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Sonstige beteiligte Institutionen
Serotonin (5-HT) has been implicated in the regulation of emotions as well as in its pathological states, such as anxiety disorders and depression. Mice with targeted deletion of genes encoding various mediators of central serotonergic neurotransmission therefore provides a powerful tool in understanding contributions of such mediators to homeostatic mechanisms as well as to the development of human emotional disorders. Within this thesis a battery of electrophysiological recordings were conducted in the dorsal raphe nucleus (DRN) and the hippocampus of two murine knockout lines with deficient serotonergic systems. Serotonin transporter knockout mice (5-Htt KO), which lack protein responsible for reuptake of 5-HT from the extracellular space and tryptophan hydroxylase 2 knockout (Tph2 KO) mice, which lack the gene encoding the neuronal 5-HT-synthesising enzyme. First, 5-HT1A receptor-mediated autoinhibition of serotonergic neuron firing in the DRN was assessed using the loose-seal cell-attached configuration. Stimulation of 5-HT1A receptors by a selective agonist, R-8-hydroxy-2-(di-n-propylamino)tetralin (R-8-OH-DPAT), showed a mild sensitisation and a marked desensitisation of these receptors in Tph2 KO and 5-Htt KO mice, respectively. While application of tryptophan, a precursor of 5-HT and a substrate of Tph2, did not cause autoinhibition in Tph2 KO mice due to the lack of endogenously produced 5-HT, data from 5-Htt KO mice as well as heterozygous mice of both KO mice lines demonstrated the presence of autoinhibitory mechanisms as normal as seen in wildtype (WT) controls. When the Tph2-dependent step in the 5-HT synthesis pathway was bypassed by application of 5-hydroxytryptophan (5-HTP), serotonergic neurons of both Tph2 KO and 5-Htt KO mice showed decrease in firing rates at lower concentrations of 5-HTP than in WT controls. Elevated responsiveness of serotonergic neurons from Tph2 KO mice correspond to mild sensitisation of 5-HT1A receptors, while responses from 5-Htt KO mice suggest that excess levels of extracellular 5-HT, created by the lack of 5-Htt, stimulates 5-HT1A receptors strong enough to overcome desensitisation of these receptors. Second, the whole-cell patch clamp recording data from serotonergic neurons in the DRN showed no differences in basic electrophysiological properties between Tph2 KO and WT mice, except lower membrane resistances of neurons from KO mice. Moreover, the whole-cell patch clamp recording from CA1 pyramidal neurons in the hippocampus of 5-Htt KO mice showed increased conductance both at a steady state and at action potential generation. Lastly, magnitude of long-term potentiation (LTP) induced by the Schaffer collateral/commissural pathway stimulation in the ventral hippocampus showed no differences among Tph2 KO, 5-Htt KO, and WT counterparts. Taken together, lack and excess of extracellular 5-HT caused sensitisation and desensitisation of autoinhibitory 5-HT1A receptors, respectively. However, this may not directly translate to the level of autoinhibitory regulation of serotonergic neuron firing when these receptors are stimulated by endogenously synthesised 5-HT. In general, KO mice studied here showed an astonishing level of resilience to genetic manipulations of the central serotonergic system, maintaining overall electrophysiological properties and normal LTP inducibility. This may further suggest existence of as-yet-unknown compensatory mechanisms buffering potential alterations induced by genetic manipulations.
Scientific surveys provide sufficient evidence that anxiety disorders are one of the most common psy-chiatric disorders in the world. The lifetime prevalence rate of anxiety disorder is 28.8% (Kessler, et al., 2005). The most widely studied anxiety disorders are as follows panic disorder (PD), post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), social phobia (or social anxiety disorder), specific phobias, and generalized anxiety disorder (GAD). (NIMH Article, 2009). Classical conditioning is the stable paradigm used from the last one century to understand the neurobi-ology of fear learning. Neurobiological mechanism of fear learning is well documented with the condi-tioning studies. In the therapy of anxiety disorders, exposure based therapies are known to be the most effective approaches. Flooding is a form of exposure therapy in which a participant is exposed to the fear situation and kept in that situation until their fear dissipates. The exposure therapy is based on the phenomena of extinction; this means that a conditioned response diminishes if the conditioned stimulus (CS) is repeatedly presented without an unconditioned stimulus (UCS). One problem with extinction as well as with exposure-based therapy is the problem of fear return (for e.g. renewal, spontaneous recov-ery and reinstatement) after successful extinction. Therefore, extinction does not delete the fear memory trace. It has been well documented that memory processes can be modulated or disrupted using several sci-entific paradigms such as behavioral (for e.g. exposure therapy), pharmacological (for e.g. drug manipu-lation), non-invasive stimulation (for e.g. non-invasive stimulation such as electroconvulsive shock (ECS), transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), etc. However, modulation of memory processes after reactivation or via non-invasive stimulation is still not clear, which is the focus of the current study. In addition, study of genetic variant suggests that genetic differences play a vital role in the psychiatric disorder especially in fear learning. Hence, it is also one of the concerns of the current dissertation to investigate the interaction between gene and reconsolidation of memory. With respect to fear-conditioning, there are three findings in the current dissertation, which are as fol-lows: (i) In the first study we investigated that non-invasive weak electrical stimulation interferes with the consolidation process and disrupts the fear consolidation to attain stable form. This might offer an effective treatment in the pathological memories, for e.g. PTSD, PD, etc. (ii) In the second study we demonstrated whether a brief single presentation of the CS will inhibit the fear recovery. Like earlier studies we also found that reactivation followed by reconsolidation douses fear return. Attenuation of fear recovery was observed in the reminder group compared to the no-reminder group. (iii) Finally, in our third study we found a statistically significant role of brain derived neurotrophic factor (BDNF) polymorphism in reconsolidation. Results of the third study affirm the involvement of BDNF variants (Met vs. Val) in the modulation of conditioned fear memory after its reactivation. In summary, we were able to show in the current thesis modulation of associative learning and recon-solidation via transcranial direct current stimulation and genetic polymorphism.
Coffin-Lowry syndrome is a rare syndromic form of X-linked mental retardation caused by heterogeneous loss-of-function mutations in the gene RPS6KA3 that encodes the RSK2 protein. Clinical features are delayed motor development, small height, progressive skeletal malformations and mental retardation.
Rsk2 deficiency affects behavioral, cellular and molecular functions. To characterize and investigate how this deficiency affects these functions, we made a series of experiments using Rsk2-deficient mice as the animal model for Coffin-Lowry syndrome.
We applied a battery of behavioral tests and included the use of the IntelliCage for the first time as a behavioral paradigm to study anxiety-like behavior and depression-like behavior in Rsk2-deficient mice. Results from the conventional behavioral tests and from the IntelliCage indicate that Rsk2-deficient mice may have an anti-anxiety and anti-depressive phenotype.
We evaluated in Rsk2 deficient mice the relative gene expression of a set of genes coding for proteins related to RSK2 which are involved in fear memory, synaptic plasticity, neurogenesis, learning, emotional behavior and stress. We found gene expression alterations in the prefrontal cortex and striatum. These results suggest that RSK2 may be involved in the expression of the genes.
RSK2 is known to be related to monoamine neurotransmitter function. We measured the levels of dopamine, serotonin and noradrenaline/norepinephrine and their metabolites in different brain regions of Rsk2-deficient mice. We found differences in the dopaminergic and noradrenergic systems suggesting an increased or decreased activity of these neurotransmission systems as a result of Rsk2 deficiency.
Adult neurogenesis is a form of neuronal plasticity and a multi-step process of cell development. We explored if this form of neuronal plasticity was affected by Rsk2-deficiency. Our results indicate that adult hippocampal neurogenesis is not influenced by lifelong Rsk2 deficiency. It would be worth to analyze in the future other aspects of neuroplasticity.
We have confirmed, that behavioral characteristics of Rsk2-deficient mice make them an interesting model to study the Coffin-Lowry syndrome by extending the behavioral characterization on the emotional level. Furthermore, we have extended the characterization of the model on a molecular level, opening new opportunities to study and understand the pathophysiological basis of the Coffin-Lowry syndrome.
Neuroimaging research has highlighted the relevance of well-balanced functional brain interactions as an essential basis for efficient emotion regulation. In contrast, abnormal coupling of fear-processing regions such as the amygdala, the anterior cingulate cortex (ACC) and the insula could be an important feature of anxiety disorders. Although activity alterations of these regions have been frequently reported in specific phobia, little is known about their functional interactions during phobogenic stimulus processing.
To explore these interrelationships in two subtypes of specific phobia – i.e., the blood-injection-injury subtype and the animal subtype – functional connectivity (FC) was analyzed in three fMRI studies. Two studies examined fear processing in a dental phobia group (DP), a snake phobia group (SP) and a healthy control group (HC) during visual phobogenic stimuli presentation while a third study investigated differences between auditory and visual stimuli presentation in DP and HC.
Due to a priori hypotheses of impaired interactions between the amygdala, the ACC and the insula, a first analysis was conducted to explore the FC within these three regions of interest. Based on emerging evidence of functionally diverse subregions, the ACC was further divided into a subgenual, pregenual and dorsal ACC and the insula was divided into a ventral-anterior, dorsal-anterior and posterior region. Additionally, an exploratory seed-to-voxel analysis using the amygdala, ACC and insula as seeds was conducted to scan for connectivity patterns across the whole brain.
The analyses revealed a negative connectivity of the ACC and the amygdala during phobogenic stimulus processing in controls. This connectivity was predominantly driven by the affective ACC subdivision. By contrast, SP was characterized by an increased mean FC between the examined regions. Interestingly, this phenomenon was specific for auditory, but not visual symptom provocation in DP. During visual stimulus presentation, however, DP exhibited further FC alterations of the ACC and the insula with pre- and orbitofrontal regions.
These findings mark the importance of balanced interactions between fear-processing regions in specific phobia, particularly of the inhibitory connectivity between the ACC and the amygdala. Theoretically, this is assumed to reflect top-down inhibition by the ACC during emotion regulation. The findings support the suggestion that SP particularly is characterized by excitatory, or missing inhibitory, (para-) limbic connectivity, reflecting an overshooting fear response based on evolutionary conserved autonomic bottom-up pathways. Some of these characteristics applied to DP as well but only under the auditory stimulation, pointing to stimulus dependency. DP was further marked by altered pre- and orbitofrontal coupling with the ACC and the insula which might represent disturbances of superordinate cognitive control on basal emotion processes. These observations strengthen the assumption that DP is predominantly based on evaluation-based fear responses.
In conclusion, the connectivity patterns found may depict an intermediate phenotype that possibly confers risks for inappropriate phobic fear responses. The findings presented could also be of clinical interest. Particularly the ACC – amygdala circuit may be used as a predictive biomarker for treatment response or as a promising target for neuroscience-focused augmentation strategies as neurofeedback or repetitive transcranial magnetic stimulation.
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.
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.
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.
Integrating neurobiological markers of depression: an fMRI-based pattern classification approach
(2010)
While depressive disorders are, to date, diagnosed based on behavioral symptoms and course of illness, the interest in neurobiological markers of psychiatric disorders has grown substantially in recent years. However, current classification approaches are mainly based on data from a single biomarker, making it difficult to predict diseases such as depression which are characterized by a complex pattern of symptoms. Accordingly, none of the previously investigated single biomarkers has shown sufficient predictive power for practical application. In this work, we therefore propose an algorithm which integrates neuroimaging data associated with multiple, symptom-related neural processes relevant in depression to improve classification accuracy. First, we identified the core-symptoms of depression from standard classification systems. Then, we designed and conducted three experimental paradigms probing psychological processes known to be related to these symptoms using functional Magnetic Resonance Imaging. In order to integrate the resulting 12 high-dimensional biomarkers, we developed a multi-source pattern recognition algorithm based on a combination of Gaussian Process Classifiers and decision trees. Applying this approach to a group of 30 healthy controls and 30 depressive in-patients who were on a variety of medications and displayed varying degrees of symptom-severity allowed for high-accuracy single-subject classification. Specifically, integrating biomarkers yielded an accuracy of 83% while the best of the 12 single biomarkers alone classified a significantly lower number of subjects (72%) correctly. Thus, integrated biomarker-based classification of a heterogeneous, real-life sample resulted in accuracy comparable to the highest ever achieved in previous single biomarker research. Furthermore, investigation of the final prediction model revealed that neural activation during the processing of neutral facial expressions, large rewards, and safety cues is most relevant for over-all classification. We conclude that combining brain activation related to the core-symptoms of depression using the multi-source pattern classification approach developed in this work substantially increases classification accuracy while providing a sparse relational biomarker-model for future prediction.
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.
The present cumulative dissertation comprises three neuroimaging studies using different techniques, functional tasks and experimental variables of diverse nature to investigate human prefrontal cortex (PFC) (dys)function as well as methodological aspects of functional near-infrared spectroscopy (fNIRS). (1) Both dopamine (DA) availability (“inverted U-model”) and excitatory versus inhibitory DA receptor stimulation (“dual-state theory”) have been linked to PFC processing and cognitive control function. Electroencephalography (EEG) was recorded during a Go/NoGo response inhibition task in 114 healthy controls and 181 adult patients with attention-deficit/hyperactivity disorder (ADHD). As a neural measure of prefrontal cognitive response control the anteriorization of the P300 centroid in NoGo- relative to Go-trials (NoGo anteriorization, NGA) was investigated for the impact of genetic polymorphisms modulating catechol-O-methyltransferase efficiency (COMT, Val158Met) in degrading prefrontal DA and inhibitory DA receptor D4 sensitivity (DRD4, 48bp VNTR). Single genes and ADHD diagnosis showed no significant impact on the NGA or behavioral measures. However, a significant COMT×DRD4 interaction was revealed as subjects with relatively increased D4-receptor function (DRD4: no 7R-alleles) displayed an “inverted U”-relationship between the NGA and increasing COMT-dependent DA levels, whereas subjects with decreased D4-sensitivity (7R) showed a U-relationship. This interaction was supported by 7R-allele dose-effects and also reflected by an impact on task behavior, i.e. intraindividual reaction time variability. Combining previous theories of PFC DA function, neural stability at intermediate DA levels may be accompanied by the risk of overly decreased neural flexibility if inhibitory DA receptor function is additionally decreased. The findings of COMT×DRD4 epistasis might help to disentangle the genetic basis of dopaminergic mechanisms underlying prefrontal (dys)function. (2) While progressive neurocognitive impairments are associated with aging and Alzheimer's disease (AD), cortical reorganization might delay difficulties in effortful word retrieval, which is one of the earliest cognitive signs of AD. Therefore, cortical hemodynamic responses were measured with fNIRS during phonological and semantic verbal fluency, and investigated in 325 non-demented, healthy subjects (age: 51-82 years). The predictive value of age, sex, verbal fluency performance and years of education for the cortical hemodynamics was assessed using multiple regression analyses. Age predicted bilaterally reduced inferior frontal junction (IFJ) and increased middle frontal and supramarginal gyri activity in both task conditions. Years of education as well as sex (IFJ activation in females > males) partly predicted opposite effects on activation compared to age, while task performance was not a significant predictor. All predictors showed small effect sizes (-.24 < β < .22). Middle frontal and supramarginal gyri activity may compensate for an aging-related decrease in IFJ recruitment during verbal fluency. The findings of aging-related (compensatory) cortical reorganization of verbal fluency processing might, in combination with other (risk) factors and using longitudinal observations, help to identify neurodegenerative processes of Alzheimer's disease, while individuals are still cognitively healthy. (3) Individual anatomical or systemic physiological sources of variance may hamper the interpretation of fNIRS signals as neural correlates of cortical functions and their association with individual personality traits. Using simultaneous fNIRS and functional magnetic resonance imaging (fMRI) of hemodynamic responses elicited by an intertemporal choice task in 20 healthy subjects, variability in crossmodal correlations and divergence in associations of the activation with trait "sensitivity to reward" (SR) was investigated. Moreover, an impact of interindividual anatomy and scalp fMRI signal fluctuations on fNIRS signals and activation-trait associations was studied. Both methods consistently detected activation within right inferior/middle frontal gyrus, while fNIRS-fMRI correlations showed wide variability between subjects. Up to 41% of fNIRS channel activation variance was explained by gray matter volume (simulated to be) traversed by near-infrared light, and up to 20% by scalp-cortex distance. Extracranial fMRI and fNIRS time series showed significant temporal correlations at the temple. Trait SR was negatively correlated with fMRI but not fNIRS activation elicited by immediate rewards of choice within right inferior/middle frontal gyrus. Higher trait SR increased the correlation between extracranial fMRI signal fluctuations and fNIRS signals, suggesting that task-evoked systemic arousal-effects might be trait-dependent. Task-related fNIRS signals might be impacted by regionally and individually weighted sources of anatomical and systemic physiological error variance. Traitactivation correlations might be affected or biased by systemic physiological arousal-effects, which should be accounted for in future fNIRS studies of interindividual differences.