The three studies conducted and reported in this thesis aimed to examine whether early adverse life experiences characterize a psychophysiological response profile many years later in adult subjects modulating psychiatric disorder and associated psychophysiological responding. We hypothesized that a subset of patients across diagnostic groups could be characterized by such a response profile, which could be related to allostatic load.
Stress Experience
As expected, psychiatric patients reported to have experienced more prenatal stress, reported more adverse experiences for the time period from birth until the individual’s onset of puberty, and more lifetime traumatic events than healthy controls (see 2.4 Summary of Results, Figure 12). The pronounced occurrence of ELS in the patient sample is in line with studies assessing the influence of ELS in psychiatric disorders (e.g., Heim, Plotsky, & Nemeroff, 2004; Read, van Os, Morrison, & Ross, 2005; Saleptsi, et al., 2004; van der Kolk, Hostetler, Herron, & Fisler, 1994). Results confirm the proposed association between the occurrence of ELS and mental disorders. However, the expected uniform effect of childhood stress load across diagnoses was refuted in the frequently reported strong association between ELS and MDD and BPD, as adverse experiences were more pronounced in these diagnostic groups than in DA and schizophrenia. These findings of unequal stress distribution across diagnoses may represent a co-construct of biological and social interaction (Baltes, Reuter-Lorenz, & Rösler, 2006). The aim to find a subgroup of ELS-patients with similar numbers of diagnoses was not reached. Results for MDD and BPD patients support hypotheses derived from literature (Bernet & Stein, 1999;
De Bellis, 2002; Gladstone, Parker, Wilhelm, Mitchell, & Austin, 1999; Heim, et al., 2004; van der Kolk, et al., 1994). Schizophrenia patients have previously been reported to express high stress load (Read, Agar, Argyle, & Aderhold, 2003; Read, et al., 2005; Lysaker, et al., 2005), so that the present findings in schizophrenia patients displaying lower ELS may be a consequence of patient selection in the local Center for Psychiatry. DA patients displayed pronounced stress experiences later in
General Discussion & Conclusion adolescence. This corresponds to the pattern similar to that found by Saleptsi, et al.
(2004).
The present data add to the evidence that emotional neglect, physical and sexual abuse, other traumatic experiences, and factors such as general violence in family or separation from the mother before puberty are experienced by many psychiatric patients (e.g., Bierer, et al., 2003; Heim & Nemeroff, 2001;
Muenzenmaier, Meyer, Struening, & Ferber, 1993). Additionally, we found an accumulation effect of adverse events assessed in different stress domains (i.e.
emotional neglect, physical and sexual abuse, and other traumatic experiences).
Hence, experiences in one stress domain go along with adverse experiences in other domains e.g., the experience of physical abuse is often accompanied and/or even intensified by emotional neglect. The relationship between ELS and adulthood psychiatric disorders support the hypothesis that ELS sensitizes for further stress experiences (Heim & Nemeroff, 2001; McEwen, 2003; McEwen, 2004; McEwen &
Stellar, 1993; van der Kolk, et al., 1994).
The Psychophysiological Response Profile
Level of Symptom Severity: Studies assessing the influence of ELS on psychopathology have been described for specific diagnostic groups. We were interested in whether affect plays a mediating role across diagnoses as a function of stress load. In patients, current negative affect and depression were related to childhood stress load (ELS and PPS) supporting affect as a mediating factor in the progress of illness (see 2.4 Summary of Results, Figure 13). BPRS-scores as marker of overall symptom severity varied with ELS, although this relationship was less pronounced compared to the affect scales. ELS was not related to impairment in functioning (GAF), and functioning was not related to negative affect. This suggests that stress effects may become manifest in specific symptoms rather than in overall severity of impairment. In schizophrenia, our results did neither reflect the high ELS reports of earlier findings nor confirm a relationship between traumatic experiences and psychotic symptoms (Read, van Os, Morrison, & Ross, 2005). As already mentioned, this may have been a consequence of the selected sample as well as of the applied symptom scales. Nevertheless, psychotic symptoms in schizophrenia such as hallucinations and delusions were related to adulthood adverse events, suggesting higher stress sensitivity to more current adverse events. In DA a different
General Discussion & Conclusion pattern was revealed. Even though DA patients reported fewer ELS experiences compared to MDD and BPD patients, BPRS-scores were most pronounced in this diagnostic group, as well as a comorbid diagnosis of personality disorder (40%). The studied DA group was beyond the withdrawal period, which may account for the low self-rating symptom severity scores in depression or negative affect scales, while a high score in BPRS might reflect more long-lasting impairments. BPRS evaluation in other diagnostic groups might have been distorted and attributed by clinicians to more diagnosis specific symptoms as these patients were just on the edge between acute and recovery phase. In the present sample the hypothesis of a single influence relationship between the experienced amount of ELS and severity of psychopathology cannot be verified because of the uneven stress distribution between diagnostic groups.
Additionally, a dose effect relationship was not only found between traumatic events, according to diagnostic criteria for PTSD, and PTSD symptom severity but also between non-traumatic ELS and psychopathology. Thus, with pronounced ELS the risk for developing psychiatric symptoms, including PTSD symptoms, is increased, perhaps through a heightened sensitivity for additional stress responses.
Janssen (2004) even found that people who had experienced child abuse of mild severity were twice as likely than non-abused participants to develop a psychosis, compared with 11-times and 48-times more likely for those who had suffered moderate and high severity of abuse respectively. Such a building block effect, i.e. a higher risk for the development of psychiatric symptoms with increasing number of traumata, has previously been described in PTSD (Neuner, et al., 2004), in schizophrenia (Hammersley, et al., 2003; Read, et al., 2005), and in other disorders (Fergusson, Horwood, & Lynskey, 1996; Mullen, Martin, Anderson, Romans, &
Herbison, 1993). It seems that extreme fear is not a necessary predictor, in that adverse events can trigger its negative influence in the perceived individual.
Emotional neglect in ELS was found as one major predictor of current comorbid PTSD, even though emotional abuse is not included in the diagnostic description of PTSD. Neglect has received little attention in literature although e.g., perceived rejection by parents or peers has previously been associated with alcohol abuse in adolescents and adulthood (Campo & Rohner, 1992). Given the cross-diagnostic sample of patients, findings replicate van der Kolk’s notion (1994) that early neglect experiences may lead to serious problems in affect regulation and thus, possibly
General Discussion & Conclusion trigger vulnerability to harmful experiences and predisposition for certain mental disorders.
Cortical Level: If ELS affects brain development, including affect mediating systems, which lead to lasting alterations, this should be evident in the cortical processing of affective stimuli. Therefore, we applied an image-based viewing task which captures the subjects’ attention with affective stimuli that vary in their hedonic valence and arousal while the MEG was recorded. Prior findings of EEG and MEG studies, i.e.
modulation of electromagnetic responses in posterior regions 160-210 ms after picture onset, were confirmed (Lang, Bradley, & Cuthbert, 1998; Peyk, Schupp, Elbert, & Junghofer, 2008; Schupp, Cuthbert, Bradley, Hamm, & Lang, 2004;
Schupp, Junghofer, Weike, & Hamm, 2003). Although, a normal initial processing of affective stimuli was found in patients, ELS was related to an altered response to salient emotional picture content (see 2.4 Summary of Results, Figure 14). Such a failure of differentiation of affective valence can be interpreted as a marker of an altered reward/defense system and is in line with findings of reciprocal reduction in defensive reactivity in subjects reporting distress (Lang, McTeague, & Cuthbert, 2007). Indeed, blunted responses have been described in schizophrenia and MDD patients (e.g., Deldin, Keller, Gergen, & Miller, 2000; Lee, et al., 2007; Moratti, Rubio, Campo, Keil, & Ortiz, 2008; Rockstroh, Junghofer, Elbert, Buodo, & Miller, 2006).
However, the association of overall EPN suppression and reduced affective modulation may also be related to diagnostic group as ELS was most represented in MDD and BPD patients. A differentiated inspection of separate, additive, or interactive effects of ELS and diagnoses cannot be assessed in this sample. The resulting dampened automatic cortical response does not necessarily predict controlled processing as indicated by subjective evaluation of affective valence.
Compensatory strategies may allow normal processing of stimuli as long as enough time and cognitive capacity is available. Importantly, present results showed that the ELS-EPN relationship is not just redundant or a merely function of AS, comorbid PTSD, or affective symptoms.
General Discussion & Conclusion Level of the HPA-axis: Salivary cortisol measures were used to assess the influence of stress experiences on HPA-axis functioning. In this study, diurnal and reactive salivary cortisol varied with early stress experiences of neglect, physical, and sexual abuse before the age of 6 years (see 2.4 Summary of Results, Figure 15). Cortisol measures were higher in subjects exposed to high ELS. Stress experienced later in life (PPS and AS) did not influence cortisol measures. The constraint of this relationship to the first six years of life suggests that this is a particularly sensitive period for stress effects on HPA-axis shaping (Karlamangla, Singer, McEwen, Rowe,
& Seeman, 2002; Lupien, McEwen, Gunnar, & Heim, 2009; McEwen, 2003b;
Nemeroff, 2004). The diagnostic group per se was not related to cortisol measures but through the combining of the ELS and diagnostic groups, the specific impact of stress and/or disorder on cortisol measures could not be investigated. However, results of elevated cortisol measures in BPD and MDD support earlier findings (e.g., Heim, Owens, Plotsky, & Nemeroff, 1997a; McEwen, 2003b; Tafet & Smolovich, 2004).
Diurnal cortisol was best predicted by ELS emotional neglect, whereas cortisol response was determined by ELS physical abuse. In patients with a comorbid PTSD diagnosis, PTSD symptom severity was related to both cortisol measures, confirming an impact of traumatic experiences on HPA-axis functioning. In this respect, diurnal salivary cortisol was best predicted by high arousal and intrusion symptoms, and cortisol response was best predicted by high avoidance in PTSD. This suggests that basal diurnal cortisol and cortisol response represent different characteristics of the HPA-axis (Hellhammer, et al., 2007; Pruessner, Kirschbaum, Meinlschmid, &
Hellhammer, 2003). Roelofs, et al. (2005) assumes that high cortisol responses during stress are associated with a decrease in active approach-avoidance behavior.
The validity of salivary cortisol results is reduced by the high interindividual variability of measures. One reason for this may have been compliance in handling diurnal salivary probes, despite hospital staff supervising in accordance to a strict protocol. Medication may have been another factor accounting for variability, as treatment with neuroleptics and antidepressants are known to reduce elevated cortisol levels (Inder, Prickett, Mulder, Donald, & Joyce, 2001; Lammers, et al., 1995;
Rinne, et al., 2002; Wik, 1995). Antidepressants are supposed to enhance GR function in humans, which has been proven in animal studies that found an up-regulation of GR in the brain, thereby decreasing stress-induced glucocorticoid
General Discussion & Conclusion secretion and enhancing HPA-axis feedback (see review Pariante & Miller, 2001).
Furthermore, salivary cortisol may be a less stable marker of HPA-axis and thus, lead to less pronounced results in smaller samples. The influences of smoking, gender, as well as the use of oral contraceptives (which have been found to influence neuroendocrinological measures) were controlled in this study. Diverging symptoms within and across disorders like in the heterogeneous nature of psychotic disorders may account for differences in cortisol levels as well, 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) have been found to show non-suppression in response to dexamethason suppression test (DEX-test). Duration of illness may also be an important factor in the determination of HPA-axis dysfunction, as for instance duration of psychotic symptoms has been negatively correlated with cortisol levels (Mazure, Quinlan, & Bowers, 1997) while hyperactivity of HPA-axis has been reported more consistently in patients experiencing their first psychotic episode (Pariante, et al., 2004). Thus, low cortisol may not be associated with low stress per se. Future research studying the HPA-axis should take into account possible influencing mediators such as the duration of illness, level of depressive symptoms, as well as control or standardize medication, and ensure rigorous implementation of the sampling protocol.
Résumé: Early adverse life experiences characterized a psychophysiological response profile in adult psychiatric patients modulating disorder and associated psychophysiological responding. In a subset of patients which had experienced high ELS, affective and PTSD symptoms were strongly related to ELS supporting a mediating function of affect (Lang, McTeague, & Cuthbert, 2007). The relationship between psychotic symptoms and stress load indicates additional disorder-specific ELS effects. On the cortical level, ELS interacted with the psychiatric disorder, which was expressed as dampened activation by affective stimuli. Neuroendocrinologically, ELS was related to elevated diurnal cortisol and a more pronounced cortisol response to affective pictures. Together, the found pattern may be related to allostatic load.
General Discussion & Conclusion Nevertheless, the uneven distribution of diagnoses within the ‘stress-related’
subgroups, with a majority of MDD or BPD patients forming the high stress groups, suggests an interaction of ELS and other more disease-specific vulnerability factors in the progress of mental illness. One possible explanation is provided by the gene-environment interaction model (Caspi & Moffitt, 2006; Caspi, et al., 2003; Heim &
Nemeroff, 2001; Heim & Nemeroff, 2002). According to this conceptualization, ELS may interact with the individual genetic plan and neurobiological circuits that regulate and program behavior and physiology and thus aggravate vulnerability to mental disorders. Whereas long-term stress effects on the HPA-axis and relevant brain systems seem to be similar across diagnostic categories, genetic and neurodevelopmental vulnerabilities together with stress experiences during critical periods could modulate specific symptom expression. To summarize, psychobiological vulnerability may be formed by an interaction of genetic diathesis and environmental influences and result in neural substrate reactivity (see Figure 16, Caspi, et al., 2003; Caspi & Moffit, 2006; Lupien, McEwen, Gunnar, & Heim, 2009).
GENOM DEVELOPMENT ENVIRONMENT
e.g., polymorphism, sex
Figure 16. A hypothetical model of psychobiological vulnerability influences on the basis of genotype-environment interaction.
e.g., early stress, alcohol & drug abuse
Coping PSYCHOBIOLOGICAL Traumatic events VULNERABILITY
Social support Chronic stress
Behavioral reaction
Physiological reaction
(endocrine, autonomic) (e.g., depression,
anxiety)
General Discussion & Conclusion Generally, current results strengthen the assumption that childhood in relation to prenatal stress is a crucial developmental period in which the individual psychobiological vulnerability is sensitive to adverse stress experiences on the basis of genetic predisposition and/or pre- and postnatal factors. On this basis, the interindividual vulnerability with its varying ability for functional adaptation could influence and determine further protection from or susceptibility to developing a mental disorder (Bradley, et al., 2008; Heim, Plotsky, & Nemeroff, 2004; Maynard, Sikich, Lieberman, & LaMantia, 2001; McEwen, 2003a; Lupien, et al., 2009).
Thereby, ELS may not be a risk factor for specific disorders, rather induce long-lasting changes in the HPA-axis (Young, Haskett, Murphy-Weinberg, Watson, & Akil, 1991). This may be caused by enhanced CRF secretion in response to stress during sensitive periods of brain plasticity prompting structural changes, sensitizing and altering feedback sensitivity of the HPA-axis (Paus, 2005; Thompson, Pogue-Geile, &
Grace, 2004; Thompson, et al., 2007) or as proposed by Charmandari, et al., (2003) by combined effects of CRF and glucocorticoids leading to stress-induced hyperactivity of the neuroendocrinological stress system altering amygdala, hippocampus, and mesocorticolimbic dopaminergic system.
Strengths and Limitations
A major goal of this study was the investigation of stress influences across diagnoses. So far, research had mostly focused on specific diagnosis assessing the impact of ELS. The studied psychopathologies seemed to be rich sets of phenomena for the study of the influence of ELS on psychophysiological responses. In terms of primary diagnoses, included psychiatric disorders were categorically distinct groups.
Secondary diagnoses may have limited results because of the overlap across primary diagnoses, which may be due to diagnostic conceptualization e.g., MDD in BPD. Nevertheless, this overlap represents clinical reality. In fact, our main interest was not contrasting diagnostic groups as we were looking for a diagnoses independent influence of early life stress.
Another advantage of this study was the assessment of adverse life events not restricted to childhood but throughout life. Many studies addressing ELS have focused primarily on this early time window. Exceptions are studies of Cascardi, et al.
(1996), Goodman, et al. (1997), and Saleptsi, et al. (2004). With the use of the ETI (Bremner, Vermetten, & Mazure, 2000), the conceptualization of stress was
General Discussion & Conclusion broadened across four domains (traumatic experiences, emotional neglect, physical and sexual abuse) and not restricted to traumatic events or sexual abuse. This allowed, for example the assessment of subjective emotional quality of life, which is otherwise difficult to assess. Findings replicate van der Kolk’s notion (1994) that early neglect experiences may lead to serious problems in affect regulation.
Major limitations of the study include the unequal distribution of ELS across diagnoses despite the large sample size of almost 100 patients. As predicted, a profile of psychological and psychophysiological (brain and endocrine) measures relating to stress load could be indentified in a subgroup of patients with a prominent childhood stress load. However, contrary to expectations this subgroup did not cut across diagnoses. In other words, not all diagnostic groups expressed similar early life stress. This unexpected unequal distribution of ELS across diagnostic disorders resulting in unequal study group sizes and thus prevented a systematic statistical dissection of the specific impact of ELS and disorder on measures of symptom severity, HPA-axis alterations, and cortical responses. If this disentanglement is a goal, studies with larger samples have to explicitly select subjects with high and low ELS histories within each diagnostic group. Still, we believe that our sample disclosed a “true” interaction of ELS effect, which primarily shapes the course of MDD and BPD (e.g., Heim, et al. 2004; van der Kolk, et al., 1994). Moreover, a gender imbalance between diagnoses as known from prevalence scores within the population was also represented in the patient sample. Even though analyses did not disclose an impact of gender, this asymmetry may further limit conclusions and specifications of ELS on the development of mental disorders. Nevertheless, this association of ELS and gender may not necessarily represent confounded variables.
ELS, but also other known and unknown variables (e.g., genetic and environmental influences respectively) may interact in their contribution to psychiatric diagnoses.
The present unbalanced distribution of patients in the low/high ELS group with more MDD and BPD patients in the high and more schizophrenic and DA patients in the low ELS group probably might represent such an interaction of contributing vulnerability factors. Separate main effects are less likely than gene x environment interactions (Caspi & Moffitt, 2006; Kendler, 2005; Turkheimer, 2000). Thus, the present thesis identified a subgroup of patients in which ELS and other risk factors may have induced depressive and borderline symptomatology, together with altered HPA-axis functioning and cortical processing. Apart from methodological limitations,
General Discussion & Conclusion the factors ELS and AS derived from psychopathology measures were each differently related to physiological measures. This too suggests a more complex interaction involving distinct dimensions including stress load as one of them in their
General Discussion & Conclusion the factors ELS and AS derived from psychopathology measures were each differently related to physiological measures. This too suggests a more complex interaction involving distinct dimensions including stress load as one of them in their