Development of quality standards for multi-center, longitudinal magnetic resonance imaging studies in clinical neuroscience

Magnetic resonance imaging (MRI) data is generated by a complex procedure. Many possible sources of error exist which can lead to a worse signal. For example, hidden defective components of a MRI-scanner, changes in the static magnetic field caused by a person simply moving in the MRI scanner room as well as changes in the measurement sequences can negatively affect the signal-to-noise ratio (SNR). A comprehensive, reproducible, quality assurance (QA) procedure is necessary, to ensure reproducible results both from the MRI equipment and the human operator of the equipment. To examine the quality of the MRI data, there are two possibilities. On the one hand, water or gel-filled objects, so-called "phantoms", are regularly measured. Based on this signal, which in the best case should always be stable, the general performance of the MRI scanner can be tested. On the other hand, the actually interesting data, mostly human data, are checked directly for certain signal parameters (e.g., SNR, motion parameters). This thesis consists of two parts. In the first part a study-specific QA-protocol was developed for a large multicenter MRI-study, FOR2107. The aim of FOR2107 is to investigate the causes and course of affective disorders, unipolar depression and bipolar disorders, taking clinical and neurobiological effects into account. The main aspect of FOR2107 is the MRI-measurement of more than 2000 subjects in a longitudinal design (currently repeated measurements after 2 years, further measurements planned after 5 years). To bring MRI-data and disease history together, MRI-data must provide stable results over the course of the study. Ensuring this stability is dealt with in this part of the work. An extensive QA, based on phantom measurements, human data analysis, protocol compliance testing, etc., was set up. In addition to the development of parameters for the characterization of MRI-data, the used QA-protocols were improved during the study. The differences between sites and the impact of these differences on human data analysis were analyzed. The comprehensive quality assurance for the FOR2107 study showed significant differences in MRI-signal (for human and phantom data) between the centers. Occurring problems could easily be recognized in time and be corrected, and must be included for current and future analyses of human data. For the second part of this thesis, a QA-protocol (and the freely available associated software "LAB-QA2GO") has been developed and tested, and can be used for individual studies or to control the quality of an MRI-scanner. This routine was developed because at many sites and in many studies, no explicit QA is performed nevertheless suitable, freely available QA-software for MRI-measurements is available. With LAB-QA2GO, it is possible to set up a QA-protocol for an MRI-scanner or a study without much effort and IT knowledge. Both parts of the thesis deal with the implementation of QA-procedures. High quality data and study results can be achieved only by the usage of appropriate QA-procedures, as presented in this work. Therefore, QA-measures should be implemented at all levels of a project and should be implemented permanently in project and evaluation routines

Interaction of developmental factors and ordinary stressful life events on brain structure in adults

An interplay of early environmental and genetic risk factors with recent stressful life events (SLEs) in adulthood increases the risk for adverse mental health outcomes. The interaction of early risk and current SLEs on brain structure has hardly been investigated. Whole brain voxel-based morphometry analysis was performed in N = 786 (64.6% female, mean age = 33.39) healthy subjects to identify correlations of brain clusters with commonplace recent SLEs. Genetic and early environmental risk factors, operationalized as those for severe psychopathology (i.e., polygenic scores for neuroticism, childhood maltreatment, urban upbringing and paternal age) were assessed as modulators of the impact of SLEs on the brain. SLEs were negatively correlated with grey matter volume in the left medial orbitofrontal cortex (mOFC, FWE p = 0.003). This association was present for both, positive and negative, life events. Cognitive-emotional variables, i.e., neuroticism, perceived stress, trait anxiety, intelligence, and current depressive symptoms did not account for the SLE-mOFC association. Further, genetic and environmental risk factors were not correlated with grey matter volume in the left mOFC cluster and did not affect the association between SLEs and left mOFC grey matter volume. The orbitofrontal cortex has been implicated in stress-related psychopathology, particularly major depression in previous studies. We find that SLEs are associated with this area. Important early life risk factors do not interact with current SLEs on brain morphology in healthy subjects

Apolipoprotein E Homozygous ε4 Allele Status: A Deteriorating Effect on Visuospatial Working Memory and Global Brain Structure

Theoretical background: The Apolipoprotein E (APOE) ε4 genotype is known to be one of the strongest single-gene predictors for Alzheimer disease, which is characterized by widespread brain structural degeneration progressing along with cognitive impairment. The ε4 allele status has been associated with brain structural alterations and lower cognitive ability in non-demented subjects. However, it remains unclear to what extent the visuospatial cognitive domain is affected, from what age onward changes are detectable and if alterations may interact with cognitive deficits in major depressive disorder (MDD). The current work investigated the effect of APOE ε4 homozygosity on visuospatial working memory (vWM) capacity, and on hippocampal morphometry. Furthermore, potential moderating roles of age and MDD were assessed.Methods: A sample of n = 31 homozygous ε4 carriers was contrasted with n = 31 non-ε4 carriers in a cross-sectional design. The sample consisted of non-demented, young to mid-age participants (mean age = 34.47; SD = 13.48; 51.6% female). Among them were n = 12 homozygous ε4 carriers and n = 12 non-ε4 carriers suffering from MDD (39%). VWM was assessed using the Corsi block-tapping task. Region of interest analyses of hippocampal gray matter density and volume were conducted using voxel-based morphometry (CAT12), and Freesurfer, respectively.Results: Homozygous ε4 carriers showed significantly lower Corsi span capacity than non-ε4 carriers did, and Corsi span capacity was associated with higher gray matter density of the hippocampus. APOE group differences in hippocampal volume could be detected but were no longer present when controlling for total intracranial volume. Hippocampal gray matter density did not differ between APOE groups. We did not find any interaction effects of age and MDD diagnosis on hippocampal morphometry.Conclusion: Our results point toward a negative association of homozygous ε4 allele status with vWM capacity already during mid-adulthood, which emerges independently of MDD diagnosis and age. APOE genotype seems to be associated with global brain structural rather than hippocampus specific alterations in young- to mid-age participants

Protocol for magnetic resonance imaging acquisition, quality assurance, and quality check for the Accelerator program for Discovery in Brain disorders using Stem cells

Objective: The Accelerator program for Discovery in Brain disorders using Stem cells (ADBS) is a longitudinal study on five cohorts of patients with major psychiatric disorders from genetically high-risk families, their unaffected first-degree relatives, and healthy subjects. We describe the ADBS protocols for acquisition, quality assurance (QA), and quality check (QC) for multimodal magnetic resonance brain imaging studies. Methods: We describe the acquisition and QC protocols for structural, functional, and diffusion images. For QA, we acquire proton density and functional images on phantoms, along with repeated scans on human volunteer. We describe the analysis of phantom data and test–retest reliability of volumetric and diffusion measures. Results: Analysis of acquired phantom data shows linearity of proton density signal with increasing proton fraction, and an overall stability of various spatial and temporal QA measures. Examination of dice coefficient and statistical analyses of coefficient of variation in test–retest data on the human volunteer showed consistency of volumetric and diffusivity measures at whole-brain, regional, and voxel-level. Conclusion: The described acquisition and QA–QC procedures can yield consistent and reliable quantitative measures. It is expected that this longitudinal neuroimaging dataset will, upon its release, serve the scientific community well and pave the way for interesting discoveries

Investigation of dimensional phenomenology and neurobiology across affective and psychotic disorders

For a long time, traditional classification systems have been used to categorize mental disorders into strict classes based on a set of specific and standardized criteria. Such classifications assume a clear cut off between disorders. However, research using these classification systems fail to identify transdiagnostic markers and “points of rarity” separating mental disorders. Categorical approaches are limited by the large neurobiological overlapping of phenomenology as well as molecular genetics, neuro-anatomy and function, and environmental risk across disorders. Moreover, categorical approaches merely consider characteristics above and below the given categorical thresholds using not otherwise specified diagnoses, not fitting to other officially specified categories. Given the limitations of categorical approaches, dimensional factor models can be used as a valuable framework providing significant progress for the understanding of the neurobiology of the major psychiatric disorders (major depressive disorder, bipolar disorder, schizophrenia spectrum disorder). Previous studies show a range of different factor models, indicating that descriptive psychopathology might be organized in a bifactorial or hierarchical framework. However, there is still a lack of comprehensive factorial models comprising a broad range of symptoms across the major psychiatric disorders. Moreover, the neuro-anatomical and neuro-cognitive correlates of transdiagnostic psychopathological factors remain largely elusive. Categorical studies on overlapping gray matter volume alterations across disorders compared to a healthy control group show paralimbic and heteromodal regions to be commonly altered across disorders. In addition, the transdiagnostic investigation of neuro-cognitive measures shows large overlaps and comparable results across disorders and domains with motor speed being the only domain separating disorders. To overcome the reported obstacles, the studies underlying this dissertation investigate the factorial structure of a broad range of psychopathological symptoms across affective and psychotic disorders. Further, dimensional factors are used to determine the underlying neuro-anatomical and neuro-cognitive correlates of descriptive psychopathology. STUDY I demonstrates a cross-validated factor model comprising five first order and two second order factors, supporting the use of hierarchical models. The extracted first order factors (depression, negative syndrome, positive formal thought disorder, paranoid-hallucinatory syndrome, increased appetite) are present in all diagnostic categories, suggesting a diagnosis-shared phenomenology. STUDY II examines the brain structural correlates of the factors derived from STUDY I. Results include a negative association of the negative syndrome with the bilateral frontal opercula. Positive formal thought disorder is negatively associated with the right middle frontal gyrus and with the left amygdala-hippocampus-complex. The paranoid-hallucinatory syndrome is negatively associated with two whole brain clusters (right fusiform gyrus and left middle frontal gyrus) as well as regions-of-interest including the left angular gyrus, bilateral thalami, left postcentral gyrus and left posterior cingulate gyrus. Investigating the neuro-cognitive correlates of psychopathological factors, STUDY III indicates state of illness-dependent associations in almost all cognitive domains. While positive formal thought disorder and the negative syndrome show most pronounced correlations, no or only weak correlations emerge for the other factors. Finally, STUDY IV investigates formal thought disorder in more detail. Results indicate a three factor model (verbosity, emptiness, disorganization) that is differentially associated with gray and white matter brain structure. The verbosity factor is negatively associated with gray matter volume of the temporo-occipital language junction and positively with the white matter microstructure of the inferior longitudinal fascicle and the posterior part of the cingulum bundle. Emptiness is negatively associated with the gray matter volume of the left hippocampus and thalamus but not with white matter. The disorganization factor associates with the white matter structure of the bilateral anterior thalamic radiation and with the hippocampal part of the right cingulum bundle. In conclusion, this dissertation can be interpreted as a first effort overcoming the limitations given by previous categorical approaches. The psychopathological factor models reported are linked to brain structural and neuro-cognitive measures, supporting the view of diagnosis shared and independent biological mechanisms. The studies of this dissertation open up completely new approaches for pathogenic and etiological research. Dimensional methods as applied in this dissertation constitute the basis for a new taxonomy that can in a next step be used to improve prediction, treatment and therapy of the major psychiatric disorders

MR-Morphometrie und subklinischer Neurotizismus

Neurotizismus ist ein Persönlichkeitsfaktor, der u. a. für affektive Störungen (MDD, BPD) den klinischen Stellenwert eines „Vulnerabilitätsmarkers“ besitzt. In den vergangenen Jahren der Erforschung neurobiologischer Korrelate dieses Traits konnten mittels MRT-Bildgebung neben zahlreichen Negativbefunden insbesondere in frontotemporalen Trakten Assoziationen mit Neurotizismus detektiert werden. Auf kortikaler Ebene sind als wesentliche Neurotizismus-Korrelate der medial orbitofrontale Cortex sowie der präfrontale Cortex zu nennen. Vor dem Hintergrund der zahlreichen Negativbefunde bleibt die Frage nach grundlegenden neuroanatomischen Neurotizismus-Korrelaten in der MRT-Bildgebung bislang ungeklärt. Ebenso fehlt in der aktuellen Literatur ein Konsens hinsichtlich der konkreten Lokalisation dieser möglichen Neurotizismus-Korrelate. Ziel dieser Studie ist die multimodale, MRT-basierte Untersuchung von neuronalen Korrelaten des Neurotizismus-Persönlichkeitsfaktors in grauer und weißer Hirnsubstanz in einer großen Stichprobe Gesunder. In der vorliegenden Stichprobe wurde die graue Substanz mittels oberflächen- bzw. volumenbasierter Bildgebungsanalyse hinsichtlich des kortikalen Volumens, der kortikalen Dicke sowie der Gyrifizierung (Gesamtkohorte, n = 670) untersucht, in einer Subgruppe davon ebenfalls die weiße Substanz mittels Diffusionsbildgebung (Teilkohorte, n = 570). Hier waren die Parameter FA (fraktionale Anisotropie) und RD (radiale Diffusivität) Gegenstand der Analyse. Es wurde TBSS zur Analyse der weißen Substanz und SPM12 / CAT12 zur Untersuchung der grauen Substanz verwendet. Die Neurotizismus-Scores der Probanden wurden unter Verwendung des NEO-FFI-Fragebogens erhoben. In der Teilkohorte korrelierte Neurotizismus unter statistischer Kontrolle von Alter, Geschlecht und Standort der Messung positiv mit den pro Trakt gemittelten FA-Werten im rechten Cingulum, rechten bzw. linken Fasciculus frontooccipitalis inferior, rechten bzw. linken Fasciculus Uncinatus, mit den pro Trakt gemittelten RD-Werten negativ im linken Cingulum, rechten bzw. linken Fasciculus frontooccipitalis inferior sowie linken Fasciculus Uncinatus. Auf Voxel-Ebene fanden sich ebenfalls FWE-korrigiert signifikante Cluster für FA zusätzlich in beiden Hemisphären in der Radiatio thalami anterior sowie im Fasciculus longitudinalis inferior. Auch hier zeigten sich durchweg positive Korrelationen von FA und Neurotizismus. In der Gesamtkohorte ergaben sich lediglich auf Ebene der kortikalen Dicke im Bereich der rechten Hirnhemisphäre im medial orbitofrontalen Cortex, superior temporalen, superior frontalen sowie im mittleren frontal rostralen Cortex unkorrigiert signifikante Cluster, welche ebenfalls positiv mit Neurotizismus assoziiert waren. In einer nachfolgenden Analyse korrelierten weiterhin die gemittelten Werte für die kortikale Dicke im rechten superior temporalen bzw. medial orbitofrontalen Cortex signifikant mit der gemittelten FA des rechten Fasciculus Uncinatus. In dieser Studie sind erhöhte Neurotizismus-Werte also insgesamt mit höherer Integrität der Mikrostruktur der weißen Substanz (FA erhöht, RD erniedrigt) assoziiert. Aufgrund konträrer Ergebnisse vorangegangener Studien und der noch unzureichenden Datenlage hinsichtlich möglicher, mit Neurotizismus korrelierenden lokalen Veränderungen der RD bedarf dieses Ergebnis der Replikation. Hierbei gilt es die Zusammensetzung der jeweils untersuchten Stichprobe, insbesondere was Aspekte wie das Alter bzw. die Verteilung der Neurotizismus-Scores der Probanden anbetrifft, als möglichen Einflussfaktor auf die Richtung der Korrelation zwischen Neurotizismus und Parametern wie u. a. der FA zu beachten. Die Evaluation der Ergebnisse aus funktioneller Sicht zeigt eine Verflechtung von Persönlichkeit, Hirnstruktur und - funktion. Insbesondere im orbitofrontalen Cortex finden sich, neben strukturellen Korrelaten, am Beispiel von Emotionsregulation auch wichtige Funktionen für die Ausprägung von Neurotizismus. Die Einordnung der vorliegenden Ergebnisse vor dem Hintergrund einer gegensätzlichen Richtung der Assoziation von Neurotizismus und Hirnstruktur in klinischen Stichproben bleibt problematisch. Eine nonlineare Entwicklung der Assoziation von Neurotizismus und Hirnstruktur im Verlauf einer psychiatrischen Erkrankung erscheint jedoch möglich

Neurobiology of schizotypal phenotypes - Schizotypy as a framework for dimensional psychiatry

Complex, dimensional phenotypes represent a valuable framework for the analysis of fundamental neurobiological mechanisms of psychiatric disorders. They facilitate the deconstruction of diagnostic entities and the study of protective processes that prevent progression into clinical domains. Within the psychosis spectrum, schizotypy describes a multidimensional personality construct with behavioural, cognitive, and emotional characteristics similar to key symptoms of schizophrenia, that can equally be grouped into the dimensions positive (magical thinking, unusual perceptions and beliefs), negative (introversion, anhedonia), and disorganised (cognitive disorganisation, eccentricity). Within a continuum model of psychosis, schizotypy is discussed as variation of healthy function, and as risk phenotype of schizophrenia and psychosis proneness, assuming a (partially) overlapping genetic architecture along the spectrum. Current aetiological models propose an impact of genetic liability, in interaction with environmental risk and modulated by protective factors like cognitive function, through disruptions in neuronal development. In fact, recent studies show that schizotypy is associated with brain structural variation, partially overlapping with regions that are also impaired in patients with schizophrenia spectrum disorders. This dissertation characterised neurobiological determinants of schizotypy regarding its genetic basis and neural networks, aiming to develop a multimodal model to integrate those into a joint framework. STUDIES I and IV investigated the genetic structure of schizotypy, demonstrating its association with common variants (single nucleotide polymorphisms, SNPs) in genes (CACNA1C and ZNF804A) involved in processes of neuronal development and identified as risk genes for schizophrenia and other psychiatric disorders (STUDY I). In this association, biological sex has a moderating role. However, a direct association of a polygenic schizophrenia risk score, based on cumulative SNP-risk, was not established (STUDY IV). STUDIES II and III analysed brain structural correlates of schizotypy dimensions, finding an association of the positive dimension (and symptom-associated distress) with grey matter volume in associative brain areas precuneus, striatum and inferior temporal gyrus. STUDY II further indicates that this relationship can be buffered by above average general cognitive function. Study V ultimately integrates the previous results into a joint multivariate model that proves to explain a substantial amount of phenotypic variance. The model shows that the interaction effect of polygenic and poly-environmental risk on positive schizotypy is mediated through brain structural variation in the precuneus, and modulated by the level of executive function. In conclusion, this dissertation shows that schizotypy is associated with genetic polymorphisms involved in neuronal development and function. While those are identified as schizophrenia risk variants, the lack of an association with polygenic schizophrenia risk suggests a limited overlap of the genetic architectures of the phenotypes. The confirmation of the multivariate model, however, indicates an indirect effect through variations in brain structure and modulated by intra- and extrapersonal factors. Accordingly, particularly positive schizotypy is associated with structural alterations in brain regions central for the integration, evaluation, and attribution of perceptual information within associative neuronal networks. Thus, schizotypy is a valuable endophenotype of the schizophrenia spectrum, showing that pathophysiological aberrations lie on a continuum with variation of healthy functioning. Schizotypy, however, also describes the manifestation of interindividual variation in behaviour, cognition, and emotion, with its underlying mechanisms representing an exemplary framework for the study of dimensional, phenotypic spectra

Urbanizität als Risikofaktor für psychische Störungen: neuronale Korrelate

Urbanicity is an established risk factor for mental illness. This has been proven in large population studies especially for schizophrenia, but also for depression and other psychiatric diagnoses. In the search for causality, imaging studies have increasingly been carried out in the last years. Heterogeneous neuronal correlates of the risk factor were shown. The aim of our study was to carry out a multimodal investigation of growing up in an urban environment on a large cohort (n=625) to make a comparison with previous studies and to minimize previous limitations. The VBM analysis did not show significant results as main effect. In a gender interaction, a positive correlation of urbanicity score and grey matter volume in the area of the entorhinal cortex could be demonstrated in male subjects at trend level. Also at trend level, a negative correlation with the urbanicity score in the area of the visual cortex, the cingulum and the precuneus could be found for the cortical thickness. Examination of gyrification did not yield any significant results. DTI showed a reduced FA in the ROI analysis of the uncinate fasciculus and the inferior frontooccipital fasciculus. Functional imaging (fMRI) showed a positive correlation between growing up in an urban environment and activation of the left amygdala by an emotional face processing task. Our study fits into the heterogeneity of previous studies. No significant results could be found in the VBM and SBM in the area of the DLPFC, which has often been described as affected. Furthermore, no global influence of growing up in an urban environment was shown for cortical thickness, but rather localized effects. The DTI analysis also produced different localizations than the comparison study. As in other studies, an altered activation of the amygdala could be demonstrated in fMRI. Related to cortical thickness, two affected systems have been discussed. First, a trend was found in the visual cortex. A possible explanation for this is the sensory perception of the environment, which differs between city and countryside. Environmental characteristics, such as green surroundings or noise pollution, could contribute to the risk of mental illness in the city. But it is also possible that the visual system is involved in processing emotions and thus in the psychopathology of various diseases. Second, two trends were found that can be associated with the default mode network (DMN). This is involved in coping with stress and thus also in the psychopathology of various disorders. In DTI, reductions in FA were found in a frontolimbic and a frontooccipital network. The frontolimbic system can be associated with stress processing and emotion regulation. In addition to the occipital cortex, the frontooccipital network also connects other cortical areas with the prefrontal cortex and has a wide range of functions. Both the frontolimbic and frontooccipital networks have been shown to be involved in various mental disorders. As in some previous studies, altered activation of the amygdala was found in connection with growing up in an urban environment. The hyperactivation by emotional stimuli found here has been specifically associated with schizophrenia and symptoms of depression. The variability of urbanicity represents an explanation for the heterogeneity of the study results. Previous studies were carried out with population-based values that did not take this variability into account. There are many aspects that could be responsible for the risk posed by urbanicity. These include social and socio-economic problems, environmental quality, medical care and much more. Ultimately, growing up in an urban area as a population-based variable is too imprecise to include all these aspects. Stress experiences and their processing could play an important role in the effect of urbanicity as a risk factor. In order to mitigate the effect as a risk factor, the goal must be to avoid harmful stress experiences. In addition to social stress, stressful experiences due to poor environmental quality were also described. The political and social tasks that result from this are large. Nevertheless, dealing with them is of great relevance in view of increasing urbanization and the social importance of mental disorders.Urbanizität ist ein etablierter Risikofaktor für psychische Erkrankungen. Dies wurde in großen Bevölkerungsstudien insbesondere für Schizophrenie, aber auch für Depressionen und weitere psychiatrische Diagnosen nachgewiesen. Auf der Suche nach einer Kausalität wurden in den letzten Jahren zunehmend bildgebende Untersuchungen durchgeführt. Hier zeigten sich heterogene neuronale Korrelate des Risikofaktors. Ziel unserer Studie war es, eine multimodale Untersuchung des urbanen Aufwachsens an einer großen Kohorte (n=625) durchzuführen, um einen Vergleich mit den bisherigen Studien durchzuführen und bisherige Limitationen zu minimieren. Bei der VBM ergaben sich als Haupteffekt keine signifikanten Resultate. In einer Gender-Interaktion konnte auf Trendlevel eine positive Korrelation von Urbanizitätsscore und Volumen der grauen Substanz im Bereich des entorhinalen Cortex bei männlichen Probanden nachgewiesen werden. Ebenfalls auf Trendlevel konnte bei der corticalen Dicke eine negative Korrelation mit dem Urbanizitätsscore im Bereich des visuellen Cortex, des Cingulums und des Precuneus gefunden werden. Die Untersuchung der Gyrifizierung brachte keine signifikanten Resultate hervor. Bei der DTI zeigte sich eine reduzierte FA in der ROI-Analyse des Fasciculus uncinatus und des Fasciculus fronto-occipitalis inferior. Die funktionelle Bildgebung (fMRI) zeigte eine positive Korrelation von urbanem Aufwachsen und der Aktivierung der linken Amygdala durch eine Aufgabe zur emotionalen Gesichterverarbeitung. Unsere Studie reiht sich in die Heterogenität der bisherigen Studien ein. So konnten in der VBM und SBM im Bereich des bisher häufig als betroffen beschriebenen DLPFC keine signifikanten Resultate gefunden werden. Des Weiteren wurde bei der corticalen Dicke kein globaler Einfluss von urbanem Aufwachsen gezeigt, sondern eher lokal begrenzte Effekte. Auch die DTI-Analyse brachte andere Lokalisationen als die Vergleichsstudie hervor. Bei fMRI konnte wie in anderen Studien eine veränderte Aktivierung der Amygdala nachgewiesen werden. Bei der corticalen Dicke wurden zwei betroffene Systeme diskutiert. Zum einen fand sich ein Trend im visuellen Cortex. Eine mögliche Erklärung hierfür ist die sensorische Wahrnehmung der Umwelt, die sich in der Stadt und auf dem Land unterscheidet. Charakteristika der Umwelt, wie grüne Umgebung oder Lärmbelastung, könnten zum Risiko für psychische Erkrankungen in der Stadt beitragen. Aber auch eine Beteiligung des visuellen Systems an der Emotionsverarbeitung und damit an der Psychopathologie verschiedener Erkrankungen ist möglich. Zum anderen wurden zwei Trends gefunden, die sich mit dem Ruhezustandsnetzwerk (DMN) in Verbindung bringen lassen. Dieses ist an der Stressverarbeitung und damit ebenfalls an der Psychopathologie verschiedener Störungen beteiligt. Bei der DTI wurden Reduktionen der FA in einem frontolimbischen und einem frontooccipitalen Netzwerk gefunden. Das frontolimbische System lässt sich mit Stressverarbeitung sowie Emotionsregulation in Verbindung bringen. Das frontooccipitale Netzwerk verbindet neben dem occipitalen Cortex auch weitere corticale Areale mit dem präfrontalen Cortex und hat vielfältige Funktionen. Sowohl für das frontolimbische als auch das frontooccipitale Netzwerk wurde eine Beteiligung an verschiedenen psychischen Störungen nachgewiesen. Wie in einigen vorherigen Studien konnte eine veränderte Aktivierung der Amygdala im Zusammenhang mit urbanem Aufwachsen festgestellt werden. Die hier gefundene Hyperaktivierung durch emotionale Stimuli wurde im Speziellen mit Schizophrenie und Symptomen der Depression in Verbindung gebracht. Einen Erklärungsansatz für die Heterogenität der Studienergebnisse stellt die Variabilität von Urbanizität dar. Bisherige Studien wurden mit populationsbasierten Werten durchgeführt, welche diese Variabilität nicht berücksichtigen. Es gibt vielfältige Aspekte, die für das Risiko durch Urbanizität verantwortlich sein könnten. Dazu zählen soziale und sozioökonomische Probleme, Umweltqualität, medizinische Versorgung und vieles mehr. Urbanes Aufwachsen als populationsbasierte Variable ist letztendlich zu ungenau, um all diese Aspekte einzubeziehen. Stresserlebnisse und deren Verarbeitung könnten eine wichtige Rolle bei der Wirkung von Urbanizität als Risikofaktor spielen. Um die Wirkung als Risikofaktor abzuschwächen, muss das Ziel die Vermeidung von schädlichen Stresserlebnissen sein. Neben sozialem Stress wurden auch Stresserlebnisse durch mangelnde Umweltqualität beschrieben. Die politischen und gesellschaftlichen Aufgaben, die sich hieraus ergeben, sind groß. Dennoch ist deren Bewältigung in Hinblick auf die zunehmende Urbanisierung und die gesellschaftliche Bedeutung psychischer Störungen von großer Relevanz

The interaction of risk and protective factors for mental disorders on psychopathology and brain morphometry

As per the diathesis-stress model, combined early risk factors (diathesis) and current risk factors (stress) determine an individual’s likelihood for the development of psychopathology. If the combined impact of diathesis and stress surpasses a certain threshold, individuals will develop psychopathology. At the same time, such threshold could be raised in the presence of protective factors, as they buffer the negative impact of risk factors, and lead to a reduced likelihood of developing psychopathology. Early risk factors for mental disorders include trait anxiety, childhood maltreatment and familial risk, and have been associated with specific brain morphometric alterations. Stressful life events, including the Covid-19 pandemic as a global example of that, constitute current risk factors. On the other hand, current literature suggests social support and conscientiousness as exemplary protective factors. These may increase resilience, a concept describing an individual’s ability to adaptively cope in the face of adversity and maintain mental health. However, contrary to risk factors, neural correlates of resilience are only sparsely known and hardly understood. Thus, to make precise predictions about the emergence of psychopathology in certain circumstances and understand possible neurobiological pathways, it is essential to jointly consider both risk and protective factors in mental health research. The aim of this dissertation was to investigate the interaction of risk and protective factors in three different but complementary contexts to gain a deeper understanding of these factors and their impact on brain morphometry and psychopathology. In STUDY I, morphometric correlates (specifically grey matter volume) of resilience were investigated. In this study, resilience was conceptualized as the maintenance of mental health despite a high risk (i.e., childhood maltreatment and familial risk). A key finding is that healthy high-risk individuals demonstrated larger grey matter volume in the left dorsolateral prefrontal cortex, an area associated with cognitive flexibility and emotional regulation skills, compared to the other groups. It seems plausible that an increased volume in this area is a neural correlate of resilience to high risk and may represent compensatory processes aiding high-risk individuals in maintaining mental health. STUDY II approached the subject in the opposite way, with transdiagnostic grey matter volume alterations in psychiatric patients compared to healthy subjects being associated with risk and protective factors. This study identified reduced volume in the left hippocampus as a transdiagnostic vulnerability marker in patients with major depression, bipolar disorder, and schizophrenia spectrum disorder. Volume in this area was further negatively associated with stressful life events, and executive and global functioning in both patients and healthy subjects. We conclude that stressful life events likely constitute a dimensional risk factor for reduced hippocampal volume and, therefore, are independent of diagnosis. STUDY III investigated the impact of a unique, acute global stressor, the Covid-19 pandemic, on healthy subjects and transdiagnostic patients. Multiple trait risk and protective factors were tested for their explanatory value of current Covid-19-related fear and isolation. This study identified trait anxiety and conscientiousness as risk factors for increased Covid-19-related fear, and social support as a protective factor against increased Covid-19-isolation. Again, the respective effect (harmful or protective) of all these factors was dimensional, i.e., relevant in both psychiatric patients and healthy subjects. STUDY III also highlighted the context-dependency of risk and protective factors: although generally considered a protective trait, increased conscientiousness was harmful in the context of a global pandemic due to the immense level of uncertainty and unpredictability. In conclusion, this dissertation identified brain correlates as potential biomarkers of psychopathology and resilience, and procedural contributors to adaptive and maladaptive responses to acute stressors. It highlighted the importance of taking protective factors, in addition to risk factors, into account in research. A major strength is the integration of multiple risk and protective factors, as such integrative approaches are crucial to advance the understanding of their complex interplay. By identifying dimensionality and context-dependency as important modulatory influences in the risk and protective factor interplay, it provided a framework for a more comprehensive understanding of the development of psychopathology, and the concept of resilience as a dynamic, continuous process of adaptation to changing environments, which enables individuals to maintain mental health even in the face of adversity