Goal-directed actions frequently require a balance between antagonistic processes (e.g., executing and inhibiting a response), often showing an interdependency concerning what constitutes goal-directed behavior. While an inter-dependency of antagonistic actions is well described at a behavioral level, a possible inter-dependency of underlying processes at a neuronal level is still enigmatic. However, if there is an interdependency, it should be possible to predict the neurophysiological processes underlying inhibitory control based on the neural processes underlying speeded automatic responses. Based on that rationale, we applied artificial intelligence and source localization methods to human EEG recordings from N = 255 participants undergoing a response inhibition experiment (Go/Nogo task). We show that the amplitude and timing of scalp potentials and their functional neuroanatomical sources during inhibitory control can be inferred by conditional generative adversarial networks (cGANs) using neurophysiological data recorded during response execution. We provide insights into possible limitations in the use of cGANs to delineate the interdependency of antagonistic actions on a neurophysiological level. Nevertheless, artificial intelligence methods can provide information about interdependencies between opposing cognitive processes on a neurophysiological level with relevance for cognitive theory.

Executive functions, like the capacity to control and organize thoughts and behavior, develop from childhood to young adulthood. Although task switching and working memory processes are known to undergo strong developmental changes from childhood to adulthood, it is currently unknown how task switching processes are modulated between childhood and adulthood given that working memory processes are central to task switching. The aim of the current study is therefore to examine this question using a combined cue- and memory-based task switching paradigm in children (N = 25) and young adults (N = 25) in combination with neurophysiological (EEG) methods. We obtained an unexpected paradoxical effect suggesting that memory-based task switching is better in late childhood than in young adulthood. No group differences were observed in cue-based task switching. The neurophysiological data suggest that this effect is not due to altered attentional selection (P1, N1) or processes related to the updating, organization, and implementation of the new task-set (P3). Instead, alterations were found in the resolution of task-set conflict and the selection of an appropriate response (N2) when a task has to be switched. Our observation contrasts findings showing that cognitive control mechanisms reach their optimal functioning in early adulthood.

In welcher Weise hängt die Dynamik eines neuronalen Systems von den Eigenschaften seiner Netzwerkstruktur ab? Diese wichtige Fragestellung der Neurowissenschaft untersuchen wir in dieser Dissertation anhand einer analytischen und numerischen Modellierung der Aktivität großer neuronaler Netzwerke mit komplexer Struktur. Im Fokus steht die Relevanz zweier bestimmter Merkmale für die Dynamik: strukturelle Heterogenität und Gradkorrelationen. Ein zentraler Bestandteil der Dissertation ist die Entwicklung einer Molekularfeldnäherung, mit der die mittlere Aktivität heterogener, gradkorrelierter neuronaler Netzwerke berechnet werden kann, ohne dass einzelne Neuronen explizit simuliert werden müssen. Die Netzwerkstruktur wird von einer reduzierten Matrix erfasst, welche die Verbindungsstärke zwischen den Neuronengruppen beschreibt. Für einige generische Zufallsnetzwerke kann diese Matrix analytisch berechnet werden, was eine effiziente Analyse der Dynamik dieser Systeme erlaubt. Mit der Molekularfeldnäherung und numerischen Simulationen zeigen wir, dass assortative Gradkorrelationen einem neuronalen System ermöglichen, seine Aktivität bei geringer externer Anregung aufrecht zu erhalten und somit besonders sensitiv auf schwache Stimuli zu reagieren. / An important question in neuroscience is how the structure and dynamics of a neuronal network relate to each other. We approach this problem by modeling the spiking activity of large-scale neuronal networks that exhibit several complex network properties. Our main focus lies on the relevance of two particular attributes for the dynamics, namely structural heterogeneity and degree correlations. As a central result, we introduce a novel mean-field method that makes it possible to calculate the average activity of heterogeneous, degree-correlated neuronal networks without having to simulate each neuron explicitly. We find that the connectivity structure is sufficiently captured by a reduced matrix that contains only the coupling between the populations. With the mean-field method and numerical simulations we demonstrate that assortative degree correlations enhance the network’s ability to sustain activity for low external excitation, thus making it more sensitive to small input signals.

Die vorliegende publikationsbasierte Dissertationsschrift erörtert auf der Basis experimenteller Untersuchungen im Tiermodell die Auswirkungen von Stress auf die Zytokinproduktion und depressionsähnliches Verhalten. Außerdem wird getestet, ob die Blockade des Zytokins Tumornekrosefaktor-α (TNF‑α) eine Möglichkeit zur antidepressiven Intervention darstellt. Einleitend werden die Zusammenhänge von Stress, Zytokinen und Depression referiert sowie das hypothetische Modell erläutert, das den publizierten Untersuchungen zugrunde liegt. Es wird hypothetisiert, dass Stress zur Erhöhung der Produktion proinflammatorischer Zytokine führt und dass die vermehrte Zytokinproduktion depressive Verhaltensweisen hervorruft. Aus dieser Annahme leitet sich die Möglichkeit ab, durch Blockade der Wirkung des proinflammatorischen Zytokins TNF‑α antidepressive Effekte zu erzielen. In den beiden Arbeiten „The impact of social isolation on immunological parameters in rats“ (Archives of Toxicology) und „Stress-induced cytokine changes in rats“ (European Cytokine Network) wurde der Einfluss von sozialer Isolation, chronischem, milden und akutem Stress auf die Zytokinproduktion untersucht. In diesen Untersuchungen führten die verschiedenen Stressarten zu einer Modulation der Produktion proinflammatorischer Zytokine. Die dritte Publikation „Antidepressant effects of TNF‑α blockade in an animal model of depression“ (Journal of Psychiatric Research) berichtet von einem Experiment, in dem untersucht wurde, ob der TNF‑α-Inhibitor Etanercept antidepressive Effekte aufweist. Tatsächlich zeigte sich unter Etanercept ein Rückgang des depressionsähnlichen Verhaltens im forced swim test (FST) analog zu Verhaltensänderungen durch das in Tierversuchen als Standard-Antidepressivum geltende Imipramin. Die Autoren schlussfolgern, dass das Zytokinsystem durch Stress moduliert wird und so in die pathophysiologische Entwicklung einer Depression involviert sein könnte. Zytokininhibitoren könnten eine neue Klasse der Antidepressiva bei Therapieresistenz werden, wenn sich die Ergebnisse dieser Tierversuche in Studien an Probanden und an Patienten replizieren lassen.

Longitudinal developmental fMRI studies just recently began to focus on within-subject reliability using the intraclass coefficient (ICC). It remains largely unclear which degree of reliability can be achieved in developmental studies and whether this depends on the type of task used. Therefore, we aimed to systematically investigate the reliability of three well-classified tasks: an emotional attention, a cognitive control, and an intertemporal choice paradigm. We hypothesized to find higher reliability in the cognitive task than in the emotional or reward-related task. 104 healthy mid-adolescents were scanned at age 14 and again at age 16 within M = 1.8 years using the same paradigms, scanner, and scanning protocols. Overall, we found both variability and stability (i.e. poor to excellent ICCs) depending largely on the region of interest (ROI) and task. Contrary to our hypothesis, whole brain reliability was fair for the cognitive control task but good for the emotional attention and intertemporal choice task. Subcortical ROIs (ventral striatum, amygdala) resulted in lower ICCs than visual ROIs. Current results add to the yet sparse overall ICC literature in both developing samples and adults. This study shows that analyses of stability, i.e. reliability, are helpful benchmarks for longitudinal studies and their implications for adolescent development.

Longitudinal developmental fMRI studies just recently began to focus on within-subject reliability using the intraclass coefficient (ICC). It remains largely unclear which degree of reliability can be achieved in developmental studies and whether this depends on the type of task used. Therefore, we aimed to systematically investigate the reliability of three well-classified tasks: an emotional attention, a cognitive control, and an intertemporal choice paradigm. We hypothesized to find higher reliability in the cognitive task than in the emotional or reward-related task. 104 healthy mid-adolescents were scanned at age 14 and again at age 16 within M = 1.8 years using the same paradigms, scanner, and scanning protocols. Overall, we found both variability and stability (i.e. poor to excellent ICCs) depending largely on the region of interest (ROI) and task. Contrary to our hypothesis, whole brain reliability was fair for the cognitive control task but good for the emotional attention and intertemporal choice task. Subcortical ROIs (ventral striatum, amygdala) resulted in lower ICCs than visual ROIs. Current results add to the yet sparse overall ICC literature in both developing samples and adults. This study shows that analyses of stability, i.e. reliability, are helpful benchmarks for longitudinal studies and their implications for adolescent development.

A história moderna da neurociência ainda está sendo escrita.1 A neurociência possui uma longa tradição quando se focaliza seu objeto.2 No entanto, enquanto ciência com status próprio, ela é recente.3 Seu campo de atuação é amplo, contribuindo com várias áreas do saber, como a biologia e medicina (contribuições na área do mapeamento das atividades cerebrais, estudos sobre a regeneração do cérebro lesionado, a atuação de drogas sobre os neurônios etc),4 psicologia (contribuições na área do comportamento humano), 5 educação (estudos que ajudam a compreender como o cérebro aprende),6 Filosofia/Teologia (reexaminando a identidade do ser humano, como se forma a consciência, a fé etc)7 e, recentemente, o marketing e a inteligência artificial.8 No âmbito da neurociência concorrem duas visões distintas de abordagem metodológica, sendo a primeira aquela que procura encontrar e associar a cada ação ou comportamento humano um neurônio específico. Nesse caso há um reducionismo do ser humano a fenômenos eletroquímicos no cérebro. A segunda visão percebe o sistema nervoso muito mais em sua dimensão holística. O objetivo, nesse caso, não seria primeiramente perguntar pelo “por que”, mas perguntar pelo “como”. Ambas as visões não são excludentes.

The modern history of neuroscience is still being written.1 Neuroscience has a long tradition of focusing on this object.2 However, while science with its status, it is recent.3 Its field of activities is broad, thereby also increasing several areas of knowledge, such as biology and medicine (contributing to the survey area of brain activities, regeneration research about the injured brain, the affect of drugs on mirror neurons, etc.),4 psychology (contributing to the survey area of human behavior),5 education (contributing to research that helps to understand how the brain learns),6 Philosophy/Theology (reconsidering the human’s identity, how conscience, faith is formed, etc)7 and, recently, artificial marketing and intelligence. In the area of neuroscience two distinct visions with correlating methodological approaches compete. The first seeks to find and associate a specific neuron with each human action or behavior. Here there is a reductionism of human beings to electrochemical phenomena in the brain. The second view perceives the nervous system with a much more holistic dimension. The objective, in that case, would not be to ask “why” first but to ask “how.” Both views are not mutually exclusive

The ability to read proficiently is key to social participation and an important premise for individual well-being and vocational success. Individuals with developmental dyslexia, a highly prevalent neurodevelopmental disorder affecting hundreds of millions of children and adults worldwide, face severe and persistent difficulties in attaining adequate reading levels. Despite years of extensive research efforts to elucidate the neurobiological origin of this disorder, its exact etiology remains unclear to date. In this context, most neuroimaging research on dyslexia in humans has focused on the cerebral cortex and has identified alterations in a distributed left-lateralized cortical language network. However, pioneering post-mortem human studies and animal models suggest that dyslexia might also be associated with alterations in subcortical sensory thalami and early sensory pathways. The largely cortico-centric view of dyslexia is due in part to considerable technical challenges in assessing the human sensory thalami non-invasively using conventional magnetic resonance imaging (MRI). As a result, the role that sensory thalami may play in dyslexia has been largely unaddressed. In this dissertation, I leveraged recent advances in high-field MRI to investigate the role of the human lateral geniculate nucleus (LGN) of the visual thalamus in adults with dyslexia in-vivo. In three multi-modal high-field MRI studies, I show that (i) dyslexia is associated with structural alterations in the direct V1-bypassing white matter pathway connecting the LGN with cortical motion-sensitive area V5/MT in the left hemisphere; (ii) the connectivity strength of which predicts a core symptom of the disorder, i.e., rapid naming ability. I further demonstrate that (iii) the two major functional subdivisions of the LGN can be distinguished non-invasively based on differences in tissue microstructure; and that (iv) adults with dyslexia show functional response alterations specifically in the magnocellular subdivision of the LGN. I also demonstrate that this subdivision deficit (v) is more pronounced in male than female dyslexics; and (vi) predicts rapid naming ability in male dyslexics only. The results of this doctoral thesis are the first to confirm previous post-mortem evidence of LGN alterations in dyslexia in-vivo and point to their relevance to key symptoms of the disorder. In synergy, our research findings offer new perspectives on explanatory models of dyslexia and bear potential implications also for prospective treatment strategies.:Contribution Statement i Acknowledgments iii Abstract v Table of Contents vii 1 General Introduction 1 1.1 Developmental Dyslexia 1 1.1.1 Diagnostic Criteria 1 1.1.2 Prevalence and Etiology 2 1.1.3 Cognitive and Behavioral Symptoms 3 1.1.4 Explanatory Models in Cognitive Neuroscience 4 1.2 Lateral Geniculate Nucleus 7 1.2.1 Anatomy and Function 7 1.2.2 Technical Challenges in Conventional MRI 8 1.2.3 High-Field MRI 9 1.3 Research Aim and Chapter Outline 10 2 Altered Structural Connectivity of the Left Visual Thalamus in Developmental Dyslexia 13 2.1 Summary 14 2.2 Results and Discussion 15 2.3 Conclusions 22 2.4 Materials and Methods 23 2.4.1 Subject Details 23 2.4.2 High-Resolution MRI Acquisition and Preprocessing 23 2.4.3 Lateral Geniculate Nucleus Definition 24 2.4.4 Cortical Region of Interest Definition 26 2.4.5 Probabilistic Tractography 27 2.4.6 Quantification and Statistical Analysis 29 2.5 Supplementary Information 30 3 Mapping the Human Lateral Geniculate Nucleus and its Cytoarchitectonic Subdivisions Using Quantitative MRI 33 3.1 Abstract 34 3.2 Introduction 35 3.3 Materials and Methods 37 3.3.1 In-Vivo MRI 37 3.3.2 Post-Mortem MRI and Histology 41 3.4 Results 44 3.4.1 Lateral Geniculate Nucleus Subdivisions in In-Vivo MRI 44 3.4.2 Lateral Geniculate Nucleus Subdivisions in Post-Mortem MRI 46 3.5 Discussion 50 3.6 Supplementary Information 54 3.6.1 In-Vivo MRI 54 3.6.2 Post-Mortem MRI and Histology 58 3.6.3 Data and Code Availability 60 4 Dysfunction of the Visual Sensory Thalamus in Developmental Dyslexia 61 4.1 Abstract 62 4.2 Introduction 63 4.3 Materials and Methods 66 4.3.1 Subject Details 66 4.3.2 High-Resolution MRI Experiments 66 4.3.3 High-Resolution MRI Acquisition and Preprocessing 67 4.3.4 Lateral Geniculate Nucleus Definition 68 4.3.5 Quantification and Statistical Analysis 69 4.4 Results 70 4.5 Discussion 75 4.6 Supplementary Information 77 4.6.1 Supporting Methods 77 4.6.2 Supporting Results 81 4.6.3 Data and Code Availability 82 5 General Conclusion 83 5.1 Summary of Research Findings 83 5.2 Implications for Dyslexia Models 84 5.2.1 Phonological Deficit Hypothesis 84 5.2.2 Magnocellular Theory 84 5.2.3 Model According to Ramus 85 5.2.4 Need for Revised Model 86 5.3 Implications for Remediation 87 5.4 Research Prospects 88 5.5 Brief Concluding Remarks 90 6 Bibliography 91 7 List of Tables 113 8 List of Figures 115 9 Selbstständigkeitserklärung 117

Die Notwendigkeit, sich über unebene, sich ständig verändernde Gelände zu bewegen, gehört zu unserem täglichen Leben. Das zentrale Nervensystem muss daher eine erhöhte Menge an Information integrieren, um mit der Unvorhersehbarkeit äußerer Störungen zurechtkommen zu können. Die Folge dieser erhöhten Beanspruchung könnte eine flexible Kombination der modularen Organisation von Bewegungssteuerung sein. Auf Kosten der Genauigkeit der Bewegung wäre es so möglich, dass das System reagiert, indem es die Robustheit (Fähigkeit mit Fehlern umzugehen) seiner Steuerung erhöht. Jedoch sind die Strategien, die das zentrale Nervensystem zur Organisation der Bewegung verwendet, immer noch schlecht verstanden. Eine Möglichkeit besteht darin, dass Bewegungen zustande kommen durch eine kleine Anzahl linear kombinierter Aktivierungsmuster (Muskelsynergien). Unter den verschiedenen Möglichkeiten der Bewegungsstörung sind das Weglassen von Schuhen und die Verwendung von unebenen Oberflächen zwei gebräuchliche Optionen. In einem ersten Schritt habe ich eine gründliche Analyse der Methoden durchgeführt, die nützlich sind für a) die Auswertung von raumzeitlichen Gangparametern mithilfe von Daten der plantaren Druckverteilung und b) die Extraktion von Muskelsynergien mittels nicht-negativer Matrixfaktorisierung. Anschließend habe ich die modulare Organisation von c) beschut und barfuß Laufen und d) Laufband Gehen und Laufen über ebener und unebener Oberfläche analysiert. Im Vergleich zum gestörten Zustand zeigte das Barfußlaufen eine zeitlichen Verschiebung der zeitabhängigen Muskelaktivierungspatterns (Motor Primitives) und eine Reorganisation der zeitunabhängigen Koeffizienten (Motor Modules). Zusammenfassend, konserviert Fortbewegung über unebener Oberfläche, im Vergleich zu ebener, Motor Modules, während Motor Primitives im Allgemeinen breiter werden. Diese Ergebnisse unterstützen die Idee einer erhöhten Robustheit in der motorischen Kontrolle während der instabilen Fortbewegung. / The need to move over uneven, continuously changing terrains is part of our daily life. Thus, the central nervous system must integrate an augmented amount of information in order to be able to cope with the unpredictability of external disturbances. A consequence of this increased demand might be a flexible recombination of the modular organisation of movement creation and control. At the expense of motion’s accuracy, it is possible that the system responds by increasing its control’s robustness (i.e. ability to cope with errors). However, the strategies employed by the central nervous system to organise movement are still poorly understood. One possibility is that movements are constructed through a small amount of linearly combined patterns of activations, called muscle synergies. Amongst the several possibilities of perturbing locomotion, the removal of footwear and the use of uneven surfaces are two valid options. In a first step, I conducted a thorough analysis of the methodologies useful for a) the evaluation of spatiotemporal gait parameters using plantar pressure distribution data and b) the extraction of muscle synergies using non-negative matrix factorisation. Afterwards, I analysed the modular organisation of c) shod and barefoot running and d) walking and running over an even- and an uneven-surface treadmill. The modular organisation of locomotion, assessed through the extraction of muscle synergies, changed when perturbations were introduced. Compared to the shod condition, barefoot running underwent, mostly due to the different foot strike pattern, a reorganisation of the time-independent coefficients (motor modules) and a time-shift of the time-dependent muscle activation patterns (motor primitives). Uneven-surface locomotion, compared to even-surface, conserved motor modules, while motor primitives were generally wider, confirming the idea of an increased robustness in motor control during unsteady locomotion.