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Previous research has indicated found that individuals with Down syndrome (DS) have difficulties in processing auditory information for the planning of movements relative to their peers with undifferentiated developmental handicaps. This modality-specific information-processing difficulty has been found for the preprogramming of goal-directed aiming movements (Le Clair & Elliott, 1995) and in simple reaction times (Davis, Sparrow, & Ward, 1991; Hermelin, 1964). The purpose of the present study was to assess whether or not a model of atypical cerebral specialization for the perception of speech sounds, proposed by Elliott and colleagues, could explain these findings. Thus, participants performed a choice reaction aiming task under three conditions. Colour-coded targets were cued by a visual cue at the target location, a visual cue remote from the target location, or a verbal cue identifying the target. Results revealed that while the reaction times did nCit differ between the two groups with handicaps, the participants with DS, unlike the two control groups, had significantly longer movement times in the verbal than in two visual conditions. These results support the model of biological dissociation. / Thesis / Master of Science (MS)

Carpal tunnel syndrome (CTS) is a common peripheral compression neuropathy which is often idiopathic in etiology. There is evidence that the development of CTS may result from circulatory disturbances. The purpose of this thesis was to improve our understanding of the vascular component to the development and progression of CTS. Ultrasound allowed for non-invasive investigation of median nerve intraneural blood flow and morphology, tissue stiffness, and mechanics of the flexor digitorum superficialis (FDS) tendon and its adjacent subsynovial connective tissue (SSCT). Nerve conduction study (NCS) allowed for investigation of median nerve function. Three studies were completed, two with patients and one involving healthy participants, to investigate the relationship between local blood flow and carpal tunnel tissue function, morphology, and mechanics. Nerve function, intraneural blood flow, individual FDS and SSCT displacements, and measures of shear strain (relative FDS-SSCT displacement and shear strain index (SSI)) were quantified in CTS patients (Chapter 2). These patients were followed-up six months later and the measures were repeated (Chapter 3), allowing me to determine the prognostic value of ultrasound measures. Results from these two studies suggested a high interdependency among intraneural blood flow velocity, nerve function, and FDS-SSCT relative displacement and SSI. Intraneural blood flow velocity, peak FDS-SSCT relative displacement, and SSI were also significant predictors of median nerve function at 6-months follow-up. To directly investigate the effects of circulatory disturbances, temporary partial ischemia of the carpal tunnel was induced in healthy participants through a 30-minute occlusion protocol (Chapter 4). Partial ischemia immediately decreased intraneural blood flow velocity. Nerve dysfunction, and increased SSI and relative displacement were observed soon after. This thesis clearly demonstrates the interrelationship among median nerve vascular dynamics, tendon-SSCT kinematics, and nerve function. Altered nerve blood flow may be a driver in the development of CTS. / Thesis / Doctor of Philosophy (PhD) / Carpal tunnel syndrome (CTS) is due to compression of the median nerve as it passes through the carpal tunnel which is located at the base of the palm. Nerve compression leads to nerve dysfunction, resulting in symptoms of tingling, numbness and weakness of the hand. The purpose of this thesis was to improve our understanding of the effects of altered blood flow on the development of CTS. I conducted three unique studies to investigate the relationship among nerve blood flow, nerve function, and motion of the tendons and connective tissue within the carpal tunnel. The use of ultrasound allowed for real-time, non-invasive investigation of function in these tissues. Results from these three studies clearly demonstrate the interrelationship between nerve function, tendon-connective tissue motion and adequate nerve blood flow. These findings have implications for individuals with cardiovascular conditions and for people working under conditions that may compromise normal blood flow.

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Contexte : La dysfonction des muscles squelettiques en hypertension artérielle pulmonaire (HTAP) contribue de manière significative à l'intolérance à l'effort. Cependant, les mécanismes sous-jacents restent incertains. Le syndrome métabolique (SxM) et la résistance à l'insuline (RI) sont couramment observés en HTAP. La déposition ectopique de lipides au niveau des organes cibles, une caractéristique de la RI, a été associée à une dysfonction mitochondriale, une lipotoxicité cardiaque et une altération de la fonction musculaire. Cependant, l'impact du SxM sur la fonction cardiaque et musculaire et sur l'intolérance à l'effort en HTAP demeure incertain. Objectifs : Nous cherchons à explorer les différences entre les profils métaboliques de patients atteints d'HTAP et de patients témoins ainsi qu'à déterminer si le SxM en HTAP est associé à une teneur plus élevée en lipides ectopiques au niveau du muscle squelettique, du foie et du cœur. Nous souhaitons déterminer si le SxM et ces accumulations lipidiques sont associés à une diminution de la force et l'endurance musculaire ainsi qu'une altération de la fonction cardiaque, entraînant une réduction de la capacité à l'exercice en HTAP. Méthodes : Dix-huit sujets HTAP et 12 sujets témoins ont fait l'objet d'une évaluation du profil métabolique. Le contenu lipidique cardiaque, musculaire et hépatique, le volume de tissu adipeux sous-cutané et viscéral et la fonction cardiaque ont été évalués par imagerie par résonance magnétique. L'état fonctionnel a été évalué par mesure de la force et l'endurance du quadriceps, de la pratique d'activité physique et par un test à l'effort. Enfin, une exploration du protéome plasmatique à des fins de comparaison entre les patients atteints d'HTAP avec et sans SxM a été réalisée. Résultats : Sept (39 %) patients atteints d'HTAP présentaient le SxM contre 1 (8 %) témoin (p = 0,07). Parmi les patients atteints d'HTAP, le SxM était sans surprise associé à un indice de masse corporelle, une glycémie à jeun, un taux de triglycérides et un tour de taille plus élevés ainsi qu'à la RI (tous p<0.05). Les volumes de tissu adipeux viscéral, sous-cutané et cardiaque, ainsi que la fraction de graisse hépatique et de la cuisse étaient plus élevés chez les patients atteints du SxM (tous p<0,05). Le SxM était associé à une classe fonctionnelle plus altérée, une capacité à l'effort et un niveau de pratique d'activité physique inférieurs. Contrairement à notre hypothèse, les patients avec et sans SxM présentaient une hémodynamie pulmonaire et une fonction musculaire et cardiaque comparables. Des analyses exploratoires de la protéomique ont suggéré que les voies impliquées en HTAP seraient semblables à celles observées au sein de la population générale présentant le SxM. Conclusion : Le SxM est courant chez les patients HTAP. Sa présence est associée à un état fonctionnel et une capacité à l'effort réduites qui ne s'expliquent pas pour autant par une altération de la fonction cardiaque ou musculaire. De plus, ces patients présentent des caractéristiques cliniques, d'imagerie et biochimiques similaires à celles observées chez les sujets atteints de SxM au sein de la population générale. Ces résultats suggèrent que le SxM peut représenter une comorbidité fréquente dans l'HTAP plutôt que d'être lié à des mécanismes intrinsèquement liés à la progression de l'HTAP. / Background: Skeletal muscle dysfunction in pulmonary arterial hypertension (PAH) significantly contributes to exercise intolerance. However, underlying mechanisms remain uncertain. In addition, metabolic syndrome (MetS) and insulin resistance (IR) are commonly observed in PAH. Ectopic lipid deposition in target organs, a feature of IR, has been associated with mitochondrial dysfunction, cardiac lipotoxicity and impaired skeletal muscle function in the general population. However, the impact of MetS on cardiac and skeletal muscle function and exercise intolerance in PAH remains elusive. Objectives: We aim to explore differences between metabolic profiles in patients affected by PAH and control participants as well as to document whether MetS in PAH would be associated with higher skeletal muscle, hepatic and cardiac ectopic lipid content. We also aim to determine whether ectopic lipid deposition is associated with decreased skeletal muscle strength and endurance as well as cardiac function, resulting in lower exercise capacity in PAH. Methods: Eighteen PAH and 12 controls subjects underwent comprehensive metabolic profile. Cardiac, visceral and skeletal muscle lipid content as well as cardiac function were assessed using magnetic resonance imaging. Subjects' functional status was assessed using skeletal muscle function measures, cardiopulmonary exercise testing and physical activity measurement. Finally, comparisons in blood sample proteome between PAH patients with and without MetS were explored. Results: Overall, 7 (39%) PAH patients presented MetS compared to 1 (8%) control (p=0.07). Amongst PAH patients, MetS was unsurprisingly associated with higher body mass index, fasting glucose, triglyceride levels and waist circumference together with IR (all p<0.05). Visceral, subcutaneous and cardiac adipose tissue volumes, as well as hepatic and thigh fat fraction were also increased in patients with MetS (all p<0.05). MetS was also associated with more impaired functional class, lower exercise capacity and daily life activity. Contrary to our hypothesis, however, patients with and without MetS had comparable quadriceps muscle and cardiac function and pulmonary hemodynamics. Exploratory proteomic analyzes suggested that pathways involved are consistent with those observed in MetS within the general population. Conclusion: MetS is common amongst PAH patients and is associated with poorer functional status and exercise capacity in PAH, which are not explained by impaired cardiac or skeletal muscle function. Moreover, these patients display clinical, imaging and biochemical features similar to those observed in subjects with MetS within the general population. These findings suggest that MetS may represent a frequent comorbidity in PAH rather than being related to mechanisms intrinsically related to PAH progression.

Non-nutritive sweeteners (NNS) have been used to replace added sugars in foods/beverages. Research related to NNS consumption and metabolic syndrome (MetS) is of great importance as NNS are often used by individuals who are looking to improve their health. The objectives of this investigation were to determine whether an association between NNS consumption (total and individual types) and MetS exists, and if any of the five risk factors for MetS were more significantly impacted by NNS consumption. Four NNS were included in this study: saccharin, sucralose, aspartame, and acesulfame potassium. Adult participants (n = 125) from Southwest Virginia were recruited for a cross-sectional investigation. Demographics, three 24-hour dietary recalls, and values for MetS (blood pressure, waist circumference, and glucose, triglyceride, and HDL levels) were collected. Statistical analyses included descriptives and multiple linear regressions models. Of the 125 participants, 63 were classified as NNS consumers and 18 met the criteria for MetS. There was a significant positive relationship between MetS and total NNS consumption (p=0.007) and MetS and aspartame (p=0.012). When looking at individual MetS risk factors, waist circumference, triglyceride and glucose values were significantly positively associated with NNS consumption (p≤0.001) and aspartame, sucralose, and saccharin (all p≤0.027). Some limitations to current NNS research were addressed, such as, examining associations between individual NNS types and not using diet soda as a proxy for NNS consumption. More research is needed to address the bias of self-reported data and the lack of randomized controlled trials to inferentially test the impact of NNS consumption. / Master of Science

Dravet syndrome (DS) is an infantile epileptic encephalopathy that is caused by loss-of-function mutations in the SCN1A gene, which encodes the voltage-gated sodium channel, NaV1.1. Haploinsufficiency of NaV1.1 in DS patients leads to imbalanced excitability across brain circuits, resulting in a broad phenotypic profile including drug-resistant convulsive and non-convulsive (absence) seizures, cognitive impairment, ataxia, and sleep disruption. Dysfunction in the somatosensory corticothalamic (CT) circuit underlies several DS phenotypes including absence seizures and sleep disturbances. Yet, the precise mechanisms underlying somatosensory CT circuit dysfunction in DS remain unclear. Here, we sought to identify the cellular and synaptic mechanisms underlying somatosensory CT circuit dysfunction in a haploinsufficiency DS mouse model. This work reveals that NaV1.1 haploinsufficiency leads to cell-type-specific changes in the excitability of reticular thalamic (nRT), ventral posterolateral (VPL), and ventral posteromedial (VPM) neurons. Further, we identified alterations in both glutamatergic and GABAergic synaptic connectivity within the somatosensory CT circuit in DS mice. These findings introduce glutamatergic neuron dysfunction and synaptic alterations as novel disease mechanisms underlying thalamic circuit dysfunction in DS, providing new targets for therapeutic intervention. In addition, we reveal that VPL and VPM neurons exhibit distinct firing properties in a healthy CT circuit, suggesting they differentially contribute to circuit-wide function in health and dysfunction in disease. / Doctor of Philosophy / The brain is composed of biological circuits made up of excitatory and inhibitory neurons, which are connected through synapses. Proper balance between excitatory and inhibitory activity in these circuits is essential for maintaining healthy brain function. Dravet syndrome (DS) is an infantile-onset epilepsy caused by mutations in the SCN1A gene, which encodes the voltage-gated sodium channel, Nav1.1. Loss of this protein in the brain leads to an imbalance of excitation and inhibition across a variety of brain circuits, resulting in drug-resistant seizures and cognitive, motor, and learning deficits. Disrupted excitability in the somatosensory corticothalamic (CT) circuit specifically leads to non-convulsive seizures and sleep disruption in DS. However, the mechanisms underlying this circuit's dysfunction remain unclear. Revealing these mechanisms is critical for identifying therapeutic targets by which we can correct circuit function. In this work, we used a mouse model of DS to reveal changes in the excitability of three distinct cell populations of the somatosensory CT circuit. Importantly, changes were exhibited in both excitatory and inhibitory thalamic neuron populations. We further identified impairments in the synapses, both excitatory and inhibitory, connecting the somatosensory CT circuit. These cell-type-specific changes in excitability and synaptic connectivity provide novel targets for therapeutic intervention in DS.

La fibrillation auriculaire (FA) est une pathologie très répandue qui affectera au sein de la population occidentale, une personne sur quatre au cours de sa vie. À partir d'extraits d'appendices auriculaires chez des patients, nous avons mesuré les niveaux d'expression de gènes et des protéines de communication intercellulaire des connexines (Cx) 40 et 43 et de marqueurs inflammatoires (TNF-a, 1TL-Ip\ IL-6, IL-8 et le Nf-icb) par PCR en temps réel, par immunobuvardage de type Western et par immunoessai de type sandwich à l'aide d'un système Bio-Plex®. Les résultats quantitatifs ont été confrontés aux données cliniques afin d'identifier des corrélations entre les résultats et certaines conditions pathologiques comme le syndrome métabolique (SM), le diabète de type II (DU) et la FA post-opératoire (FAPO). Notre étude n'a pas démontré de relation entre la FAPO et l'expression des marqueurs inflammatoires et des protéines de communication intercellulaire. Une sous-expression de la Cx40 chez les individus atteints de SM et de DU et une surexpression de IL-1P chez le groupe de DU ont été observées. La FAPO est une pathologie complexe qui émerge d'une combinaison de variables physiologiques mais aussi opératoires souvent imprévisibles.

Le syndrome du QT long (LQTs) et le syndrome de Brugada (BS) sont deux maladies cardiaques héréditaires, pouvant causer la mort subite en relation avec des torsades de pointe dues à une fibrillation ventriculaire. SCN5A est le gène codant pour la sous-unité a du canal Na4 dépendant du voltage, exprimé dans le cœur humain. Objectif : Dans la présente étude, deux mutations (R1193Q et F1344S) dans le gène SCN5A ont été identifiées. La mutation R1193Q a été trouvée chez deux patients après le test de provocation à la procainamide par voie intraveineuse. Un des patients est atteint de BS et l'autre est atteint à la fois de BS et de LQTs. La mutation F1344S a été trouvée chez un autre patient atteint uniquement de BS. Méthode : Les canaux mutants ont été exprimés dans un système d'expression de mammifère (lignée cellulaire tsA 201) et les propriétés biophysiques ont été étudiées avec la technique de patch clamp en configuration cellule entière. Résultats : L'analyse des séquences montre un changement de G à A à la position 3587 sur l'exon 20. La mutation RI 193Q montre un déplacement négatif de 5mV de l'inactivation et un courant Na+ persistant. Le déplacement vers des potentiels négatifs de l'inactivation est responsable d'une perte de fonction causant l'élévation du segment ST chez le patient atteint de BS. La présence du courant persistant est responsable du gain de fonction causant l'augmentation de l'intervalle QT chez le patient avec LQTs. La mutation F1344S montre une manifestation typique de BS sur l'électrocardiogramme pendant une période de fièvre. Le séquençage a révélé un changement de T à C à la position 4031 sur l'exon 23. L'analyse biophysique montre une perte de fonction due au déplacement de la courbe d'activation vers des potentiels positifs à 23°C et ce déplacement est exacerbé à 40.5°C avec une pente plus lente. Conclusion : Les différentes manifestations cliniques de ces deux mutations sont la conséquence des anormalités électrophysiologiques distinctes du canal Na+ cardiaque mutant décrites dans cette étude. Pour les patients porteurs de R1193Q, la prescription de quelques drogues pouvant provoquer le LQTs et le BS doit être limitée. Pour éviter les épisodes de fibrillation ventriculaire, l'hyperthermie doit être contrôlée chez les patients porteurs de la mutation F1344S. / Long QT syndrome (LQTs) and Brugada syndrome (BS) are two distinct hereditary cardiac diseases, causing sudden cardiac death related to torsade de pointes and ventricular tachycardia (VT) / ventricular fibrillation (VF). SCN5A is the gene encoding the principal voltage-gated Na+ channel a-subunit, which is only expressed in the human heart. Objective: In present study, two mutations (R1193Q and F1344S) in SCN5A have been identified. RI 193Q mutation was found in two patients, one with BS and another with an overlap of BS and LQTs after the intravenous procainamide test. F1344S mutation was found in another patient with BS. Method: The mutant channels were expressed in a mammalian expression System (tsA 201 cell Une) and the biophysical properties were studied by the patch clamp technique with whole cell configuration. Results: The sequence analysis showed a G to A base change at position 3587 in exon 20. The R1193Q mutation produced a negative shift for 5 mV of inactivation and a persistent Na+ current. The negative shift of inactivation is responsible for loss of the function, leading to ST segment elevation in BS. The persistent Na+ current is responsible for gain of function, causing QT interval prolongation in LQTs. The F1344S mutation presented a typical BS manifestation on ECG during fever period. The sequencing analysis revealed a T to C base change at position 4031 in exon 23. The biophysical analysis showed loss of function due to significantly positive shift of activation at both 23°C and 40.5°C, but the shift was more important at 40.5°C with a slower slope factor. Conclusion: The different clinical manifestations of these two mutations probably derive from the distinct electrophysiological abnormalities of the mutant cardiac Na+ channels reported in this study. For patients with RI 193Q mutation, some drugs that likely precipitate LQTs and BS should be limited to prescribe. To prevent from VT/VF events, hyperthermia should be effectively controlled in the patients with F1344S mutation.

Thesis (M.Sc.)--Memorial University of Newfoundland, 2004. / Restricted until May 2005. Bibliography: leaves 62-68.