The consequences of myo-cardial ischemia are examined from the standpoint of the neural control system of the heart, a hierarchy of three neuronal centers residing in central command, intrathoracic ganglia, and intrinsic cardiac ganglia. The basis of the investigation is the premise that while this hierarchical control system has evolved to deal with "normal" physiological circumstances, its response in the event of myocardial ischemia is unpredictable because the singular circumstances of this event are as yet not part of its evolutionary repertoire. The results indicate that the harmonious relationship between the three levels of control breaks down, because of a conflict between the priorities that they have evolved to deal with. Essentially, while the main priority in central command is blood demand, the priority at the intrathoracic and cardiac levels is heart rate. As a result of this breakdown, heart rate becomes less predictable and therefore less reliable as a diagnostic guide as to the traumatic state of the heart, which it is commonly used as such following an ischemic event. On the basis of these results it is proposed that under the singular conditions of myocardial ischemia a determination of neural control indexes in addition to cardiovascular indexes has the potential of enhancing clinical outcome.

A model is proposed in which the relationship between individual neurons within a neural network is dynamically changing to the effect of providing a measure of "plasticity" in the control of heart rate. The neural network on which the model is based consists of three populations of neurons residing in the central nervous system, the intrathoracic extracardiac nervous system, and the intrinsic cardiac nervous system. This hierarchy of neural centers is used to challenge the classical view that the control of heart rate, a key clinical index, resides entirely in central neuronal command (spinal cord, medulla oblongata, and higher centers). Our results indicate that dynamic networking allows for the possibility of an interplay among the three populations of neurons to the effect of altering the order of control of heart rate among them. This interplay among the three levels of control allows for different neural pathways for the control of heart rate to emerge under different blood flow demands or disease conditions and, as such, it has significant clinical implications because current understanding and treatment of heart rate anomalies are based largely on a single level of control and on neurons acting in unison as a single entity rather than individually within a (plastically) interconnected network.

The consequences of myo-cardial ischemia are examined from the standpoint of the neural control system of the heart, a hierarchy of three neuronal centers residing in central command, intrathoracic ganglia, and intrinsic cardiac ganglia. The basis of the investigation is the premise that while this hierarchical control system has evolved to deal with "normal" physiological circumstances, its response in the event of myocardial ischemia is unpredictable because the singular circumstances of this event are as yet not part of its evolutionary repertoire. The results indicate that the harmonious relationship between the three levels of control breaks down, because of a conflict between the priorities that they have evolved to deal with. Essentially, while the main priority in central command is blood demand, the priority at the intrathoracic and cardiac levels is heart rate. As a result of this breakdown, heart rate becomes less predictable and therefore less reliable as a diagnostic guide as to the traumatic state of the heart, which it is commonly used as such following an ischemic event. On the basis of these results it is proposed that under the singular conditions of myocardial ischemia a determination of neural control indexes in addition to cardiovascular indexes has the potential of enhancing clinical outcome.

A model is proposed in which the relationship between individual neurons within a neural network is dynamically changing to the effect of providing a measure of "plasticity" in the control of heart rate. The neural network on which the model is based consists of three populations of neurons residing in the central nervous system, the intrathoracic extracardiac nervous system, and the intrinsic cardiac nervous system. This hierarchy of neural centers is used to challenge the classical view that the control of heart rate, a key clinical index, resides entirely in central neuronal command (spinal cord, medulla oblongata, and higher centers). Our results indicate that dynamic networking allows for the possibility of an interplay among the three populations of neurons to the effect of altering the order of control of heart rate among them. This interplay among the three levels of control allows for different neural pathways for the control of heart rate to emerge under different blood flow demands or disease conditions and, as such, it has significant clinical implications because current understanding and treatment of heart rate anomalies are based largely on a single level of control and on neurons acting in unison as a single entity rather than individually within a (plastically) interconnected network.

Les saccades verticales sont importantes pour l'exploration du monde visuel 3D. Ces mouvements complexes nécessitent le contrôle de la distribution d'innervation aux six muscles extraoculaires de chaque ¿il. Peu d'études existent chez quelques adultes. Elles montrent une asymétrie haut/bas : latence plus courte pour les saccades vers le haut, convergence pendant les saccades vers le bas et divergence pendant les saccades vers le haut. Une controverse persiste concernant l'origine centrale versus musculaire de la vergence. Cette thèse apporte des données de référence sur le développement des saccades verticales en interaction avec la vergence chez des enfants de 6 à 17 ans. Le résultat marquant est une convergence pendant toutes les saccades verticales qui diminue avec l'âge pour les saccades vers le haut, tendant vers la divergence de l'adulte. Ainsi, les asymétries haut/bas évoluent avec l'âge ; nos résultas plaident en faveur d'une synergie continue saccade-vergence qui soutiendrait un biais perceptif (champ visuel haut perçu comme plus lointain en profondeur que le champ visuel bas). Cette thèse étudie aussi le contrôle postural, focalisant sur l'interaction vision-oculomotricité-posture des enfants de 6 à 17 ans sains et des enfants avec strabisme. Les résultats montrent un effet stabilisateur de la vergence sur la posture, l'existence d'un espace privilégié pour la stabilité posturale (lointain pour strabismes divergents, mais proche pour strabismes convergents et enfants sains) et un bénéfice de la vision bi-oculaire rudimentaire présente chez des strabiques. Cette thèse ouvre des pistes multiples de recherche fondamentale en clinique. / Vertical saccades eye movements are very important for exploration of the 3-D space. There are complex movements, requiring control of the distribution of innervation to the six extraocular muscles of each eye. Few studies exist in some adults subjects. These showed up/down anisotropies: shorter latency for upward saccades, convergence during downward and divergence during upward saccades. A controversy remains about the origin, central versus muscular, of the vergence. This thesis provides referential developmental data of vertical saccades in interaction with vergence in children from 6 to 17 years. The striking result is a convergence of the eyes during all vertical saccades that decrease with age for upward saccades, tending towards divergence like adults. Thus up/down asymmetries changed with age, in line with a continuous saccade-vergence synergy that supports a perceptual bias (upper visual field further away in depth than lower visual field). This thesis studied also postural control, focusing on the vision-oculomotricity-posture interaction in children from 6 to 17 years old, and in children with strabismus. Our results showed a stabilizing effect of vergence on posture, the existence of a favorite space for postural stability in strabismic children (near for convergent and healthy children and far for divergent strabismus) and a benefit of bi-ocular visual stimulation. This thesis opens multiple avenues for fundamental research in clinic.

A recuperação da frequência cardíaca pós-exercício (RecFC) é determinada pela reativação vagal e retirada simpática. Essas respostas, por sua vez, são reguladas pela ação integrada dos diversos mecanismos de controle cardiovascular, como o comando central, o mecanorreflexo muscular, o metaborreflexo muscular e a termorregulação. Na hipertensão arterial sistêmica (HAS) ocorre redução da RecFC, refletindo a presença de disfunção autonômica e sugerindo prejuízos nos mecanismos de controle cardiovascular, que precisam ser investigados. Dessa forma, esta tese visou avaliar e comparar a influência dos mecanismos de controle cardiovascular sobre a RecFC e sua regulação autonômica em normotensos (NT) e hipertensos nunca-tratados (HT). Para tanto, 23 homens HT (45±8 anos; 142±8/96±3 mmHg) e 25 NT (43±8 anos; 114±4/77±2 mmHg) realizaram, de forma aleatória, 5 sessões experimentais compostas de: período pré-exercício, 30 min de exercício em cicloergômetro (70% do VO2pico) e 5 min de recuperação. A recuperação diferiu entre as sessões, seguindo os protocolos: a) recuperação inativa (RI) - ausência de movimento; b) recuperação ativa (RA) - manutenção do movimento pelo próprio voluntário; c) recuperação passiva (RP) - manutenção do movimento por força externa; d) recuperação com oclusão (RO) - ausência de movimento e oclusão total da circulação da coxa; e e) recuperação com resfriamento (RR) - ausência de movimento e resfriamento por ventilação. A atividade eletrocardiográfica, a respiração e a pressão arterial foram continuamente registradas. A RecFC foi avaliada por meio do cálculo dos índices: a) RecFC30s, RecFC60s, RecFC300s: i.e., redução da FC após 30s, 60s e 300s de recuperação; b) constante de tempo de curta duração da RecFC (T30) e; c) constante de tempo de longa duração da RecFC (RecFCt). A comparação da RecFC entre RA e RP permitiu avaliar a influência do comando central sobre a RecFC. A RecFC foi mais lenta na RA em comparação à RP (RecFC30s = 11±6 vs. 13±7 bpm, p<0,01), não havendo diferença entre os grupos nessa resposta. A comparação de RP e RI foi utilizada para avaliar o mecanorreflexo. A RecFC foi mais lenta na RP em comparação à RI (T30 = 351±167 vs. 267±128 s, p<0,01) e esse efeito foi maior no grupo HT (+160±154 vs. +32±147 s, p=0,03). A comparação de RI e RO foi utilizada para avaliar o metaborreflexo. A RecFC foi mais lenta na RO que na RI (RecFC300s = 25±14 vs. 37±10 bpm, p<0,01), e esse efeito foi maior nos HT (-16±11 vs. -8±15 bpm, p=0,05). Por fim, a comparação de RI e RR foi utilizada para avaliar a termorregulação. A RecFC foi mais rápida na RR em comparação à RI (RecFC300s = 39±12 vs. 37±10 bpm, p<0,01), não havendo diferença entre os grupos nessa resposta. Conclui-se, que a RecFC é influenciada pela atuação do comando central, mecanorreflexo muscular, metaborreflexo muscular e termorregulação. Em adição, a redução na RecFC na HAS está relacionada, pelo menos em parte, à maior sensibilidade do mecanorreflexo e do metaborreflexo musculares / Post-exercise heart rate recovery (HRR) is determined by vagal reactivation and sympathetic withdrawal. These responses are regulated by the integrated action of several cardiovascular control mechanisms, such as central command, muscle mechanoreflex, muscle metaboreflex and thermoregulation. The reduction in HRR occurs in hypertension, which indicates the presence of autonomic dysfunction and suggests impairments of the cardiovascular control mechanisms that need to be studied. Thus, this thesis assessed and compared the influence of the cardiovascular control mechanisms on HRR and its autonomic regulation in normotensives (NT) and never-treated hypertensives (HT). For this purpose, 23 HT (45±8 years; 142±8/96±3 mmHg) and 25 NT (43±8 years; 114±4/77±2 mmHg) men performed, in a random order, 5 experimental sessions composed by: pre-exercise period, 30 min of cycle ergometer exercise (70% VO2peak) and 5 min of recovery. The recovery was different between the sessions, as follow: a) inactive recovery (IR) - absence of movement; b) active recovery (AR) - maintenance of movement by the own voluntary; c) passive recovery (PR) - maintenance of movement by an external force; d) occlusion recovery (OR) - absence of movement and total circulatory occlusion of hips\' circulation; and e) cooling recovery (CR) - absence of movement and cooling using a fan. Electrocardiographic activity, respiration and blood pressure were continuously registered. HRR was assessed by the calculation of the following indices: a) HRR30s, HRR60s and HRR300s: i.e. heart rate reduction after 30s, 60s and 300s of recovery; b) short-term time-constant of HRR (T30); and c) long-term time-constant of HRR (HRRt). The comparison of HRR between AR and PR allowed the assessment of the central command influence on HRR. HRR was slower in AR in comparison with PR (HRR30s = 11±6 vs. 13±7 bpm, p<0.01), and there were no difference between the groups in this response. The comparison of HRR between PR and IR allowed the assessment of the mechanoreflex influence on HRR. HRR was slower in PR in comparison with IR (T30 = 351±167 vs. 267±128 s, p<0.01), and this effect was greater in the HT (+160±154 vs. +32±147 s, p=0.03). The comparison of HRR between OR and IR allowed the assessment of the metaboreflex influence on HRR. HRR was slower in OR in comparison with IR (HRR300s = 25±14 vs. 37±10 bpm, p<0.01), and this effect was greater in the HT (-16±11 vs. -8±15 bpm, p=0,05). Finally, the comparison of HRR between IR and CR allowed the assessment of the thermoregulation influence on HRR. HRR was accelerated in CR in comparison with IR (HRR300s = 39±12 vs. 37±10 bpm, p<0.01), and there were no difference between the groups in this response. In conclusion: HRR is influenced by the action of central command, muscle mechanoreflex, muscle metaboreflex and thermoregulation. In addition, the reduction in HRR in hypertension is, at least in part, related to a greater sensitivity of the muscle mechanoreflex and metaboreflex

A recuperação da frequência cardíaca pós-exercício (RecFC) é determinada pela reativação vagal e retirada simpática. Essas respostas, por sua vez, são reguladas pela ação integrada dos diversos mecanismos de controle cardiovascular, como o comando central, o mecanorreflexo muscular, o metaborreflexo muscular e a termorregulação. Na hipertensão arterial sistêmica (HAS) ocorre redução da RecFC, refletindo a presença de disfunção autonômica e sugerindo prejuízos nos mecanismos de controle cardiovascular, que precisam ser investigados. Dessa forma, esta tese visou avaliar e comparar a influência dos mecanismos de controle cardiovascular sobre a RecFC e sua regulação autonômica em normotensos (NT) e hipertensos nunca-tratados (HT). Para tanto, 23 homens HT (45±8 anos; 142±8/96±3 mmHg) e 25 NT (43±8 anos; 114±4/77±2 mmHg) realizaram, de forma aleatória, 5 sessões experimentais compostas de: período pré-exercício, 30 min de exercício em cicloergômetro (70% do VO2pico) e 5 min de recuperação. A recuperação diferiu entre as sessões, seguindo os protocolos: a) recuperação inativa (RI) - ausência de movimento; b) recuperação ativa (RA) - manutenção do movimento pelo próprio voluntário; c) recuperação passiva (RP) - manutenção do movimento por força externa; d) recuperação com oclusão (RO) - ausência de movimento e oclusão total da circulação da coxa; e e) recuperação com resfriamento (RR) - ausência de movimento e resfriamento por ventilação. A atividade eletrocardiográfica, a respiração e a pressão arterial foram continuamente registradas. A RecFC foi avaliada por meio do cálculo dos índices: a) RecFC30s, RecFC60s, RecFC300s: i.e., redução da FC após 30s, 60s e 300s de recuperação; b) constante de tempo de curta duração da RecFC (T30) e; c) constante de tempo de longa duração da RecFC (RecFCt). A comparação da RecFC entre RA e RP permitiu avaliar a influência do comando central sobre a RecFC. A RecFC foi mais lenta na RA em comparação à RP (RecFC30s = 11±6 vs. 13±7 bpm, p<0,01), não havendo diferença entre os grupos nessa resposta. A comparação de RP e RI foi utilizada para avaliar o mecanorreflexo. A RecFC foi mais lenta na RP em comparação à RI (T30 = 351±167 vs. 267±128 s, p<0,01) e esse efeito foi maior no grupo HT (+160±154 vs. +32±147 s, p=0,03). A comparação de RI e RO foi utilizada para avaliar o metaborreflexo. A RecFC foi mais lenta na RO que na RI (RecFC300s = 25±14 vs. 37±10 bpm, p<0,01), e esse efeito foi maior nos HT (-16±11 vs. -8±15 bpm, p=0,05). Por fim, a comparação de RI e RR foi utilizada para avaliar a termorregulação. A RecFC foi mais rápida na RR em comparação à RI (RecFC300s = 39±12 vs. 37±10 bpm, p<0,01), não havendo diferença entre os grupos nessa resposta. Conclui-se, que a RecFC é influenciada pela atuação do comando central, mecanorreflexo muscular, metaborreflexo muscular e termorregulação. Em adição, a redução na RecFC na HAS está relacionada, pelo menos em parte, à maior sensibilidade do mecanorreflexo e do metaborreflexo musculares / Post-exercise heart rate recovery (HRR) is determined by vagal reactivation and sympathetic withdrawal. These responses are regulated by the integrated action of several cardiovascular control mechanisms, such as central command, muscle mechanoreflex, muscle metaboreflex and thermoregulation. The reduction in HRR occurs in hypertension, which indicates the presence of autonomic dysfunction and suggests impairments of the cardiovascular control mechanisms that need to be studied. Thus, this thesis assessed and compared the influence of the cardiovascular control mechanisms on HRR and its autonomic regulation in normotensives (NT) and never-treated hypertensives (HT). For this purpose, 23 HT (45±8 years; 142±8/96±3 mmHg) and 25 NT (43±8 years; 114±4/77±2 mmHg) men performed, in a random order, 5 experimental sessions composed by: pre-exercise period, 30 min of cycle ergometer exercise (70% VO2peak) and 5 min of recovery. The recovery was different between the sessions, as follow: a) inactive recovery (IR) - absence of movement; b) active recovery (AR) - maintenance of movement by the own voluntary; c) passive recovery (PR) - maintenance of movement by an external force; d) occlusion recovery (OR) - absence of movement and total circulatory occlusion of hips\' circulation; and e) cooling recovery (CR) - absence of movement and cooling using a fan. Electrocardiographic activity, respiration and blood pressure were continuously registered. HRR was assessed by the calculation of the following indices: a) HRR30s, HRR60s and HRR300s: i.e. heart rate reduction after 30s, 60s and 300s of recovery; b) short-term time-constant of HRR (T30); and c) long-term time-constant of HRR (HRRt). The comparison of HRR between AR and PR allowed the assessment of the central command influence on HRR. HRR was slower in AR in comparison with PR (HRR30s = 11±6 vs. 13±7 bpm, p<0.01), and there were no difference between the groups in this response. The comparison of HRR between PR and IR allowed the assessment of the mechanoreflex influence on HRR. HRR was slower in PR in comparison with IR (T30 = 351±167 vs. 267±128 s, p<0.01), and this effect was greater in the HT (+160±154 vs. +32±147 s, p=0.03). The comparison of HRR between OR and IR allowed the assessment of the metaboreflex influence on HRR. HRR was slower in OR in comparison with IR (HRR300s = 25±14 vs. 37±10 bpm, p<0.01), and this effect was greater in the HT (-16±11 vs. -8±15 bpm, p=0,05). Finally, the comparison of HRR between IR and CR allowed the assessment of the thermoregulation influence on HRR. HRR was accelerated in CR in comparison with IR (HRR300s = 39±12 vs. 37±10 bpm, p<0.01), and there were no difference between the groups in this response. In conclusion: HRR is influenced by the action of central command, muscle mechanoreflex, muscle metaboreflex and thermoregulation. In addition, the reduction in HRR in hypertension is, at least in part, related to a greater sensitivity of the muscle mechanoreflex and metaboreflex

This thesis is concerned with the neurocircuitry that underpins the cardiovascular response to exercise, which has thus far remained incompletely understood. Small animal studies have provided clues, but with the advent of functional neurosurgery, it has now been made possible to translate these findings to humans. Chapter One reviews the background to the studies in this thesis. Our current understanding of the cardiovascular response to exercise is considered, followed by a discussion on the anatomy and function of various brain nuclei. In particular, the rationale for targeting the periaqueductal grey (PAG) and the subthalamic nucleus (STN) is reviewed. Chapter Two reviews the use of deep brain stimulation (DBS), in which deep brain stimulating electrodes are implanted into various brain nuclei in humans, in order to treat chronic pain and movement disorders. This technique not only permits direct electrical stimulation of the human brain, but also gives the opportunity to record the neural activity from different brain regions during a variety of cardiovascular experiments. This chapter also gives a detailed methodological description of the experimental techniques performed in the studies in this thesis. Chapter Three identifies the cardiovascular neurocircuitry involved in the exercise pressor reflex in humans using functional neurosurgery. It shows for the first time in humans that the exercise pressor reflex is associated with significantly increased neural activity in the dorsal PAG. The other sites investigated, which had previously been identified as cardiovascular active in both animals and humans, seem not to have a role in the integration of this reflex. Chapter Four investigates whether changes in exercise intensity affect the neurocircuitry involved in the exercise pressor reflex. It demonstrates that the neural activity in the PAG is graded to increases in exercise intensity and corresponding increases in arterial blood pressure. This chapter also provides evidence to suggest that neural activity in the STN corresponds to the cardiovascular changes evoked by the remote ischaemic preconditioning stimulus in humans. Chapter Five identifies the cardiovascular neurocircuitry involved during changes in central command during isometric exercise at constant muscle tension using muscle vibration. It shows that, in humans, central command is associated with significantly decreased neural activity in the STN. Furthermore, the STN is graded to the perception of the exercise task, i.e. the degree of central command. The other sites investigated appear not to have as significant a role in the integration of central command during the light exercise task that was undertaken. Chapter Six studies the changes in muscle sympathetic nerve activity (MSNA) during stimulation of various brain nuclei in humans. Regrettably, the results presented in this chapter are not convincing enough to support the hypothesis that stimulation of particular subcortical structures corresponds to changes in MSNA. However, the cardiovascular changes that were recorded during stimulation of the different subcortical structures are congruous with previous studies in both animals and humans. Chapter Seven presents a brief summary of the findings in this thesis.