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People who suffer Social Anxiety Disorder (SAD) are under substantial personal distress and endure impaired normal functioning in at least some parts of everyday life. Next, to the personal suffering, there are also the immense public health costs to consider, as SAD is the most common anxiety disorder and thereby one of the major psychiatric disorders in general. Over the last years, fundamental research found cognitive factors as essential components in the development and maintenance of social fears. Following leading cognitive models, avoidance behaviors are thought to be an important factor in maintaining the developed social anxieties. Therefore, this thesis aims to deepen the knowledge of avoidance behaviors exhibited in social anxiety, which allows to get a better understanding of how SAD is maintained.
To reach this goal three studies were conducted, each using a different research approach. In the first study cutting-edge Virtual Reality (VR) equipment was used to immerse participants in a virtual environment. In this virtual setting, High Socially Anxious (HSA) individuals and matched controls had to execute a social Approach-Avoidance Task (AAT). In the task, participants had to pass a virtual person displaying neutral or angry facial expressions. By using a highly immersive VR apparatus, the first described study took the initial step in establishing a new VR task for the implicit research on social approach-avoidance behaviors. By moving freely through a VR environment, participants experienced near real-life social situations. By tracking body and head movements, physical and attentional approach-avoidance processes were studied.
The second study looked at differences in attention shifts initiated by gaze-cues of neutral or emotional faces. Comparing HSA and controls, enabled a closer look at attention re-allocation with special focus on social stimuli. Further, context conditioning was used to compare task performance in a safe and in a threatening environment. Next to behavioral performance, the study also investigated neural activity using Electroencephalography (EEG) primarily looking at the N2pc component.
In the third study, eye movements of HSA and Low Socially Anxious (LSA) were analyzed using an eye-tracking apparatus while participants executed a computer task. The participants’ tasks consisted of the detection of either social or non-social stimuli in complex visual settings. The study intended to compare attention shifts towards social components between these two tasks and how high levels of social anxiety influence them. In other words, the measurements of eye movements enabled the investigation to what extent social attention is task-dependent and how it is influenced by social anxiety.
With the three described studies, three different approaches were used to get an in-depth understanding of what avoidance behaviors in SAD are and to which extent they are exhibited. Overall, the results showed that HSA individuals exhibited exaggerated physical and attentional avoidance behavior. Furthermore, the results highlighted that the task profoundly influences attention allocation. Finally, all evidence indicates that avoidance behaviors in SAD are exceedingly complex. They are not merely based on the fear of a particular stimulus, but rather involve highly compound cognitive processes, which surpass the simple avoidance of threatening stimuli. To conclude, it is essential that further research is conducted with special focus on SAD, its maintaining factors, and the influence of the chosen research task and method.
Gambling is a popular activity in Germany, with 40% of a representative sample reporting having gambled at least once in the past year (Bundeszentrale für gesundheitliche Aufklärung, 2014). While the majority of gamblers show harmless gambling behavior, a subset develops serious problems due to their gambling, affecting their psychological well-being, social life and work. According to recent estimates, up to 0.8% of the German population are affected by such pathological gambling. People in general and pathological gamblers in particular show several cognitive distortions, that is, misconceptions about the chances of winning and skill involvement, in gambling. The current work aimed at elucidating the biopsychological basis of two such kinds of cognitive distortions, the illusion of control and the gambler’s and hot hand fallacies, and their modulation by gambling problems. Therefore, four studies were conducted assessing the processing of near outcomes (used as a proxy for the illusion of control) and outcome sequences (used as a proxy for the gambler’s and hot hand fallacies) in samples of varying degrees of gambling problems, using a multimethod approach.
The first study analyzed the processing and evaluation of near outcomes as well as choice behavior in a wheel of fortune paradigm using electroencephalography (EEG). To assess the influence of gambling problems, a group of problem gamblers was compared to a group of controls. The results showed that there were no differences in the processing of near outcomes between the two groups. Near compared to full outcomes elicited smaller P300 amplitudes. Furthermore, at a trend level, the choice behavior of participants showed signs of a pattern opposite to the gambler’s fallacy, with longer runs of an outcome color leading to increased probabilities of choosing this color again on the subsequent trial. Finally, problem gamblers showed smaller feedback-related negativity (FRN) amplitudes relative to controls.
The second study also targeted the processing of near outcomes in a wheel of fortune paradigm, this time using functional magnetic resonance imaging and a group of participants with varying degrees of gambling problems. The results showed increased activity in the bilateral superior parietal cortex following near compared to full outcomes.
The third study examined the peripheral physiology reactions to near outcomes in the wheel of fortune. Heart period and skin conductance were measured while participants with varying degrees of gambling problems played on the wheel of fortune. Near compared to full outcomes led to increased heart period duration shortly after the outcome. Furthermore, heart period reactions and skin conductance responses (SCRs) were modulated by gambling problems. Participants with high relative to low levels of gambling problems showed increased SCRs to near outcomes and similar heart period reactions to near outcomes and full wins.
The fourth study analyzed choice behavior and sequence effects in the processing of outcomes in a coin toss paradigm using EEG in a group of problem gamblers and controls. Again, problem gamblers showed generally smaller FRN amplitudes compared to controls. There were no differences between groups in the processing of outcome sequences. The break of an outcome streak led to increased power in the theta frequency band. Furthermore, the P300 amplitude was increased after a sequence of previous wins. Finally, problem gamblers compared to controls showed a trend of switching the outcome symbol relative to the previous outcome symbol more often.
In sum, the results point towards differences in the processing of near compared to full outcomes in brain areas and measures implicated in attentional and salience processes. The processing of outcome sequences involves processes of salience attribution and violation of expectations. Furthermore, problem gamblers seem to process near outcomes as more win-like compared to controls. The results and their implications for problem gambling as well as further possible lines of research are discussed.
Pavlovian fear conditioning describes a form of associative learning in which a previously neutral stimulus elicits a conditioned fear response after it has been temporally paired with an aversive consequence. Once acquired, the fear response can be extinguished by repeatedly presenting the former neutral stimulus in the absence of the aversive consequence. Although most patients suffering from anxiety disorders cannot recall a specific conditioned association between a formerly neutral stimulus and the feeling of anxiety, the produced behavioral symptoms, such as avoidance or safety behavior to prevent the anticipated aversive consequence are commonly exhibited in all anxiety disorders. Moreover, there is considerable similarity between the neural structures involved in fear and extinction in the rodent and in the human. Translational research thus contributes to the understanding of neural circuitries involved in the development and maintenance of anxiety disorders, and further provides hypotheses for improvements in treatment strategies aiming at inhibiting the fear response.
Since the failure to appropriately inhibit or extinguish a fear response is a key feature of pathological anxiety, the present preclinical research focuses on the interplay between the amygdala and the medial prefrontal cortex (mPFC) during fear learning with particular regard to the prefrontal recruitment during fear extinction and its recall. By firstly demonstrating an increased mPFC activity over the time course of extinction learning with functional near-infrared spectroscopy, the main study of this dissertation focused on repetitive transcranial magnetic stimulation (rTMS) as brain stimulation technique suitable to enhance extinction learning. Since hypofrontality is assumed to underlie the maintenance of pathological anxiety, rTMS application revealed an increased mPFC activity, which resulted in a decreased fear response on the behavioral level both during extinction learning as well as during the recall of extinction 24 hours later and in the absence of another stimulation. The following attempt to improve the generalization of extinction with rTMS from an extinguished stimulus to a second stimulus which was reinforced but not extinguished was at least partially evidenced. By revealing an increased prefrontal activity to the non-extinguished stimulus, the active and the placebo rTMS condition, however, did not differ on behavioral parameters. These preclinical findings were discussed in the light of genetic and environmental risk factors with special regard to the combination of a risk variant of the neuropeptide S receptor 1 gene polymorphism (NPSR1 rs324981) and anxiety sensitivity. While the protective homozygous AA genotype group showed no correlation with anxiety sensitivity, the NPSR1 T genotype group exhibited an inverse correlation with anxiety sensitivity in the presence of emotionally negative stimuli. In light of other findings assuming a role of the NPSR1 T allele in panic disorder, the revealed hypofrontality was discussed to define a risk group of patients who might particularly benefit from an augmentation of exposure therapy with rTMS.
Taken together, the presented studies support the central role of the prefrontal cortex in fear extinction and suggest the usefulness of rTMS as an augmentation strategy to exposure therapy in order to decrease therapy relapse rates. The combination of rTMS and extinction has been herein evidenced to modulate fear processes in a preclinical approach thereby establishing important implications for the design of future clinical studies.
Theories of attention deficit hyperactivity disorder (ADHD) aetiology have placed a focus on impaired behavioural inhibition presumably leading to executive function (EF) deficits. Neuroimaging studies report neurophysiological findings consistent with these hypothesised impairments, and investigations of functional brain activation from a network perspective report hypoactivation in the frontoparietal network as well as hyperactivation in the dorsal attention network. Studies investigating the acute effects of stimulant medication on EF show an improvement on behavioural EF measures including working memory. In addition, methylphenidate (MPH) was shown to up-regulate the task-positive/ frontoparietal network in children and adolescents with ADHD. So far, there are only few studies investigating the impact of ADHD on behavioural and neurophysiological EF measures as well as the effect of several weeks of stimulant medication in adult patients.
The importance of the catechol-O-methyltransferase (COMT) enzyme for subcortical and cortical dopaminergic and noradrenergic functioning furthermore led to studies investigating a potential interactive impact of COMT genotype and ADHD on neuropsychological functioning, with a particular focus on working memory. The results of these studies were very heterogeneous. In addition, as none of the studies compared the results of ADHD patients to those of a healthy control group, possible differential effects of COMT in patients and healthy controls could not be examined.
The aim of this dissertation was to investigate selective attention properties of the central executive component during a working memory task and to transfer this task to fMRI. A third study then aimed to investigate the effects of adult ADHD (aADHD), MPH, and COMT genotype on working memory with a particular focus on activation of the task-positive network during the analysis of the fMRI data.
The first study (EEG) could replicate and extend the results from previous research. This study could furthermore connect the overall activation in frontal areas to suppression efficiency in posterior visual areas as well as establish the impact of hyperactive/ impulsive ADHD symptoms on task performance. The second study (fMRI) allowed the successful transfer of the paradigm to fMRI, and the further replication and extension of previous findings. In addition, this study showed the sensitivity of the task to the effects of the COMT genotype. The third study (fMRI) was one of the first studies that exploratorily investigated the effects COMT in a sample of aADHD patients and a comparable healthy control group. This study showed an interactive effect of these two factors on neuropsychological measures as well as on fMRI activation during a classic n-back working memory task. In addition, this task led to more activation in the task-positive network of the aADHD group compared to a healthy control group in the absence of performance differences, pointing towards compensatory activation in the aADHD group. Furthermore, activation in the frontal cortex was increased in patients taking MPH compared to a placebo. The fMRI data from the selective attention task moreover showed decreased activation in the right DLPFC of the patient group, which was associated with reduced suppression efficiency across all participants. The clinical effect of MPH in the third study was visible but did not reach significance, which is probably attributable to a lack of experimental power.
The studies in this dissertation could successfully replicate and extend previous findings. A goal for future studies should be the further investigation of the interactive effects of COMT genotype and aADHD on neuropsychological test results and fMRI activation, but also on medication response and adverse effects. In this context, the adaptation of a network perspective during the analysis of fMRI data seems to be the best way to detect existing between-group differences.
In this study, we examined the regional grey matter density in 35 spider phobic patients and 33 age, gender and education matched healthy controls. We used a method called Voxel-Based Morphometry, which allowed us to conduct a voxel- by-voxel analysis of the entire brain. We also tried to determine if there was any relationship between the severity of fear (expressed in BAT and SPQ score) and grey matter density. Based on previous findings, we expected to find structural changes in the following brain regions:
- prefrontal cortex;
- orbitofrontal cortex;
- anterior cingulate cortex;
- insula;
- visual and associative cortices.
Between-group comparison of spider phobic patients and healthy controls yielded no significant results. Additionally, and as expected, we did not find a between- group difference in TIV. Surprisingly, however, we found several brain regions whose GMD was significantly correlated with severity of spider phobia.
The score that correlated with several regions GMD and yielded the largest cluster was the SPQ. SPQ was positively correlated with dorsal anterior cingulate, right insula and left inferior parietal lobule. Final distance in centimetres was correlated with left superior frontal gyrus and right paracentral lobule densities. All correlations were observed at a cluster level and no significant results at peak level were found. Interestingly, out of all BAT fear values, only BAT when the spider was taken away had a positive correlation with GMD (vermis). There were no indications of reduced GMD in spider phobic patients.
Overall, our regions of significance were in line of those of other structural and functional neuroimaging studies in the field of specific phobia. As expected, we found GMD changes in the prefrontal cortex, ACC, insula and the associative
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cortices. The functions of these regions such as processing of disgust, attention, autonomous responses, consolidation of memory and regulation of affect support the possible involvement of these structures in SP.
We did, however, also yield some unexpected results (vermis, right paracentral lobule). Interestingly and in contrast to other studies, our results were only limited to the phobic group itself- we found no regions of significance in the SP-HC between-group analysis.
In the future, more VBM studies with larger size of spider phobic subjects should be conducted, further investigating both the between-group differences and the correlation between spider phobia severity and GMD. Additionally, studies should investigate the relationship between structural changes and activation patterns observed in fMRI, find out whether brain changes precede the clinical symptoms or vice versa and see, if structural changes normalize in response to CBT the same way functional changes do.
Due to the global aging society and the enormous global incidence and prevalence rates that will result in the coming years, Alzheimer's Dementia (AD) represents a growing challenge for the health care system. The pathogenesis, which is unclear in parts, the chronic progression of AD, which often lasts for years, as well as insufficient diagnostic and therapeutic options complicate an adequate psychotherapeutic and medical approach to the disease. To date, AD is also considered an incurable disease.
Therefore, it is essential to gain deeper insights into the early detection or even prevention of AD. Consideration of prodromal syndromes such as Mild Cognitive Impairment (MCI) can provide significant evidence about high-risk groups for AD progression and differentiate cognitively "normal" aging individuals from those with pathological cognitive decline. Thus, for example, functional Near-Infrared Spectroscopy (fNIRS) imaging helps identify early neurodegenerative processes. In contrast, potential risk factors and predictors of later-onset clinical symptoms of MCI and AD can most often be revealed and quantified via the use of neuropsychiatric test batteries.
The present thesis consists of four studies and aimed to assess and describe the pathological cognitive decline in a sample of elderly study participants (age: ≥ 70 years; N = 604 at baseline) of the longitudinal, observational, and prospective "Vogel Study" from Würzburg, Germany, who were primarily healthy at baseline, over two measurement time points approximately 3 years apart, to differentiate between healthy and diseased study participants and to define predictors of MCI/AD and longitudinal study dropout.
Studies 1 and 2 differentiated healthy study participants from MCI patients based on the baseline hemodynamic response of the parietal cortex recorded by fNIRS during the processing of a paradigm (here: Angle Discrimination Task [ADT]) for visual-spatial processing performance. Neuronal hypoactivity was found in the MCI patients, with both healthy study participants and MCI patients showing higher superior and right hemispheric activation. MCI patients had more difficulty resolving the paradigm. Thus, no evidence of possible compensatory mechanisms was uncovered in the MCI patients.
Study 3 first defined the four latent factors declarative memory, working memory, attention, and visual-spatial processing based on structural equation model (SEM) calculations of the sample using adequate measurement (in-)variant confirmatory factor models from the baseline assessment to the first of a total of two follow-up assessments after approximately 3 years. This allowed a dimensional assessment of pathological cognitive decline versus classificatory-categorical assignment (healthy/diseased) of the sample. In addition, the superiority of the latent factor approach over a composite approach was demonstrated. Next, using a mixed-model approach, predictive analyses were calculated for the prediction of latent factors at first follow-up by baseline risk factors. The sex of study participants proved to be the best predictor of cognitive change in all the cognitive domains, with females performing better than men in the memory domains. Specifically, for declarative memory, older age predicted lower performance regardless of sex. Additional predictive evidence emerged for low serum levels of Brain-Derived Neurotrophic Factor (BDNF) on lower attention performance and higher depression symptoms on lower visual-spatial processing performance.
Study 4 further reported baseline predictors of study dropout at first follow-up. Cognitive performance, as defined in Study 3 using the four latent cognitive factors, was a predictor of study dropout for cognitive decline in the domains of declarative memory, attention, and visual-spatial processing. Conspicuous dementia screening on the Mini-Mental Status Examination (MMSE) also predicted dropout.
Overall, both the use of fNIRS imaging to detect visual-spatial processing performance in the parietal cortex during applying ADT and the dimensional perspective of the neuropsychiatric test battery in the context of prediction and dropout analyses were found to be suitable for early detection research of MCI and AD. Finally, the results will be interpreted in the overall context and implications, limitations, and perspectives will be discussed.
Predictability of threat is one of the key modulators of neural activity in fear and anxiety-related threat processes and there is a considerable number of studies focusing on the exact contribution of centromedial amygdala and Bed nucleus of stria terminalis (BNST) in animals as well as in humans. In this research field, some studies already investigated the differential involvement of both areas during temporally predictable and unpredictable threat processes in humans. However, these studies showed several limitations e.g. small sample size, no predictable threat conditions, no separation of anticipation and confrontation processes, which should be addressed in future studies. Furthermore, evidence for group-based inter-individual differences of amygdala and BNST activity during predictable and unpredictable threat processes have not been studied extensively.
Several studies suggest a relevant role of the amygdala and BNST activity in phobic processes in patients with specific phobia, but no study so far has investigated the exact contribution of centromedial amygdala (CM) and BNST during temporally predictable and unpredictable threat processes in specific phobia.
This thesis consisted of three studies and aimed to evaluate the exact contribution of CM and BNST during temporally predictable and unpredictable threat anticipation and confrontation with the use of an optimized functional magnetic resonance imaging (fMRI) paradigm, which aimed to solve methodological limitations of recent studies. Study 1 used a large sample of healthy participants who were grouped based on NPSR1 genotype, and study 2 and study 3 used a sample of patients with spider phobia. In sum, the results of all three studies indicated, that BNST is more relevant for anticipation processes as compared to the CM. Contrary, during the confrontation phase the CM displays a greater relevance for threat confrontation processes.
In recent years, various studies have investigated the extent to which treatment success can be predicted in patients with anxiety disorders based on pre-treatment fMRI activity. Therefore, this was investigated for the first time in study 3 in patients with spider phobia during temporally predictable and unpredictable threat processes. Results indicated that independent of temporal predictability lower anterior cingulate cortex (ACC) activity during threat anticipation and engaged BNST during threat confrontation might be benefitting factors for successful therapy response in spider phobia.