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The etiology of anxiety disorders is multifactorial with contributions from both
genetic and environmental factors. Several susceptibility genes of anxiety disorders or
anxiety-related intermediate phenotypes have been identified, including the
serotonin transporter gene (5-HTT) and the neuropeptide S receptor gene (NPSR1),
which have been shown to modulate responses to distal and acute stress experiences.
For instance, gene-environment interaction (GxE) studies have provided evidence
that both 5-HTT and NPSR1 interact with environmental stress, particularly
traumatic experiences during childhood, in the moderation of anxiety traits, and
both 5-HTT and NPSR1 have been implicated in hypothalamic-pituitary-adrenal
(HPA) axis reactivity – an intermediate phenotype of mental disorders – in response
to acute stress exposure. The first part of this thesis aimed to address the interplay of
variations in both 5-HTT and NPSR1 genes and distal stress experiences, i.e.
childhood trauma, in the moderation of anxiety-related traits, extended by
investigation of the potentially protective effect of positive influences, i.e. elements of
successful coping such as general self-efficacy (GSE), on a GxE risk constellation by
introducing GSE as an indicator of coping ability (“C”) as an additional dimension in
a GxExC approach conferring – or buffering – vulnerability to anxiety. Increased
anxiety was observed in 5-HTTLPR/rs25531 LALA genotype and NSPR1 rs324981 AA
genotype carriers, respectively, with a history of childhood maltreatment but only in
the absence of a person’s ability to cope with adversity, whereas a dose-dependent
effect on anxiety traits as a function of maltreatment experiences irrespective of
coping characteristics was observed in the presence of at least one 5-HTT S/LG or
NSPR1 T allele, respectively. The second part of this thesis addressed the respective
impact of 5-HTT and NPSR1 variants on the neuroendocrine, i.e. salivary cortisol
response to acute psychosocial stress by applying the Maastricht Acute Stress Test
(MAST). A direct effect of NPSR1 – but not 5-HTT – on the modulation of acute
stress reactivity could be discerned, with carriers of the more active NPSR1 T allele
Summary
III
displaying significantly higher overall salivary cortisol levels in response to the MAST
compared to AA genotype carriers.
In summary, study 1 observed a moderating effect of GSE in interaction with
childhood maltreatment and 5-HTT and NPSR1, respectively, in an extended GxExC
model of anxiety risk, which may serve to inform targeted preventive interventions
mitigating GxE risk constellations and to improve therapeutic interventions by
strengthening coping ability as a protective mechanism to promote resilient
functioning. In study 2, a modulation of HPA axis function, considered to be an
endophenotype of stress-related mental disorders, by NPSR1 gene variation could be
discerned, suggesting neuroendocrine stress reactivity as an important potential
intermediate phenotype of anxiety given findings linking NPSR1 to dimensional and
categorical anxiety. Results from both studies may converge within the framework of
a multi-level model of anxiety risk, integrating neurobiological, neuroendocrine,
environmental, and psychological factors that act together in a highly complex
manner towards increasing or decreasing anxiety risk.
Renewal of fear is one form of relapse that occurs after successful therapy, resulting from an encounter with a feared object in a context different from the context of the exposure therapy. According to Bouton (1994), the return of fear, provoked by context change, indicates that the fear was not erased in the first place. More importantly, the return of fear indicates that during the exposure session a new association was learned that connected the feared object with “no fear”; yet, as Bouton further argues, this association is context dependent. Such dependence could explain effects like renewal. In a new context, the therapeutic association will not be expressed and thus will no longer inhibit the fear. The assumption that an association is context dependent has been tested and showed robust results (Balooch & Neumann, 2011; Siavash Bandarian Balooch, Neumann, & Boschen, 2012; Culver, Stoyanova, & Craske, 2011; Kim & Richardson, 2009; Neumann & Kitlertsirivatana, 2010). Research for the treatment of anxiety disorders, aiming to reduce fear and, more importantly, prevent relapse, is flourishing. There are several exposure protocols currently under investigation: multiple contexts exposure (MCE), which aims at reducing the return of fear due to renewal (e.g., Balooch & Neumann, 2011); prolonged exposure (PE), which aims at strengthening the inhibitory association during the extinction learning (e.g., Thomas, Vurbic, & Novak, 2009); and reconsolidation update (RU), which aims at “updating” the reconsolidation process by briefly exposing the CS+ before the actual extinction takes place (Schiller et al., 2010). So far, however, few clinical studies conducted on humans have investigated these novel treatment protocols, and as far as I know none has investigated the mechanisms of action behind these protocols with a human clinical sample. The present thesis has three main goals. The first is to demonstrate that exposure therapy in multiple contexts reduces the likelihood of renewal. The second is to examine the mechanisms contributing to the effect of MCE and the third is to shed light on the concept of context in the framework of the conditioning and extinction paradigm. To this end, three studies were conducted. The first study investigated the effect of MCE on renewal, the second and third studies examined working mechanisms of MCE. In the first study thirty spider-phobic participants were exposed four times to a virtual spider. The exposure trials were conducted either in one single context or in four different contexts. Finally, all participants completed both a virtual renewal test, with the virtual spider presented in a novel virtual context, and an in vivo behavioral avoidance test with a real spider. This study successfully demonstrated the efficacy of MCE on reducing renewal. Study 2 investigated the working mechanisms behind MCE by utilizing a differential conditioning paradigm and conducting the extinction in multiple contexts, targeting similar renewal attenuation as achieved in study 1. This was followed by two tests that attempted to reveal extinction-relevant associations like ones causing context inhibitory effects. This study had three main hypotheses: (1) The extinction context is associated with the exposure, and thus operates as a safety signal at some point during the extinction; it will therefore compete with the safety learning of the CS, leading to a decreased extinction effect on the CS if the extinction is conducted in only one context. (2) The elements (e.g., room color, furniture) of the extinction context are connected to the therapeutic association and therefore should serve as reminders of the extinction, causing a stronger fear inhibition when presented during a test. (3) Therapy process factors, according to emotional processing theory, determine the renewal effect (e.g., initial fear activation, and within-session and between-session activation are correlated with the strength of renewal). In this study, however, no differences between the groups at the renewal phase were observed, presumably because the extinction was too strong to enable a renewal of fear at the test phase conducted immediately following the extinction. This hence rendered the two inhibitory tests useless. Study 3 aimed at defining the concept of context in the conditioning and exposure framework. Study 3 utilized the phenomenon known as generalization decrement, whereby a conditioned response is reduced due to change in the environment. This allowed context similarity to be quantified. After an acquisition phase in one context, participants were tested in one of three contexts, two of which differed in only one dimension (configuration of objects vs. features). The third group was tested in the same context and served as control group. The goal was to show that both configuration and features play an important role in the definition of context. There was, however, no significant statistical difference between the groups at the test phases, likely because of context novelty effects (participants exposed to a new context following extinction in another context expected a second extinction phase, and thus demonstrated greater fear than expected in all three groups).
Adapting defensive behavior to the characteristics of a threatening situation is a fundamental function of the brain. Particularly, threat imminence plays a major role for the organization of defensive responses. Acute threat prompts phasic physiological responses, which are usually associated with an intense feeling of fear. In contrast, diffuse and potentially threatening situations elicit a sustained state of anxious apprehension. Detection of the threatening stimulus defines the key event in this framework, initiating the transition from potential to acute threat. Consequently, attention to threat is crucial for supporting defensive behavior. The functions of attention are finely tuned to the characteristics of a threatening situation. Potential threat is associated with hypervigilance, in order to facilitate threat detection. Once a threatening stimulus has been identified, attention is selectively focused on the source of danger. Even though the concepts of selective attention and hypervigilance to threat are well established, evidence for their neural correlates remain scarce. Therefore, a major goal of this thesis is to elucidate the neural correlates of selective attention to acute threat and hypervigilance during potential threat. A second aim of this thesis is to provide a mechanistic account for the interaction of fear and anxiety. While contemporary models view fear and anxiety as mutually exclusive, recent findings for the neural networks of fear and anxiety suggest potential interactions. In four studies, aversive cue conditioning was used to induce acute threat, while context conditioning served as a laboratory model of potential threat. To quantify neural correlates of selective attention and hypervigilance, steady-state visual evoked potentials (ssVEPs) were measured as an index of visuocortical responding. Study 1 compared visuocortical responses to acute and potential threat for high versus low trait-anxious individuals. All individuals demonstrated enhanced electrocortical responses to the central cue in the acute threat condition, suggesting evidence for the neural correlate of selective attention. However, only low anxious individuals revealed facilitated processing of the contexts in the potential threat condition, reflecting a neural correlate of hypervigilance. High anxious individuals did not discriminate among contexts. These findings contribute to the notion of aberrational processing of potential threat for high anxious individuals. Study 2 and 3 realized orthogonal combinations of cue and context conditioning to investigate potential interactions of fear and anxiety. In contrast to Study 1 and 2, Study 3 used verbal instructions to induce potentially threatening contexts. Besides ssVEPs, threat ratings and skin conductance responses (SCRs) were recorded as efferent indices of defensive responding. None of these studies found further evidence for the neural correlates of hypervigilance and selective attention. However, results for ratings and SCRs revealed additive effects of fear and anxiety, suggesting that fear and anxiety are not mutually exclusive, but interact linearly to organize and facilitate defensive behavior. Study 4 tested ssVEPs to more ecologically valid forms of context conditioning, using flickering video stimuli of virtual offices to establish context representations. Contrary to expectations, results revealed decreased visuocortical responses during sustained presentations of anxiety compared to neutral contexts. A disruption of ssVEP signals eventually suggests interferences by continuously changing video streams which are enhanced as a function of motivational relevance. In summary, this thesis provided evidence for the neural correlates of attention only for isolated forms of fear and anxiety, but not for their interaction. In contrast, an additive interaction model of fear and anxiety for measures of defensive responding offers a new perspective on the topography of defensive behavior.
Regulating our immediate feelings, needs, and urges is a task that we are faced with every day in our lives. The effective regulation of our emotions enables us to adapt to society, to deal with our environment, and to achieve long‐term goals. Deficient emotion regulation, in contrast, is a common characteristic of many psychiatric and neurological conditions. Particularly anxiety disorders and subclinical states of increased anxiety are characterized by a range of behavioral, autonomic, and neural alterations impeding the efficient down‐regulation of acute fear. Established fear network models propose a downstream prefrontal‐amygdala circuit for the control of fear reactions but recent research has shown that there are a range of factors acting on this network. The specific prefrontal cortical networks involved in effective regulation and potential mediators and modulators are still a subject of ongoing research in both the animal and human model. The present research focused on the particular role of different prefrontal cortical regions during the processing of fear‐relevant stimuli in healthy subjects. It is based on four studies, three of them investigating a different potential modulator of prefrontal top‐down function and one directly challenging prefrontal regulatory processes. Summarizing the results of all four studies, it was shown that prefrontal functioning is linked to individual differences in state anxiety, autonomic flexibility, and genetic predisposition. The T risk allele of the neuropeptide S receptor gene, a recently suggested candidate gene for pathologically elevated anxiety, for instance, was associated with decreased prefrontal cortex activation to particularly fear‐relevant stimuli. Furthermore, the way of processing has been found to crucially determine if regulatory processes are engaged at all and it was shown that anxious individuals display generally reduced prefrontal activation but may engage in regulatory processes earlier than non‐anxious subjects. However, active manipulation of prefrontal functioning in healthy subjects did not lead to the typical behavioral and neural patterns observed in anxiety disorder patients suggesting that other subcortical or prefrontal structures can compensate for an activation loss in one specific region. Taken together, the current studies support prevailing theories of the central role of the prefrontal cortex for regulatory processes in response to fear‐eliciting stimuli but point out that there are a range of both individual differences and peculiarities in experimental design that impact on or may even mask potential effects in neuroimaging research on fear regulation.
Anxiety disorders (AD) are common, disabling mental disorders, which constitute the most prevalent mental health condition conveying a high individual and socioeconomic burden. Social anxiety disorder (SAD), i.e. fear in social situations particularly when subjectively scrutinized by others, is the second most common anxiety disorder with a life time prevalence of 10%. Panic disorder (PD) has a life time prevalence of 2-5% and is characterized by recurrent and abrupt surges of intense fear and anticipatory anxiety, i.e. panic attacks, occurring suddenly and unexpected without an apparent cue.
In recent years, psychiatric research increasingly focused on epigenetic mechanisms such as DNA methylation as a possible solution for the problem of the so-called “hidden heritability”, which conceptualizes the fact that the genetic risk variants identified so far only explain a small part of the estimated heritability of mental disorders.
In the first part of this thesis, oxytocin receptor (OXTR) gene methylation was investigated regarding its role in the pathogenesis of social anxiety disorder. In summary, OXTR methylation patterns were implicated in different phenotypes of social anxiety disorder on a categorical, neuropsychological, neuroendocrinological as well as on a neural network level. The results point towards a multilevel role of OXTR gene hypomethylation particularly at one CpG site (CpG3, Chr3: 8 809 437) within the protein coding region of the gene in SAD.
The second part of the thesis investigated monoamine oxidase A (MAOA) gene methylation regarding its role in the pathogenesis of panic disorder as well as – applying a psychotherapy-epigenetic approach – its dynamic regulation during the course of cognitive behavioural therapy (CBT) in PD patients. First, MAOA hypomethylation was shown to be associated with panic disorder as well as with panic disorder severity. Second, in patients responding to treatment MAOA hypomethylation was shown to be reversible up to the level of methylation in healthy controls after the course of CBT. This increase in MAOA methylation along with successful psychotherapeutic treatment was furthermore shown to be associated with symptom improvement regarding agoraphobic avoidance in an independent replication sample of non-medicated patients with PD.
Taken together, in the future the presently identified epigenetic patterns might contribute to establishing targeted preventive interventions and personalized treatment options for social anxiety disorder or panic disorder, respectively.