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The relationship between Alzheimer's-related brain atrophy patterns and sleep macro-architecture
(2022)
Introduction
Sleep is increasingly recognized as a major risk factor for neurodegenerative disorders such as Alzheimer's disease (AD).
Methods
Using an magnetic resonance imaging (MRI)–based AD score based on clinical data from the Alzheimer's Disease Neuroimaging Initiative 1 (ADNI1) case-control cohort, we investigated the associations between polysomnography-based sleep macro-architecture and AD-related brain atrophy patterns in 712 pre-symptomatic, healthy subjects from the population-based Study of Health in Pomerania.
Results
We identified a robust inverse association between slow-wave sleep and the AD marker (estimate: −0.019; 95% confidence interval: −0.03 to −0.0076; false discovery rate [FDR] = 0.0041), as well as with gray matter (GM) thicknesses in typical individual cortical AD-signature regions. No effects were identified regarding rapid eye movement or non–rapid eye movement (NREM) stage 2 sleep, and NREM stage 1 was positively associated with GM thickness, mainly in the prefrontal cortical regions.
Discussion
There is a cross-sectional relationship between AD-related neurodegenerative patterns and the proportion of sleep spent in slow-wave sleep.
Childhood abuse was inconsistently related to whole-brain cortical thickness in former studies. However, both childhood abuse and cortical thickness have been associated with depressive symptoms. We hypothesised that childhood abuse moderates the association between depressive symptoms and cortical thickness. In 1551 individuals of the general population, associations between whole-brain cortical thickness and the interaction of childhood abuse (emotional, physical, and sexual) and depressive symptoms were analysed using an ANCOVA. Linear regression analyses were used to estimate the same effect on the cortical thickness of 34 separate regions (Desikan-Killiany-atlas). A significant interaction effect of childhood abuse and depressive symptoms was observed for whole-brain cortical thickness (F(2, 1534) = 5.28, p = 0.007). A thinner cortex was associated with depressive symptoms in abused (t value = 2.78, p = 0.025) but not in non-abused participants (t value = − 1.50, p = 0.224). Focussing on non-depressed participants, a thicker whole-brain cortex was found in abused compared to non-abused participants (t value = − 2.79, p = 0.025). Similar interaction effects were observed in 12 out of 34 cortical regions. Our results suggest that childhood abuse is associated with reduced cortical thickness in subjects with depressive symptoms. In abused subjects without depressive symptoms, larger cortical thickness might act compensatory and thus reflect resilience against depressive symptoms.
Stigma of Mental Illness in Germans and Turkish Immigrants in Germany: The Effect of Causal Beliefs
(2019)
Background: Stigma poses an additional burden for people suffering from mental illness, one that often impairs their social participation and can prevent them from seeking adequate help. It is therefore crucial to understand how stigma develops in order to counteract it by setting up effective evidence-based anti-stigma interventions. The present study examines the effect of causal beliefs on stigmatizing behavioral intentions, namely people's desire to distance themselves from persons with mental illness. In addition, we draw cross-cultural comparisons between native Germans and Turkish immigrants to investigate the influence of culture on stigma and causal beliefs and to broaden knowledge on the biggest immigrant group in Germany and on immigrants in Western countries in general.
Methods: n = 302 native Germans and n = 173 Turkish immigrants were presented either a depression or a schizophrenia vignette. Then, causal beliefs, emotional reaction and desire for social distance were assessed with questionnaires. Path analyses were carried out to investigate the influence of causal beliefs on the desire for social distance and their mediation by emotional reactions for Germans and Turkish immigrants, respectively.
Results: We found an influence of causal beliefs on the desire for social distance. Emotional reactions partly mediated this relationship. Causal attribution patterns as well as the relationship between causal attributions and stigma varied across both subsamples and mental illnesses. In the German subsample, the ascription of unfavorable personal traits resulted in more stigma. In the Turkish immigrant subsample, supernatural causal beliefs increased stigma while attribution to current stress reduced stigma.
Conclusion: Our study has implications for future anti-stigma interventions that intend to reduce stigmatization of mentally ill people. Targeting the ascription of unfavorable personal traits and supernatural causal attributions as well as promoting current stress as the cause for mental illness appears to be of particular importance. Also, the mediating influence of emotional responses to causal beliefs needs to be addressed. Furthermore, differential interventions across cultural groups and specific mental illnesses may be appropriate.
The hypothalamus–pituitary–adrenal axis is the main physiological stress response system and regulating the release of cortisol. The two corticoid receptors encoded by the genes NR3C1 and NR3C2 are the main players in regulating the physiological response to cortisol. This biological system has been linked to neurocognitive processes and memory, yet the mechanisms remain largely unclear. In two independent general population studies (SHIP, total sample size > 5500), we aim to diseantangle the effects of genetic variation, gene expression and cortisol on verbal memory and memory associated brain volume. Especially for NR3C1 results exhibited a consistent pattern of direct an interactive effects. All three biological layers, genetic variation (rs56149945), gene expression for NR3C1 and cortisol levels, were directly associated with verbal memory. Interactions between these components showed significant effects on verbal memory as well as hippocampal volume. For NR3C2 such a complex association pattern could not be observed. Our analyses revealed that different components of the stress response system are acting together on different aspects of cognition. Complex phenotypes, such as cognition and memory function are regulated by a complex interplay between different genetic and epigenetic features. We promote the glucocorticoid receptor NR3C1 as a main target to focus in the context of verbal memory and provided a mechanistic concept of the interaction between various biological layers spanning NR3C1 function and its effects on memory. Especially the NR3C1 transcript seemed to be a key element in this complex system.
Psychiatric disorders are highly heritable. But the underlying molecular mechanisms are largely unknown or not understood. For many disorders, candidate genes have been proposed which are biologically driven or based on large GWAS studies. In this work different approaches were shown to investigate the impact of genetic risk factors for major psychiatric disorders in the general population. These genetic risk variants include single nucleotide polymorphisms associated with schizophrenia or major depression and were analyzed using the whole-genome information in polygenic scores or candidate marker analysis in GxE studies. Genetic data from SHIP-0 and SHIP-TREND have been used to calculate a polygenic risk score for schizophrenia. Here, the association between this genetic score and brain alterations is shown in three independent samples (SHIP-2, SHIP-TREND and BIG) which revealed no hint of a common genetic basis for schizophrenia and brain structure. These results are in line with other studies that also failed to find a genetic overlap. The same polygenic scores had been used in a PHEWAS analysis in SHIP-0 where an inverse association to migraine was found. This association could be attributed to the NMDA receptor activation via D-serine at the glutamatergic synapse. To assess the impact of environmental factors on the path from genes to phenotype, gene-environment interactions were applied. A significant interaction could be observed between rs7305115 (TPH2) and rs25531 (5-HTTLPR) and childhood abuse on current depression score in SHIP-LEGEND and SHIP-TREND. In summary, genetic variants associated with major psychiatric disorders can exhibit pleiotropic effects on common phenotypes in the general population.
Background: A telemedicine care concept based on telephone contacts and individualized text messages was developed for patients with mental disorders to continue treatment after therapy in a psychiatric day hospital. The primary objective of this study was to evaluate the effectiveness of the telemedicine interventions. Methods: The study had a 3-armed, randomized design with 2 intervention arms (intervention 1: telephone contacts; intervention 2: telephone contacts and short text messages; both took place over a period of 6 months and in addition to usual care), and a control group with usual care. Primary outcomes were 18-item Brief Symptom Inventory (BSI-18) scores for anxiety, depression and somatization. All participants were recruited from psychiatric day hospitals. The study was registered in the German Clinical Trials Register (DRKS00000662). Results: 113 participants were analyzed 6 months after starting the intervention. The average BSI-18 anxiety score after 6 months was -2.04 points lower in intervention group 2 than in the control group (p value: 0.042). The difference in BSI depression score between these two groups was marginally significant (p value: 0.1), with an average treatment effect of -1.73. In an exploratory sensitivity analysis restricted to the 75% of patients with the highest symptom scores at baseline, intervention group 1 yielded a significant effect for anxiety and depression compared to the control group (p = 0.036 and 0.046, respectively). Conclusions: Telemedicine provides a novel option in psychiatric ambulatory care with statistically significant effects on anxiety. A positive tendency was observed for depression, especially in cases with higher symptom load at baseline.
Background: The mechanism of how childhood trauma leads to increased risk for adult dissociation is not sufficiently understood. We sought to investigate the predicting effects and the putatively mediating roles of PTSD and alexithymia on the path from childhood trauma to adult dissociation. Methods: A total of 666 day-clinic outpatients were administered the Childhood Trauma Questionnaire (CTQ), the Toronto Alexithymia Scale (TAS-20), the Posttraumatic Diagnostic Scale (PDS), and the Dissociative Experiences Scale (DES) and controlled for sex, age, and the Global Symptom Index (GSI). Linear regression analyses and mediation analyses were applied. Results: Independent predictive effects on dissociation were found for childhood trauma, alexithymia and PDS, even after adjusting for GSI. Effects of childhood neglect on dissociation were slightly stronger than of abuse. Alexithymia did not mediate the path from childhood trauma to dissociation. Mediation by PDS was specific for childhood abuse, with all PTSD symptom clusters being significantly involved. Conclusions: Childhood abuse and neglect are important predictors of dissociation. While the effects of abuse are mediated by PTSD, the mechanism of how neglect leads to dissociation remains unclear. The results further support the predictive value of alexithymia for adult dissociation above and beyond the effects of childhood trauma, PTSD, and GSI scores.
Background: Alexithymia is a personality trait characterized by difficulties in identifying and describing emotions and associated with various psychiatric disorders. Neuroimaging studies found evidence for morphological and functional brain alterations in alexithymic subjects. However, the neurobiological mechanisms underlying alexithymia remain incompletely understood. Methods: We study the association of alexithymia with cortical correlation networks in a large community-dwelling sample of the Study of Health in Pomerania. Our analysis includes data of n = 2,199 individuals (49.4% females, age = 52.1 ± 13.6 years) which were divided into a low and high alexithymic group by a median split of the Toronto Alexithymia Scale. Cortical correlation networks were constructed based on the mean thicknesses of 68 regions, and differences in centralities were investigated. Results: We found a significantly increased centrality of the right paracentral lobule in the high alexithymia network after correction for multiple testing. Several other regions with motoric and sensory functions showed altered centrality on a nominally significant level. Conclusions: Finding increased centrality of the paracentral lobule, a brain area with sensory as well as motoric features and involvement in bowel and bladder voiding, may contribute to explain the association of alexithymia with functional somatic disorders and chronic pain syndromes.
Abstract
During fear conditioning, a cue (CS) signals an inevitable distal threat (US) and evokes a conditioned response that can be described as attentive immobility (freezing). The organism remains motionless and monitors the source of danger while startle responses are potentiated, indicating a state of defensive hypervigilance. Although in animals vagally mediated fear bradycardia is also reliably observed under such circumstances, results are mixed in human fear conditioning. Using a single‐cue fear conditioning and extinction protocol, we tested cardiac reactivity and startle potentiation indexing low‐level defensive strategies in a fear‐conditioned (n = 40; paired presentations of CS and US) compared with a non‐conditioned control group (n = 40; unpaired presentations of CS and US). Additionally, we assessed shock expectancy ratings on a trial‐by‐trial basis indexing declarative knowledge of the previous contingencies. Half of each group underwent extinction under sham or active transcutaneous vagus nerve stimulation (tVNS), serving as additional proof of concept. We found stronger cardiac deceleration during CS presentation in the fear learning relative to the control group. This learned fear bradycardia was positively correlated with conditioned startle potentiation but not with declarative knowledge of CS‐US contingencies. TVNS abolished differences in heart rate changes between both groups and removed the significant correlation between late cardiac deceleration and startle potentiation in the fear learning group. Results suggest, fear‐conditioned cues evoke attentive immobility in humans, characterized by cardiac deceleration and startle potentiation. Such defensive response pattern is elicited by cues predicting inevitable distal threat and resembles conditioned fear responses observed in rodents.
Objective: Little is known about the specific psychological features that differentiate persistent depressive disorder (PDD) and episodic depression (ED). Thus, the present study aimed to investigate differences in social cognition and interpersonal problems between these two forms of depression and healthy controls. In addition, we aimed to examine childhood maltreatment (CM) as a possible origin of these alterations.
Methods: In a cross-sectional study, adult patients with a current PDD (n = 34) or in a current episode of ED (n = 38), and healthy controls (n = 39) completed questionnaires about depression severity, empathy, interpersonal problems, and CM, as well as tests of affective theory of mind and facial emotion recognition.
Results: Patients with PDD reported higher empathic distress than patients with ED and healthy controls. Both depressive groups recognized angry faces with higher accuracy and reported more interpersonal problems, with no differences between PDD and ED. Empathic distress and interpersonal problems mediated the link between CM and depression in the combined sample.
Limitations: Patient groups were not drug-naïve and antidepressant intake might have influenced social-cognitive functions. Self-report measures of empathy and interpersonal problems are vulnerable to bias. The cross-sectional design does not allow causal conclusions.
Conclusion: Depressed patients may not show deficits in decoding the affective states of others and in feeling with others. However, depressed individuals—in particular patients with PDD—may feel easily overwhelmed by emotionally tense situations, resulting in empathic distress and avoidant/submissive interpersonal behavior. Exposure to CM might be an origin of alterations in social cognition and interpersonal problems.
Background: Alcohol dependence is among the most severely stigmatized mental disorders. We examine whether negative stereotypes and illness beliefs related to alcohol dependence have changed between 1990 and 2011. Methods: We used data from two population surveys with identical methodology that were conducted among German citizens aged ≥18 years, living in the ‘old' German states. They were conducted in 1990 and 2011, respectively. In random subsamples (1990: n = 1,022, and 2011: n = 1,167), identical questions elicited agreement with statements regarding alcohol dependence, particularly with regard to the illness definition of alcohol dependence and blame. Results: Overall, agreement with negative stereotypes did not change in the course of 2 decades. About 55% of the respondents agreed that alcohol dependence is an illness like any other, >40% stated that it was a weakness of character and 30% endorsed that those affected are themselves to blame for their problems. Conclusions: It is apparent that promoting an illness concept of alcohol dependence has not been an easy solution to the problem of stigma. We discuss how the normative functions of alcohol dependence stigma might have prevented a reduction of negative stereotypes.
The experience of abuse in the period of childhood and youth is a key stressor that has con-sequences on the developing brain and is associated with the genesis of mental disorders. Childhood abuse and depression often cooccur together and have both been associated with cortical thickness resulting in a difficulty to detangle the influence of each factor. In prior studies, childhood abuse and depression were inconsistently related to whole-brain cortical thickness. Thus, this thesis aims to investigate the link between childhood abuse, depres-sive symptoms, and alterations of the cortex.
Therefore, this study analyses 1,551 individuals of the general population. A significant in-teraction effect of childhood abuse and depressive symptoms is observed for whole-brain cortical thickness. Yet, the results indicate no influence of childhood abuse or depression alone. A thinner cortex was associated with more severe depressive symptoms in the abused, but not in the non-abused group. In non-depressed participants, an increased whole-brain cortex was found in the abused, compared to the non-abused group. Similar interaction effects were observed in 12 out of 34 cortical regions.
The results suggest, in line with prior findings, that depressed individuals with a history of childhood abuse are a specific ecophenotype which is also reflected in specific brain altera-tions. Cortical regions that are distinct associated with the interaction of depressive symp-toms and childhood abuse are involved in various fields such as sensory processing, self-conception, and memory. Greater cortical thickness in subjects with childhood abuse and without depressive symptoms might act compensatory and thus reflect resilience against depressive symptoms.
Practical implications concern the treatment and diagnostic system as well as the im-portance of early prevention programs. An individualised treatment is necessary as various studies found a less favourable outcome in depressive patients with a history of maltreat-ment. Therefore, it seems urgent to assess experiences of childhood abuse at the beginning of psychiatric and psychotherapeutic treatment. In addition, early prevention programs are in need to support vulnerable family systems and thereby strengthening the economic, health and social system.
Background: There is evidence that the borderline symptomatology of the mother longitudinally predicts the number of borderline criteria met by the children. However, possible underlying mechanisms have rarely been examined. In line with transactional models of borderline personality disorder (BPD), we analyzed a broad concept of maladaptive mother-child interactions of mothers with BPD symptoms towards their children, including insensitive parenting and mother-child discrepancies, in reporting the child's psychopathological behavior. Sampling/Methods: The sample was drawn from the population-based Greifswald Family Study and consisted of 295 children and their biological mothers. Both were examined at two points in time, first when the children were about 15 years old (T₀) and again 5 years later (T<sub>1</sub>), using path analyses. Results: Maladaptive mother-child interactions (especially an overprotective and rejecting parenting style and high discrepancies regarding internalizing problems) mediate the longitudinal transmission of borderline symptoms from mother to child. Furthermore, our data revealed that this result is consistent for various youth symptoms which are associated with BPD such as impulsivity or dissociation. Conclusion: The data of the current study imply that the transmission of borderline symptoms from mother to child is mediated by maladaptive mother-child interactions. For this reason early and professional support may be useful to prevent these children from developing severe psychopathology.
Objective
Obesity, often associated with non-alcoholic fatty liver disease (NAFLD), is characterized by an imbalance between energy expenditure and food intake, which is also reflected by desensitization of fibroblast growth factor 21 (FGF21). FGF21 is strongly influenced, among others, by TNFα, which is known to be upregulated in obesity-induced inflammation. Successful long-term treatments of NAFLD might be dietary modification, exercise, or fasting.
Materials and methods
Whether succeeded NAFLD recovery is linked with improved FGF21 sensitivity and finally reverted FGF21 resistance was the focus of the present study. For this purpose, mice received a high-fat diet (HFD) for 6 months to establish obesity. Afterward, the mice were subjected to three different weight loss interventions, namely, dietary change to low-fat diet (LFD), treadmill training, and/or time-restricted feeding for additional 6 months, whereas one group remained on HFD.
Results
In addition to the expected decrease in NAFLD activity with dietary change, this was also observed in the HFD group with additional time-restricted feeding. There was also an associated decrease in hepatic TNFα and FGF21 expression and an increase in ß-klotho expression, demonstrated mainly by using principal component analysis. Pearson correlation analysis shows that independent of any intervention, TNFα expression decreased with improved NAFLD recovery. This was accompanied with higher FGF21 sensitivity, as expressed by an increase in β-klotho and FGFR1c expression and concomitantly decreased FGF21 levels.
Conclusion
In summary, we conclude that successful NAFLD therapy is associated with a reversion of the TNFα-triggered FGF21-resistant state or desensitization.