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Implicit theory of mind in neurotypical and neurodivergent social cognitive development
Get PDFIn social interactions, people reason about their own mental states—such as beliefs, desires, or intentions—and ascribe mental states to others in order to predict or explain their behavior. This ability, referred to as Theory of Mind, is central to successful social interaction and develops in childhood. Explicit Theory of Mind, a conscious and verbally expressible understanding of mental states, typically emerges around age 4. In contrast, the earlier development of implicit Theory of Mind, an unconscious, non-verbal sensitivity to others’ mental states, remains debated due to inconsistent findings across various experimental paradigms. Theory of Mind abilities are closely associated with both the use and understanding of mental state language. In mental state language understanding research, empirical evidence demonstrates that children verbally distinguish between epistemic verbs—such as know, think or, believe—from around the ages of 4 to 5. However, it remains unclear whether implicit mental state language understanding is already present earlier due to limited research. In neurodivergent social cognitive development, such as in autism, recent predictive coding accounts link difficulties in Theory of Mind reasoning to attenuations in predictive processing. Since implicit Theory of Mind relies on unconscious predictions about others’ mental states, differences between autistic and neurotypical individuals may reflect alterations in the underlying predictive mechanisms, thereby offering a potential explanation for challenges in social interaction. However, neural findings remain elusive. Based on these considerations, the following key questions arise: How robust are existing paradigms for measuring implicit Theory of Mind across the lifespan? Does implicit mental state language understanding developmentally precede an explicit one? Does predictive processing in Theory of Mind brain regions differ between autistic and neurotypical individuals?
The aim of this dissertation was to systematically investigate these questions. To this end, four empirical studies were conducted, each addressing different aspects of implicit Theory of Mind within neurotypical and/or neurodivergent social cognitive development. Study 1 validated a novel web-based eye-tracking method with toddlers aged 18 to 27 months (N = 125). Within an anticipatory looking paradigm, goal-based action anticipation was measured and compared with findings from a laboratory study. The results showed that with our web-based setting goal-based action anticipation can be successfully measured, although the proportion of anticipatory looking was slightly lower, and exclusion rate was higher. Study 2 also used the anticipatory looking paradigm and tested whether toddlers (N = 521) and adults (N = 703) differ in their action anticipation based on epistemic states such as knowledge and ignorance. Adults clearly distinguished between knowledge and ignorance, as indicated by their anticipatory looking behavior. Unexpectedly, toddlers did not show this differentiation, highlighting the need for further research. Study 3 investigated the implicit understanding of the epistemic verbs “know” and “think” in toddlers aged 27 (N = 199) and 36 months (N = 131). The results revealed that toddlers as young as 27 months were able to differentiate between these verbs, with a spontaneous preference for speaker certainty (i.e., “know”). This indicates that implicit mental state language understanding seems to precede an explicit one. Study 4 investigated predictive processing in the Theory of Mind network of non-autistic (N = 61 in Experiment 1; N = 30 in Experiment 2) and autistic (N = 30 in Experiment 2) adults using functional magnetic resonance imaging. Contrary to our expectations, predictive processing was absent in the Theory of Mind network in either group. However, in autistic (in comparison to non-autistic) adults a reduced repetition suppression was observed in a specific scene involving complex Theory of Mind processes. This provides preliminary neural evidence for the predictive coding theory in autism. Together, the four studies contribute to a more differentiated understanding of implicit Theory of Mind abilities across development and neurodiversity. They offer methodological innovations for implicit measurement of early social cognitive abilities, highlight both the potential and limitations of current theoretical accounts and empirical paradigms, and point to directions for future research.In sozialen Interaktionen denken Menschen über ihre eigenen mentalen Zustände —wie Überzeugungen, Wünsche oder Absichten —nach und schreiben auch anderen Personen mentale Zustände zu, um deren Verhalten vorherzusagen oder zu erklären. Diese Fähigkeit, die als Theory of Mind bezeichnet wird, ist zentral für gelingende soziale Interaktion und entwickelt sich im Kindesalter. Explizite Theory of Mind, ein bewusstes und verbal ausdrückbares Verständnis mentaler Zustände, entwickelt sich typischerweise im Alter von etwa 4 Jahren. Im Gegensatz
dazu ist die frühere Entwicklung der impliziten Theory of Mind, einem unbewussten, nicht-verbalen Zugang zu mentalen Zuständen anderer, weiterhin umstritten, da Befunde aus verschiedenen experimentellen Paradigmen inkonsistent sind. Theory of Mind-Fähigkeiten stehen in engem Zusammenhang sowohl mit der Verwendung als auch mit dem Verstehen mentaler Zustandssprache. Die Forschung im Bereich des Verstehens mentaler Zustandssprache zeigt, dass Kinder ab etwa 4 bis 5 Jahren verbal zwischen epistemischen Verben—wie wissen, glauben oder denken—unterscheiden können. Es bleibt jedoch unklar, ob diese Fähigkeit bereits früher vorhanden ist, da Forschung in diesem Bereich bislang begrenzt ist. Bei neurodivergenter sozial-kognitiver Entwicklung, etwa bei Autismus, bringen aktuelle Predictive Coding-Ansätze Schwierigkeiten in Theory of Mind-Fähigkeiten mit einer Abschwächung in der prädiktiven Verarbeitung in Verbindung. Da implizite Theory of Mind auf unbewussten Vorhersagen über mentale Zustände anderer beruht, könnten Unterschiede zwischen autistischen und neurotypischen Personen auf Veränderungen in zugrunde liegenden prädiktiven Mechanismen hinweisen und somit eine mögliche Erklärung für Herausforderungen in der sozialen Interaktion liefern. Dennoch bleiben eindeutige neuronale Befunde bislang aus. Vor diesem Hintergrund ergeben sich folgende zentrale Fragen: Wie robust sind die bestehenden Paradigmen zur Erfassung impliziter Theory of Mind über die Lebensspanne hinweg? Entwickelt sich das implizite Verständnis epistemischer Sprache vor dem expliziten? Unterscheidet sich die prädiktive Verarbeitung in Theory of Mind-relevanten Gehirnregionen zwischen neurotypischen und autistischen Personen?
Ziel dieser Dissertation war es, diese Fragen systematisch zu untersuchen. Zu diesem Zweck wurden vier empirische Studien durchgeführt, die jeweils unterschiedliche Aspekte impliziter Theory of Mind im Rahmen neurotypischer und/oder neurodivergenter Entwicklung beleuchteten. In Studie 1 wurde ein neues web-basiertes Eye-Tracking-Verfahren bei Kleinkindern im Alter von 18 bis 27 Monaten (N = 125) validiert. Im Rahmen eines antizipatorischen Blickverhalten-Paradigmas (engl. anticipatory looking paradigm) wurde zielgerichtete Handlungsantizipation erfasst und mit Ergebnissen einer Laborstudie verglichen. Die Ergebnisse zeigten, dass zielgerichtete Handlungsantizipation in unserem web-basierten Setting zuverlässig messbar ist, wenngleich der Anteil des antizipatorischen Blickverhaltens etwas geringer und die Ausschlussrate höher war. Studie 2 nutzte ebenfalls das Paradigma aus Studie 1, das antizipatorisches Blickverhalten misst, und untersuchte, ob sich die Handlungsantizipation von Kleinkindern (N = 521) und Erwachsenen (N = 703) basierend auf den epistemischen Zuständen Wissen und Unwissen unterscheiden. Erwachsene unterschieden klar zwischen Wissen und Unwissen, was sich in ihrem antizipatorischen Blickverhalten widerspiegelte. Unerwarteterweise zeigten Kleinkinder diese Differenzierung nicht, was die Notwendigkeit weiterer Forschung unterstreicht. Studie 3 untersuchte das implizite Verstehen der epistemischen Verben „wissen“ und „glauben“ bei 27-monatigen (N = 199) und 36-monatigen Kindern (N = 131). Die Ergebnisse ergaben, dass bereits 27 Monate alte Kinder zwischen diesen Verben differenzieren konnten und spontan das Verb „wissen“ präferierten. Dies deutet darauf hin, dass ein implizites Verständnis epistemischer Verben dem expliziten vorauszugehen scheint. Studie 4 untersuchte prädiktive Prozesse im Theory of Mind-Netzwerk bei nicht-autistischen (N = 61 in Experiment 1; N = 30 in Experiment 2) und autistischen Erwachsenen (N = 30 in Experiment 2) mittels funktioneller Magnetresonanztomographie. Entgegen den Erwartungen fanden sich in keiner der beiden Gruppen Hinweise auf prädiktive Verarbeitung im Theory of Mind-Netzwerk. Allerdings zeigte sich bei autistischen (im Vergleich zu nicht-autistischen) Erwachsenen eine reduzierte Abschwächung der neuronalen Antwort bei wiederholter Präsentation (engl. repetition suppression) in einer Szene, die komplexe Theory of Mind-Prozesse erforderte. Diese ersten neuronale Hinweise stützen die Theorie der prädiktiven Kodierung bei Autismus. Gemeinsam tragen die vier Studien zu einem differenzierteren Verständnis impliziter Theory of Mind Fähigkeiten über Entwicklungsverläufe und Neurodiversität hinweg bei. Sie bieten methodische Innovationen zur impliziten Erfassung früher sozial-kognitiver Fähigkeiten, zeigen sowohl Potenziale als auch die Grenzen bestehender theoretischer Ansätze und empirischer Paradigmen auf und weisen auf mögliche Richtungen für zukünftige Forschung hin
Understanding the effects of plasmacytoid dendritic cells on acinar cell damage in Autoimmune Pancreatitis
Get PDFA Tibetan Cradle of Evolution - in-situ speciation and Out of Tibet radiations in passerine model species
Get PDFComprehensive insights into Obsessive-Compulsive Disorder
Get PDFObsessive-Compulsive Disorder (OCD) is a heterogeneous and debilitating condition that remains frequently under- and misdiagnosed, delaying not only effective treatment but also worsening long-term outcomes. In addition to diagnostic challenges, the underlying mechanisms contributing to OCD remain insufficiently understood. This thesis addresses these gaps by enhancing symptom assessment and investigating key mechanisms implicated in the disorder’s development and maintenance, specifically anger suppression and attentional biases.
To enhance assessment of OCD symptoms and diagnostic precision, Study I and
Study II translated and validated the 12- and 4-item Obsessive Compulsive Inventory (OCI-12 and OCI-4, respectively), testing the factor structure, reliability, validity, and diagnostic accuracy in clinical and non-clinical samples. Participants with OCD (n = 102), anxiety-related disorders (n = 69), and non-clinical controls (n = 248) were recruited and asked to fill out several online questionnaires assessing OCD symptoms, but also other symptoms such as anxiety, depression, and worry. The German version of the OCI-12 replicated the four-factor structure representing the most common OCD symptom clusters (i.e., checking, washing, ordering, and obsessing), with a higher-order factor for general OCD symptoms accounting for their covariance and improving model fit. Both, the OCI-4 and OCI-12, showed good reliabilities, moderate-to-good construct validity, and good-to-excellent diagnostic accuracy. Thereby, the findings support these measures as resource-efficient and clinically applicable screening tools, providing standardised cut-off criteria for improved assessment in routine care and research.
To contribute to a more comprehensive understanding of underlying factors of OCD, Study III and Study IV examine the role of anger suppression and attentional biases, respectively. Considering the divergent views of psychodynamic and cognitive theories on anger suppression, Study III explores whether anger suppression precedes or emerges as a consequence of OCD symptoms. The temporal relationship between anger suppression, the sense of responsibility, and OCD symptoms was investigated in participants with OCD
(n = 48), who were recruited as part of an intervention study evaluating the effects of a metacognitive intervention for OCD. Obsessive beliefs, OCD symptoms, and anger suppression were assessed at three timepoints: pre-intervention, post-intervention, and at a six-month follow-up. Results of the structural equation models indicated that OCD symptoms predicted increased anger suppression over time, independent of depressive symptoms and medication intake. The reverse directionality, with anger suppression predicting OCD symptoms, did not yield significant results, further corroborating the cognitive perspective. The association between an inflated sense of responsibility and anger suppression was less clear and appeared to be present only in individuals with high levels of checking-related symptoms, who generally exhibit greater responsibility concerns and increased anger suppression. While OCD symptoms significantly decreased throughout the metacognitive intervention, anger suppression remained stable, indicating differential treatment effects on these mechanisms. Overall, these results provide further support for cognitive models of OCD, highlighting the role of emotion regulation processes (i.e., anger suppression) and cognitive beliefs (i.e., sense of responsibility) in OCD, with their associations differing across specific OCD symptom clusters.
Study IV tested cognitive-behavioural theories on attentional biases in OCD, addressing inconsistencies in prior research. Using a free-viewing eye-tracking paradigm, attentional processes were examined in individuals with OCD (n = 51), spider phobia (n = 50), and non-clinical controls (n = 64). Stimuli were individually rated for their idiosyncratic disorder relevance, allowing for a more tailored analysis. Strikingly, of those pictures deemed OCD-related on average only one-third was considered actually OCD-relevant by participants with OCD, highlighting the need for idiosyncratic material in this heterogeneous disorder. Contrary to theoretical expectations, the multilevel models did not provide evidence for a vigilance bias, as participants with OCD were neither more likely to fixate first nor did they fixate more quickly on disorder-relevant stimuli. Furthermore, no general maintenance bias (i.e., longer fixation durations) emerged for OCD-relevant images. However, attentional maintenance seemed to be more fine-grained, as analyses revealed symptom-specific effects, with avoidance of contamination/washing-related pictures but increased maintenance on checking-related pictures in OCD. As individuals with spider phobia showed a general strategic avoidance of phobia-relevant pictures, the findings challenge that anxiety-based models on attentional biases can be transferred to OCD. Instead, the possibility of distinct underlying emotions that drive different attentional and behavioural responses is discussed. Accordingly, the importance of considering both the heterogeneity of OCD symptoms and emotional experiences in basic research to enhance the understanding of underlying mechanisms in OCD is emphasised.
Overall, this thesis advances symptom assessment for the heterogeneous nature of OCD while emphasising the need for refined theoretical conceptualisations that account for both diverse symptom presentations and underlying emotional experiences. By validating the OCI-4 and OCI-12, this thesis contributes to improving early OCD diagnosis and enabling more precise symptom assessment in both clinical and research settings. Furthermore, the findings on underlying factors of OCD challenge the assumption of universal mechanisms in its development, instead highlighting symptom-specific cognitive-affective processes, such as anger suppression in checking-related compulsions or attentional biases shaped by distinct symptoms and presumably linked to specific emotional states. The discussion underscores the need for further investigation into the interplay between cognitive, behavioural, and affective processes, considering both theoretical implications and methodological challenges. The potential for refining theoretical models and returning to basic research to investigate the emotional facets of OCD is highlighted. Moreover, as cognitive-behavioural factors addressed in the current thesis can be related to emotion regulation frameworks, the role of emotion regulation difficulties as a potential factor underlying OCD is discussed. If successfully replicated, these findings could inform clinical practice, leading to more personalised interventions that integrate emotion regulation and symptom-specific mechanisms, thereby potentially enhancing the effectiveness of OCD treatment
Phenotyping of the visceral and subcutaneous adipose tissue in pigs using Magnetic Resonance Imaging (MRI) and Dual Energy X-ray Absorptiometry (DXA)
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Mechanisms of browning and cell death in thermogenic adipocytes
Get PDFObesity is a major risk factor for cardiovascular diseases, the most common cause of death in Germany. Studies in rodents have shown that the activation of BAT is a promising way to fight obesity and cardiovascular disease utilizing the inborn mechanism of NST. Among the many unanswered questions about BAT biology are the mechanisms of involution of the tissue during infancy and how to translate findings in rodents to humans.
In the first publication I investigated the role of the recently discovered cell death mechanism “ferroptosis” in brown adipose tissue. I discovered that ferroptosis compromises the UPS in brown adipocytes, a pathway that has been shown to be essential for brown adipose tissue homeostasis. NFE2L1 acts as a master regulator of the UPS and can restore proteasomal activity during proteotoxic stress. Surprisingly, NFE2L1 is strongly activated by inducers of ferroptosis. Genetic depletion of NFE2L1 lead to increased sensitivity towards ferroptosis in brown adipocytes and tumor cell lines. On top of that patient-derived fibroblasts carrying a mutation in the anti-ferroptotic enzyme GPX4 replicated this phenotype, proving the relevance of NFE2L1 in ferroptosis protection in multiple models. Mice lacking Nfe2l1 in BAT present whitening of the tissue with a loss of thermogenic capacity. Signatures of ferroptosis were also observed in brown adipose tissue of mice lacking Nfe2l1, hinting at a possible role of ferroptosis in BAT involution. In summary, we discovered a novel anti-ferroptotic mechanism in brown adipocytes, in which NFE2L1 promotes proteasomal activity to prevent ferroptosis.
Adipose tissue research is usually performed using the mouse as a model organism. Due to the vastly reduced prevalence of BAT in humans it is necessary to find mechanisms in thermogenic adipose tissue that are functional in humans.
In the second study we found the human specific long non-coding RNA AATBC to be a modulator of thermogenesis. Using transcriptomic analysis from human adipose tissue and cell lines we found AATBC to be enriched in thermogenic conditions. Modulating the expression levels of AATBC revealed a positive correlation with markers of thermogenesis and mitochondrial activity. As mitochondrial abundance was unaltered, we observed changes in mitochondrial dynamics with AATBC promoting mitochondrial fission, which is associated with thermogenesis. Since AATBC is only expressed in humans, we used virus-mediated overexpression in mouse adipose tissue to study the effects of the lncRNA in vivo. We found leptin levels to be suppressed in animals expressing AATBC, which could also be observed in independent human cohorts. In humans, AATBC expression is furthermore negatively correlated with bodyweight and body mass index, and positively correlated with markers of adipose tissue browning. In conclusion, we describe a novel human-specific lncRNA that promotes adipose tissue browning my shifting mitochondrial dynamics to fission-like phenotype.Adipositas ist ein Risikofaktor für kardiovaskuläre Erkrankungen, die häufigste Todesursache in Deutschland. Studien im Tiermodell haben gezeigt, dass die Aktivierung von braunem Fettgewebe (BAT) eine vielversprechende Methode zur Bekämpfung von Adipositas und kardiovaskulären Erkrankungen darstellt, indem sie den angeborenen Mechanismus der zitterfreien Thermogenese nutzt. Zu den vielen unbeantworteten Fragen gehören die Mechanismen der BAT-Involution des Gewebes im Säuglingsalter und wie sich Erkenntnisse aus dem Tiermodell auf den Menschen übertragen lassen. In der ersten Publikation untersuchte ich die Rolle des kürzlich entdeckten Zelltodmechanismus "Ferroptose" im braunen Fettgewebe. Ich stellte fest, dass Ferroptose das UPS in braunen Adipozyten beeinträchtigt, welches für die Homöostase des braunen Fettgewebes als wesentlich gilt. NFE2L1 fungiert als Hauptregulator des UPS und kann die proteasomale Aktivität während proteotoxischem Stress wiederherstellen. Überraschenderweise lässt sich bei Induktion von Ferroptose eine substanzielle Aktivierung von NFFE2L1 feststellen. Die genetische Depletion von NFE2L1 führte zu erhöhter Empfindlichkeit gegenüber Ferroptose in braunen Adipozyten und Tumorzelllinien. Dieses Phänomen konnte in Fibroblasten eines Patienten mit einer Mutation im anti-ferroptotischen Enzym GPX4 repliziert werden, was die Relevanz von NFE2L1 im Schutz vor Ferroptose in mehreren Modellen beweist. Mäuse ohne Nfe2l1 im BAT zeigen eine Aufhellung des Gewebes und einen Verlust der thermogenen Kapazität. In diesen lassen sich ebenfalls Anzeichen von Ferroptose beobachten, was auf eine mögliche Rolle der Ferroptose bei der Involution von BAT hindeutet. Zusammenfassend haben wir einen neuartigen anti-ferroptotischen Mechanismus in braunen Adipozyten entdeckt, bei dem NFE2L1 durch Aufrechterhaltung der proteasomalen Aktivität Ferroptose verhindert. Die Forschung an Fettgewebe wird üblicherweise am Mausmodell durchgeführt. Aufgrund der stark reduzierten Prävalenz von BAT beim Menschen ist es notwendig, Mechanismen im thermogenen Fettgewebe zu finden, die beim Menschen funktional sind. In der zweiten Studie fanden wir, dass die, spezifisch im Menschen exprimierte, long non-coding RNA AATBC ein Modulator der Thermogenese ist. Mittels Transkriptomanalyse von menschlichem Fettgewebe und Zelllinien stellten wir fest, dass AATBC vermehrt unter thermogenen Bedingungen vorliegt. Durch Modulation der Expression von AATBC zeigte eine positive Korrelation mit Markern der Thermogenese und mitochondrialer Aktivität. Da die Anzahl an Mitochondrien unverändert war, untersuchten wir Veränderungen in der mitochondrialen Dynamik. AATBC förderte die mitochondriale fission, die mit Thermogenese assoziiert ist. Da AATBC nur im Menschen exprimiert ist, nutzten wir virusvermittelte Überexpression im Mausfettgewebe, um die Effekte der lncRNA in vivo zu untersuchen. Wir stellten fest, dass die Leptin-Spiegel in Tieren mit AATBC verringert waren, was wir auch in unabhängigen Patientenkohorten beobachten konnten. In klinischen Studien korreliert die AATBC-Expression negativ mit dem Körpergewicht und Body-Mass-Index und positiv mit Markern der Thermogenese des Fettgewebes. Zusammenfassend beschreiben wir eine neuartige, menschenspezifische lncRNA, die die Thermogenese fördert, indem sie die mitochondriale Dynamik hin zu einem fission-ähnlichen Phänotyp verschiebt
