than the menopause of the woman (around the 50th year of life). Andropause is associated with a increasingly lower production of male sex hormones. © The Editor(s) (if applicable) and The Author(s), under exclusive license to SpringerVerlag GmbH, DE, part of Springer Nature 2023 R. H. Straub, Early Trauma as the Origin of Chronic Inflammation, https://doi.org/10.1007/978-3-662-66751-4

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Although the man’s fertility remains basically until old age, the probability of late fatherhood decreases significantly. Antigens, Autoantigens  Antigens are recognized by our immune system as foreign and are attacked. Antigens are often surface-located structures of bacteria or viruses (e.g. tetanus toxin). The attack is carried out with exactly matching antibodies and immune cells with exactly matching receptors. The immunologist speaks of autoantigens when the antigens consist of body-own material (just auto), against which an immune reaction and an inflammatory reaction are erroneously initiated. Antibodies  Antibodies are produced by immune cells (more precisely: by B cell-­ derived plasma cells). Antibodies always target antigens (for example, virus components, in COVID-19 it is the spike protein). In many cases, the antigen is neutralized and the antigen is taken up and destroyed by phagocytes. Atherosclerosis  Sometimes called “artery calcification”. It is a disease of the vessel walls of the arteries with increasing hardening (increase in connective tissue), inflammation and deposition of blood fats and calcium. It is the platform for the formation of sudden blood clots that can break off (embolism) or completely block the vessel (heart attack, stroke, vascular occlusion). Arthritis  Joint inflammation. As rheumatoid arthritis, it is a chronic joint inflammation, an autoimmune disease. ATP  Adenosine triphosphate is the universally accepted currency of energy that is produced in mitochondria. A molecule of ATP consists of 10 carbon atoms, 16 hydrogen atoms, 5 nitrogen atoms, 13 oxygen atoms, and 3 (hence triphosphate) phosphorus atoms. ATP is needed by the cell in many metabolic steps and in cell growth. The production of a single protein molecule of medium size requires approximately 2000 ATP molecules. Acetylcholine  The important neurotransmitter of the parasympathetic nervous system, or the vagus nerve. Autoimmune disease  An immunological disease in which the target structure is body tissue. The cause is an incorrect immune response to self. The attack is against body protein structures, called autoantigens. The body tissue deteriorates as part of an inflammatory reaction. An example is rheumatoid arthritis. B cell The B cell belongs to the lymphocytes and is responsible for the production of antibodies. It is called a B cell because it was first discovered in a lymph organ of birds - the Bursa fabricii (bursa, Latin for bag; fabricii from Italian anatomist Girolamo Fabrizio, 1619). It belongs to the adaptive immune system. B-memory cells can maintain B-cell memory for decades. The descendants of B cells with memory and antibody production are called plasma cells, and they live long-term in the bone marrow. Bariatric surgery  Operation in the area of the stomach and/or small intestine, which is carried out in case of severe obesity if conservative measures fail. These operations are very successful with regard to weight loss.

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Basal metabolic rate  Basic requirement of energy. This amount of energy is required in absolute rest in the morning in a warm bed. It serves the basic supply of all organs and organ systems. The basal metabolic energy cannot be negotiated between different organs. Body-Mass-Index  Body measure for the assessment of obesity (weight by body height squared). See explanation 7. Chronic obstructive lung disease  Here, the smallest airways are increasingly narrowed (obstruction) by remodeling processes within the lungs. Consequences are chronic wall thickening of the smallest airways and increased mucus production. Asthma or smoking is often the starting point for chronic obstructive lung disease (COPD). Citrullination of antigens  Antigens consist of amino acids. The amino acid arginine may be present in the antigen. Citrulline can be formed from arginine, which is called citrullination. Since citrulline is not a typical amino acid, it hardly occurs during the maturation process of the immune system. Later formed citrulline within a self-protein can be recognized and attacked as a foreign substance. In rheumatoid arthritis, this process is important. Cortisol  Cortisol is the active hormone of the adrenal cortex (people say cortisone, but that is the inactive degradation product). Cortisol is a stress hormone of the selfish brain. Cortisol leads to the release of energy rich substrates from stores such as fat tissue and liver. This can increase levels of fatty acids and sugar in the blood. At the same time it is anti-inflammatory. See also glucocorticoids. CRH (Corticotropin Releasing Hormon)  Hierarchically considered, the highest hormone in the hypothalamus for controlling the HPA axis (Fig. 4.9). Cytokines  Cytokines are the messenger substances of immune cells and other cells that act in the immediate vicinity of the cells. We can call cytokines messenger substances for the immediate neighborhood or “neighbor’s messenger substances”. See messenger substances. Sometimes cytokines can have an effect at a distance, like IL-6. Diabetes mellitus  Sugar disease, i.e. the sugar levels in the blood are too high. In type 1 diabetes mellitus, there is an autoimmune disease in which the immune system recognizes proteins of the insulin-producing pancreas as “foreign”. Through the inflammatory destruction of insulin production, these patients need insulin as a permanent therapy. These patients are usually younger. In type 2 diabetes mellitus (age-related diabetes), on the other hand, insulin production is intact for a long time until it runs out after years of overproduction (exhaustion of the pancreas). The latter disease is not an autoimmune disease. Epigenetics  Influence of genes and thus the production of proteins by environmental factors that inhibit or promote the reading of genes. The composition of the genes (the sequence of nucleotides) is not changed. The Barker phenomenon was an example. See explanation 1.

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Epithelial cell  These are the cells of the inner and outer surfaces of the skin or mouth, nose, intestine, lung, urinary tract and others. In addition, the endocrine organs are made up of epithelial cells, as they develop from the surface tissues. Executive functions  These include self-control, emotion regulation, planning, working memory and conscious attention control. In addition, self-motivation, will formation and action initiative belong to this block of executive functions. The better the executive functions are, the higher the competence and resilience. Fatty acids  Basic unit of stored fat. Genome, genome-wide Genetic material, totality of all genes of a cell. Geneticists understand this to mean the totality of the inheritable information of an individual. A genome-wide study includes all the genes of the individual. Glucocorticoids  These hormones come from the adrenal cortex and are called that because they are involved in the release of glucose from stores into the bloodstream. Cortisol is the major stress hormone in humans and it is the key hormone of the HPA axis. Cortisone is the biologically inactive breakdown product of cortisol. Glucocorticoid resistance Means lack of cortisol effect through its glucocorticoid receptor. This is an important platform why the anti-inflammatory cortisol does not properly inhibit inflammation. Glucose  Glucose is an important basic unit of carbohydrates. Glucose is an important energy source that is used especially under oxygen-poor conditions to generate ATP (energy). Glucose can be stored in the form of starch. HPA axis  Hypothalamus-pituitary-adrenal axis (Fig. 4.9). Hippocampus  Hippocampus is a region in the brain, more precisely: in the inner middle temporal lobe. It is closely associated with the formation of memory. Especially the memory for places is stored there. The hippocampus is closely linked to the limbic system. Human genome-wide A human genome-wide study includes all genes of the individual. Hypothalamus  A brain area in which the upper centers of the hormones and the autonomic nervous system are integrated. The control of the brain goes from there to hormone pathways or autonomic nervous pathways. There is the eating and satiety center, the center for body temperature, etc. Insulin  It is the storage hormone par excellence from the pancreas, because it promotes the uptake of glucose and fatty acids into the storage organs (fat tissue, muscle, liver). Furthermore, it is a growth factor for many tissues, including the immune system. Diabetics with high blood glucose levels receive insulin therapeutically so that the blood glucose level decreases and is transported to the storage organs. Interleukin, IL-1, IL-6  For example, interleukin-1 or interleukin-6. These are immunological hormones or cytokines that act in the immediate vicinity (local action). Some cytokines like interleukin-6 have long-range effects by being transported to distant locations via circulation. See cytokines and TNF.

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Leptin  The “thin hormone” leptin (gr. leptos, thin) is produced in fat tissue, acts in the brain to suppress appetite, and activates the sympathetic nervous system and fat breakdown. Leptin is part of the feedback loop to maintain fat mass. At the same time, it affects many immunological processes in a stimulating way. Leukocytes  White blood cells. This includes the antigen-presenting cells discussed in the book, macrophages, lymphocytes (T-cells and B-cells). Limbic system  It is a functional unit as a delimited region between the cerebral cortex and the brainstem. It is closely linked to emotions, smell, fear, drives, mood and memory. There are close connections to many other regions of the brain, including the top hormone centers and centers of the autonomic nervous system. Metabolic syndrome  Metabolic syndrome is characterized by the following symptoms: abdominal obesity (large energy-storing memory), high blood pressure (sign of high sympathetic activity), altered blood lipid values (high triglyceride levels), insulin resistance (the main storage hormone no longer works, and energy-rich substrates like glucose and fatty acids are no longer stored properly). Meta-analysis  In a meta-analysis, the data from many individual studies are combined. The evaluation can be done with a larger number of people. The conduct of a meta-analysis is strictly standardized. Mitochondria  Mitochondria are the energy producers of our cells. They produce ATP (adenosine triphosphate), which is needed everywhere. ATP is the energy coin that is paid for almost everywhere. ATP production is continuous and everywhere. Multimorbidity  When a patient suffers from several diseases, the doctor speaks of multimorbidity. Myokines  Factors of the muscle that have a hormone-like or cytokine-like effect in other parts of the body and in the muscle. Noradrenaline  Noradrenaline is primarily a messenger of the sympathetic nerve fiber. When noradrenaline is considered in flowing blood, it is sometimes called a hormone. In addition, immune cells can locally produce noradrenaline. See sympathetic nervous system. Nucleus accumbens  Important core area in the reward system (Fig. 3.1). Obesity  The term obesity is used by doctors when a person’s body mass index is 30 kg/m2 or higher (body mass index = weight in kg divided by height in m squared). People are considered to be of normal weight if their body mass index is between 18.5 and 25 kg/m2. Between 25 and 30 kg/m2 is considered overweight. Parasympathetic nervous system The opponent of the sympathetic nervous system. Where the sympathetic nervous system is responsible for attack and flight, the parasympathetic nervous system is responsible for digestion and uptake of energy-rich substrates (glucose, fatty acids, amino acids). Parasympathetic and sympathetic nervous system are opponents: If one system is more active, the other is quite inactive. Personality traits  See explanation 5.

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Phenome  The totality of all externally visible characteristics of an individual, accessible to the senses, including, for example, height, weight, blue eyes, thick lips, protruding chin, intelligence, behavior, etc. A phenome-wide study includes all externally visible characteristics of the individual. Plasma cell  It is the descendant of a naive B cell that has seen antigen and has developed into an antibody-producing cell. It lives long-term in the bone marrow. Pleiotropic gene The same variant of a gene called X that causes different things at two separate locations in the body is called pleiotropic by the geneticist (from Greek pleíōn, more; Greek tropein, change). In other words, through a variant of the gene X, more than one thing is changed at different locations in the body. Positively selected  see selection. Psoriasis vulgaris  Psoriasis is a chronic inflammatory autoimmune skin disease that is associated with an increased keratinisation reaction and the formation of scales. The areas of the skin affected by psoriasis do not usually heal spontaneously. Psychomotor system The functional unit of the brain and skeletal muscle. Skeletal muscle cannot decide how much energy it wants to spend per day. The brain dictates the daily energy expenditure of skeletal muscle by deciding on the physical activities. Therefore, it is a functional unit for the sake of energy consumption. Renin-angiotensin-aldosterone  The RAA hormones Renin, Angiotensin, and Aldosterone have a main role in blood pressure stabilisation. During stressful events, blood pressure must rise. The sympathetic nervous system with its messenger substances noradrenaline and adrenaline stimulates the RAA hormone system. The RAA hormone system and the sympathetic nervous system increase blood pressure by reducing water excretion in the kidney and constricting blood vessels. So the increased water remains in the constricted vascular system, and this increases blood pressure. Receptor  A protein structure that can bind a molecule (a chemical stimulus) and thus be activated, and that transmits this activation to the interior of the cell (signal transduction). The receptor can be on the cell membrane and inside the cell. Comes from the Latin recipere = to receive. Rheumatoid arthritis Joint inflammation at multiple joints, usually the hands and feet, less often the large joints and spine. The disease can also affect tissue outside the joints. It is an autoimmune disease in which the immune system mistakenly recognizes the body’s own tissue as foreign and attacks it. Since the immune system is active, these patients need more energy for this immune system. The above-mentioned citrullination of antigens plays an important pathophysiological role in this disease. Selection, positively selected The individuals better adapted to the respective environment have the greater chance of surviving in the competition and reproducing more easily. We say of a species that still exists today that it has been positively selected or that it has experienced positive selection. This means that the species or a

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characteristic of this species (e.g. red comb in the cock) experienced positive selection after many generations, so the species or the characteristic is still there. In contrast, all species that no longer exist and are extinct experienced negative selection, they were negatively selected. Stress axes  The stress axes are switched on in acute stress. They serve the acute redistribution of energy-rich substrates from the stores (fat tissue, liver) to the consumers (brain, muscles, heart muscle, immune system). In essence, stress axes are the hypothalamus-pituitary-adrenal axis (end product: cortisol) and the brain-sympathetic nervous system axis (end products: adrenaline from the adrenal gland and noradrenaline from the sympathetic nerve fibers). In addition, stress also activates the thyroid and the RAA hormones (see there). Somatic pain  Pain that can be precisely localized in the area of ​​muscles, bones, ligaments, tendons and skin. Sympathetic nervous system  The central stress system of the human body with the two messenger substances adrenaline and noradrenaline. Adrenaline comes from the adrenal gland. The nerve fibers of the sympathetic nervous system are called sympathetic nerve fibers, which are virtually everywhere in the body. Noradrenaline is located in the terminal buttons of the sympathetic nerve fibers. Synapse  Connection point between two nerve cells, through which information can be forwarded. Systemic lupus erythematosus  Systemic lupus erythematosus (SLE for short) is characterized by a colorful picture of disease manifestations, with a skin involement, kidney inflammation, a vascular inflammation, a brain involvement, a joint inflammation, a depletion of blood cells and other things. It is an autoimmune disease. T cell  The T stands for thymus. T cells are part of the lymphocytes and have two main functions: 1) They can kill other cells (using an enzyme machinery). They like to do this if the cells are virus-infected. 2) They can help other cells of the immune system (preferably B cells) by activating or inhibiting their function. Various T helper cell types are distinguished by their production of key cytokines (type 1: interferon-γ; type 2: IL-4, IL-5, IL-13; type 3: TGF-β; type 9: IL-9; type 17: IL-17A; type 22: IL-22). Telomere  Telomeres consist of repeating units of DNA at the end of chromosomes (Fig. 3.8). If these repeating pieces become smaller over the course of a cell’s life, this is an indication of cell aging. TNF  TNF stands for tumor necrosis factor, because this cytokine can destroy tumors. When scientists first described it, this tumor-destroying property was primary. Today, TNF is considered one of the most important pro-inflammatory factors of the activated immune system. TNF is relevant to infections and autoimmune diseases, among other things. There are now therapeutic inhibitors of TNF. Vagus  The vagus nerve is the main nerve of the parasympathetic nervous system, which controls the digestive system. It arises in the medulla oblongata within the skull and

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is responsible for the continuous movement of the stomach and intestine. It also promotes the release of digestive enzymes and insulin from the pancreas. It supplies the intestine up to the middle of the large intestine. After that, the large intestine is subject to the sympathetic nervous system alone – especially with regard to the release of stool. The vagus nerve contains many sensory nerve fibers that send information about stimuli from the gastrointestinal tract back to the brain. Visceral pain These pains come from pain-sensing nerve fibers from internal organs like the gut, the lungs, heart, stomach, intestine, bladder, etc.