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Institute
- Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie (260) (remove)
Sonstige beteiligte Institutionen
- Clinical Trial Center (CTC) / Zentrale für Klinische Studien Würzburg (ZKSW) (2)
- Department of Nuclear Medicine, Kanazawa University (1)
- Interdisziplinäres Zentrum für Klinische Forschung (IZKF) Würzburg (1)
- Johns Hopkins School of Medicine, Baltimore, MD, U.S. (1)
- Johns Hopkins University School of Medicine (1)
- Maastricht University, Department of Psychiatry and Neuropsychology (1)
Emotional-associative learning processes such as fear conditioning and extinction are highly relevant to not only the development and maintenance of anxiety disorders (ADs), but also to their treatment. Extinction, as the laboratory analogue to behavioral exposure, is assumed a core process underlying the treatment of ADs. Although exposure-based treatments are highly effective for the average patient suffering from an AD, there remains a gap in treatment efficacy with over one third of patients failing to achieve clinically significant symptom relief. There is ergo a pressing need for intensified research regarding the underlying neural mechanisms of aberrant emotional-associative learning processes and the neurobiological moderators of treatment (non-)response in ADs.
The current thesis focuses on different applications of the fundamental principles of fear conditioning and extinction by using two example cases of ADs from two different multicenter trials. First, we targeted alterations in fear acquisition, extinction, and its recall as a function of psychopathology in panic disorder (PD) patients compared to healthy subjects using fMRI. Second, exposure-based therapy and pre-treatment patient characteristics exerting a moderating influence on this essential learning process later on (i.e. treatment outcome) were examined using multimodal functional and structural neuroimaging in spider phobia.
We observed aberrations in emotional-associative learning processes in PD patients compared to healthy subjects indicated by an accelerated fear acquisition and an attenuated extinction recall. Furthermore, pre-treatment differences related to defensive, regulatory, attentional, and perceptual processes may exert a moderating influence on treatment outcome to behavioral exposure in spider phobia. Although the current results need further replication, on an integrative meta level, results point to a hyperactive defensive network system and deficient emotion regulation processes (including extinction processes) and top-down control in ADs. This speaks in favor of transdiagnostic deficits in important functional domains in ADs.
Deficits in transdiagnostic domains such as emotion regulation processes could be targeted by enhancing extinction learning or by means of promising tools like neurofeedback. The detection of pre-treatment clinical response moderators, for instance via machine learning frameworks, may help in supporting clinical decision making on individually tailored treatment approaches or, respectively, to avoid ineffective treatment and its related financial costs. In the long run, the identification of neurobiological markers which are capable of detecting non-responders a priori represents an ultimate goal.
Empathy, the act of sharing another person’s affective state, is a ubiquitous driver for helping others and feeling close to them. These experiences are integral parts of human behavior and society. The studies presented in this dissertation aimed to investigate the sustainability and stability of social closeness and prosocial decision-making driven by empathy and other social motives. In this vein, four studies were conducted in which behavioral and neural indicators of empathy sustainability were identified using model-based functional magnetic resonance imaging (fMRI).
Applying reinforcement learning, drift-diffusion modelling (DDM), and fMRI, the first two studies were designed to investigate the formation and sustainability of empathy-related social closeness (study 1) and examined how sustainably empathy led to prosocial behavior (study 2). Using DDM and fMRI, the last two studies investigated how empathy combined with reciprocity, the social norm to return a favor, on the one hand and empathy combined with the motive of outcome maximization on the other hand altered the behavioral and neural social decision process.
The results showed that empathy-related social closeness and prosocial decision tendencies persisted even if empathy was rarely reinforced. The sustainability of these empathy effects was related to recalibration of the empathy-related social closeness learning signal (study 1) and the maintenance of a prosocial decision bias (study 2). The findings of study 3 showed that empathy boosted the processing of reciprocity-based social decisions, but not vice versa. Study 4 revealed that empathy-related decisions were modulated by the motive of outcome maximization, depending on individual differences in state empathy.
Together, the studies strongly support the concept of empathy as a sustainable driver of social closeness and prosocial behavior.
Fear and anxiety disorders – interaction of AVP and OXT brain systems with the serotonergic system
(2023)
Anxiety disorders pose a great burden onto society and economy and can have devastating consequences for affected individuals. Treatment options are still limited to psychopharmacotherapy originally developed for the treatment of depression and behavioral therapy. A combination of genetic traits together with aversive events is most likely the cause of these diseases. Gene x environment studies are trying to find a link between genetic traits and specific negative circumstances. In a first study, we focused on social anxiety disorder (SAD), which is the second most-common anxiety disorder after specific phobias. We used a social fear conditioning (SFC) paradigm, which is able to mimic the disease in a mouse model. We wanted to investigate protein levels, as well as mRNA expression of immediate early genes (IEGs), to determine brain areas affected by the paradigm. We also included genes of the vasopressin (AVP)-, oxytocin (OXT)-, neuropeptide Y (NPY)-, and the serotonin system, to investigate the effects of SFC on neurotransmitter gene expression levels in brain regions related to social as well as fear-related behavior. AVP and OXT regulate a lot of different social and anxiety-related behaviors, both positive and negative. Finding a link between different neurotransmitter systems in the development of anxiety disorders could help to identify potential targets for new treatment approaches, which are desperately needed, because the rate of patients not responding to available treatment is very high.
We were able to show altered gene expression of the IEGs cFos and Fosl2, as well as a change in number and density of cFOS-positive cells in the dorsal hippocampus, indicating an influence of SFC on neuronal activity. Our results reveal a possible involvement of anterior dentate gyrus (DG), as well as cornu ammonis area 1 (CA1) and CA3 in the dorsal hippocampus during the expression of social fear. Contrary to our hypothesis, we were not able to see changes in neuronal activity through expression changes of IEGs in the amygdala. Significant higher IEG immunoreactivity and gene expression in the dorsal hippocampus of animals without fear conditioning (SFC-), compared to animals with fear conditioning (SFC+), indicate an involvement of different hippocampal regions in two possible scenarios. Either as elevated gene expression in SFC- animals compared to SFC+ animals or as reduction in SFC+ animals compared to SFC- animals. However, this question cannot be answered without an additional control of basal IEG-activity without social interaction. The NPY system in general and the neuropeptide y receptor type 2 in particular seem to be involved in regulating the response to social fear, mostly through the septum region. In addition to that, a possible role for the induction of social fear response could be identified in the serotonergic system and especially the serotonin receptor 2a of the PVN.
In a second study we focused on changes in the serotonergic system. A polymorphism in the human serotonin transporter (5-HTT) gene is associated with higher risks for the development of anxiety disorders. This makes the 5-HTT a widely used target to study possible causes and the development of anxiety disorders. In mice, a genetically induced knockout of the 5-Htt gene is associated with increased anxiety-like behavior. High amounts of stress during pregnancy, also known as prenatal stress, significantly increase the risk to develop psychiatric disorders for the unborn child. We utilized a prenatal stress paradigm in mice heterozygous for the 5-Htt gene. Some of the animals which had been subjected to prenatal stress showed noticeably “unsocial” interaction behavior towards conspecifics. Again, we were searching for links between the serotonergic system and AVP- and OXT systems. Through quantitative gene expression analysis, we were able to show that both AVP and OXT neuromodulator systems are affected through prenatal stress in female mice, but not in male mice. The 5-Htt genotype seems to be only slightly influential to AVP, OXT or any other neurotransmitter system investigated. Gene expression of AVP and OXT brain systems is highly influenced through the estrous cycle stages of female mice. Additionally, we analyzed the AVP and OXT neuropeptide levels of mice with different 5-Htt genotypes and in both sexes, in order to see whether the production of AVP and OXT is influenced by 5-Htt genotype. On neuropeptide level, we were able to identify a sex difference for vasopressin-immunoreactive (ir) cells in the PVN, with male mice harboring significantly more positive cells than female mice.
Social contact is an integral part of daily life. Its health-enhancing effects include reduced negative affective experiences of fear and anxiety, a phenomenon called social buffering. This dissertation studied different forms of social contact and their anxiety-buffering effects with diverse methodologies.
The laboratory-based first study investigated minimal social contact in the context of pain relief learning. Results showed that the observed decreased autonomic and increased subjective fear responses following pain relief learning were independent of social influence. The minimalistic and controlled social setting may have prevented social buffering. Study 2 targeted social buffering in daily life using Ecological Momentary Assessment. We repeatedly assessed individuals’ state anxiety, related cardiovascular responses, and aspects of social interactions with smartphones and portable sensors on five days. Analyses of over 1,500 social contacts revealed gender-specific effects, e.g., heart rate-reducing effects of familiarity in women, but not men. Study 3 examined anxiety, loneliness, and related social factors in the absence of social contact due to social distancing. We constructed and validated a scale measuring state and trait loneliness and isolation, and analysed its link to mental health. Results include a social buffering-like relation of lower anxiety with more trait sociability and sense of belonging.
In sum, the studies showed no fear reduction by minimal social contact, but buffering effects relating to social and personal factors in more complex social situations. Anxiety responses during daily social contacts were lower with more familiar or opposite-gender interaction partners. During limited social contact, lower anxiety related to inter-individual differences in sociability, social belonging, and loneliness. By taking research from lab to life, this dissertation underlined the diverse nature of social contact and its relevance to mental health.
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.
Even though exposure-based cognitive behavioral therapy (CBT) constitutes a first-line treatment for anxiety disorders, a substantial proportion of patients does not respond in a clinically significant manner. The identification of pre-treatment patient characteristics that are associated with treatment outcome might aid in improving response rates. Therefore, the present doctoral thesis aimed at investigating moderators of treatment outcome in anxiety disorders: first, we investigated the neural correlates of comorbidity among primary panic disorder/agoraphobia (PD/AG) and secondary social anxiety disorder (SAD) moderating treatment outcome towards exposure-based CBT. Second, pre-treatment functional resting-state connectivity signatures of treatment response in specific phobia were studied. Within the first study, we compared PD/AG patients with or without secondary SAD regarding their clinical and neurofunctional outcome towards a manualized CBT treatment focusing on PD/AG symptoms. Prior to treatment, PD/AG+SAD compared to PD/AG-SAD patients exhibited a specific neural signature within the temporal lobe, which was attenuated to the level of PD/AG-SAD patients afterwards. CBT was equally effective in both groups. Thus, comorbidity among those two anxiety disorders did not alter treatment outcome substantially. This might be due to the high overlap of shared pathophysiological features within both disorders. In the second study, we assessed pre-treatment functional resting-state connectivity within a sample of spider phobic patients that were treated with massed in virtuo exposure. We found responders already prior to treatment to be characterized by stronger inhibitory frontolimbic connectivity as well as heightened connectivity between the amygdala and regions related to the ventral visual stream. Furthermore, patients demonstrating high within-session extinction exhibited pronounced intrinsic prefrontal connectivity. Our results point to responders exhibiting a brain prepared for the mechanism of action of exposure. Taken together, results highlight the major impact of pre-treatment characteristics on treatment outcome. Both, PD/AG+SAD patients as well as responders within the SpiderVR study exhibited heightened activation or connectivity within the ventral visual pathway and the amygdala. Pronounced visual processing together with enhanced executive control and emotion regulation seem to constitute a fruitful soil for successful exposure. The results provide starting points for personalized treatment approaches in order to improve treatment success in the anxiety disorders. Future studies are needed to investigate the benefit of neuroscientifically informed CBT augmentation strategies such as repetitive transcranial magnetic stimulation.
While the healthy brain works through balanced synaptic communication between
glutamatergic and GABAergic neurons to coordinate excitation (E) and inhibition (I), disruption
of E/I balance interferes with synaptic communication, information processing, and ultimately
cognition. Multiple line of evidence indicates that E/I imbalance represents the
pathophysiological basis of a wide spectrum of mental disorders. Genetic screening
approaches have identified Cadherin-13 (CDH13). as a risk gene across neurodevelopmental
and mental disorders. CDH13 regulates several cellular and synaptic processes in brain
development and neuronal plasticity in adulthood. In addition to other functions, it is specifically
localized at inhibitory synapses of parvalbumin- and somatostatin-expressing GABAergic
neurons. In support of CDH13’s function in moderating E/I balance, electrophysiological
recordings of hippocampal slices in a CDH13-deficient mouse model revealed an increase in
basal inhibitory but not excitatory synaptic transmission. Moreover, the search for genetic
variants impacting functional expression of the CDH13 gene identified SNP (single nucleotide
polymorphism)) rs2199430 in intron 1 to be associated with differential mRNA concentrations
in human post-mortem brain across the three genotypes CDH13G/G, CDH13A/G and CDH13A/A
.
This work therefore aimed to further validate these findings in a complementary human model
by using induced pluripotent stem cells (iPSCs). The application of human iPSCs in research
has replaced the use of embryonic cells, resolving the ethical conflict of destructive usage of
human embryos. Investigating CDH13’s mode of action in inhibitory synapses was predicted
to facilitate mechanistic insight into the effects of CDH13 gene variants on E/I network activity,
which can then be targeted to reinstate balance.
Genome-wide association studies have identified rare copy number variants (CNVs) resulting
in a deletion (or duplication) of CDH13. To reduce genetic background variance, a set of
isogenic iPSC lines with a gene dose-dependent deficiency of CDH13 (CDH13-/- and CDH13+/-
) was generated by using the Clustered Regulatory Interspaced Short Palindromic
Repeats/CRISPR-associated protein 9 (CRISPR/Cas9) system. These CRISPRed iPSCs
carrying a single or two allele(s) with CDH13 inactivation facilitate investigation of CDH13
function in cellular processes, at inhibitory synapses and in neuronal network activity. In
addition, iPSCs carrying allelic SNP rs2199430 variants were used to study the effects of
common genetic variation of CDH13. These cell lines were differentiated into pure
glutamatergic and GABAergic neurons and co-cultured to generate neuronal networks allowing
its activity to be measured and correlated with electrophysiological signatures of differential
CDH13 genotypes. The work towards assessment of neuronal network activity of the iPSC
lines was subdivided into three major steps: first, generating rtTA/Ngn2 and rtTA/Ascl1-positive
iPSCs via a lentivirus-mediated approach; second, differentiating pure glutamatergic and
GABAergic neurons from the genetically transduced iPSCs and co-culturing of pure
glutamatergic and GABAergic neurons in a pre-established ratio (65:35) by direct
differentiation upon supplementation with doxycycline and forskolin on a microelectrode array
(MEA) chip; and, finally, recording of neuronal network activity of iPSC lines after 49 days in
vitro, followed by extraction and analyses of multiple MEA parameters.
x
Based on the MEA parameters, it was confirmed that complete CDH13 knockout as well as
heterozygous deficiency influence E/I balance by increasing inhibition. It was further revealed
that common SNP variation alters the signature of neuronal network activity. Specifically,
CDH13 deficiency resulted in a significant reduction in network burst duration (NBD), reduced
number of detected spikes within a network burst and reduction in network burst rate (NBR)
compared to the control (CDH13G/G). CDH13A/G and CDH13A/A showed similarities with the
CRISPRed CDH13-deficient networks by showing a significant reduction in the NBD and a
reduced number of detected spikes within a network compared to CDH13G/G. Strikingly. there
was a significant increase in the NBR of the CDH13A/G and CDH13A/A compared to CDH13G/G
networks. CDH13A/G networks exhibited significant differences in both parameters. At the
cellular level, this indicates that signalling pathways which determine the length and frequency
of network bursts differ among allelic variants of SNP rs2199430, thus confirming functional
relevance of this intronic SNP.
In summary, CDH13-deficient isogenic iPSC lines were generated using CRISPR/Cas9, iPSCs
were genetically transduced via a lentivirus approach, direct differentiation of
glutamatergic/GABAergic neurons derived from transduced iPSCs were used to establish a
scalable co-culture system, and network activity was recorded by MEA using pre-established
parameters to extract and analyze activity information. The results indicate that iPSC-derived
neuronal networks following CRISPR/Cas9-facilitated CDH13 inactivation, as well as networks
with allelic SNP variants of CDH13, moderate E/I balance, thus advancing understanding of
CDH13 function at inhibitory synapses and elucidating the effects of rare and common CDH13
gene variation.
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.
Aggression and deficient cognitive control problems are widespread in psychiatric disorders, including major depressive disorder (MDD). These abnormalities are known to contribute significantly to the accompanying functional impairment and the global burden of disease. Progress in the development of targeted treatments of excessive aggression and accompanying symptoms has been limited, and there exists a major unmet need to develop more efficacious treatments for depressed patients. Due to the complex nature and the clinical heterogeneity of MDD and the lack of precise knowledge regarding its pathophysiology, effective management is challenging. Nonetheless, the aetiology and pathophysiology of MDD has been the subject of extensive research and there is a vast body of the latest literature that points to new mechanisms for this disorder. Here, we overview the key mechanisms, which include neuroinflammation, oxidative stress, insulin receptor signalling and abnormal myelination. We discuss the hypotheses that have been proposed to unify these processes, as many of these pathways are integrated for the neurobiology of MDD. We also describe the current translational approaches in modelling depression, including the recent advances in stress models of MDD, and emerging novel therapies, including novel approaches to management of excessive aggression, such as anti-diabetic drugs, antioxidant treatment and herbal compositions.
There is still limited knowledge about alterations of blood concentrations of psychotropic drugs during pregnancy, the transfer of psychotropic drugs into breastmilk and the effects on exposed children. We investigated changes in concentrations of psychopharmacological medication during pregnancy and lactation in serum and breastmilk at different time points in a naturalistic sample of 60 mothers and observed the development of the exposed children in the first 12 months. We found a decrease in serum concentrations from the first to the second trimester of amitriptyline, duloxetine, escitalopram, quetiapine and sertraline. Citalopram stayed rather stable during pregnancy, sertraline levels interestingly increased again from the second to the third trimester. High concentration-by-dose ratios in breastmilk were found for venlafaxine as well as lamotrigine, low for quetiapine and clomipramine. Similarly, clomipramine and quetiapine showed low milk/serum–penetration ratios. Regarding the birth outcome measures in children, we found no significant differences between in utero exposed compared to nonexposed newborns. There were no significant differences in the development in the first 12 months. Psychotropic medication in the peripartum needs a balancing of risks and benefits and a continuous therapeutic drug monitoring can be a guidance for clinicians to monitor drug alteration patterns, which are likely to occur due to physiological pregnancy-associated changes in pharmacokinetics. Accordingly, therapeutic drug monitoring can optimize a medication in pregnancy and lactation with the lowest effective dose.