Patients suffering from different forms of neurodegenerative diseases, such as: Creutzfeldt Jacob Disease (CJD), Alzheimer disease (AD), mild cognitive impairment (MCI), frontotemporal dementia and Parkinson’s disease (PD) were examined with Positron Emission Tomography (PET) and the combination of different radiotracers: 15O-water, N-[11C-methyl]-L-deuterodeprenyl (DED), [18F] 2-fluorodeoxyglucose: (FDG), N-methyl-[11C]2-(4-methylaminophenyl)-6-hydroxybenzothiazole (PIB) and L-[11C]-3,4-dihydroxiphenyl-alanine (DOPA). The radiotracers and the combinations of different radiotracers were selected with the intention to detect, in the brain, patterns of neuronal dysfunction, astrocytosis, axon degeneration or protein aggregation (amyloid), in the brain which are pathognomonic for specific diseases and may contribute to improve clinical differential diagnoses. Examinations in healthy volunteers were performed to allow comparisons with patients. In addition, animal studies were conducted to complement the information. In some cases, the PET findings could be compared with the results of autopsies. In contrast to the micropathology, in which only a limited part of a tissue (obtained post-mortem or by biopsy) is inspected, one PET acquisition provides an image of the whole system (e.g.: the brain and the cerebellum). This form of imaging pathology is “in vivo”, where the examination is innocuous for the patient. This thesis is an attempt to stimulate the development of new tracers, new tracer combinations and methods that directly or indirectly describe the anatomo-physiopathological changes produced in the brain in neurodegenerative diseases. A better description of different diseases can be obtained, confirming or questioning the clinical diagnoses and widening our understanding of the mechanisms underlying neurodegeneration. Different pathologies can produce similar symptoms and thus causing confusion regarding clinical diagnosis. The used PET combinations improved the accuracy of the diagnoses. The incipient knowledge emerging from a new neuroimaging pathology in combination with other disciplines may open the way to new classifications of dementias and neurodegenerative diseases based on an “in vivo” pathology.

Although consciousness has been studied since ancient time, how the brain implements consciousness is still considered a great mystery by most. This thesis investigates the neural correlates of consciousness by measuring brain activity with functional magnetic resonance imaging (fMRI) while specific contents of consciousness are defined and maintained in various experimental settings. Study 1 showed that the brain works differently when creating a new conscious percept compared to when maintaining the same percept over time. Specifically, sensory and fronto-parietal regions were activated for both conditions but with different activation patterns within these regions. This distinction between creating and maintaining a conscious percept was further supported by Study 2, which in addition showed that there are both differences and similarities in how the brain works when defining a visual compared to an auditory percept. In particular, frontal cortex was commonly activated while posterior cortical activity was modality specific. Study 3 showed that task difficulty influenced the degree of frontal and parietal cortex involvement, such that fronto-parietal activity decreased as a function of ease of identification. This is interpreted as evidence of the non-necessity of these regions for conscious perception in situations where the stimuli are distinct and apparent. Based on these results a model is proposed where sensory regions interact with controlling regions to enable conscious perception. The amount and type of required interaction depend on stimuli and task characteristics, to the extent that higher-order cortical involvement may not be required at all for easily recognizable stimuli.

This work improved the radiosynthesis of a known M2 muscarinic receptor imaging agent, [18F]FP-TZTP, and subsequent syntheses and in vitro evaluation of several novel TZTP derivatives highlighted a lead compound which exhibited M4 potency and selectivity, the thioether fluoro-polyethyleneglycol, which was then adapted for radiolabelling (23% radiochemical yield (uncorrected), >99% radiochemical purity, reaction time of 37 minutes). The present study also seeked to utilize aziridines as intermediates in [18F]-radiolabelling chemistry for the facile radiosynthesis of [18F]-labelled beta-blockers. Novel [18F]-labelled amines were synthesized via ring-opening and deprotection to yield the [18F]-1-fluoro-2-propanamine moiety (85%) favourably over the regioisomer [18F]-2-fluoro-1-propanamine (15%). Subsequent attempts to use these amine synthons in the synthesis of the beta-blocker [18F]Exaprolol resulted in poor radiochemical yields (1-3%). The chemistry of aziridine ring-opening with 19F-fluoride sources was thoroughly explored in order to understand the fundamentals of this chemistry, and the 1-fluoro-2-propanamine moiety was characterized by X-ray crystallography and NMR spectroscopy.

This work improved the radiosynthesis of a known M2 muscarinic receptor imaging agent, [18F]FP-TZTP, and subsequent syntheses and in vitro evaluation of several novel TZTP derivatives highlighted a lead compound which exhibited M4 potency and selectivity, the thioether fluoro-polyethyleneglycol, which was then adapted for radiolabelling (23% radiochemical yield (uncorrected), >99% radiochemical purity, reaction time of 37 minutes). The present study also seeked to utilize aziridines as intermediates in [18F]-radiolabelling chemistry for the facile radiosynthesis of [18F]-labelled beta-blockers. Novel [18F]-labelled amines were synthesized via ring-opening and deprotection to yield the [18F]-1-fluoro-2-propanamine moiety (85%) favourably over the regioisomer [18F]-2-fluoro-1-propanamine (15%). Subsequent attempts to use these amine synthons in the synthesis of the beta-blocker [18F]Exaprolol resulted in poor radiochemical yields (1-3%). The chemistry of aziridine ring-opening with 19F-fluoride sources was thoroughly explored in order to understand the fundamentals of this chemistry, and the 1-fluoro-2-propanamine moiety was characterized by X-ray crystallography and NMR spectroscopy.

The aim of this essay is to give an overview of the topic of intrinsic motivation based on psychological an neuroimaging research. More specifically, the objective is to give an overview of the various benefits of intrinsic motivation, discuss its relationship to extrinsic rewards, and review the existing neuroimaging research that has explicitly explored intrinsic motivatoin. A positive relationship betweeen intrinsic motivation and persistence, conceptual learning, creativity, and both hedonic and eudaimonic well-being has been demonstrated. A wealth of studies has shown that extrinsic rewards undermine intrinsic motivation, while the validity of these findings has been debated. Initial neuroimaging studies concerning the neural basis of intrinsic motivation have been conducted, showing unique activations in the intrinsic motivation conditions in e.g. the anterior precuneus and the right insular cortex. Conceptual and methodological problems have been discussed, and it is suggested that the neuroscientific findings mentioned above can be interpreted in terms of the neural distinction between wanting and liking, rather than in terms of intrinsic and extrinsic motivation, and that psychological research can draw on neuroscientific findings in order to make its research more precise.

Brain decoding involves the determination of a subject’s cognitive state or an associated stimulus from functional neuroimaging data measuring brain activity. In this setting the cognitive state is typically characterized by an element of a finite set, and the neuroimaging data comprise voluminous amounts of spatiotemporal data measuring some aspect of the neural signal. The associated statistical problem is one of classification from high-dimensional data. We explore the use of functional principal component analysis, mutual information networks, and persistent homology for examining the data through exploratory analysis and for constructing features characterizing the neural signal for brain decoding. We review each approach from this perspective, and we incorporate the features into a classifier based on symmetric multinomial logistic regression with elastic net regularization. The approaches are illustrated in an application where the task is to infer from brain activity measured with magnetoencephalography (MEG) the type of video stimulus shown to a subject. / Graduate

Patients with Amyotrophic lateral sclerosis (ALS) often experience cognitive impairment that accompanies degeneration of the motor system. A valuable tool for assessing cognitive control over behaviour is the antisaccade task which requires: 1) inhibition of the automatic response to look towards an eccentric visual stimulus (prosaccade) to instead 2) redirect gaze in the opposite direction of the stimulus (antisaccade). Psychometric tests were used to quantify the degree of impairment, while eye tracking, functional magnetic resonance imaging (fMRI) and structural MRI were combined to identify the neural correlates of cognitive impairment in ALS. We predict ALS patients will have executive dysfunction and grey matter loss in executive and oculomotor control areas that will affect antisaccade performance and will alter the corresponding brain activation. ALS patients and age-matched controls participated in a rapid-event-related fMRI design with interleaved pro- and antisaccade trials. Catch trials (no stimulus presented after instructional cue to prepare pro- or antisaccade) allowed us to discern the preparatory period from the execution period. ALS patients were biased towards automatic saccade responses, and had greater difficulty with antisaccades relative to controls in terms of correct and timely responses. We found that worsened antisaccade performance in ALS correlated with the degree of cognitive impairment. Generally, we found trends of increased brain activation during the preparatory period of antisaccades in ALS patients compared to controls in most oculomotor areas; meanwhile few differences were seen during execution. Structural analyses revealed ALS patients had decreased grey matter thickness in frontotemporal and oculomotor regions such as the frontal and supplementary eye fields (FEF, SEF) and the dorsolateral prefrontal cortex (DLPFC). These findings suggest that loss of structural integrity and executive dysfunction may elicit compensation mechanisms to improve functional and behavioural performance. Despite this compensation, ALS patients still performed worse on antisaccades than controls. Further investigation to expand the current data set should improve our ability to assuredly identify the neural correlates of cognitive decline in ALS, and may provide a model system to use for critical evaluation of future therapies and interventions for ALS. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2011-09-22 14:20:39.704

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L’âge, le génotype et les traumatismes crâniens (TCC) sont trois facteurs de risque majeurs du développement de la maladie d’Alzheimer (MA). Avec une accumulation d’évidences démontrant la persistance d’anomalies cérébrales suite aux plus légers des TCC, qui affichent d’ailleurs la plus haute incidence, il devient impératif de tester l’hypothèse selon laquelle même les commotions cérébrales puissent interagir avec l’âge et les gènes afin de précipiter la neurodégénération. Trente ex-athlètes de haut niveau (âge M = 60 ans), dont la moitié a subi des commotions cérébrales il y a plus de 30 ans, ont été évalués en neuropsychologie, en neuroimagerie multimodale ainsi qu’en génétique. De nombreuses mesures neuroanatomiques, dont l’expansion du volume des ventricules latéraux, se trouvent à corréler avec divers déficits cognitifs (mémoire différée et de reconnaissance) détectés chez les participants commotionnés. D’un intérêt particulier, certains de ces résultats sont modulés par le polymorphisme nucléotidique simple du gène Apolipoprotéine E. Ces résultats appuient l’hypothèse selon laquelle la commotion cérébrale chez de jeunes athlètes serait un facteur de risque de neurodégénération dans le vieillissement normal. / Age, genotype and traumatic brain injury (TBI) are three of the most important risk factors of Alzheimer’s Disease. With a growing body of evidence showing the persistent deleterious effects of the mildest form of TBI, it becomes imperative to test the hypothesis that sports concussion could interact with aging to precipitate neurodegeneration. Thirty former high-level athletes (mean age = 60 yrs), half of them having sustained sports concussion during their young adulthood, underwent neuropsychological, neuroanatomical and APOE genotype examination. Data analysis revealed numerous neurobiological anomalies, such as ventricular enlargement, correlating with cognitive deficits (delayed and recognition memory) in concussed participants. Of particular interest, some neuroanatomical measures were found to be modulated by APOE single-nucleotide polymorphisms. These findings support the idea that sports concussions sustained in early adulthood are a risk factor of neurodegeneration in late adulthood.

Research in the last decades has shown that individuals with high degrees in the personality trait of alexithymia not only have difficulties in identifying and recognizing own feelings, but also show deficits in reading emotions from facial expressions of other people. Therefore, the current dissertation investigates the neural correlates of recognizing emotional facial expressions as a function of alexithymia. Initially, a theoretical introduction is given and existing findings from behavioral as well as structural and functional neuroimaging research are presented. Open questions are identified and addressed in one structural and two functional magnetic resonance imaging studies that were compiled into three original research articles. Study 1 examined the gray matter profile of high and low alexithymic individuals in selected brain regions relevant for processing emotional faces. In Study 2, functional neuroimaging was used to investigate the neural correlates of high alexithymic individuals\' difficulties in labeling briefly presented (≤ 100 ms) facial expressions of emotion. Study 3 investigated neural activations as a function of alexithymia during the labeling of emotional facial expressions when these are presented with little temporal constraints (≥ 1 s). The results of these studies are summarized and integrated with the existing literature. Finally, open issues are discussed and ideas for further research are outlined.