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Charakterisierung neuraler Vorläuferzellen im pränatalen Neokortex des Nördlichen Spitzhörnchens (Tupaia belangeri) Einleitung: Im Verlauf der Evolution entwickelte sich der Neokortex zum komplexesten Anteil des Säugetiergehirns. Ausdifferenzierungen und eine immense Expansion des Neo-kortex, vor allem in der Primatenabstammungslinie, waren die Folge. Der größte Teil der neokortikalen Neurone wird während der Embryonal- und Fetalphase gebildet und stammt von sogenannten neuralen Stamm- und Progenitorzellen (NPCs) ab. Diese entstehen in zwei unterschiedlichen Keimschichten, der Ventrikulärzone (VZ) und der Subventrikulärzone (SVZ). Vorangegangene Studien zeigten, dass sich die Dicke der SVZ als auch das Vorhan-densein und die Häufigkeit bestimmter NPCs, besonders die der basalen radialen Gliazelle (bRG), zwischen lissenzephalen Nagetieren und gyrenzephalen Primaten erheblich unter-scheidet. Bislang werden überwiegend Nagetiere in Untersuchungen zu gehirnassoziierten Fragestellungen eingesetzt, wohlwissentlich dass es deutliche Unterschiede in der neokorti-kalen Entwicklung (d.h. in der Abundanz und Verteilung der unterschiedlichen NPCs) zwi-schen Mensch und Nagetier gibt. Die Etablierung eines Tiermodells, das eine ähnliche NPC- Ausstattung wie der Mensch besitzt, ist für das bessere Verständnis der humanen Neokorte-xentwicklung sowie neokortikaler Entwicklungsstörungen und Erkrankungen essenziell. Das nördliche Spitzhörnchen (Tupaia belangeri) ist ein rattengroßes Tier mit einem hohen Ge-hirn-Körpermasse-Verhältnis und steht phylogenetisch zwischen den Nagetieren und den Primaten. Ziel der Untersuchung: Ziel dieser Arbeit war es, die Präsenz, die Abundanz und die Ver-teilung der bRGs und anderer NPCs in den Keimzonen (VZ und SVZ) des sich entwickeln-den Neokortex des Tupaia belangeri zu erfassen. Die erhobenen Daten wurden mit vorhan-denen Daten von Makaken, Frettchen, Ratte und Maus verglichen, um zu erfahren, ob Schlüsselmerkmale der Neokortexentwicklung größere Gemeinsamkeiten zu gyrenzepha-len Primaten oder lissenzephalen Nagetieren zeigen. Tiere, Material und Methoden: Die Tupaiagehirne stammen von Tieren aus dem Institut für Biologie der Universität Leipzig, Fakultät für Biowissenschaften, Pharmazie und Psycho-logie und dem Institut für Zoologie der Tierärztlichen Hochschule Hannover. Das Alter der Proben bewegte sich von Embryonaltag 32 (n=2), 37 (n=2), 45 (n=2) bis hin zu Postnataltag (P) 1 (n=2). Die exakte Bestimmung des Alters der Tiere erfolgte über eine Scheitel-Steißlängen-Wachstumskurve. Die Gehirne wurden entnommen, fixiert und das gesamte Telenzephalon wurde von rostral nach kaudal in Einzelschnitte von 30 µm Dicke geschnitten und immunhistochemisch gefärbt. Dabei wurden fluoreszenmarkierte sekundäre Antikörper verwendet. Die visuelle Darstellung erfolgte mittels eines konfokalen Lasermikroskops (Leica SP8). Die Aufnahmen wurden mittels Fiji und Adobe Photoshop Software prozessiert. Die Quantifizierung der Zellen erfolgte mittels Fiji Software (Multiclass Cell Counter plug in). Die statistische Auswertung erfolgte durch R Software. Im Rahmen einer Ranganalyse wurden nichttransformierte Werte verschiedener neokortikaler Parameter unterschiedlicher Spezies verglichen und mit dem Kruskal-Wallis-Test mit anschließendem Conover post-hoc-Test auf eine statistische Signifikanz (p <0.05) geprüft. Darüber hinaus wurde nach Standardisierung mittels z-Score eine Hauptkomponentenanalyse, euklidische Distanzberechnung und hierar-chisches Clustern durchgeführt. Ergebnisse: Drei grundlegende Erkenntnisse stellen sich dar. Der sich entwickelnde Neo-kortex des Tupaia belangeri verfügt über (i) eine relativ große SVZ, (ii) eine hohe Abundanz von Pax6+ NPCs in der SVZ sowie über (iii) einen hohen Prozentsatz von bRGs zum Zeit-punkt der Bildung der oberen Kortexschichten. Durch die statistische Auswertung stellte sich heraus, dass bestimmte Schlüsselmerkmale in der Neokortexentstehung des Tupaia (d.h. Entwicklung der Keimzonen, Verteilung und Abundanz von unterschiedlichen NPCs) größe-re Ähnlichkeiten zu denen der gyrenzephalen Primaten als zu denen der lissenzephalen Na-getiere aufweisen. Beim Rangvergleich der untersuchten Parameter wurde eine statistische Signifikanz (siehe Tiere, Material und Methoden mit p <0.05) festgestellt. Schlussfolgerung: Die Ergebnisse dieser Arbeit zeigen, dass große Ähnlichkeiten zwischen den NPC Populationen im sich entwickelnden Neokortex von gyrenzephalen Primaten und Tupaia belangeri bestehen. Somit wird mit dem Tupaia belangeri der biomedizinischen For-schung und translationalen Medizin für die Untersuchung von entwicklungsbedingten Fehl-bildungen und Erkrankungen des Neokortex ein besonders geeignetes Tiermodell - als Al-ternative zu Maus, Ratte, Frettchen und Primaten - zur Verfügung gestellt. Darüber hinaus bieten die gewonnenen Ergebnisse weitreichende Einsichten in die Evolution des Gehirns und die Phylogenese der NPCs der Säugetiere und sind somit für die Grundlagenforschung von großer Bedeutung.

Ein bezüglich Datenakquisition und Nachverarbeitung optimiertes Visualisie-rungsprotokoll zur dreidimensionalen Darstellung der Hirnnerven V-VIII im Be-reich der basalen Zisternen wird vorgestellt. Auf der Basis von hochauflösen-den MRT Daten und unter Verwendung der Volume-Rendering-Technik entstanden insgesamt 10 Standardansichten der genannten Hirnnerven, die deren vollständige und zeiteffektive intrazisternale Abbildung mit besonderer Beachtung pathophysiologisch relevanter Zonen ermöglichen. Das Protokoll zeigte in der Evaluation an Patienten mit neurovaskulären Konflikten und an-deren neuralen Kompressionssyndromen im Bereich des Kleinhirnbrücken-winkels seine Eignung bezüglich Bildqualität und diagnostischer Wertigkeit. Probleme traten vor allem aufgrund von Pulsations- und Bewegungsartefakten im akquirierten MRT-Datensatz, sowie zu enger Zisternen auf der Höhe der virtuellen Kameraposition auf. Diese ließen sich in den meisten Fällen jedoch durch leichte Parametervariationen beheben. Zur genauen Identifikation der Gefäße und zur Vermeidung der Weitergabe von Fehlzuordnungen war zu-sätzlich zu den Rekonstruktionen die Betrachtung des Originaldatensatzes er-forderlich. Die Nachverfolgung der mit dem beschriebenen Protokoll virtuell zisternoskopisch untersuchten Patienten ergab bei der weit überwiegenden Zahl der verfolgbaren Patienten Konsequenzen hinsichtlich Diagnose und/oder Therapie. Die Korrelation mit intraoperativen Befunden konnte nur bei zwei Patienten mit Akustikusneurinomen erfolgen, wobei hier eine Über-einstimmung festgestellt werden konnte. Ursache für die nur geringe Zahl der zur Verfügung stehenden intraoperativen Befunde ist die lange Latenz zwi-schen Bildgebung und neurochirurgischer Intervention bei neurovaskulären Konflikten. Zusammenfassend lässt sich feststellen dass die virtuelle Zister-noskopie nach dem vorgestellten Protokoll eine komplementäre Bildgebungs-technik ist, die wichtige räumliche Informationen zu neurovaskulären Interakti-onen in den basalen Zisternen liefert. Weitere Untersuchungen, insbesondere die intraoperative Befundkorrelation, sind jedoch erforderlich. / The following thesis presents a protocol for the three-dimensional visualization of the cranial nerves V-VIII within the basal cisterns, being optimized with regard to data acquisition and postprocessing. Based on high resolution MRI datasets and using the volume rendering technique, 10 standardized views of the aforementioned cranial nerves were developed. Thus, the complete and time effective intracisternal depiction was intended to be made possible, focussing on pathophysiological important areas of the nerves. The protocol showed its suitability concerning image quality and diagnostic value in evaluation of patients with neurovascular conflicts or other neural compression syndromes in the cerebello-pontine angle. Problems mainly occurred as a result of pulsation and motion artefacts in the MR dataset and narrow cisterns in the level of the virtual camera position. In most cases they could be solved by slight variations of the postprocessing parameters. To guaranty the correct identification of the vessels and to avoid the risk of giving incorrectly assigned anatomic information to subsequent readers, the additional inspection of original dataset is necessary. In the follow up of the examined patients consequences in diagnosis and/or therapy were found in the most cases. The correlation of the virtual cisternoscopic images with the intraoperative results could only be performed in two patients with acoustic neuromas and was successful. The reason for the small amount of available intraoperative results is the latency between imaging and neurosurgical intervention in neurovascular conflicts. Concluding the virtual cisternoscopy following the introduced protocol is a complementary imaging technique that provides important spatial information about neurovascular interactions within the basal cisterns. Yet further investigations, especially the intraoperative correlation of the results, are necessary.

No description available.

Le but de ce travail de thèse a été de caractériser in vivo chez l’Homme, la connectivité cérébrale sur son versant fonctionnel, par le biais de deux techniques: la stéréoélectroencéphalographie (SEEG) et l’IRM fonctionnelle (IRMf) de repos. Ces travaux se sont intégrés dans le cadre du bilan préchirurgical des épilepsies du lobe temporal pharmacorésistantes, dont le but est de déterminer la zone épileptogène à réséquer pour traiter ces patients. Alors que plusieurs études en électrophysiologie ont montré que durant les crises, il existait une synchronisation anormalement élevée entre les structures impliquées dans les processus épileptogènes, aucune donnée de connectivité n’était disponible en période intercritique. Pourtant, la période intercritique est le siège d’anomalies interictales enregistrées en EEG, de profonds remaniements morphologiques, et est associée à des troubles cognitifs. Nous apportons avec ce travail, grâce au recueil et au traitement de signaux SEEG et IRMf enregistrés durant la période intercritique, de nouvelles connaissances i) sur l’organisation de la connectivité fonctionnelle basale (CFB) chez les sujets sains ; ii) sur les altérations de la CFB chez des groupes de patients mais également au niveau individuel ; iii) sur le rapport entre ces anomalies de CFB et les troubles cognitifs observés chez ces patients ; iv) enfin, sur les différences et les similitudes de la CFB évaluée par SEEG et IRMf chez les mêmes sujets, ouvrant ainsi de nouvelles perspectives dans la compréhension des relations entre le signal BOLD et le signal EEG. / The aim of this thesis was to characterize the Human brain functional connectivity in vivo based on signals recorded using stereoelectroencephalography (SEEG) and resting-state functional MRI (fMRI). This work was conducted during the presurgical assessment of drug resistant temporal lobe epilepsy, which aims at determining the epileptogenic zone to be removed to treat these patients. While several electrophysiological studies have shown high synchronization between structures involved in the epileptogenic process during seizure, no similar connectivity data was available during inter-critical period. However, the interictal period is characterized by spikes recorded on EEG, morphological alterations and cognitive impairment. By analyzing fMRI and SEEG signals recorded during the interictal period, this work provides new insights into, i) basal functional connectivity (BFC) organization in healthy subjects, ii) BFC alterations in patients groups but also at the individual level, iii) the relationship between these BFC abnormalities and cognitive impairment observed in these patients; iv) the differences and similarities of BFC evaluated by SEEG and fMRI in the same subjects, thus opening up new perspectives in better understanding of relationships between BOLD and SEEG signal coupling.

: Les plantes ont développé au cours de leur évolution un système d’immunité innée constitué de barrières préformées et de réponses de défense induites contre les agents pathogènes. Ce travail s’inscrit dans l’étude des résistances induites chez Arabidopsis thaliana soit naturellement contre les agents pathogènes racinaires Fusarium oxysporum spp. (Fo), ou après application de phosphite (Phi), contre le parasite foliaire Hyaloperonospora arabidopsidis (Hpa). Dans la première partie du travail, les rôles des métabolites secondaires (MS) et des formes réactives de l’oxygène (ROS) dans les résistances racinaires basale et non-hôte, respectivement aux formes spéciales conglutinans (Foco) et melonis (Fom) de Fo, ont été analysés. Nous avons démontré la participation de la camalexine, une phytoalexine indolique, dans la résistance basale d’Arabidopsis à Foco. En revanche, la scopolétine, une phytoalexine phénolique, et les ROS jouent des rôles essentiels dans la résistance non-hôte à Fom. Ces données soulignent le rôle clé des MS et des ROS dans les résistances hôte et non-hôte d’Arabidopsis. Dans une deuxième partie de ce travail, le mode d’action du Phi, un oxyanion de l’acide phosphoreux (H3PO3) protégeant Arabidopsis contre l’isolat Noco2 de Hpa, a été étudié. L’effet de faibles doses de Phi est aboli chez des mutants d’Arabidopsis affectés dans la voie de transduction du signal acide salicylique (SA) indiquant que l’induction de résistance à Hpa est médiée par des mécanismes dépendants du SA. Le Phi potentialise les réponses de défense contre Hpa Noco2 via EDS1-PAD4, deux composants essentiels de la résistance basale, NPR1 et la protéine de défense PR1. L’expression de la MAP kinase MPK4, un régulateur négatif de la résistance à Hpa, est diminuée par le Phi, lors de l’inoculation par Hpa Noco2. Nos résultats démontrent que la potentialisation des réponses de défense par le Phi est associée à la régulation négative de MPK4. / Plants have developed during their evolution an innate immunity system consisting of preformed barriers and induced defence responses against pathogens. This work studies resistances in Arabidopsis thaliana induced either naturally against the root pathogen Fusarium oxysporum spp. (Fo), or after application of phosphite (Phi) against the leaf pathogen Hyaloperonospora arabidopsidis (Hpa). In a first part, roles of secondary metabolites (SM) and reactive oxygen species (ROS) in basal and non-host resistances of roots to the special forms conglutinans (Foco) and melonis (Fom) of Fo, respectively, were analyzed. We demonstrated the involvement of the indolic phytoalexin camalexin, in basal resistance of Arabidopsis to Foco. In contrast, the phenolic phytoalexin, scopoletin, and ROS play essential roles in non-host resistance to Fom. These data underscore the key role of MS and ROS in basal and non-host resistances of Arabidopsis. In a second part, the mode of action of Phi, an oxyanion of phosphorous acid (H3PO3) protecting Arabidopsis against the Hpa isolate Noco2 was studied. Effect of low doses of Phi is abolished in Arabidopsis mutants affected in salicylic acid (SA) signalling, indicating that induced resistance to Hpa is mediated by SA-dependent mechanisms. Phi primes defence responses against Hpa Noco2 via EDS1-PAD4, two essential components of basal resistance, as well as NPR1 and PR1. Expression of the MAP kinase MPK4, a negative regulator of resistance to Hpa, is decreased by Phi after inoculation with Hpa Noco2. Our results demonstrate that priming of defence responses by Phi is associated with down-regulation of MPK4.

Theory of Mind (ToM) is the ability to infer others’ mental states and thus to predict their behavior (Perner, 1991). Therefore, ToM is essential for the adequate adjustment of behavior in social situations. ToM can be divided into: 1) cognitive ToM encompassing inferences about intentions and beliefs and 2) affective ToM encompassing inferences about emotions (Shamay-Tsoory, Harari, Aharon-Peretz, & Levkovitz, 2010). Well-functioning skills of both ToM aspects are much-needed in the developmental period of adolescence because in this age phase peer relationships become more important and romantic relationships arise (Steinberg & Morris, 2001). Importantly, affective psychopathological disorders often have their onset in adolescence. ToM development in adolescence might be based on underlying cognitive mechanisms such as the ability to inhibit one’s own thoughts in order to understand another person’s thoughts (Carlson & Moses, 2001). Another possible mechanism relates to functional brain development across adolescence (Blakemore, 2008). Therefore, neurocognitive mechanisms may underlie ongoing ToM development in adolescence. First studies indicate an ongoing behavioral and functional brain development of ToM (e.g. Blakemore, 2008). However, ToM development in adolescence and how this might relate to underlying (neuro)cognitive functions remains largely underexamined. The major aims of the current thesis were first to answer the overall question whether there is an ongoing development of ToM in adolescence. This question relates to both behavioral and functional brain development. As a second major aim, the present work sought to elucidate possible (neuro)cognitive mechanisms of ongoing ToM development across adolescence. Specifically, these cognitive mechanisms might be basic cognitive functions as well as executive functions. Additionally, the present work aimed at exploring potential (neuro)cognitive mechanisms through an integration of both behavioral and functional brain studies. The current experimental work spans three cross-sectional studies investigating adolescents (aged around 12-15 years) and young adults (aged around 18-22 years) to examine for the first time both the behavioral (studies I and II) and functional brain development of ToM (study III) in adolescence and its underlying (neuro)cognitive mechanisms. In all three studies, more complex, advanced ToM tasks were employed to avoid ceiling effects. Study I was aimed at investigating if cognitive and affective ToM continues to develop in adolescence and at exploring if basic cognitive variables such as verbal ability, speed of processing, and working memory capacity underlie such development. Hence, two groups of adolescents and young adults completed tasks of ToM and basic cognitive abilities. Large age effects were revealed on both measures of ToM: adolescents performed lower than adults. These age differences remained significant after controlling for basic cognitive variables. However, verbal ability covaried with performance in affective ToM. Overall, results support the hypothesis of an ongoing development of ToM from adolescence to adulthood on both cognitive and affective aspects. Results may further indicate verbal ability being a basic cognitive mechanism of affective ToM. Study II was designed to further explore if affective ToM, as measured with a dynamic realistic task, continues to develop across adolescence. Importantly, this study sought to explore executive functions as higher cognitive mechanisms of developing affective ToM across adolescence. A large group spanning adolescents and young adults evaluated affective mental states depicted by actors in video clips. Additionally, participants were examined with three subcomponents of executive functions, inhibition, updating, and shifting following the classification of Miyake et al. (2000). Affective ToM performance was positively related to age and all three executive functions. Specifically, inhibition explained the largest amount of variance in age related differences of affective ToM performance. Overall, these results indicate the importance of inhibition as key underlying mechanism of developing an advanced affective ToM in adolescence. Study III set out to explore the functional brain development of affective ToM in adolescence by using functional magnetic resonance imaging (fMRI). The affective ToM measure was the behavioral developmentally sensitive task from study II. An additional control condition consisted of the same emotional stimuli with the instruction to focus on physical information. This study faced methodical challenges of developmental fMRI studies by matching performance of groups. The ventromedial prefrontal cortex (vMPFC) was significantly less deactivated in adolescents in comparison to adults, which might suggest that adolescents seem to rely more on self-referential processes for affective ToM. Furthermore, adolescents compared to adults showed greater activation in the dorsolateral prefrontal cortex (DLPFC) in the control condition, indicating that adolescents might be distracted by the emotional content and therefore needed to focus more on the physical content of the stimulus. These findings suggest affective ToM continues to develop on the functional brain level and reveals different underlying neurocognitive strategies for adolescents in contrast to adults. In summary, the current thesis investigated whether ToM continues to develop in adolescence until young adulthood and explored underlying (neuro)cognitive mechanisms. Findings suggest that there is indeed an ongoing development of both the cognitive and affective aspect of ToM, which importantly contributes to the conceptual debate. Moreover, the second benefit to the debate is to demonstrate how this change may occur. As a basic cognitive mechanism verbal ability and as an executive functioning mechanism inhibition was revealed. Furthermore, neurocognitive mechanisms in form of different underlying neurocognitive strategies of adolescents compared to adults were shown. Taken together, ToM development in adolescence seems to mirror a different adaptive cognitive style in adolescence (Crone & Dahl, 2012). This seems to be important for solving the wealth of socio-emotional developmental tasks that are relevant for this age span.

Theory of Mind (ToM) is the ability to infer others’ mental states and thus to predict their behavior (Perner, 1991). Therefore, ToM is essential for the adequate adjustment of behavior in social situations. ToM can be divided into: 1) cognitive ToM encompassing inferences about intentions and beliefs and 2) affective ToM encompassing inferences about emotions (Shamay-Tsoory, Harari, Aharon-Peretz, & Levkovitz, 2010). Well-functioning skills of both ToM aspects are much-needed in the developmental period of adolescence because in this age phase peer relationships become more important and romantic relationships arise (Steinberg & Morris, 2001). Importantly, affective psychopathological disorders often have their onset in adolescence. ToM development in adolescence might be based on underlying cognitive mechanisms such as the ability to inhibit one’s own thoughts in order to understand another person’s thoughts (Carlson & Moses, 2001). Another possible mechanism relates to functional brain development across adolescence (Blakemore, 2008). Therefore, neurocognitive mechanisms may underlie ongoing ToM development in adolescence. First studies indicate an ongoing behavioral and functional brain development of ToM (e.g. Blakemore, 2008). However, ToM development in adolescence and how this might relate to underlying (neuro)cognitive functions remains largely underexamined. The major aims of the current thesis were first to answer the overall question whether there is an ongoing development of ToM in adolescence. This question relates to both behavioral and functional brain development. As a second major aim, the present work sought to elucidate possible (neuro)cognitive mechanisms of ongoing ToM development across adolescence. Specifically, these cognitive mechanisms might be basic cognitive functions as well as executive functions. Additionally, the present work aimed at exploring potential (neuro)cognitive mechanisms through an integration of both behavioral and functional brain studies. The current experimental work spans three cross-sectional studies investigating adolescents (aged around 12-15 years) and young adults (aged around 18-22 years) to examine for the first time both the behavioral (studies I and II) and functional brain development of ToM (study III) in adolescence and its underlying (neuro)cognitive mechanisms. In all three studies, more complex, advanced ToM tasks were employed to avoid ceiling effects. Study I was aimed at investigating if cognitive and affective ToM continues to develop in adolescence and at exploring if basic cognitive variables such as verbal ability, speed of processing, and working memory capacity underlie such development. Hence, two groups of adolescents and young adults completed tasks of ToM and basic cognitive abilities. Large age effects were revealed on both measures of ToM: adolescents performed lower than adults. These age differences remained significant after controlling for basic cognitive variables. However, verbal ability covaried with performance in affective ToM. Overall, results support the hypothesis of an ongoing development of ToM from adolescence to adulthood on both cognitive and affective aspects. Results may further indicate verbal ability being a basic cognitive mechanism of affective ToM. Study II was designed to further explore if affective ToM, as measured with a dynamic realistic task, continues to develop across adolescence. Importantly, this study sought to explore executive functions as higher cognitive mechanisms of developing affective ToM across adolescence. A large group spanning adolescents and young adults evaluated affective mental states depicted by actors in video clips. Additionally, participants were examined with three subcomponents of executive functions, inhibition, updating, and shifting following the classification of Miyake et al. (2000). Affective ToM performance was positively related to age and all three executive functions. Specifically, inhibition explained the largest amount of variance in age related differences of affective ToM performance. Overall, these results indicate the importance of inhibition as key underlying mechanism of developing an advanced affective ToM in adolescence. Study III set out to explore the functional brain development of affective ToM in adolescence by using functional magnetic resonance imaging (fMRI). The affective ToM measure was the behavioral developmentally sensitive task from study II. An additional control condition consisted of the same emotional stimuli with the instruction to focus on physical information. This study faced methodical challenges of developmental fMRI studies by matching performance of groups. The ventromedial prefrontal cortex (vMPFC) was significantly less deactivated in adolescents in comparison to adults, which might suggest that adolescents seem to rely more on self-referential processes for affective ToM. Furthermore, adolescents compared to adults showed greater activation in the dorsolateral prefrontal cortex (DLPFC) in the control condition, indicating that adolescents might be distracted by the emotional content and therefore needed to focus more on the physical content of the stimulus. These findings suggest affective ToM continues to develop on the functional brain level and reveals different underlying neurocognitive strategies for adolescents in contrast to adults. In summary, the current thesis investigated whether ToM continues to develop in adolescence until young adulthood and explored underlying (neuro)cognitive mechanisms. Findings suggest that there is indeed an ongoing development of both the cognitive and affective aspect of ToM, which importantly contributes to the conceptual debate. Moreover, the second benefit to the debate is to demonstrate how this change may occur. As a basic cognitive mechanism verbal ability and as an executive functioning mechanism inhibition was revealed. Furthermore, neurocognitive mechanisms in form of different underlying neurocognitive strategies of adolescents compared to adults were shown. Taken together, ToM development in adolescence seems to mirror a different adaptive cognitive style in adolescence (Crone & Dahl, 2012). This seems to be important for solving the wealth of socio-emotional developmental tasks that are relevant for this age span.:Abstract 1 1 General Introduction 4 1.1 Concept of ToM: cognitive and affective aspects 7 1.2 ToM Development 8 1.2.1 ToM Development until Adolescence 9 1.2.2 ToM Development in Adolescence 12 1.3 Cognitive Mechanisms 14 1.3.1 Basic Cognitive Functions 15 1.3.2 Executive Functions 17 1.4 Neurocognitive Mechanisms 19 1.4.1 Functional brain development of ToM 20 1.4.2 Integrating behavioral and functional brain studies 21 2 Outline and Central Questions 24 2.1 Does ToM continue to develop in adolescence? 24 2.1.1 Does ToM continue to develop on the behavioral level? 24 2.1.2 Does ToM continue to develop on the level of brain function? 25 2.2 What are (neuro)cognitive mechanisms of ToM development in adolescence? 26 2.2.1 What are basic cognitive and executive functioning mechanisms? 26 2.2.2 Can mechanisms be concluded from the integration of behavioral data and functional brain processes? 26 3 Study I – ToM Development in Adolescence and its Basic Cognitive Mechanisms 28 3.1 Introduction 28 3.2 Method 32 3.2.1 Participants 32 3.2.2 Materials 33 3.3 Results 36 3.3.1 Age Effects 36 3.3.2 Influence of puberty on social cognition 37 3.3.3 Controlling for Basic Cognitive Abilities 39 3.4 Discussion 40 3.4.1 Overview 40 3.4.2 Age differences in social cognition 40 3.4.3 Influence of puberty on social cognition 42 3.4.4 Covariates of age differences in social cognition 42 3.4.5 Conclusions 43 4 Study II – ToM Development in Adolescence and its Executive Functioning Mechanisms 45 4.1 Introduction 45 4.2 Method 49 4.2.1 Participants 49 4.2.2 Materials 49 4.3 Results 52 4.3.1 Decomposing the Age Effect in Affective Theory of Mind 54 4.4 Discussion 55 4.4.1 Overview 55 4.4.2 Conclusions 57 5 Study III – ToM Development in Adolescence and its Neurocognitive Mechanisms 59 5.1 Introduction 59 5.2 Method 61 5.2.1 Participants 61 5.2.2 Stimuli, design and procedure 62 5.2.3 Statistical analysis of behavioral data 65 5.2.4 Functional imaging 65 5.2.5 Statistical analysis of fMRI data 66 5.3 Results 67 5.3.1 Behavioral results 67 5.3.2 fMRI results 68 5.4 Discussion 71 5.4.1 Developmental differences in brain activations 71 5.4.2 Conclusions 74 6 General Discussion 75 6.1 Summary of empirical findings 75 6.2 Discussion and integration of the main empirical findings 76 6.2.1 Continued ToM development in adolescence 76 6.2.2 (Neuro)cognitive mechanisms of ToM development in adolescence 80 6.3 Implications and outlook 89 6.3.1 Current findings and their conceptual fit to present models of ToM 90 6.3.2 Underpinning the concept of cognitive and affective ToM 91 6.3.3 Conceptual and methodical implications of performance matching 92 6.3.4 The role of puberty on ToM 94 6.3.5 Predicting other’s economic behavior 95 6.3.6 Structural brain development 96 6.3.7 Applied perspective 97 6.4 Summary 98 References 99