Feeding behavior is a complex phenomenon involving homeostatic signals, and non-homeostatic inputs such as visual cues. In primates, exposure to food-related sensory cues has been shown to elicit cephalic phase responses as well as trigger central appetitive processing, in a motivationally-dependent manner. Neural structures consistently implicated in such responses and/or in the regulation of ingestive behavior in general, in both monkeys and in humans, include the amygdala, insula, striatum, hypothalamus, and frontal and occipital cortices. In humans however, the cerebral response to visual food stimulation remains minimally explored. / Functional Magnetic Resonance Imaging (fMRI) provides information about state-dependent changes in local neuronal activity in vivo. Using fMRI, the present dissertation examined changes in human brain activity to food and nonfood pictures following the pharmacological induction of hunger with the orexigenic hormone ghrelin (Study 1), and following manipulation of the cognitive state of food expectation (Study 2). / Our data reinforce the involvement of a distributed frontal-limbic-paralimbic circuit in the central processing of food imagery, under both experimental conditions. The first study revealed that intravenous ghrelin administration potently modulated food-associated neural responses III areas involved in reward, motivation, memory, and attention (amygdala, insula, orbitofrontal cortex, striatum, hippocampus, midbrain, visual areas). This suggests that metabolic signals such as ghrelin may promote food consumption by enhancing the appetitive response to food cues via engagement of the hedonic network. / The second study revealed that brain regions activated in the 'expectant' state (i.e. when subjects were anticipating food reward) were at least partially dissociable from those in the 'not expectant' state. In particular, recruitment of the dorsolateral prefrontal cortex, a principal component in the cognitive control network, exclusively in the 'not expectant' condition, may signal an attempt to suppress appetite in the absence of food expectation. Areas of convergence were observed in the amygdala and insula. / Obesity is rapidly becoming the major cause of excess mortality worldwide; therefore, understanding how the central nervous system controls appetite and nutrient consumption is of considerable interest. The projects in this thesis offer significant insights regarding the effects two select factors (one intrinsic and the other extrinsic) on the neural reaction to visual food stimuli, in healthy male participants.

Pyrithiamine-induced thiamine deficiency in rats is a well-established animal model of Wernicke's Encephalopathy (WE). This thesis project, submitted as four articles, presents an examination of metabolic events that contribute to the selective neuronal lesions observed in the medial thalamus (MT) of thiamine-deficient (TD) rat. In addition, the phenomenon of glucose-precipitated worsening of neurological status in WE patients (Wallis et al., 1978; Watson et al., 1981) is explored. / Lactate accumulation is known to occur selectively in regions of the TD brain, which ultimately express neuronal cell death (McCandless, 1982; Munujos et al., 1996). In Article 1, the metabolic origin and cellular localization of region-selective lactate accumulation in the MT of TD rats was studied using combined 1H and 13C nuclear magnetic resonance (NMR) spectroscopy. Parallel studies were performed to examine the effects of glucose loading on regional brain lactate synthesis in TD animals. Thiamine deficiency caused focal increases in the de novo synthesis of lactate via elevated glycolytic flux in the MT, while contribution via pyruvate recycling and the periphery remained nominal. Lactate levels remained unaltered in the frontal cortex (FC), a brain region that is spared in thiamine deficiency. Administration of a glucose load intensified the selective increases in lactate de novo synthesis and accumulation in the MT of TD rats, positing a role for lactic acidosis in the glucose-precipitated worsening of neurological status in TD patients. Accordingly, Article 2 addresses the effect of glucose loading on local cerebral pH in the vulnerable MT, compared to the FC, of TD rats. Administration of a glucose load resulted in detrimental decreases in regional pH selectively in the MT, implying that alterations of brain pH contribute to the pathogenesis of thalamic neuronal damage and consequent cerebral dysfunction in WE. / Region-specific alterations in the steady state levels of cerebral amino acid neurotransmitters have been well-documented in experimental animal models of thiamine deficiency (Butterworth et al., 1979; Butterworth & Heroux, 1989; Gaitonde et al., 1975; Plaitakis et al., 1979); however, the dynamics of these changes have never been systematically explored. In Article 3, we examined the metabolic fluxes through thiamine-dependent pyruvate dehydrogenase (PDH) and alpha-ketoglutarate dehydrogenase (alpha-KGDH) using multinuclear NMR spectroscopy. Furthermore the cellular localization of the metabolic changes in relation to regional vulnerability to thiamine deficiency was addressed. Our studies clearly demonstrate that early decreases m metabolic flux through alpha-KGDH result in commensurate declines in aspartate concentrations in the MT of TD rats. Impairments to PDH flux manifest secondarily to the metabolic block at alpha-KGDH, likely due to depleted oxaloacetate pools. As a result of impaired pyruvate oxidation, declines in the de novo synthesis of glutamate and GABA ensue. The present findings also suggest that inhibition of flux through alpha-KGDH in TD brain occurs primarily in the neurons, while astrocytes possess compensatory mechanisms, i.e. the anaplerotic pathway, to replenish oxaloacetate concentrations via metabolic pathways that do not involve thiamine-dependent enzymes. / In Article 4, we investigated the regional effects of thiamine deficiency on the activity of thiamine-dependent branched-chain alpha-ketoacid dehydrogenase (BCKDH) and the resultant effects on regional cerebral branched-chain amino acid (BCAA) oxidation. Thiamine deficiency resulted in significant impairments in BCKDH activity; while parallel studies on enzyme distribution confirmed a lower oxidative capacity for BCAAs in the MT compared with the Fe. / The data presented in these four articles confirm and extend findings for the region-selective impairments in thiamine-dependent metabolic processes as the foundation of vulnerability of the MT to thiamine deficiency. In addition, glucose loading of TD rats exacerbates both lactic acidosis and impaired pyruvate oxidation in this vulnerable brain region, positing a role for these processes in the glucose-precipitated worsening of neurological status in TD patients. Impaired oxidative metabolism of glucose and BCAAs in the MT leads to the accumulation of potentially harmful metabolic intermediates, contributing to the mitochondrial dysfunction, cellular energy failure and ultimately neuronal cell death observed in thiamine deficiency.

Le sous-marinage, apparaissant lorsque la ceinture pelvienne glisse au-dessus des épines iliaques antérosupérieures (E.I.A.S.) du bassin, est la cause principale des lésions abdominales sévères. Ce phénomène, conditionné par l'angle relatif entre la ceinture pelvienne et le bassin, est fortement lié à la cinématique du bassin au cours du choc. Cette dernière dépend des efforts et moments qui y sont appliqués, provenant principalement de la colonne lombaire, des hanches, du contact avec l'assise du siège ainsi que de la ceinture pelvienne. L'objectif est de caractériser le comportement de la population au regard du sousmarinage. Cela passe par l'identification des paramètres individuels influents sur le phénomène et par l'étude de leur distribution sur la population. Pour cela, neuf essais sur sujets humains post-mortem (S.H.P.M.) ont été effectués dans un environnement simplifié. Trois configurations de choc, chacune testée sur trois sujets, ont été définies. Les résultats ont ensuite servi de base pour la validation d'un modèle éléments finis d'être humain. Le modèle a été amélioré de façon globale vis-à-vis des corridors définis par les réponses S.H.P.M. et personnalisé au niveau de la géométrie, de la répartition des masses et du comportement de la colonne lombaire pour correspondre à chacun des neuf sujets. La personnalisation de ces paramètres a permis de reproduire les comportements observés en essais. Enfin, le modèle a été utilisé dans une étude numérique pour approfondir la compréhension de la cinématique du bassin, d'une part, et identifier les paramètres individuels influençant le sous-marinage, d'autre part. La répartition des masses, la raideur de la colonne lombaire et l'orientation initiale du bassin influencent l'apparition du sous-marinage. L'ouverture des ailes iliaques, la position des E.I.A.S par rapport au point H, la profondeur de l'échancrure iliaque et l'épaisseur des tissus entre le bassin et la ceinture jouent aussi un rôle.

Motor response selection is the process by which an intention to act is transformed into an action; this multifaceted process occurs at the interface between cognitive and motor systems. Despite the importance of response selection, the nature and neural implementation of this process is still a subject of debate (Thompson-Schill et al, 1997; Botvinick et al., 2001; Rushworth et al., 2004; Nachev et al., 2007). While previous research has demonstrated that the selection of finger movements relies on a distributed network involving premotor and prefrontal areas, the specific contribution of these regions, however, remains unclear. It is also unclear if the selection of words engages similar processes as the selection of finger movements, that is, if response selection is a domain-general or a domain-specific process. In order to address these issues, a set of four complementary studies using functional magnetic resonance imaging (fMRI) and repetitive transcranial magnetic stimulation (rTMS) was developed in which different factors affecting response selection were examined: selection mode, response type (words vs. oral movements), attention and response competition (conflict). / The results of these studies provide new insights into the neural architecture of response selection by uncovering the respective contribution of premotor areas (pre-SMA and PMA) and prefrontal areas (DLPFC and IFG). A preliminary two-stage model of response selection is proposed, in which the PMA is generating a set of response alternatives from which the pre-SMA performs selection using one of two different mechanisms (response facilitation and response inhibition). In general, these findings do not support the hypothesis of a medio-lateral gradient of control (Goldberg, 1985) but confirm the fundamental role of the lateral (PMA) and medial (pre-SMA) premotor areas in the process of selecting motor responses. / Importantly, the results also demonstrate that selection is a domain-general (response-independent) process. Uncovering the general, multifaceted nature of brain mechanisms is essential to reveal the basic units of control in the central nervous system; this knowledge is fundamental to broaden current understanding of the basic brain operations that are used to produce language. Theoretical and clinical implications of these findings are discussed.

Copy and recall drawings of the Rey Complex Figure obtained during the standard clinical testing of patients with well-localized epileptic foci before and after left frontal-, left temporal-, right temporal-lobe resection were re-scored blind as to lesion site using standard protocol (18 elements scored 0, 1/2, 1, or 2 based on whether they are drawn and placed correctly for a total out of 36). They were also scored for which, and how many, elements were missing, distorted, displaced, and/or repeated. Contrary to previous findings, no main effects of side or lobe or side-by-lobe interactions were found on copy and recall scores obtained either before or after surgery, and all patients' recall improved equally from pre-operative to follow-up testing. Furthermore, patients' lesion site could not be predicted on the basis of any single measure or across all measures of performance. While group differences had been found on the previously assigned scores, the between-group overlap was almost complete and the original scoring was not done blindly. These results suggest that, despite previous claims, the Rey Complex Figure, a widely-used measure of non-verbal memory, is not an effective tool for localizing neural disturbance in temporal- and frontal-lobe epilepsy patients.

<p>Schizophrenia is a complex and debilitating psychiatric illness characterized by positive symptoms like hallucinations and delusions and negative symptoms like blunting of affect, avolition, and poverty of thought. This constellation of symptoms is hypothesized to result from dopaminergic dysfunction, glutamatergic dysfunction, and dysfunctional stress-reactivity. Prior to the onset of schizophrenia there is a prodromal period when individuals begin to experience sub-clinical symptoms and decreased functioning. This period is important to study not only to help elucidate biologic mechanisms of the illness but also to potentially alter the course of the illness through early treatment. The difficulty of studying this period lies in its recognizing it prospectively. To address this researchers have begun to study the at-risk mental state, a state that is associated with a high but not inevitable risk of conversion to psychosis. The studies described in this dissertation are aimed at a neurofunctional characterization of the at-risk mental state in three primary domains: reward-anticipation, hippocampus-dependent learning, and stress-reactivity. Individuals at-risk for psychosis and age-matched healthy volunteers underwent functional magnetic resonance imaging while performing tasks targeting these domains. In the reward-anticipation task, at-risk individuals showed decreased ventral tegmental area (VTA) and dorsolateral prefrontal cortex (DLPFC) responses to reward anticipation. In the hippocampus-dependent learning task, at-risk individuals showed deficits in hippocampus-dependent memory, decreased VTA engagement, and increased DLPFC activation during learning of associations between items. In the stress-reactivity task, at-risk individuals showed increased activation in the bed nucleus of the stria terminalis/basal forebrain (BNST), anterior cingulate cortex (ACC), and medial prefrontal cortex (mPFC) in response to neutral faces. Collectively, these experiments show that neurofunctional deficits in reward-anticipation, hippocampus-dependent learning, and stress-reactivity are present in the putative prodrome, prior to the onset of psychosis. Regions implicated are those that would be expected based on current models of schizophrenia and neurofunctional studies in those with frank psychosis.</p> / Dissertation

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common disorders of childhood. It is theorized to be caused by catecholamine dysfunction in the striatum (Str) and frontal cortex (FC). The spontaneously hypertensive rat (SHR) has been used as a model for ADHD because of its attention deficits, impulsiveness, and hyperactivity. Prior studies of dopamine (DA) in the Str and FC have revealed conflicting results in the SHR compared to control, indicative of a need for a better understanding of DA dynamics in this model. In addition to the DA hypothesis, studies have begun implicating glutamate in the etiology of ADHD. Previous evaluations of the SHR model of ADHD found that the SHR have increased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activity and elevated calcium levels in the FC, suggesting that altered glutamatergic neurotransmission exists in the SHR. The first set of studies presented here suggest that increased surface expression of DA transporters may exist in the SHR model of ADHD, lowering basal DA levels. Second, we discovered that the glutamate system in the FC of the SHR model of ADHD is hyperfunctional, thus raising the possibility that targeting glutamate dysfunction in the FC could lead to the development of novel therapeutics for the treatment of ADHD. The third and fourth set of studies explored glutamate signaling in the awake rodent to fully understand glutamate neurotransmission as well as the effects of methylphenidate (MPH) on glutamate signaling in the prelimbic cortex, a region heavily implicated in ADHD. The SHR displayed similar phasic glutamate signaling compared to control; however, in the SHR but not the WKY control, chronic treatment with MPH lowered phasic glutamate amplitude. Additionally, intermediate treatment with MPH increased tonic glutamate in the SHR only, whereas chronic MPH treatment increased tonic levels in both the SHR and WKY compared to saline. Taken together, this body of work characterizes DA and glutamate signaling in the anesthetized SHR model of ADHD. Additionally, glutamate dynamics and the effects of the stimulant medication MPH were explored in the awake animal, providing evidence that glutamate is a likely target for future neuropharmacology for the treatment of ADHD.

Frontal and parietal areas have been shown to subtend different cognitive processes such as attentional orienting, decision making and access to consciousness, with bearing on visual performance. In spite of prior evidence supporting an implication of those regions in visual cognition, their contributions to the processing of low-contrast unmasked stimuli and the characteristic spatiotemporal activity patterns underlying them remain to be fully explored and causation is lacking. We here addressed a thorough exploration of such contributions in humans, with an emphasis on the dynamics of neural activity and visual performance enhancements as probed by patterns of noninvasive manipulation of local brain oscillatory activity. To this end, we tested in healthy participants the effects of either single pulses or short bursts of active vs. sham transcranial magnetic stimulation (TMS), delivered to the frontal eye field (FEF) and the intraparietal sulcus (IPS) prior to the presentation of a lateralized low-contrast near-threshold Gabor stimulus, on the visual discrimination and conscious detection of such stimulus. Our findings contribute to better substantiate the oscillatory basis of visual cognition and its associated behaviors and to set the stage for the development of novel therapies based on noninvasive manipulation of dysfunctional brain oscillatory activity.

De nombreuses études en imagerie ont rapporté des différences d'activation cérébrale par rapport aux fonctions liées au contrôle attentionnel, telles que l'inhibition, l'alternance et l'attention divisée. Toutefois, les différences liées à l'âge dans les patrons d'activation dans plus d'une tâche de contrôle attentionnel à la fois ont rarement été étudiées chez les mêmes groupes de participants. Deux études ont donc été effectuées : la première porte sur une comparaison directe de l'inhibition et de l'alternance, alors que la seconde se penche sur l'effet de la priorisation en attention divisée. Dans l'étude 1, de jeunes adultes (n = 21) et des aînés (n = 19) ont complété une version modifiée de la tâche de Stroop qui inclut une condition d'interférence et une d'alternance, alors que l'activation du cortex préfrontal est mesurée à l'aide de la spectroscopie proche infrarouge fonctionnelle (SPIRf). Bien que la condition interférence n'ait révélé aucune activation significative chez les jeunes adultes, la condition alternance a produit une augmentation de l'activation bilatérale au niveau du cortex préfrontal dorso-latéral (CPFDL) et du cortex préfrontal ventro-latéral (CPFVL). Chez les aînés, une activation isolée au niveau du CPFDL bilatéral a été observée même dans les conditions non-exécutives de la tâche de Stroop (dénomination de couleur), et la condition interférence a révélé une activation principalement localisée dans le CPFDL postérieur gauche et dans le CPFVL bilatéral, ainsi qu'une petite composante au niveau du CPFDL antérieur droit. Chez les aînés spécifiquement, l'alternance a produit un étalement bilatéral de l'activation du cortex préfrontal au niveau du CPFDL antérieur bilatéral, du CPFDL postérieur gauche et du CPFVL bilatéral. Ces résultats suggèrent que chez les aînés et les jeunes adultes, les mécanismes d'inhibition et d'alternance sont associés à des patrons différents d'activation préfrontale, ce qui conforte la théorie selon laquelle ces deux mécanismes sont distincts. De plus, les patrons d'activation diffèrent entre les jeunes et les aînés, de sorte que l'activation préfrontale semble être plus étendue à différents sites chez les aînés. Les disparités observées entre l'inhibition et l'alternance en termes d'activation révèlent aussi que ces deux mécanismes se modifient différemment au cours du vieillissement normal. La seconde étude montre les différences liées à l'âge par rapport à la capacité d'accomplir deux tâches simultanément. L'effet de l'âge sur les performances en double-tâche est maintenant étudié en neurosciences au moyen de deux paradigmes, la période réfractaire psychologique (PRP) et la double-tâche (DT). Les études de PRP évaluent les participants lorsqu'ils donnent priorité à une tâche par rapport à l'autre (compléter la tâche A et ensuite la tâche B), alors que les participants des études en DT doivent se concentrer sur les deux tâches simultanément (compléter la tâche A et B). Il est logique de penser que cette condition ajoute une composante exécutive de contrôle additionnelle à la tâche, puisque les participants doivent spontanément gérer leur attention entre les tâches. Cette composante additionnelle pourrait expliquer les divergences de résultats entre les études de PRP et DT. La présente étude vise à vérifier cette hypothèse en évaluant l'effet des instructions de priorité (priorisées vs égales) sur les performances en double-tâche. En plus des mesures comportementales, l'activité cérébrale de jeunes adultes (n = 16) et de personnes âgées (n = 19) a été mesurée à l'aide de la SPIRf. Dans la condition priorisée, on observe une activation du cortex préfrontal droit pendant l'exécution de la DT chez les jeunes adultes. Chez les personnes âgées, l'activation devient bilatérale, mais restreinte à des aires spécifiques, et implique le CPFDL gauche et le CPFVL bilatéral. Dans la condition égale, la condition DT montre une activation isolée dans le CPFDL et CPFVL gauches et CPFDL postérieur droit chez les jeunes adultes, et un étalement bilatéral de l'activation en CPFDL chez les participants âgés. Ces résultats montrent que tant chez les jeunes adultes que les personnes âgées, les effets de priorité sont associés à des patrons d'activation préfrontale distincts. En condition égale, les activations impliquent des régions frontales plus étendues et bilatérales comparativement aux conditions à priorité fixe. Ces résultats supportent l'hypothèse que la condition égale (en DT) exige davantage de contrôle attentionnel. Des différences liées à l'âge existent, le vieillissement étant associé à un étalement de l'activation à différents sites chez les personnes âgées, mais surtout lorsque l'instruction de donner une priorisation égale aux deux tâches est donnée. Les résultats de ces deux études montrent des patrons d'activation préfrontale différents pour les mécanismes d'inhibition, d'alternance et d'attention divisée. Ces résultats ont des implications pratiques et théoriques. Sur le plan pratique, ils montrent que la SPIRf peut mesurer de façon précise les patrons d'activation des mécanismes de contrôle attentionnel distincts et ce, tant chez les jeunes adultes que chez les personnes âgées. Sur le plan théorique, ces résultats apportent un appui aux propositions selon lesquelles il existe des mécanismes distincts de contrôles attentionnels supportés par différents ensembles de régions ou de réseaux préfrontaux du cortex cérébral. De plus, les résultats suggèrent que ces mécanismes impliquent des régions frontales plus étendues chez les personnes âgées que chez les jeunes. Les résultats appuient principalement l'hypothèse du Scaffolding Theory of Aging and Cognition (STAC). Ce modèle indique que les aînés réussissent à maintenir un haut niveau de fonctionnement, étant donné l'engagement continu d'un échafaudage compensatoire, soit le recrutement de circuits additionnels étayant les structures en déclin dont le fonctionnement est devenu bruité, inefficace ou les deux. Cet échafaudage dynamique est une propriété d'un cerveau qui s'adapte à son déclin afin de maintenir la meilleure homéostasie possible (Park & Reuter-Lorenz, 2009). Le niveau du fonctionnement cognitif est alors déterminé par le niveau de la détérioration neuronale, le niveau de la détérioration fonctionnelle et le niveau de compensation créé par l'échafaudage (Drag & Bieliauskas, 2010; Park & Reuter-Lorenz, 2009) ______________________________________________________________________________ MOTS-CLÉS DE L’AUTEUR : contrôle attentionnel, vieillissement normal, SPIRf, lobes frontaux

Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2008.