Influence of early life stress on psychophysiology in psychiatric patients

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INFLUENCE OF EARLY LIFE STRESS ON PSYCHOPHYSIOLOGY IN PSYCHIATRIC

PATIENTS

Dissertation

zur Erlangung des akademischen Grades des Doktors der Naturwissenschaften

Eingereicht an der Mathematisch-Naturwissenschaftlichen Sektion der Universität Konstanz

Fachbereich Psychologie

v orgelegt von Katja Weber Konstanz, Juli 2009

Tag der mündlichen Prüfung: 05. November 2009 1. Referentin: Prof. Dr. Brigitte Rockstroh

2. Referentin: Prof. Dr. Johanna Kissler

Konstanzer Online-Publikations-System (KOPS) URN: http://nbn-resolving.de/urn:nbn:de:bsz:352-opus-89809

URL: http://kops.ub.uni-konstanz.de/volltexte/2009/8980/

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DANKESCHÖN!

Ein Abschnitt geht zu Ende … und so möchte ich die Gelegenheit nutzen, mich bei all den Helfern zu bedanken, die aktiv im Vordergrund oder stützend im Hintergrund zum Gelingen dieser Arbeit beigetragen haben.

Zu Beginn möchte ich die zahlreichen freiwilligen Teilnehmer erwähnen, ohne die diese Studie nicht durchzuführen gewesen wäre. Sie haben bereitwillig und offen von ihren privaten Erfahrungen berichtet sowie an den für sie zumeist sehr anstrengenden Untersuchungen teilgenommen. Ihnen gebührt meine Anerkennung!

In diesem Zusammenhang bedanke ich mich auch bei den vielen Helfern, die dieses Projekt in der Phase der Datenerhebung unterstützt haben. Allen voran das Team des SOSS B5 Projekts: Bärbel, Jens, Tzvetan, Katharina, Monika und Simone, Dank aber auch den Ärzten, Psychologen und Pflegekräften der Stationen 33, 51, 60, 61 und 71 des ZfP Reichenau. Nur durch Eure unendliche Bereitschaft und fleißigen Hände, teilweise sogar an Samstagen, war die Datenerhebung möglich.

Toll war auch die Unterstützung, die mir von vielen Seiten während der Datenaufbereitung und –analyse zuteil wurde. Ganz lieben Dank an Anne, Bärbel, Christian, Carsten, Jens, Johanna, Harald, Patrick und Ursel. Eure Hilfe, Tipps und Tricks sowie Eure Geduld und Zuversicht, wenn’s mal wieder schief ging, hat mich in manch verzweifelter Lage gerettet und motiviert weiterzumachen.

Ein extra Absatz soll Brigitte zuteil werden. Sie ist und war zu jeder Zeit der treibende Motor des Projekts, der mit beständigem sanftem Druck, aber auch dem gewissen Weitblick, zahlreichen Ideen und ganz praktischer Unterstützung die Arbeit vorantrieb. Mit Deiner Erfahrung und Hilfe warst Du selbst am Wochenende immer erreichbar. Ganz herzlichen Dank, dass ich die Möglichkeit hatte unter Deiner Anleitung die Promotion durchzuführen!

Eine wichtige Unterstützung waren in den vergangenen 3 Jahren auf ganz persönlicher Ebene einige Freunde, die ich erwähnen möchte. Anne, Hannah, Nadja und Vera: durch Euch waren nicht nur die Kaffeepausen die schönste Zeit im ZfP ☺. Ina und Manu: Danke für Eurer „da sein“ in jeder Lebenslage. Und an all diejenigen, die ich jetzt nicht genannt habe: Danke, dass Ihr einfach da seid!

Loïck, Du bist wahrscheinlich der Mensch, der am meisten unter meiner Abwesenheit und der vielen Arbeit gelitten hat. Ganz lieben Dank für Deine täglichen Ermutigungen, Deine Unterstützung und Zuversicht, die leider oft nur aus der Ferne möglich war. Ich freu mich auf unsere gemeinsame Zukunft!

Zu guter letzt möchte ich meiner Familie ein paar Zeilen widmen. Ihr habt mir erst die Möglichkeit gegeben, meinen Weg zu suchen und zu finden. Ihr wart immer unterstützend und ermutigend für mich da, auch wenn ich mal „gestolpert“ bin.

Danke für Eure Liebe und Vertrauen!

Ihr alle habt mich auf Eure ganz persönliche Art und Weise unterstützt, inspiriert und mein Leben bereichert. Ich wünsche auch Euch alles Gute für Euren Weg!

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Abbreviations

AD antidepressant ALDH1A1 aldehyde dehydrogenase-1 Atyp atypical neuroleptics

AS adulthood stress

ACTH adrenocorticotropin hormone

AUCG area under the curve with reference to ground AUCI area under the curve with reference to increment AVP arginine vasopressin

BDI Beck Depression Inventory BNDF brain-derived neurotrophic factor

BPD borderline personality disorder BPRS Brief Psychiatric Rating Scale

COMT catechol-O-methyltransferase CRH/CRF corticotropin-releasing hormone / factor

CRHR1 corticotropin-releasing hormone type 1 receptor

DA drug addiction

DAT1 9-repeat allele of dopamine transporter ECG Electrocardiogram

EEG electroencephalogram ELS early life stress

EOG electrooculogram

ETI Early Trauma Inventory (German version: Inventar zur Erfassung stressreicher Lebenserfahrungen, IFTL)

ERP event-related brain potential

fMRI functional magnetic resonance imaging GAF General Assessment of Functioning GC glucocorticoid

GR glucocorticoid receptor

HPA-axis hypothalamic-pituitary-adrenal-axis IAPS International Affective Picture System

ICD 10 International Classification of Diseases and Related Health Problems 10^th Rev.

MAO monoamine oxidase inhibitors MDD major depressive disorder

MEG magnetoencephalogram Met methionine

MINI Mini-International Neuropsychiatric Interview

MR mineralcorticoid receptor

MRI magnetic resonance imaging N neuroleptics

NA negative affect

Ntyp typical neuroleptics

PA positive affect

PANAS Positive and Negative Affect Scale

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PANSS Positive and Negative Symptom Scale PDS Posttraumatic Stress Diagnostic Scale PET positron emission tomography

PPS prepubertal stress

PSQ Prenatal Stress Questionnaire

PTPRB protein tyrosine phosphatease receptor type beta PTSD posttraumatic stress disorder

ROI region of interest

SAM sympathetic-adrenal-medullary system

SSRI/SNRI selective serotonin reuptake inhibitor / serotonin-norepinephrine reuptake inhibitor

TCA tricyclic antidepressants OPRM1 µ-opioid receptor gene

Val Valine

5-HTTLPR serotonin transporter gene-linked polymorphic region

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Summary

The role of stress in the development and continuation of psychiatric disorders has been addressed in the context of different mental disorders. This dissertation aims at clarifying the effects of adverse experiences in psychiatric patients, which may add to the individual vulnerability for a psychiatric disorder. Drawing on the concept of allostatic load, we aimed to characterize a subgroup of patients through their specific stress-related psychophysiological response profile (symptom severity, altered neuroendocrine measures, and altered functional brain response), independent of the psychiatric diagnosis.

Adult inpatients (n= 102) with diagnoses of major depressive disorder, schizophrenia, borderline personality disorder, and drug addiction were compared to healthy subjects (n= 31) comparable in age and gender distribution to the patient group.

Adverse experiences were determined through interview (ETI and PDS), which retrospectively assessed experiences of emotional neglect, physical abuse, sexual abuse and/or traumatic events in different periods of life (between birth and present age). Stressful experiences of the mother during pregnancy were also a subject of enquiry. Psychiatric patients had experienced more prenatal stress, more adverse experiences in the time period from birth and the individual onset of puberty, and more lifetime traumatic events than healthy controls. Stress load before puberty in all participants was related to emotional, clinical, cortical, and neuroendocrine measures. A subset of patients with high early life stress (ELS) exhibited a characteristic psychophysiological response profile: high ELS was related to affective symptoms and PTSD, severity of disorder, dampened cortical activation by affective stimuli, elevated diurnal salivary cortisol profile and more pronounced salivary cortisol response to the magnetoencephalographic session, in which participants monitored affective pictures. As ELS was not evenly distributed among diagnoses, the assumption that can be drawn is that stress load during sensitive periods of brain development interacts with other environmental and vulnerability factors in its influence on mental illness. Results are discussed on the basis of current literature and a model integrating candidate variables in their impact on development of psychiatric disorders is suggested.

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Zusammenfassung

Der Einfluss von Stresserfahrungen auf die Entwicklung von psychischen Störungen wurde in verschiedenen Diagnosegruppen untersucht. Diese Dissertation hat zum Ziel, den Einfluss von Stress auf die individuelle Vulnerabilität für schwere psychiatrische Störungen störungsübergeifend zu präzisieren. Auf der Grundlage des Konzepts der ‚Allostasis’ und dem damit verbundenen ‚Allostic Load’ soll eine Gruppe von Patienten identifiziert werden, die sich durch ein von Stress verändertes psychophysiologisches Profil auszeichnet (Psychopatholgie, endokrine und elektrokortikale Kennwerte).

Zu diesem Zweck wurden insgesamt 102 psychiatrische Patienten mit depressiver Erkrankung, Schizophrenie, Borderline Persönlichkeit oder Drogenabhängigkeit untersucht sowie 31 gesunde Vergleichsprobanden. Stressvolle Ereignis wurden in einem standardisierten Interview erhoben, in welchem traumatische Erlebnisse, physische Gewalt, emotionale Vernachlässigung und sexueller Missbrauch erfragt wurden. Ebenso wurden, wenn möglich, die Mütter zu pränatalen Belastungen während der Schwangerschaft befragt. Psychiatrische Patienten erlebten im Vergleich zu der Kontrollgruppe mehr Kindheitsstress bis zur Pubertät, mehr traumatischen Erfahrungen sowie höhere pränatale Stressbelastung. Die Erhebung von Stresserfahrungen in unterschiedlichen Lebensphasen ergab Zusammenhänge zwischen der Stressbelastung in der Kindheit und elektrokortikalen, endokrinen und psychopathologischen Kennwerten. So zeigten Patienten mit hoher kindlicher Stressbelastung ein verändertes psychophysiologisches Profil. Sie hatten eine höhere Belastung von affektiven und posttraumatischen Symptomen, zeigten eine Unterdrückung kortikaler Hirnantworten auf emotionale Bilder sowie ein erhöhtes Speicheltageskortisolprofil und verstärkte Kortisolantwort auf die leicht stressige Untersuchung der kortikalen Hirnaktivität. Eine unerwartete ungleiche Verteilung der Stressbelastung zwischen den diagnostischen Gruppen und entsprechende diagnosespezifische Zusammenhänge zwischen den Kennwerten allostatischer Belastung legt jedoch die Annahme komplexer Wechselwirkungen zwischen frühem Stress und anderen Vulnerabilitätsfaktoren in ihrer Wirkung auf Ausbruch und Verlauf psychischer Störungen nahe. Ausgehend von neueren Studien zur Interaktion von Vulnerabilitätsfaktoren und den Ergebnissen dieser Untersuchung wird ein Wechselwirkungsmodell vorgeschlagen. Die Ergebnisse werden diskutiert.

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Introduction

1 Introduction

Epidemiological and clinical studies have shown that adverse events, especially those experienced early in life, are associated with an increased risk for the development of severe mental disorders. Similar biological alterations have been found in most psychiatric disorders like diverse changes in neuroanatomy, neurofunctioning, and neurochemistry, as well as changes in the neuroendocrine, autonomic, and immunological systems, which altogether have been labeled as

“neural substrate reactivity” (Caspi & Moffit, 2006). Until now, the striking heterogeneity of symptomatology and psychopathology in most of the major mental disorders challenged etiological models, diagnostics, and treatment. A genetic contribution to mental disorders of an estimated 40-50% indicates that their psychopathology cannot be reduced to genetic basis alone. Even though current and past life experiences clearly contribute to the development of psychiatric disorders, it is not yet understood how environmental factors influence genetic expression.

This thesis focuses on the modulating effects of early life stress (ELS) in the development of mental disorders. Based on the assumption that ELS functions as a general non-specific environmental pathogen across mental disorders according to International Classification of Diseases (ICD) criteria (i.e. schizophrenia, major depressive disorder (MDD), drug addiction (DA), and borderline personality disorder (BPD)), the present project aims to explore whether a psychophysiological profile related to high stress during sensitive periods in brain development would add to the understanding of the development of mental disorders. A description of a stress- related vulnerability across traditional diagnostic categories should prospectively advance our understanding of psychopathology and offer strategies for treatment.

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Introduction

1.1 Stress = Allostatic Load

‘Stress’ encompasses a range of concepts in the fields of medicine and psychology. For example, biological or physiological definitions of stress refer to the non-specific response of the body to factors that threaten homeostasis, while current psychological concepts of stress refer to a process of stimulus appraisal and evaluation, including a coping response (Lazarus & Folkman, 1984). Thus, the ability to adjust or habituate to repeated stressors is also determined by the way one perceives a situation (McEwen, 1998). In this thesis, stress is defined as a response to external events, which causes the individual to experience distress or anxiety.

The most common approach to assessing the experience of stress by individuals is the ‘life event’ method, in which the number of stressful experiences or events during a defined time window is counted. This approach assumes that intensity of distress correlates with the number of stressful experiences.

The physiological response to acute stress exposure involves an adaptive process referred to as allostasis (Sterling & Eyer, 1988), in which bodily responses meet perceived and anticipated demands of the situation. Allostatis, meaning

“achieving stability through change”, helps the body to maintain homeostasis when confronted with stressors (McEwen, 1998; McEwen, 2002). Thus, physiological responses to life-threatening situations are quite adaptive in the short term.

Whenever major stressors persist (e.g., combat or repeated sexual abuse) or a persons fails to adapt to minor stressors (e.g., public speaking) appropriately, homeostatic recovery capacities are exhausted, leading to deleterious effects on psychological and physiological functioning. This is called “allostatic load”. In allostatic load, the mediators produced by the immune, autonomic nervous, and hypothalamic-pituitary-adrenal (HPA) systems remain active, wearing and tearing away the body and brain (Bremner, 1999; overview Elbert & Rockstroh, 2003;

McEwen, 1998). The concept of allostasis and allostatic load link the protective and survival features of the acute stress response to a stressor to adverse consequences that result if the initial response endures (McEwen, 1998; McEwen & Stellar, 1993).

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Introduction

1.2 Stress Affects Endocrine and Brain Development

When confronted with a stressor, the brain coordinates a physiological response involving the autonomic, neuroendocrine, metabolic, and immune systems (Lupien, McEwen, Gunnar, & Heim, 2009). Besides the sympathetic-adrenal- medullary (SAM) system which mediates the rapid phases of flight or fight responses to threat, the HPA-axis system, which is a key system, moderates the physiological response to psychological and physiological stressors in mammals and functions as a supervisor in order to maintain homeostasis (O’Brian, 1997; Sapolsky, Romero, &

Munck, 2000; see Figure 1). Neural signals associated with a stressor are transduced into an endocrine response at the level of the hypothalamus. There, nerve terminals in the median eminence in the hypothalamus, the paraventricular nucleus, a complex integration center that receives and coordinates neuroendocrine, autonomic, cognitive, and emotional input, is responsible for initiating glucocorticoid secretion (see review Lopez, Akil, & Watson, 1999). The physiological stress response is primarily mediated by the release of hypothalamic corticotropin-releasing factor (CRF), also known as corticotropin-releasing hormone (CRH), and to a lesser extent by arginine vasopressin. Both are secreted into the hypophyseal portal system where they reach the anterior pituitary gland and synergistically stimulate the release of adrenocorticotropin hormone (ACTH). ACTH is transported via the bloodstream to the adrenal cortex where it stimulates the release of glucocorticoids (GC).

Additionally, the adrenal medulla releases catecholamines (adrenalin and noradrenalin). The release of GCs is ultimately inhibited through a negative feedback mechanism in order to shut down the HPA-axis and return to homeostasis once the perceived threat has subsided.

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Introduction

Stress

-

Figure 1. Schematic illustration of the HPA-axis. ACTH: adrenocorticotropin hormone; AVP: arginine vasopressin; CRF: corticotropin releasing hormone; GR:

glucocorticoid receptors; MR: mineralcorticoid receptors; - negative feedback.

The GC cortisol is a key mediator of the physiological stress response and impacts on many physiological systems to allow the body to react to a stressor.

Cortisol release is linked with stress exposure throughout life (Kirschbaum &

Hellhammer, 1989) and affects the whole body. GC receptors are found in various areas of the brain (e.g., hippocampus and medial prefrontal cortex) that are responsible for feedback regulation of the HPA-axis (Corcoran, et al., 2003). Acute time-limited rise in cortisol levels are adaptive, but long-term elevation may have negative effects on the central nervous system, and has been associated with ventricular dilation, cerebral atrophy, cognitive impairment (O’Brian, 1997), and possibly neurotoxicity (Sapolsky, et al., 2000). Prolonged heightened cortisol levels are known to damage the hippocampus, thereby reducing negative feedback further.

This vicious cycle is often referred to as the ‘glucocorticoid cascade’ (Sapolsky, Krey,

& McEwen, 1985). In response to repeated stress, pathophysiological changes also occur in the autonomic nervous system, metabolic hormones, and inflammatory

- -

-

Anterior pituitary

Adrenal cortex

MR GR

AVP CRH

ACTH

Cortisol

Hypothalamus Hippocampus/

prefrontal cortex

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Introduction cytokines. These systems and factors are affected by the HPA-axis and, in turn, affect HPA function (Lupien, McEwen, Gunnar, & Heim, 2009).

To summarize, stress-induced hyperactivity of the stress system induces, by way o

ness of stress systems have been related to a w

f combined effects of CRF and GCs, plastic changes in the amygdala, the hippocampus, and the mesocorticolimbic dopaminergic system (Charmandari, Kino, Souvatzoglou, & Chrousos, 2003; Kaufman, Plotsky, Nemeroff, & Charney, 2000;

McEwen, 1999). This might account for altered brain development, neuropsychological deficits, increased levels of psychiatric symptoms, and subjective distress found in maltreated children and adolescents (De Bellis, et al., 1999; De Bellis, et al., 1994). Charney (2004) and the group of Yehuda (2006) employed the model of allostatic load to describe the biological reaction of people exposed to traumata. They tried to understand why some people develop posttraumatic stress disorder (PTSD) while others are resilient (Charney, 2004; Yehuda, Flory, Southwick,

& Charney, 2006) and found that chronic stress, which results in long term elevations of cortisol in the bloodstream, weakens the immune system and sensitizes or even induces depression, and other psychiatric disorders. On this basis it is understandable how, for instance, the normal adolescence-associated increase in the HPA-axis responsivity together with a concomitant increase of stress experience (and thus, stress-induced activation of the HPA-axis) may result in a positive feedback loop, triggering onset or exacerbation of psychopathology (Thompson, Pogue-Geile, & Grace, 2004), depending on an individual’s vulnerability to develop a mental disorder (e.g., genetic disposition).

In general, inappropriate responsive

ide variety of impairments including psychiatric conditions. Their development and severity depends on the specific type of exposure to adverse environmental factors, as well as timing-duration, and developmental stage.

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Introduction

1.3 Early Life Stress and Mental Disorder

Historically, two models had been proposed to understand the heterogeneity of symptomatology in major mental disorders. The first approach assumed that individuals who develop a psychiatric disorder differ premorbidly from those who do not develop a disorder (Adler & Hillhouse, 1996). The second approach suggested stress as a crucial factor in the development of psychological problems (Kendler, Karkowski, & Prescott, 1999). Meanwhile the widely held view is that a complex interaction of genetics, ELS, and ongoing stress may ultimately determine the individual’s vulnerability to severe psychiatric disorders (Charney, 2004; Mueser, Rosenberg, Goodman, & Trumbetta, 2002; Norman & Malla, 1993; Read, Agar, Barker-Collo, Davies, & Moskowitz, 2001; Yank, Bentley, & Hargrove, 1993). The gene-environment approach (Caspi & Moffit, 2006; Caspi, et al., 2003) endeavors to disentangle this interaction and considers psychobiological vulnerability as a function of genetic and neurodevelopment pathology of brain systems potentially modulated by ELS. This interaction may be related to mental illness, for instance through maladaptive brain organization. Cumulative evidence in humans and animals has shown that many systems, including nervous, immune, and metabolic systems, undergo complex developmental processes that can potentially be influenced by environmental pathogens such as ELS (Lupien, McEwen, Gunnar, & Heim, 2009;

Rhind, Rae, & Brooks, 2003). Graham et al. (Graham, Heim, Goodman, Miller, &

Nemeroff, 1999), assume that early adverse events result in an increased sensitivity to stress events later in life and thus render an individual vulnerable to stress-related psychiatric disorders. They also hypothesize that the vulnerability is mediated by persistent changes in CRF-containing neurons, the HPA-axis, and the sympathetic nervous system. In other words, stress experiences encountered early in life are linked to long-term programming of behavior, responsiveness to stress, and health status later in life thus, comprising one major risk factor for subsequent onset of severe mental illness (Saleptsi, et al., 2004).

This thesis addresses the role of early life stress as a major factor contributing to the development of severe mental disorders. The concept of allostatic load provides an approach understanding how stress in sensitive periods of brain development influences the genesis of mental disorders. In addition to genetic vulnerability for mental disorders, the impact of adverse life events, especially ELS, in

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Introduction the pathogenesis of psychiatric disorders has been investigated by various diagnostic groups and integrated into psychopathological and pathogenetic models (e.g., in MDD: Heim, Owens, Plotsky, & Nemeroff, 1997; Heim, Plotsky, & Nemeroff, 2004; in PTSD: Scheller-Gilkey, Moynes, Cooper, Kant, & Miller, 2004; van der Kolk, Roth, Pelcovitz, Sunday, & Spinazzola, 2005; in schizophrenia: Corcoran, et al., 2003;

Thompson, Pogue-Geile, & Grace, 2004; in BPD: Goodman, New, & Siever, 2004; in DA: De Bellis, 2002; Reed, Anthony, & Breslau, 2007). So far, environmental risk factors have been specified for distinct diagnoses. In this thesis, the question of whether ELS can be considered as a cross-diagnostic pathogen is addressed. To test the moderating impact of ELS influences across diagnostic groups, a psychophysiological profile will be measured on three levels: symptom severity, cortical affective processing assessed through the magnetoencephalogram (MEG) in an attention capture picture viewing task, as well as diurnal salivary cortisol and reactive salivary cortisol in response to a mildly stressful picture viewing task as markers of HPA-axis functioning.

1.3.1 What is Early Life Stress?

Heim et al. (2004) classified ELS in humans as adverse experiences occurring before the onset of sexual maturation. Thereby they found that ELS often occurs as ongoing adversity and that typically various forms of ELS accumulate (Heim, Meinlschmidt, & Nemeroff, 2003). Furthermore, the effects of stress experiences during different periods in life interact with each other (Lupien, McEwen, Gunnar, &

Heim, 2009). Stress events can range from accidents, surgeries, chronic illnesses, natural disasters, war terrorism-related events to less tangible experiences such as unstable families, inadequate parenting, dysfunctional dynamics between a parent and their child, and poverty. The most salient forms are sexual, physical, and emotional maltreatment, as well as parental loss (Heim, Plotsky, & Nemeroff, 2004).

Dickerson and Kemeny (2004) specified that stress responses occur when motivated performance tasks are uncontrollable or characterized by social-evaluative threat. In this study we employ ELS within this above described definition.

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Introduction 1.3.2 Pre- and Postnatal Influences

Very early in life, at least two mechanisms between maternal stress and an offspring’s abnormal psychological well-being and behavior are conceivable. Firstly, prenatal stress of the mother has an impact on fetal brain development and thus, on infant behavior and emotion regulation. Investigations in rodents and humans have shown that excessively high or low levels of stress hormones (e.g., GCs) are detrimental to the development of brain structures like the hippocampus (Buitelaar, Huizink, Mulder, de Medina, & Visser, 2003; Oberlander, et al., 2008; Sapolsky &

Meaney, 1986). Several epidemiologic studies have demonstrated that adverse prenatal events including loss of the father (Huttunen & Niskanen, 1978), infection with influenza (Mednick, Machon, Huttunen, & Bonett, 1988), natural (Selten, van der Graaf, van Duursen, Gispen-de Wied, & Kahn, 1999) or man-made disasters (Yaktin

& Labban, 1992) increase the long-term likelihood that the offspring will develop a psychiatric illness (Weinstock, 2001). These adverse events possibly exert their influence by their increased HPA neuroendocrine activity (Hauser, Feldon, & Pryce, 2006; Lupien, McEwen, Gunnar, & Heim, 2009). Fetal GC exposure is an important factor in prenatal programming (De Kloet, Vreugdenhil, Oitzl, & Joels, 1998; Lupien, et al., 2009; Meyer, et al., 2006; Oberlander, et al., 2008; Owen, Andrews, &

Matthews, 2005). Prenatal glucocorticoid exposure affects the developing dopaminergic system, which is involved in reward processes, such as drug-seeking behavior (Piazza & Le Moal, 1996). Trautman et al. (1995) found that overexposure to glucocorticoids in utero and prenatal stress also increases the expression of fear behavior in adult rats, and in humans chronic gestational glucocorticoid treatment is associated with increased shyness and timidity in infancy. Thus, maternal environment can exert long-term effects on offspring development. The hippocampal complex influenced by GC during maternal pregnancy is known to be involved in the regulation of functions that are the biological basis for individual temperament characteristics. Buitelaar, et al. (2003) showed in a prospective study in humans that increased maternal stress was one of the determinants for temperamental variation and delay of development in infants and thus, a general risk factor for developing psychopathology later in life. The research group led by Ehlert (Emini, Erni, & Ehlert, 2009; Erni, Emini, & Ehlert, 2009) adds to this evidence, and found that coping and psychosocial deficits, as well as reduced health and life quality in 10 year old children who were exposed to prenatal stress.

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Introduction A second mechanism of prenatal influences might be that stress experienced by the mother persists into the postpartum period and compromises maternal behavior in mother-infant interaction. According to Papousek (2000), the infant’s self- regulatory competencies develop within the context of the parents’ intuitive co- regulatory support. This parental support compensates for the infant’s initial maturational constraints in regulating affective arousal, self-soothing, and transition to sleep. An array of factors, including postnatal emotional distress, might interfere with the intuitive parental competence. Wurmser, et al. (2006) found in a prospective study that the infants of mothers who experienced persisting adverse life changes (i.e. family roles, financial situation, interpersonal roles, working conditions, lifestyle, physical integrity, minor law conflicts) exhibited more crying and fussing in the first half year after birth. Early infancy appears to be an especially critical period as a process of negative mother-infant reciprocities may interfere with the developing parent-infant relationship (see also Hogdall, Vestermark, Birch, Plenov, & Toftager- Larsen, 1991; Rautava, Helenius, & Lehtonen, 1993). This assumption is fostered by Becker, et al. (2007), who upon applying neonatal separation stress found a wide range of altered responses in newborn rodents (e.g., lower levels of CRF-positive fibers in the central amygdala, higher numbers of CRF-immunoreactive neurons in the basolateral amygdaloid complex, and elevated exploratory behavior). Severe and early stressors such as abnormal postnatal mother-infant manipulations in animals (Pryce, et al., 2005) or early physical, emotional, and sexual maltreatment in humans (Heim, Plotsky, & Nemeroff, 2004) were for instance established as factors contributing to the pathophysiology of depression and constituting a major risk factor for MDD in adulthood. Kaufman, et al. (2000) assume that effects of neonatal adverse experiences, which alter the development of the HPA-axis and other stress involved systems, promote structural and functional alterations in brain regions.

Altogether, it has been found that stressful experiences during prenatal and early postnatal brain development interfere with the development of CRF-containing neurons, particularly in brain regions essential for emotion regulation (Becker, Abraham, Kindler, Helmeke, & Braun, 2007). These very early adverse life events might render the human individual vulnerable to the effects of stress later in life, resulting in an increased risk for developing psychopathology via long-lived alterations in CRF-containing neural circuits and hyperactivity in CRF systems as well as alterations in other neurotransmitter systems, resulting in increased stress

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Introduction responsiveness (Heim, Newport, Bonsall, Miller, & Nemeroff, 2001; Heim, Owens, Plotsky, & Nemeroff, 1997a). Clinical studies support that exposure to ELS is associated with neurobiological changes in children and adults, which may underlie the increased risk of psychopathology. Again, stress-related enhancement of CRF secretion during ‘sensitive periods’ of brain plasticity in childhood and adolescence (Paus, 2005; Steinberg, 2005; Thompson, Pogue-Geile, & Grace, 2004) can prompt hippocampal volume loss, sensitization, and altered feedback properties of the HPA axis, which in turn promote endocrine hyperresponsivity to subsequent social stress.

In the following section specific alteration caused by ELS will be outlined for diagnostic subgroups.

1.3.3 ELS in Diagnostic Groups

Major Depressive Disorders (MDD): MDD have consistently been described as intimately related to stress experience and stress responding. In human and animal studies (see reviews Heim, Plotsky, & Nemeroff, 2004; Pryce, et al., 2005; van Praag, de Kloet, & van Os, 2004) the nature and magnitude of harmful stress and their relationship to sensitive developmental periods and neurobiological mediators of stress effects in MDD have been disclosed. Evidence that ELS increases the risk for depression arises from a variety of studies. For example, a significantly high rate of ELS was found in MDD (McCauley, et al., 1997) and conversely, a significantly elevated risk for MDD, which was correlated with symptom severity, was shown in individuals who suffered ELS (Mullen, Martin, Anderson, Romans, & Herbison, 1996).

Childhood abuse has been shown to be connected to earlier onset and chronic course of depression (Heim & Nemeroff, 2001; Heim, et al., 2004) and parental loss to be associated with increased risk for MDD (Agid, et al., 1999). Kendler, et al.

(1992, 1993, 2002) affirmed the above findings in studies of twins. Several factors are discussed which influence the development of depression after ELS experiences.

Genetic variations are reported to moderate ELS experiences (Caspi, et al., 2003) and mediating influences are found by the extent to which ELS results in family disruption or dysfunction (Agid, Kohn, & Lerer, 2000). Weiss, et al. (1999) suggested sex as one moderating variable, finding that men are less likely to develop depression after ELS. Furthermore, depression in adulthood is often found to be exacerbated by ongoing stress (Kendler, et al., 1992; Heim, et al., 2004), but equally

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Introduction as often are other coexisting psycho- and physiopathological states which are aggravated by current adverse experiences (see review Agid, et al., 2000; Heim &

Nemeroff, 2001) indicating that ELS sensitizes for subsequent stress (Heim, et al., 2004). To recapitulate, Heim et al. (1997, 2001) proposed a model that early adverse life events render the human individual vulnerable to the effects of stress later in life, resulting in an increased risk for developing psychopathology via long-lived alterations in CRF-containing neural circuits and hyperactivity in CRF systems as well as alterations in other neurotransmitter systems. This in turn increases stress responsiveness. Charmandari et al. (2003) pointed out that in particular, chronic dysphoric mood, HPA-alteration, as well as immunosuppression in MDD are possible consequences of ELS.

Clinical studies suggested that exposure to ELS is associated with neurobiological changes in children and adults, which may underlie the increased risk of psychopathology. During critical periods, i.e. periods with substantial plasticity of the developing central nervous system, ELS may lead to major, even irreversible damage in certain brain regions (Weiss & Wagner, 1998). Gratton and Sallivan (2005) assumed that stress hormones affecting the prefrontal cortex are responsible for functional abnormalities and altered hemispheric asymmetries. These alterations include limbic and cortical structures related to emotional and motivational processing (e.g., prefrontal cortex, amygdala, anterior cingulate cortex, and hippocampus). Magnetic resonance imaging (MRI) studies reported decreased hippocampal volumes in adults with various types of ELS (Bremner, et al., 1997;

Stein, Koverola, Hanna, Torchia, & McClarty, 1997; Vythilingam, et al., 2002). Since hippocampal volume loss is not observed in abused young children or young adults (Teicher, Andersen, Polcari, Anderson, & Navalta, 2002), it has been suggested that repeated bursts of cortisol secretion over the course of time may eventually lead to progressive hippocampal volume loss (Brunson, Eghbal-Ahmadi, Bender, Chen, &

Baram, 2001). Research regarding this type of increase in CGs has been reported in women currently suffering from depression, who had been abused as children. These women showed greater cortisol and heart rate responses than controls in laboratory stress tests (Heim, et al., 2000). Abused women have also been found to hypersecrete CRF upon further stress exposure, resulting in depression and pituitary CRF receptor downregulation (Heim & Nemeroff, 2001). Similar sensitization has been shown for adults with early parental loss (Luecken, 1998). Moreover altered

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Introduction norepinephrine and serotonin function has been detected in relation to the experience of ELS (Heim & Nemeroff, 2001).

Aside from structural alterations, positron emission tomography (PET) studies revealed functional changes of frontal cortical regions during mental imagery in abused women with PTSD versus abused women without PTSD (Bremner, et al., 1999; Shin, et al., 1999). This may also be an indicator of an association between ELS and long-term neurobiological changes in humans and an enhanced risk for psychopathology, including depression. Studies about affective processing have shown that depressed states are characterized by under-responsiveness to pleasant stimuli and over-responsiveness to negative stimuli, especially negative social scenes. Gollan, et al. (2008) found that current depression had significant effects on the intensity perception of negative affective stimuli, on the speed of processing sad affective information (which is delayed), and biases towards interpreting neutral faces as unhappy. Fales, et al. (2008) reported that MDD patients show an enhanced amygdala response to unattended fear-related stimuli relative to unattended neutral ones. Lee, et al. (2007) found on the contrary in a functional magnetic resonance imaging (fMRI) study reduced hippocampus and insula activity to unpleasant and reduced ACC and amygdala activity to pleasant pictures (Lee, et al., 2007). Moratti, et al. (2008) reported an overall weak arousal modulation in right temporal regions for pictures. Altogether, a mood-congruent processing bias is found in depression in that ambiguous or positive events tend to be perceived as negative.

Depression has been found to be moderated by genetic background. One common polymorphism is the length variation of the serotonin transporter (5-HTT) gene (Lesch, et al., 1996). Caspi, et al. (2003) found that the serotonin transporter gene-linked polymorphic region (5-HTTLPR) confers a predisposition to depression in association with life stresses, even though it is not selective to depression (Lesch, Greenberg, Higley, Bennet, & Murphy, 2002). It affects the promoter of the serotonin- transporter gene, reducing uptake of the neurotransmitter serotonin into the presynaptic cell in the brain (Lesch, et al., 1996). However, a recent meta-analysis yielded no evidence for an influencing effect of the 5-HTTLPR polymorphism in depression neither alone nor in interaction with adverse life experiences (Risch, et al., 2009). Another genetic modulation of the stress-related vulnerable of MDD is suggested by an atypical corticosteroid receptor that mediates enhanced CRF release (Muller & Wurst, 2004). Thereby, ELS interacts with polymorphisms (any of

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Introduction 15 single nucleotide polymorphisms) on the corticotropin-releasing hormone type 1 receptor (CRHR1) gene to modulate risk for the development of depression in adulthood (Bradley, et al., 2008). These polymorphisms, particularly a haplotype formed by 3 SNPs located in intron 1 of the CRHR1 gene, help protect against the development of depression in adults with a history of child abuse (Bradley, et al., 2008). A third polymorphism influenced in MDD has so far been detected in a single- nucleotide of the human brain-derived neurotrophic factor (BDNF) gene, a methionine (Met) substitution for valine (Val) at codon 66 (Val66Met), which is associated with alterations in brain anatomy and memory (Chen, Bath, McEwen, Hempstead, & Lee, 2008). It has been shown that decreases in hippocampal BDNF levels are correlated with stress-induced depressive behavior (Duman & Monteggia, 2006). Moreover, the BDNF gene as well as the Val66Met polymorphism have been associated with an increased risk of depression (Schumacher, et al., 2005; Strauss, et al., 2005).

In summary, studies on the influence of ELS on brain and neuroendocrine abnormalities in depression have defined a subset of patients, who show elevated stress hormones and a distorted diurnal rhythm of cortisol (McEwen, 2003), adrenal hypertrophy and hypersensitivity (Heim, et al., 1997), altered cortisol-serotonine regulation (Tafet & Smalovich, 2004), amygdala overactivity and reduced hippocampal volumes (Heim, et al., 2004; McEwen, 2003; Tafet & Smalovich, 2004;

Pryce, et al., 2005), as well as dysfunctional limbic-prefrontal interaction (Mayberg, 2003). The individual stress history (Tafet & Smolovich, 2004) is believed to account for individual variation of symptom severity, for increased cortisol secretion confronted with stress, as well as for the correlation of depressive episode frequency and cortisol responsivity (Sher, et al., 2005). Additionally, in MDD patients with a history of ELS it has been shown that psychotherapy is superior to antidepressant therapy (Nemeroff, et al., 2003).

Schizophrenia: Apart from prenatal and birth influences, ELS in schizophrenia has been underappreciated for a long time. A pronounced impact of stress has been shown for prenatal maternal stress, pre/perinatal complications, and infections (Doering, et al., 1998; Meyer, et al., 2006). There is now evidence linking ELS to schizophrenia (Maynard, Sikich, Lieberman, & LaMantia, 2001; Meyer, Taiminen, Vuori, Aijala, & Helenius, 1999; Read, van Os, Morrison, & Ross, 2005; Scheller-

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Introduction Gilkey, Moynes, Cooper, Kant, & Miller, 2004; Thompson, Pogue-Geile, & Grace, 2004). Schizophrenic patients who are victims of child abuse have been found to show higher positive, disorganized, and overall symptom severity, as well as a more severe course of illness including comorbid substance abuse and depression (Agid, Kohn, & Lerer, 2000; Lysaker, Meyer, Evans, Clements, & Marks, 2001; Scheller- Gilkey, Thomas, Woolwine, & Miller, 2002). For the time period from birth to adolescence (Read, et al. 2005) found a strong relation and dose-effect between symptoms indicative of psychosis, such as hallucinations, childhood abuse and neglect. Similar results have been described by Ucok and Bilmaz (2007) assessing childhood experiences and symptom scores in first-episode schizophrenia. Traumata and comorbid PTSD are frequent in first-break or newly admitted patients (Neria, Bromet, Sievers, Lavelle, & Fochtmann, 2002; Shaw, McFarlane, & Bookless, 1997) and a history of trauma may affect the course and symptom presentation of schizophrenia (see review Lysaker, Buck, & LaRocco, 2007). Additionally, ELS in schizophrenia has been linked to an earlier first admission, longer and more frequent hospitalization, longer seclusion time, the need for more medication, and a higher tendency to self-mutilate and attempt to commit suicide (Goff, Brotman, Kindlon, Waites, & Amico, 1991; Lysaker, et al., 2007; Read, 1998; Read, et al., 2005). Early stress and traumatic experiences in childhood are thought to increase or even induce vulnerability for schizophrenia, thereby predisposing for this disease (Maynard, Sikich, Lieberman, & LaMantia, 2001; Meyer, et al., 1999; Read, et al., 2005). In turn, schizophrenic symptoms increase the likelihood of stress exposure (Mueser, Rosenberg, Goodman, & Trumbetta, 2002; Read & Ross, 2003) like hospitalization, unemployment, or early onset of drug use/abuse (Doering, et al., 1998). Independent undesirable life events (including workload or interpersonal stress addressed in the expressed emotions concept) have been found to predict relapse or exacerbation (Lewine, 2005). Stress responsivity to everyday stressors is enhanced as well (Corcoran, et al., 2003).

Since the diatheses-stress model of Walker and Diforio (1997) has become established in schizophrenia, it is out of question that the HPA axis is somehow involved in the development of psychotic disorders, even though the mechanisms are not fully understood (Corcoran, et al., 2003; Phillips, et al., 2006). Neuroendocrine pathways, through which stress and particularly cortisol secretion are mediated by the HPA-axis, influences dopamine transmission (Walker & Diforio, 1997). Thus,

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Introduction further stress exposure may trigger or exacerbate psychotic symptoms by augmenting dopamine activity, particularly in the subcortical region of the limbic circuits (Corcoran, et al., 2003; Jones & Fernyhough, 2007). Nevertheless, results of studies evaluating HPA-axis functioning in schizophrenia have been varied (see review Phillips, et al., 2006). Hyperactivity of the HPA-axis has been demonstrated via higher baseline cortisol levels in patients; increased cortisol being associated with symptom severity in the majority of studies (Jones, et al., 2007; McEwen, 2004;

Shirayama, Hashimoto, Suzuki, & Higuchi, 2002; Walker, et al., 2001; Walker &

Diforio, 1997) and a heightened sensitivity to stress (Tse, 1999) causing an early onset (Phillips, et al., 2006). Other studies (e.g., Jansen, Gispen-de Wied, & Kahn, 2000) found a blunted salivary cortisol response or no elevation of basal cortisol levels, respectively. Mediating factors could be the heterogeneous nature of psychotic disorders e.g., individuals experiencing a comorbid depression (e.g., Belanoff, Kalehzan, Sund, Fleming Ficek, & Schatzberg, 2001; Yehuda, Boisoneau, Mason, & Giller, 1993) or high levels of negative symptoms (e.g., Coppen, et al., 1983; Newcomer, Faustman, Whiteford, Moses, & Csernansky, 1991). Duration of illness may also be important in determination of HPA-axis dysfunction as, for example, duration of psychotic symptoms has been negatively correlated with cortisol levels (Mazure, Quinlan, & Bowers, 1997), while hyperactivity of the HPA-axis has been reported more consistently in patients experiencing their first psychotic episode or being newly hospitalized as opposed to chronically ill patients (Pariante, et al., 2004). That high cortisol levels in first episode patients are not a product of experiencing psychosis has been evidenced by Walker and Diforio (1997), who found higher cortisol levels immediately before a psychotic episode rather than during recovery. Treatment with neuroleptic medication has been found to reduce cortisol levels (Wik, 1995) and treatment with antidepressants, which can upregulate GR in the brain, also have been proven to decrease stress-induced GC secretion thereby enhancing HPA-axis feedback (see review Pariante & Miller, 2001).

Reduced hippocampal and adrenal volume, reduced hippocampal cell size, as well as reduced hippocampal glucocorticoid receptor numbers have been found in schizophrenia patients, which may be a result of frequent HPA-axis hyperactivity and thus, results are consistent with findings of blunted cortisol response to stressors in chronic patients (Jones & Fernyhough, 2007; Thompson, et al., 2007). It remains unclear whether ELS does damage the hippocampus in early years or whether

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Introduction changes in medial temporal lobes and the hippocampus occur close to the onset of the first full psychotic episode (Pantelis, et al., 2003). Structural and functional abnormalities in limbic and prefrontal structures described in animal (e.g., Daenen, Wolterink, Gerrits, & Van Ree, 2002; Lipska, Khaing, Weickert, & Weinberger, 2001) and human studies (e.g., Kawasaki, et al., 2004; Shenton, Dickey, Frumin, &

McCarley, 2001) suggest that these abnormalities precede the onset of psychoses and vary with schizophrenic pathology (Goldman & Mitchell, 2004; Northoff, et al., 2004).

The aforementioned structural alterations are associated with affect regulation.

Thus, negative symptoms in schizophrenia, such as anhedonia and a lack of responsiveness to social reinforcers (Silversetin & Wilkniss, 2004), point to alterations in the processing of affective material with potential impact on behavioral performance. Altered affective modulation, including reduced differentiation of affective valence, has been observed in schizophrenia patients. Neuroimaging studies indicate reduced limbic and paralimbic activation by facial expressions or other emotionally salient visual stimuli (e.g., Gur, et al., 2002; Paradiso, et al., 2003;

Schneider, et al., 1998; Taylor, Phan, Britton, & Liberzon, 2005), which complements findings of smaller event-related potential (ERP) components to emotional facial expressions (e.g., An, et al., 2003; Horley, et al., 2001; Streit, Wolwer, Brinkmeyer, Ihl, & Gaebel, 2001). Event-related magnetic responses in schizophrenia have been found to hardly vary as a function of affective valence 200 ms after stimulus onset, in contrast to the expected quadratic trend (larger responses to unpleasant and pleasant compared to neutral stimuli) found in PTSD and controls. Automatic pre- attentive processing of emotionally potent stimuli seems to be deficient and has further been shown as being less differentiated in schizophrenia but not in controls (Rockstroh, et al., 2006) in left posterior regions to affective versus neutral stimuli 90- 300 ms after picture onset applying a 3 Hz rapid serial visual presentation (RSVP) design (Junghöfer, et al., 2001, 2003). Altogether, schizophrenia patients primarily show suppressed activation in response to affective salient stimuli and reduced modulation of brain activity as a function of stimulus valence (see review Rockstroh, Junghofer, Elbert, Buodo, & Miller, 2006). Additionally, less arousal by slides depicting images that were regarded as unpleasant is reported by schizophrenia in contrast to PTSD patients, as well as lower heart rate acceleration to unpleasant

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Introduction pictures and reduced startle blink amplitudes in a 6 sec paradigm ERP design are shown (Keil, et al., 2002).

Abnormalities of prefrontal cortical function have been associated with genetic risk, suggesting that susceptibility genes for schizophrenia may impact on the molecular mechanisms of prefrontal function. Consistent with other evidence that dopamine enhances prefrontal neuronal function, the catechol-O-methyltransferase (COMT) Val108/158Met polymorphism has been related to prefrontal dopamine catabolism impairing prefrontal cognition and physiology, thereby slightly increasing the risk for schizophrenia (Egan, et al., 2001). Other studies contradict this and have found that this polymorphism is neither related to age of onset or levels of clinical symptoms after long-term antipsychotic treatment (Numata, et al., 2007), nor to any working memory/executive function measures (Ho, Wassink, O'Leary, Sheffield, &

Andreasen, 2005). The polymorphism BDNF gene Val66Met has been related to the onset age of schizophrenia and levels of clinical symptoms that remain after long- term antipsychotic treatment, but not to clinical symptoms (Numata, et al., 2006).

Distinguishing subtypes of schizophrenia with positive symptoms associated with hyperresponsitivity to stress albeit with adequate neuropsychological functioning, and negative symptoms associated with poor neuropsychological functioning but with normal response to stress, cognitive impairment seems to modulate stress sensitivity (Myin-Germeys, Krabbendam, Jolles, Delespaul, & van Os, 2002). The perceived stress and the intensity with which the individual reacts to stressors may be more predictive of the course of schizophrenic pathology than the objective amount and type of experienced stress (Lewine, 2005). The degree of HPA-system dysfunction in schizophrenic patients seems to be of a lesser magnitude than in patients with affective disorders (Lammers, et al., 1995). Nevertheless, similar effects and consequences of stress are described for schizophrenia and MDD, even though diagnostic categories differ, in that the impact of ELS has been less consistently reported for schizophrenia than for MDD. As Dohrenwend, et al. (1992) has argued, social factors are a larger contributor in depression and personality disorders than in schizophrenia.

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Introduction Borderline Personality Disorder (BPD): Causal factors for BPD are only partly known, but adverse events during childhood and genetic factors are believed to contribute to the development of the disorder (Goodman, New, & Siever, 2004; Lieb, Zanarini, Schmahl, Linehan, & Bohus, 2004; van der Kolk, Hostetler, Herron, &

Fisler, 1994). ELS, especially sexual and physical abuse, as well as childhood neglect are frequently reported (Golier, et al., 2003; Herman, Perry, & van der Kolk, 1989; Zanarini, Gunderson, Marino, Schwartz, & Frankenburg, 1989) and related to borderline symptomatic severity (affect, cognition, impulsivity, and disturbed interpersonal relationships) as well as to psychosocial impairment (Bryer, Nelson, Miller, & Krol, 1987; Zanarini, et al., 2002). The majority of abused BPD patients has been severely abused e.g., with physical violence or in the case of sexual abuse on at least a weekly basis, for a minimum of one year by a parent or a person well acquainted to the patient, and by two or more perpetrators (Zanarini, et al., 2002).

Furthermore, BPD patients frequently report witnessing serious domestic violence (Herman, et al., 1989) and early family disruption (Shearer, Peters, Quaytman, &

Ogden, 1990). Craine, et al. (1988) found in one study that 66% of BPD patients met the diagnostic criteria for PTSD although none had received that diagnosis.

Childhood trauma has been found to be a predictor of dissociative symptoms in BPD (Brodsky, Cloitre, & Dulit, 1995). The severity of abuse experiences seems to play a crucial role in developing BPD as abuse histories are less common in patients with borderline traits and least common in subjects with no borderline diagnosis (Herman, et al., 1989).

The HPA-axis is widely implicated in BPD. Rinne, et al. (2002) reported hyperresponsiveness of the HPA-axis in BPD with a history of ELS. Upon comparison to healthy controls, BPD patients displayed higher overall diurnal salivary cortisol and more non-suppression to dexamethason suppression test, which indicates that increased adrenal activity and lowered feedback sensitivity of the HPA- axis may be a characteristic (Lieb, et al., 2004). Elzinga, et al. (2002) found enhanced cortisol reactivity compared to PTSD patients and controls examining cortisol reactivity to traumatic and abandonment scripts. This seems to be logically consistent, as BPD patients are known to have pronounced stress intolerance (Simeon, Knutelska, Smith, Baker, & Hollander, 2007).

Affective dysregulation and other symptoms that have been hypothesized to be related to dysfunction of limbic brain areas are frequently associated with BPD

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Introduction (Ebner-Priemer, et al., 2005; Schmahl, Vermetten, Elzinga, & Douglas Bremner, 2003; Tebartz van Elst, et al., 2007). Prefrontal and limbic structural abnormalities such as decreased brain volumes in prefrontal, limbic, and parietal areas (e.g., smaller amygdala and hippocampal volume; Rusch, et al., 2007; Rusch, et al., 2003;

Schmahl, et al., 2003; Tebartz van Elst, et al., 2007) and a thinner isthmus of the corpus callosum have been reported compared to healthy controls (Rusch, et al., 2007). Rusch, et al. (2007) also found a history of childhood sexual abuse to be related to a thinner posterior body of the corpus callosum, which indicates that interhemispheric structural connectivity involving parietal and temporal areas may be impaired in women with BPD. Recent models are more and more suggesting impaired structural and functional connectivity in this condition. A dysfunction of dorsolateral and medial prefrontal cortex including anterior cingulate, left temporal cortex, and visual association cortex are assumed to mediate symptoms in BPD (Schmahl, Elzinga, et al., 2003). For example, dual frontolimbic brain pathology has been suggested as a possible correlate of impulsivity and aggressive behavior (Tebartz van Elst, et al., 2003). While volume loss of a single brain structure like the hippocampus is regarded as an unspecific finding in neuropsychiatry, the patterns of volume loss of the amygdala, hippocampus, left orbitofrontal, and right anterior cingulate cortex might differentiate BPD from other neuropsychiatric conditions and may contribute to core characteristics of BPD, in particular impulsivity (Berlin, Rolls, &

Iversen, 2005; Tebartz van Elst, et al., 2003).

There is no long empiric research tradition examining processing of emotion in BPD. Linehan (1993) proposed that affective hyperresponsiveness includes high sensitivity to emotional stimuli, high emotional intensity, and slow subside of emotional arousal to baseline. This hypothesis of emotional hyperresponsiveness (Linehan, 1993) is strengthened by studies applying priming tasks or providing biased information prior to cortical processing (Herpertz, 2003). Emotional dysregulation, which is mainly known to be mediated by the amygdala, has also been investigated with the startle response (Ebner-Priemer, et al., 2005), in which BPD patients showed an enhanced response to startling tones compared to controls.

Furthermore, patients with low dissociative experiences revealed enhanced responses whereas patients with high dissociative experiences showed reduced responses, which is in accordance with the corticolimbic disconnection model of dissociation (Sierra & Berrios, 1998). Findings in facial recognition experiments have

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Introduction been mixed (Levine, Marziali, & Hood, 1997; Wagner & Linehan, 1999). Although Levine (1997) found lower levels of emotional awareness, lower accuracy at recognizing facial expressions of emotion, and more intense responses to negative emotions in BPD than in controls, Wagner and Linehan (1999) observed a primarily accurate perception of others' emotions in BPD although a tendency toward heightened sensitivity on fear recognition was also found. Hajcak, et al. (2008) suggests impaired emotional processing and increased affective interference based on findings of an emotionally interruptive task in which emotional stimuli elicited increased reaction times and decreased ERP components for target stimuli placed in a stream of affective images. Koenigsberg, et al. (2009) employed fMRI to assess patterns of regional brain activation while positive and negative social emotional stimuli were presented. Thereby, BPD patients showed greater amygdala activity and heightened activity of visual processing regions relative to controls in the processing of negative social emotional pictures compared with rest. Such an enhanced processing of emotionally negative stimuli is supported by the findings of Hurlemann, et al. (2007), who additionally found a relative lack of processing of emotionally positive stimuli.

The impulsive self- and other-damaging behaviors seen in BPD have substantial comorbidity with depression but are associated with the experience of more severe environmental stressors than MDD (Lyons-Ruth, et al., 2007). Thus, it is not surprising that the short allele of the serotonin transporter linked polymorphic region (5-HTTLPR) has also been related to BPD (Lyons-Ruth, et al., 2007; Wagner, Baskaya, Lieb, Dahmen, & Tadic, 2009). Wagner, et al. (2009) suggest an interaction between serious life events and the 5-HTTLPR S/L polymorphism in the development of impulsivity in BPD. Another polymorphism associated with BPD and comorbid depression has been reported for the 9-repeat allele of the dopamine transporter (DAT1; Joyce, et al., 2006). This association was more pronounced in older patients, which indicates that the 9-repeat allele may be associated with a poorer prognosis of BPD. An interactive effect between the gene variants of the 5-HTTLPR polymorphism and the COMT low-activity Met(158) has been suggested by Tadic, et al. (2009) with an involvement of altered dopaminergic and/or noradrenergic neurotransmission, but also interactive gene-effects.

In summary, it can be assumed that severity of ELS plays a major role in the development and course of BPD.

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Introduction

Drug addiction (DA): Child abuse has been shown to play a major role in substance abuse disorders (De Bellis, 2002; Gordon, 2002; Kendler, et al., 2000; Reed, Anthony, & Breslau, 2007). Epidemiological studies have shown that individuals exposed to ELS and/or ongoing stress are more likely to abuse alcohol and use illicit drugs or undergo relapse (Dawes, et al., 2000; Gordon, 2002; Kosten, Miserendino,

& Kehoe, 2000; Kosten, Rounsaville, & Kleber, 1986; Sinha, 2005; Sinha, Fuse, Aubin, & O'Malley, 2000). Among school-aged children, those who reported physical and sexual abuse showed more frequent drug-taking behavior and in turn a history of ELS was shown to be associated with early initiation of substance abuse (Bensley, Van Eenwyk, Spieker, & Schoder, 1999; Harrison, Fulkerson, & Beebe, 1997;

Kendler, et al., 2000). Looking for the impact of family structure on substance abuse, Barrett and Turner (2006) found that offspring of single-parent families were at greater risk than those from mother-father families especially in combination with deviant peers and exposure to stress. Among female substance abusers the rate of victimization, most commonly physical and/or sexual assault, ranged from 50% to nearly 100%, while rates for men were two to three times lower and typically stem from combat or crime traumata (see review Najavits, Weiss, & Shaw, 1997). Thus, drug abusers were not only three times more likely to report traumatic events but also to fulfill criteria for a comorbid PTSD diagnosis (Cottler, Compton, Mager, Spitznagel,

& Janca, 1992). Reed, et al. (2007) assumed that PTSD might be a causal determinant of drug use disorders, possibly representing a dysfunctional coping strategy to deal with trauma-associated memories, nightmares, or hyperarousal symptoms. In animals, ELS has been proven to carry over into adulthood, making them susceptible to further stress and thus affecting their responsivity to illicit drugs (Kosten, Miserendino, & Kehoe, 2000; Piazza, Deminiere, le Moal, & Simon, 1990).

Learning or performance differences played no role in this responsivity. In a meta- analysis, high stress has been selected as predictive factor leading to continuous drug use among e.g., opiate addicts (Brewer, Catalano, Haggerty, Gainey, &

Fleming, 1998), and exposure to personal stress situations led in drug-free cocaine abusers, who were in treatment at this time, to suffering from constant cravings (Sinha, Catapano, & O'Malley, 1999; Sinha, et al., 2000). Hence, current stressors facilitate the reinstatement of drug taking even after prolonged periods of withdrawal.

Studies of animals found that stress induced a relapse to heroin (Shaham & Stewart,

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Introduction 1995), cocaine (Ahmed & Koob, 1997; Erb, Shaham, & Stewart, 1996; Kosten, et al., 2000), and alcohol (Lê, et al., 1998) abuse.

Findings of increased drug intake and higher risk of relapse under stress become comprehensible when one considers the overlap of neural circuits underlying stress with those involved in drug reward (Kreek & Koob, 1998; Piazza & Le Moal, 1998; Piazza & Le Moal, 1996; Sinha, 2005). Stress, corticosterone, and mesencephalic dopaminergic neurons seem to be organized in a pathophysiological chain determining this vulnerability (Piazza & Le Moal, 1996). As CRF, ACTH, and cortisol increase dopaminergic neurotransmission in the mesocorticolimbic ‘reward’

system, stress co-activates stress and reward circuits simultaneously. Vice versa, commonly abused drugs that stimulate the mesocorticolimbic dopaminergic systems activate the HPA-axis (Stewart, 2000). This may facilitate a vicious cycle with stress promoting drug intake and abuse altering stress-mediating and reward-mediating brain systems, whereupon these changes increase drug-seeking behavior (Piazza &

Le Moal, 1998). Therefore dopamine, which is required for reward and reinforcement (e.g., acute reward and initiation of action) seems to be impaired by addictive drugs (Kropotov, 2009). In summary, an increased corticosterone secretion (either naturally present in certain individuals or induced by stress) but also a higher sensitivity to the effects of this hormone increases the vulnerability to develop drug intake via an enhancement of the activity of mesencephalic dopaminergic neurons (Piazza &

Le Moal, 1996).

Functional abnormalities in drug addicts have been reported for the amygdala (e.g., in cocaine dependent individuals), which is instrumental in reward and drug craving (Makris, et al., 2004). This volume reduction was even present in short term users and uncorrelated to drug use severity. It may point to the conclusion that earlier adverse events play a role in the course of drug use. Current literature also states that frontal regions, which are involved in mediating reward and stress effects, are dysfunctional in addiction (Bremner, 2002; McEwen, 2004; Kropotov, 2009) and have been discussed as a common pathway for drug relapse (Ventura, Alcaro, & Puglisi- Allegra, 2005). Abnormalities have been reported for inferior frontal regions: patients with cocaine or opiate dependency have greater lesions in frontal lobes and insular regions than healthy subjects (Lyoo, et al., 2004). These findings suggest disruption of functional connectivity between prefrontal cortex and paralimbic regions involved in the processing of emotional states. Moeller, et al. (2005) added evidence, finding

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Introduction abnormalities in white matter regions of the anterior corpus callosum, which may cause some alterations in prefrontal cortex functions. Chang, et al. (2002) applying fMRI also showed decreased regional cerebral blood flow in insular cortices and inferior frontal regions, as well in the right lateral parietal region in long-term abstinent methamphetamine dependent subjects. Overall, findings in structural and functional imaging studies indicate that major neural substrates are affected in drug abusers (Verdejo-Garcia, Rivas-Perez, Vilar-Lopez, & Perez-Garcia, 2007). It should be noted that almost no study has found correlations between reported abnormalities in morphological and structural indices of the brain and measures of drug abuse severity, frequency, age of onset, or peak use (Verdejo-Garcia, et al., 2007) possibly indicating that brain abnormalities may have been existent, at least to some extend, before the onset of drug abuse.

Studies focusing on the processing of emotional facial expressions in long- term abusers found impaired recognition and overestimation of the intensity of facial expressions depicting different emotional states (e.g., fear, anger, disgust, and happiness; Hoshi, Bisla, & Curran, 2004; Kano, et al., 2003; Kornreich, et al., 2001;

Kornreich, et al., 2003; Townshend & Duka, 2003) as well as deficits in decision making, and self-regulation (Verdejo-Garcia, et al., 2007). Imaging studies on craving in addicts showed that drug related stimuli are able to strongly activate brain regions involved in emotional evaluation and reward processing, while natural reinforcing stimuli (food or sex) only elicited blunted activation (Garavan, et al., 2000; George, et al., 2001; Kilts, Gross, Ely, & Drexler, 2004; Tapert, Brown, Baratta, & Brown, 2004).

ERP studies have revealed reduced P300 amplitudes in substance abusers relative to subjects with no history of drug dependency in various oddball tasks (Bauer, 2001;

Cohen, Ji, Chorlian, Begleiter, & Porjesz, 2002; Hada, Porjesz, Begleiter, & Polich, 2000; Papageorgiou, et al., 2004; Porjesz, et al., 2005) with no differentiation among patients with different histories of drug abuse (e.g., cocaine, cocaine and alcohol, or heroine dependency). It should be noted that continued abstinence was shown to be associated with a trend towards P300 normalization.

A genetic predisposition is an established concept in DA (e.g., Porjesz, et al., 2005), but it is known that drug addiction is a complex disease in which many genes and environmental factors interact. Much research has concentrated on influences of alleles responsible in coding genes that express phenotypic transmitter production and distribution involving endorphins, dopamine, and serotonin (e.g., dopamine D2

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Introduction receptor: Uhl, Liu, & Naiman, 2002). Some polymorphisms have been proved to contribute to substance abuse vulnerability: BNDF Val66Met (Cheng, et al., 2005), Ser127Gly polymorphism in protein tyrosine phosphatease receptor type beta (PTPRB: Ishiguro, Gong, Hall, Arinami, & Uhl, 2008), and aldehyde dehydrogenase-1 (ALDH1A1), which plays a role in acetaldehyde oxidation and central dopamine metabolism (Lind, Eriksson, & Wilhelmsen, 2008). A functional polymorphism within the reward associated µ-opioid receptor gene (OPRM1 +118A) has been identified to an increased risk for use and abuse of drugs in general (Schinka, et al., 2002). This risk does not appear to be related to a particular drug (including alcohol and nicotine), and is found in nearly 90% of DA searching treatment.

The body of literature agrees that stress is a major vulnerable factor predisposing an individual to drug seeking behavior but further investigations are needed in order to understand to what extent environmental influences such as ELS influence drug addiction.

1.3.4 Résumé

This brief review of findings in distinct diagnostic categories demonstrates that stress effects in patients can be understood in terms of allostatic load (McEwen, 2003; McEwen, 2004). Psychopathology, brain, and neuroendocrine functions can be related to early, chronic, and/or severe stress against the background of a psychobiological vulnerability. Evidence suggests that these long-term changes in brain systems involve plastic changes of limbic and prefrontal systems mediating affect processing. The relationship between psychological vulnerability factors such as subclinical symptoms and dysfunctional coping strategies, which appear upon earlier stressful experiences, are themselves risk factors for further stressful life events or stressful experience of life events (Brown, Harris, & Hepworth, 1994) suggesting a dynamic vicious cycle in which a ‘stress-shaped’ personality influences and responds to its environment via its perception, response bias and/or (mal)adaptive stress responses. It is even possible that higher rates of (re-) victimization in such individuals are driven in part by mal-adaptation to earlier protracted stress. The examples of specific findings about subsets of individuals with psychiatric disorders provide compelling evidence of a stress-mediated mechanism central to many cases of severe psychopathology. Symptoms such as negative

Influence of early life stress on psychophysiology in psychiatric patients