Metabolomics is a powerful tool that can provide a comprehensive insight into the complexity of human biology and the pathophysiology of diseases. By analyzing the metabolome, which refers to the... Show moreMetabolomics is a powerful tool that can provide a comprehensive insight into the complexity of human biology and the pathophysiology of diseases. By analyzing the metabolome, which refers to the complete set of small (endogenous) molecules (with a mass <1500 Da) present within a given biological system, a direct functional read-out of an organism's physiological status can be obtained. In particular, metabolomics has emerged as a promising approach for neuroscience research, as it helps to shed light on the molecular mechanisms underlying neurodegenerative and neuropsychiatric diseases. One of the main challenges in (brain) metabolomics studies is the reliable and sensitive analysis of volume-limited biological samples. Therefore, in this thesis, innovative microscale analytical workflows based on capillary electrophoresis (CE) coupled to mass spectrometry (MS) are developed in order to generate metabolic profiles in volume-restricted samples. The ultimate aim of this thesis is to showcase that the technical reproducibility, detection sensitivity, and metabolic coverage of CE-MS are sufficient to allow use for different material-limited matrices of interest for neuroscience research. Show less
The aim of this thesis was to identify functional biomarkers for migraine attack prediction based on neurophysiological readout parameters. The main focus of this work was on the development of... Show moreThe aim of this thesis was to identify functional biomarkers for migraine attack prediction based on neurophysiological readout parameters. The main focus of this work was on the development of methodologies to measure brain excitability over the migraine cycle, with special emphasis on identifying changes in excitability of the visual system and the occipital cortex. Applying such measures over the course of a migraine cycle could help elucidate factors that initiate the migraine attack, and might lead to better (or better timing of) preventive measures. The research described in this thesis is divided into two parts. The first part reports on the development and application of several methodologies to measure excitability of the visual system including the cortex in migraine patients and a migraine mouse model. The second part consists of two studies employing transcranial magnetic stimulation (TMS) in combination with concurrent electroencephalography (EEG) recordings to provide direct measures of cortical excitability in migraine and epilepsy. Show less
Humans have a strong need for social connections, which provide social security and a feeling of social acceptance. Across adolescence, peers emerge as important social interaction partners to... Show moreHumans have a strong need for social connections, which provide social security and a feeling of social acceptance. Across adolescence, peers emerge as important social interaction partners to fulfill the need for social connections. In her dissertation, Elisabeth Schreuders highlights adolescence as a sensitive period for pursuing personal goals and social development through interactions with different familiar peers, particularly friends.Neural reward-related processes and neural processes underlying prosocial behavior were examined using longitudinal and ecologically valid research designs. The findings show involvement of changes in ventral striatum reward sensitivity from early to mid-adolescence in the motivation to pursue personally valued goals, including stable friendships. It was furthermore found that adults who to a lesser extent adhered to the social norm of behaving in a prosocial manner toward friends yielded greater activity in the supplementary motor area and anterior insula. Additionally, exploratory analyses showed that mid-adolescents with greater social competence yielded greater activity in several brain areas implicated in prosocial decision-making involving friends, including the putamen and superior parietal lobule. Together, these findings highlight adolescence as a sensitive period for self and social development, in which social motivations are reflected in interactions with different types of peers. Show less
Investigating potential pharmacodynamic effects in an early phase of central nervous system (CNS) drug research can provide valuable information for further development of new compounds. A... Show moreInvestigating potential pharmacodynamic effects in an early phase of central nervous system (CNS) drug research can provide valuable information for further development of new compounds. A computerized and thoroughly validated battery of neuropsychological and neurophysiological tests has been shown to be sensitive to detect drug-induced effects of multiple new and existing compounds. The test battery covers the main CNS domains, which have been shown to respond to drug effects and can be repeatedly administered following drug administration to characterize the concentration-effect profile of a drug.The standard tests in the battery are saccadic eye movement, smooth pursuit eye movement, the Bowdle visual analog scale (VAS), the Bond and Lader VAS, body sway, adaptive tracking, visual verbal learning, and quantitative electroencephalography (qEEG). However, the test battery is adaptive in nature, meaning that it can be composed and adjusted with tests fit to investigate specific drug classes, or even specific receptors.Showing effects of new cholinergic drugs designed to have a pro-cognitive outcome has been difficult. The pharmacological challenge model is a tool for early proof-of-pharmacology. Here, a marketed drug is used to induce temporary and reversible disease-like symptoms in healthy subjects, via a pharmacological mechanism related to the disease that is targeted as indication for the new compound. The test battery was implemented to investigate the potential of the nicotinic receptor antagonist mecamylamine to be used as a challenge model for cholinergic dysfunction, as seen in neurodegenerative disorders.A worsening of scores in a dose dependent manner on the visual verbal learning test (VVLT; a test for learning and memory abilities) and the adaptive tracking test (a measure of visuomotor control and arousal), in particular, showed that the test battery is sensitive to showing acute pharmacodynamic effect after administration of anti-cholinergic drugs. Show less
Mutations in the CACNA1A gene, encoding neuronal Cav2.1 calcium channels, cause a wide spectrum of human neurological diseases, including familial hemiplegic migraine type 1 (FHM1). The role of... Show moreMutations in the CACNA1A gene, encoding neuronal Cav2.1 calcium channels, cause a wide spectrum of human neurological diseases, including familial hemiplegic migraine type 1 (FHM1). The role of Cav2.1 channels is to mediate neurotransmitter release. Using electrophysiological techniques, this thesis investigates the effects of several CACNA1A mutations on neurotransmitter release at the mouse neuromuscular junction (NMJ). It is concluded that the FHM1 mutations R192Q and S218L increase neurotransmitter release and do not result in compensatory contributions of other types of calcium channels. Furthermore, it is shown that spontaneous neurotransmitter at the mouse NMJ is partly Cav2.1 channel-dependent, whereas evoked release relies entirely on Cav2.1 channels. Studies on the Cav2.1 mouse mutant Rolling Nagoya show that spontaneous and evoked neurotransmitter release are controlled independently. Studies on mouse mutants that lack auxiliary Cav2.1 channel subunits revealed that these subunits are redundant and/or absent at the mouse NMJ. The studies presented in this thesis provide novel insights into the synaptic dysfunction caused by Cav2.1 channel mutations. Synaptic effects on central synapses are likely to share many features with those observed at the mouse NMJ and thought to underlie (some of) the neurological symptoms of human and mouse disorders associated with Cav2.1 channel dysfunction Show less
