This thesis aims at clarifying the influence of adverse early stress experiences on individual vulnerability to severe psychiatric disorders and whether ELS is a crucial moderating pathogen across mental disorders. The goal is not to replace conventional categorical diagnoses but to identify stress-related mechanisms common to several disorders. Drawing on the concept of allostasis and allostatic load (McEwen, 2004), it is of interest as to whether a subset of patients can be characterized by a stress related psychophysiological response profile. This line of enquiry addresses adult inpatients with diagnoses of MDD, schizophrenia, BPD, and DA, as well as a matched healthy control group for participation in all three parts of the study (see chapter 2).
1.4.1 Stress Experience
As described above, a higher than normal stress load has been reported for specific psychiatric disorders (e.g., MDD: Heim, Plotsky, & Nemeroff, 2004;
schizophrenia: Read, van Os, Morrison, & Ross, 2005; BPD: Goodman, New, &
Siever, 2004; DA: Reed, Anthony, & Breslau, 2007). Neither prospective research, nor experimental approaches are ethically tenable in humans to assess the impact of ELS on adult psychiatric disorders. Retrospective studies have shown that ELS can be assessed in mental disorders and be related to early adverse experiences (e.g., Briere & Zaidi, 1989; Dalenberg & Palesh, 2004; Ellason, Ross, Sainton, & Mayran, 1996; Heim, Owens, Plotsky, & Nemeroff, 1997b; Mullen, Martin, Anderson, Romans,
& Herbison, 1996; Read & Ross, 2003; Saleptsi, et al., 2004). Concern about the reliability and accuracy of retrospective stress reports, especially those of events experienced early in life and given by psychiatric patients, is understandable but these concerns are unjustified. Reports of abuse by psychiatric patients are highly reliable (Goodman, et al., 1999; Margo & McLees, 1991; Meyer, Muenzenmaier, Cancienne, & Struening, 1996). It has even been found that psychiatric patients tend to underestimate rather than over-report ELS (Briere & Zaidi, 1989; Read, 1997).
Several studies have shown that a history of social stress can be assessed by
Introduction retrospective reports in patients with mental illness, in ways that are meaningful for their psychopathology (e.g., Heim & Nemeroff, 2001; Read, 1998).
On this basis, this study assesses number, type, and frequency of adverse events experienced from birth until current age in four major psychiatric diagnostic groups (MDD, schizophrenia, BPD, and DA) and in a matched healthy control group.
Additionally, prenatal stress influences are assessed insofar that parents of patients are available for questioning.
(A) We hypothesize that a higher stress load, especially until sexual maturation, is prevalent in psychiatric patients as opposed to healthy subjects.
(B) Furthermore, we expect a uniform distribution of stress load across diagnostic categories.
1.4.2 The Psychophysiological Response Profile
Psychopathology and brain/body responses will be studied in relation to social stress on the ‘psychobiological background’ (Lewine, 2005) of patients treated for psychiatric disorders. Following the positive-feedback model of Thompson, et al.
(2004), we assume that psychopathology results from a dynamic vicious cycle that involves adverse stress experiences during sensitive periods of brain plasticity, altered brain systems mediating affect and reward, and altered HPA axis functioning with consequent enhancement of stress vulnerability and (mal)adaptive responses to additional social stress. Based upon the present state of knowledge, we test possible influences of ELS on the level of psychopathology, HPA-axis, and cortical affective processing. These profiles reflect allostatic load in that they can be related to severe and chronic stress experience during sensitive periods (childhood and adolescence).
Level of Symptom Severity: Stress may influence functional and structural systems in the developing brain altering affect and emotional response. We are interested whether affect plays a mediating role in the progression of illness across diagnoses and as a function of stress load. Besides affect, ELS may influence cognitive and executive functions contributing to disorder specific symptoms (e.g., higher levels of discomfort and hallucinations in schizophrenia: Lysaker, Beattie, Strasburger, &
Introduction Davis, 2005; Read, van Os, Morrison, & Ross, 2005) and reduce coping capacity interacting with the progress of psychopathology (e.g., Bellack, Mueser, Wade, Sayers, & Morrison, 1992; Glaser, van Os, Portegijs, & Myin-Germeys, 2006; Mueller
& Bale, 2007). Additionally, a “building block effect”, as has been described in PTSD (Neuner, et al., 2004) and schizophrenia (Read, et al., 2005) may increase the risk for mental disorders on the background of high ELS load. Thus, on the level of psychopathology our focus is on symptom severity i.e. negative affect, depression, disorder specific symptoms like hallucinations, and comorbid drug abuse.
(C) We hypothesize a relationship between the amount of stress load experienced early in life (before the onset of puberty) and symptom severity in patients.
Markers of illness severity will vary with the ‘stress-related’ profile in a subset of patients across diagnostic categories: schizophrenia, MDD, DA, and BPD, and this profile can be predicted in this subset from more severe and chronic social stress ranging from birth until adolescence (ELS and PPS).
(D) Furthermore, we propose a dose effect between adverse experiences and symptom severity as has been described for traumatic events and PTSD symptoms or hallucinations (Butler, Mueser, Sprock, & Braff, 1996; Hammersley, et al., 2003).
Cortical Level: Based on the assumption that ELS affects brain development including affect-mediating systems, leading to enduring alterations, we believe that a history of ELS affects cortical processing of emotional stimuli. Stress-induced hyperactivity of the stress-response system (Charmandari, Kino, Souvatzoglou, &
Chrousos, 2003) or the defense system (Lang, Davis, & Ohman, 2000) during sensitive periods of development (e.g., before the age of six years) have been suggested to mediate changes in brain structure and function involved in affect regulation. These alterations may endure into adulthood and thus, be reflected in blunted cortical responses to emotional stimuli. Cortical processing has consistently been shown to be modulated by salience and valence of affective stimuli (e.g., Bradley, et al., 2003; Junghofer, Bradley, Elbert, & Lang, 2001; Sabatinelli, Bradley, Fitzsimmons, & Lang, 2005; Schupp, Flaisch, Stockburger, & Junghofer, 2006;
Schupp, Junghofer, Weike, & Hamm, 2003; Schupp, Junghofer, Weike, & Hamm, 2004). Enhanced early posterior negativity (EPN) amplitudes, which are associated
Introduction with the involuntary capture of attention with increasing degree of arousal in pleasant and unpleasant stimuli, have been verified in healthy subjects (Junghöfer, et al., 2001; Schupp, et al., 2003) in occipito-parieto-temporal brain regions associated with visual processing (Peyk, Schupp, Elbert, & Junghofer, 2008) around 120-300 ms after stimulus onset. This is in line with the bivariate motivational model of emotion (Bradley, Codispoti, Cuthbert, & Lang, 2001; Lang, Bradley, & Cuthbert, 1997).
Affective processing has been found to be altered in psychiatric patients (see chapter 1.3.3) and vice versa ELS has been proposed to alter brain development and affective processing (e.g., Heim, Plotsky, & Nemeroff, 2004; Kendler, Kuhn, Vittum, Prescott, & Riley, 2005). So far, ELS influences on affective processing have been rarely studied (in healthy subjects: Pole, et al., 2007). Social stress and allostatic load affect brain systems mediating affective-motivational responses to external stimuli that have positive (reward) or threatening (defense system) implications. Lang, et al.
(2007) related distress and negative affect to diminished activity of the defense system in anxious and depressive patients emphasizing that the defense and reward system overlap with the stress system. In this project, event-related electromagnetic brain responses to affective stimuli serve as measures of a dampened and/or hyperactive reward and defense system. Cortical affective processing is conceptualized in an image-based viewing task which captures the subjects’
attention with affective stimuli that vary in their hedonic valence and arousal while the magnetoencephalogram (MEG) is recorded.
(E) We propose a reduced modulation in response to salient affective stimuli in patients with a ‘stress-related profile’, which can be interpreted as a marker of an altered reward/defense system. Such a blunted response to pleasant and unpleasant stimuli would resonate with findings of reciprocal reduction in defensive reactivity in subjects reporting distress (Lang, et al., 2007).
Level of the HPA-axis: ELS exerts its influence on the developing brain including the neuroendocrine system thereby altering basal functioning and increasing stress sensitivity (Charmandari, Kino, Souvatzoglou, & Chrousos, 2003; Thompson, et al., 2007). In animal and human studies, ELS has been described to impact on the dysregulation of the HPA-axis, especially on CRH, with lasting consequences for the vulnerability to severe mental disorders (e.g., Meaney, et al., 1996; Nemeroff, 1996;
Introduction Strome, et al., 2002). Salivary cortisol measures are used to assess the influence of stress experience on HPA-axis functioning. Diurnal salivary cortisol is measured as an indicator of basal activity of the HPA-axis. On a separate day, salivary cortisol reactivity is assessed in the above-described affective image based viewing task, based upon the assumption that this task would be experienced as a mild stressor.
Immediately prior to and after the experimental MEG session, salivary cortisol is sampled. This experimental challenge is proposed to relate an altered reward/defense system to allostatic load.
(F) We propose a relationship between ELS and salivary cortisol measures. A relationship should be indicative that stress in sensitive developmental periods exerts long-lasting alterations on the HPA-axis.
Childhood Stress Affects Psychopathology