This thesis focuses on amyloid proteins, a class of proteins that convert into amyloid fibrils. Such proteins are of high interest because they are related to many of the neurodegenerative diseases... Show moreThis thesis focuses on amyloid proteins, a class of proteins that convert into amyloid fibrils. Such proteins are of high interest because they are related to many of the neurodegenerative diseases. In the brains of patients with neurodegenerative diseases, plaques of β-sheet amyloid aggregates are found, but the mechanism of their formation and their role vis-à-vis the disease are unknown. Aggregation is difficult to study because amyloids are intrinsically disordered proteins that lack an ordered structure in solution. Here we apply electron paramagnetic resonance (EPR) as a new technique to better understand the properties of amyloid oligomers and their formation. Show less
Top-down guidance of behavior in a complex and dynamically changing world is often based on information held in working memory. Such guidance serves to bias decision-making processes in directions... Show moreTop-down guidance of behavior in a complex and dynamically changing world is often based on information held in working memory. Such guidance serves to bias decision-making processes in directions consistent with externally set rules or internally maintained intentions. Orthogonal to this goal-driven guidance, decisions may be biased also by stimulus-driven factors, such as the automatic reactivation of episodic associations that accompanied the current stimulus in a previous instance. We investigated whether top-down and bottom-up processes account for variation in context based decision making as measured by the AX-CPT in a behavioral [1] and fMRI study [2]. Moreover, several behavioural studies have indicated that transiently induced positive affect modulates control processes in context-based decision making, generally leading to enhanced flexibility. Using ERPs in a classic AX-CPT, we studied the temporal dynamics of a positive affect induction on control processes in context-based decision making [3]. Additionally, we studied learning the associations between a situation, the response to it, and the outcome of that decision and the effect of basal ganglia modulations on this learning process by means of a Parkinson’s patient study. Studies [1] and [2] pointed out that in decisions with rapidly changing environmental demands, goal-driven preparation is often beneficial but may also hamper performance which can be overcome by applying increased control. Moreover, this top-down bias is regulated more efficiently when the specific stimulus is presented in the same context it was previously associated with, compared to when it is presented in a new and unusual context. Additionally, fMRI study shed light on the way these stimulus-driven performance changes may be represented in the brain. Study [3] showed that a positive affect induction influenced reactive and evaluative components of control (indexed by the N2 elicited by the target, and by the Error-Related Negativity elicited after incorrect responses) in an AX-CPT task, whereas cue-induced preparation and maintenance processes remained largely unaffected (as reflected in the P3b and the Contingent Negative Variation components of the ERP). The patient studies suggest that moderate dopaminergic medication and STN stimulation in Parkinson’s patients [chapter 5,6] both improve learning functions relying on caudate and putamen. However, the improvement induced by dopaminergic medication largely depended on individual patient characteristics. Show less
