Dissertations / Theses on the topic 'Hemodynamic responses'

Since the 1900s, the number of deaths attributable to cardiovascular disease has steadily risen. With the advent of antihypertensive drugs and non-invasive surgical procedures, such as intravascular stenting, these numbers have begun to level off. Despite this trend, the number of patients diagnosed with some form of cardiovascular disease has only increased. By 2030, prevalence of coronary heart disease is expected to increase approximately by 18% in the United States. By 2050, prevalence of peripheral arterial occlusive disease is expected to increase approximately by 98% in the U.S. No single drug or surgical intervention offers a complete solution to these problems. Thus, a multi-faceted regimen of lifestyle changes, medication, and device or surgical interventions is usually necessary. A potential adjunct therapy and cost-effective solution for treating cardiovascular disease that has been overlooked is neurostimulation. Recent studies show that using neurostimulation techniques, such as transcutaneous electrical nerve stimulation (TENS), can help to reduce ischemic pain, lower blood pressure, increase blood flow to the periphery, and decrease systemic vascular resistance. The mechanisms by which these hemodynamic changes occur is still under investigation. The primary aim of this thesis is to elucidate these mechanisms through a thorough synthesis of the existing literature on this subject. Neurostimulation, specifically TENS, is thought to modulate both the metaboreflex and norepinephrine release from sympathetic nerve terminals. To test the hypothesis that TENS increases local blood flow, decreases mean arterial pressure, and decreases cutaneous vascular resistance compared to placebo, in which the electrodes are attached but no electrical stimulation is applied, a protocol was developed to test the effect of neurostimulation on healthy subjects. Implementation of this protocol in a pilot study will determine if neurostimulation causes significant changes in blood flow using the most relevant perfusion measurement instrumentation. Before conducting this study, pre-pilot comparison studies of interferential current therapy (IFC) versus TENS, low frequency (4 Hz) TENS versus high frequency (100 Hz) TENS, and electrode placement on the back versus the forearm were conducted. The only statistically significant difference found was that the application of IFC on the back decreased the reperfusion time, meaning that the time required to reach the average baseline perfusion unit value after occlusion decreased. Further pre-pilot work investigating these different modalities and parameters is necessary to ensure that favorable hemodynamic changes can be detected in the pilot study.

Maintenance of neuronal function depends on the timely delivery of oxygen and glucose through changes in blood flow that are linked to the level of ongoing neuronal and glial activity, yet the mechanisms underlying this stimulus-dependent control of blood flow remain unclear. Here, using transgenic mice expressing channelrhodopsin-2 in a subset of layer 5b pyramidal neurons, we report that changes in intrinsic optical signals and blood flow can be evoked by activation of channelrhodopsin-2 neurons without direct involvement of other cell types. We have used a combination of imaging and pharmacology to examine the importance of glutamatergic synaptic signaling in neurovascular coupling. In contrast to sensory-evoked responses, we observed that glutamate-dependent neuronal signalling is not essential for the production of channelrhodopsin-evoked hemodynamic responses. Our results rather suggest that ChR2-activated neurons are coupled to the surrounding vasculature through a glutamate-dependent astrocytic pathway mediated by the Group I metabotropic glutamate receptor mGluR5.

To assess the relationships of body mass index (BMI) on arterial stiffness at rest and post-maximal treadmill graded exercise testing (GXT). Forty-four apparently healthy, young adult males (22.1 ± 0.48 years) were recruited and divided into either a healthy weight (H, ≤24.9 kg/m2), overweight (OV, 24.9-29.9 kg/m2) or obese (OB, ≥29.9 kg/m2) group based on BMI. All subjects underwent arterial stiffness (carotid-femoral pulse wave velocity, cfPWV), blood pressure (BP), pulse pressure (PP), mean arterial pressure (MAP) and body composition (bioelectrical impedance analysis, BIA) measurements at rest. Following the GXT, measures of arterial stiffness (cfPWV) and BP were acquired. Resting measures of cfPWV, BMI, systolic BP, diastolic BP, MAP, and PP were significantly (p <0.05) greater in OV and OB compared with H. Compared with OV, OB had a greater BMI. Relative peak oxygen consumption (VP2peak) was greater in H compared with OV and OB (p<0.05). systolic BP was positively associated, whereas VO2peak was inversely related to cfPWV (p<0.05). No significant inter-group interactions were observed with cfPWV after the GXT. However, interactions were observed for SBP, DBP and PP (p<0.05). In young men with varying BMI, SBP and VO2peak were associated with resting cfPWV. However, similar cardiovascular responses were observed between groups after a maximal GXT.

Hypertension afflicts one in four American adults and is a major risk factor for cardiovascular disease. Studies have shown that a family history of hypertension is an important predictor of future hypertension. Two hemodynamic factors control blood pressure (BP); cardiac output (CO) and total peripheral resistance (TPR). Although children of hypertensive parents may exhibit normal levels of these hemodynamic variables at rest, the response of these variables during exercise stress may differ. Therefore, the present study was designed to investigate whether children with a positive family history of hypertension exhibit an exaggerated BP response due to either an increased CO or an attenuated decrease in TPR during dynamic submaximal exercise compared to children of normotensive parents. Eleven children 12.2 ± 1.8 yr (M ± SE) of normotensive parents and 11 children 12.0 ± 2.4 yr of at least one hypertensive parent completed an orientation session, graded maximal cycle ergometer test, and a submaximal exercise bout consisting of 6 minutes of steady state cycling at 50 and 80% of maximal heart rate reserve. Blood pressure, CO and TPR were measured during the last 3 minutes of each submaximal exercise stage. An independent t-test was used to determine differences in the resting measures. The changes in TPR, BP and CO from rest through 80% intensity stage were examined using a twoway (group x intensity) ANOVA. The groups were evenly matched for age, weight, height, and body fatness. The children with a positive family history of hypertension had significantly higher resting systolic BP, diastolic BP (DBP), and mean arterial pressure (MAP) (p<0.05) compared to those children with a negative family history. Although there were no significant interactions among any of the variables studied, there was a tendency for TPR to be higher (p>0.05) at rest and throughout exercise in the positive history group. MAP and DBP were significantly higher in the positive family history group at rest and remained higher throughout exercise. In conclusion children of hypertensive parents exhibit a modest but significantly higher MAP and DBP at rest and during submaximal exercise. This subtle difference in BP control reflects an early trend toward increased TPR.
School of Physical Education

The purpose of this study was to determine the association of age, gender, and cardiorespiratory fitness level upon normative heart rate and systolic blood pressure (SBP) responses per MET during the BSU/Bruce Ramp protocol. This research was delimited to 451 subjects, 201 men (mean age 46.5 ± 11.9 yrs) and 250 women (mean age 42.9 ± 11.4 yrs), low to moderate risk subjects. The majority of subjects were tested to enter the Ball State University Adult Physical Fitness Program. These subjects were tested using the BSU/Bruce Ramp protocol between 1992 and 1998.Multiple regression showed gender had a positive association upon submaximal SBP values. Gender's association with heart rate was negative between minute 3-6 and positive between minute 6-9. Age only had an association upon submaximal heart rate, which was negative. Cardiorespiratory fitness had a negative association upon SBP between minute 6-9 and a negative association with heart rate between minute 3-6.SBP increased 6.6 ± 4.4 and 6.0 ± 4.2 mmHg/MET between minute 3-6 for men and women, respectively. Analysis of variance demonstrated gender was not statistically significant between minute 3-6. SBP increased 4.7 ± 3.1 and 3.8 + 2.7 mmHg/MET between minute 6-9 for men and women, respectively. Gender was statisticallysignificant between minute 6-9 (p<.05). Heart rate increased 8.5 + 2.3 and 10.7 + 3.3 bpm/MET between minute 3-6 for men and women, respectively. Analysis of variance demonstrated gender was statistically significant between minute 3-6 (p<.05). The increase was 9.5 + 2.3 and 9.2 + 2.7 bpm/MET between minute 6-9 for men and women, respectively. Gender was not statistically significant between minute 6-9.In conclusion, this study demonstrated that the normative hemodynamic responses during the BSU/Bruce Ramp protocol are similar to submaximal normative data previously reported in the literature for incremental type protocols.
School of Physical Education

The primary goal of my thesis was to address my hypothesis that: there is preferential perfusion of the hindbrain regions, controlling autonomic function. To test this hypothesis I developed a system for delivering hypoxic challenges to volunteers while they were in the MRI. I developed NIRS protocols that allowed monitoring of the cerebellum. And I developed MRI methods that allowed for PC MRI to be used to monitor flow to the forebrain and hindbrain. Finally I combined these elements to investigate how the brain would react to hypoxia. Ultimately neither NIRS nor MRI detected systematic differences between the forebrain and hindbrain response to hypoxia but the developed methods are available for future studies that aim to explore the hemodynamic response in the developing brain or in adults with pathological conditions.

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 1998.
Includes bibliographical references (leaves 75-77).
The vast majority of previous functional magnetic resonance imaging (fMRI) studies have used simple 'block' experimental designs. 'Block' designs are those designs in which the same stimulus is presented to the subject over a relatively long period of time. These studies are limited in their ability to probe brain function in that they only explore steady-state differences, are confounded by cognitive babituation effects, and cannot be compared to traditional behavioral and electrophysiological experiments. Event­related (brief ,timulus presentation) techniques of electrophysiological experiments have recently been applied to fMRI, although most efforts have been far from optimal. The overall goal of this work was to develop efficient and robust techniques to estimate brain activity for event-related fMR.I experiments. We first performed two experiments to assess the steady-state linearity of the hemodynamic system in prinwy visual cortex (Vl) for an event-related visual stimuli. In agreement with previous studies, we found that the system was approximately linear. Given this result, we used linear estimation techniques to estimate the hemodynamic response during rapid, event-related experiments using two different design strategies. We found that designs using a geometric distribution of presentation intervals were insensitive to nonlinearities, and that these designs enabled very rapid presentation experiments. We then developed a general statistical hypothesis framework to test for activated brain regions during event-related experiments. In particular, we made spatially local and global estimates of the underlying physiological noise process. The sensitivity and specificity of three different hypothesis tests were validated with synthetic noise, actual fMRI noise, actual fMR.I noise plus synthetic activation, and actual fMR.I activation and noise data. The overall work allows for more efficient and appropriate fMR.I response detection and potentially new classes of fMRI experiments.
by Marc Alexander Burock.
S.M.

BACKGROUND: Pulmonary system dysfunction is a hallmark of cystic fibrosis (CF) disease. In addition to impaired cystic fibrosis transmembrane conductance regulator protein, dysfunctional β2-adrenergic receptors (β2AR) contribute to low airway function in CF. Recent observations suggest CF may also be associated with impaired cardiac function that is demonstrated by attenuated cardiac output (Q), stroke volume (SV), and cardiac power (CP) at both rest and during exercise. However, β2AR regulation of cardiac and peripheral vascular tissue, in-vivo, is unknown in CF. We have previously demonstrated that the administration of an inhaled β-agonist increases SV and Q while also decreasing SVR in healthy individuals. Therefore, we aimed to assess cardiac and peripheral hemodynamic responses to the selective β2AR agonist albuterol in individuals with CF. METHODS: 18 CF and 30 control (CTL) subjects participated (ages 22 ± 2 versus 27 ± 2 and BSA = 1.7 ± 0.1 versus 1.8 ± 0.0 m2, both p < 0.05). We assessed the following at baseline and at 30- and 60-minutes following nebulized albuterol (2.5mg diluted in 3.0mL of normal saline) inhalation: 12-lead ECG for HR, manual sphygmomanometry for systolic and diastolic blood pressure (SBP and DBP, respectively), acetylene rebreathe for Q and SV. We calculated MAP = DBP + 1/3(SBP-DBP); systemic vascular resistance (SVR) = (MAP/Q)•80; CP = Q•MAP; stroke work (SW) = SV•MAP; reserve (%change baseline to 30- or 60-minutes). Hemodynamics were indexed to BSA (QI, SVI, SWI, CPI, SVRI). RESULTS: At baseline, CF demonstrated lower SV, SVI, SW, and SWI but higher HR than CTL (p < 0.05); other measures did not differ. At 30-minutes, CF demonstrated higher HR and SVRI, but lower Q, SV, SVI, CP, CPI, SW, and SWI versus CTL (p < 0.05). At 60-minutes, CF demonstrated higher HR, SVR, and SVRI, whereas all cardiac hemodynamics were lower than CTL (p < 0.05). Reserves of CP, SW, and SVR were lower in CF versus CTL at both 30 and 60-minutes (p < 0.05). CONCLUSIONS: Cardiac and peripheral hemodynamic responsiveness to acute β2AR stimulation via albuterol is attenuated in individuals with CF, suggesting β2AR located in cardiac and peripheral vascular tissue may be dysfunctional in this population.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Aeronautics and Astronautics, 2011.
Cataloged from PDF version of thesis.
Includes bibliographical references (p. 123-135).
Adequate blood supply and circulation in bones is required to maintain a healthy skeleton, and inadequate blood perfusion is associated with numerous bone pathologies and a decrease in bone mineral density (BMD). Bone hemodynamics remains poorly understood and loss of BMD is still one of the limiting factors to long duration human spaceflight. Developments in photoplethysmography (PPG) hardware have made it a promising tool for non-invasive bone hemodynamic measurements. The aims of this thesis are to: 1) validate the use of PPG as a tool for non-invasive bone hemodynamic measurements, 2) characterize bone hemodynamic responses to changes in external pressure, and 3) identify the predominant mechanisms regulating bone hemodynamic responses to pressure changes. A new PPG device capable of measuring bone hemodynamic responses was designed and tested. It represents the state-of-the-art in deep-tissue PPG instrumentation. Validation experiments including arterial occlusion, cold exposure, skin occlusion and nitroglycerin exposure were performed. Single-limb pressure chamber experiments were performed over a range of pressures from -50 to +50 mmHg to characterize the responses to changes in external pressure and to identify the predominant control mechanisms. Our results support the use of PPG as a valid tool for measuring bone hemodynamic responses. Bone hemodynamic responses to changes in external pressure have been characterized for the first time. We also present the first report of a myogenic response in bone and show that the myogenic effect is the predominant control mechanism in bone over a wide range of pressure levels. Myogenic-induced vasoconstriction is observed at all negative pressure levels, with increasing vasoconstriction at the more extreme pressure differences. At positive pressures we observed an initial myogenic-induced vasodilation followed by activation of the intramuscular pressure receptors at +30 mmHg which overrides the initial response and causes vasoconstriction at the highest positive pressure. The availability of a new tool for non-invasive bone hemodynamic measurements opens the door to several new research opportunities with clinical, Earth-based as well as human spaceflight applications.
by Jaime Mateus.
Ph.D.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior
The aim of this study was to evaluate the hemodynamic and metabolic responses of L-Glutamine in sedentary subjected to physical exertion. The sample consisted of 11 sedentary volunteers (05 men and 06 women between 30 - 45 years). We conducted a clinical study, crossover, randomized, double-blind. The protocol was divided into two stages. The protocols used participant (0.5 g / kg) of L-glutamine or calcium caseinate added to a milk drink Nescau Light (200ml) for seven consecutive days, with an interval of one week of completion of a protocol and early other. The volunteers were evaluated for cardiopulmonary and metabolic response during cardiopulmonary exercise testing on a treadmill. Were determined in each individual oxygen consumption (VO2 Max), respiratory quotient (RQ), the workload performed, heart rate (HR), systolic and diastolic blood pressure (SBP / DBP) in phases: pre - effort, the anaerobic threshold, maximal effort and during the recovery effort. Were also evaluated serum concentrations of glucose and lactate in four stages: fast (at least 8 hours), immediately before the effort at the end of exercise and 30 minutes after exercise. The prior offer of L-glutamine (0.5 g / kg in sedentary individuals, orally for seven days did not cause hemodynamic changes during physical exertion. On the other hand modified the metabolic response by reducing the lactacemia before the physical activity (3, 68 Â 0.8 versus 2.2 Â 0.9, p = 0.01) in the presence of maximal (12.4 Â 5.1 versus 10.3 Â 3.2, p = 0.04), and at the end of the exercise stress test (6.9 Â 3.6 versus 5.02 Â 1.77, p = 0.01). L-glutamine in nutraceutical doses is recommended for use to practitioners of physical activity and not hemodynamic features.
The aim of this study was to evaluate the hemodynamic and metabolic responses of L-Glutamine in sedentary subjected to physical exertion. The sample consisted of 11 sedentary volunteers (05 men and 06 women between 30 - 45 years). We conducted a clinical study, crossover, randomized, double-blind. The protocol was divided into two stages. The protocols used participant (0.5 g / kg) of L-glutamine or calcium caseinate added to a milk drink Nescau Light (200ml) for seven consecutive days, with an interval of one week of completion of a protocol and early other. The volunteers were evaluated for cardiopulmonary and metabolic response during cardiopulmonary exercise testing on a treadmill. Were determined in each individual oxygen consumption (VO2 Max), respiratory quotient (RQ), the workload performed, heart rate (HR), systolic and diastolic blood pressure (SBP / DBP) in phases: pre - effort, the anaerobic threshold, maximal effort and during the recovery effort. Were also evaluated serum concentrations of glucose and lactate in four stages: fast (at least 8 hours), immediately before the effort at the end of exercise and 30 minutes after exercise. The prior offer of L-glutamine (0.5 g / kg in sedentary individuals, orally for seven days did not cause hemodynamic changes during physical exertion. On the other hand modified the metabolic response by reducing the lactacemia before the physical activity (3, 68 Â 0.8 versus 2.2 Â 0.9, p = 0.01) in the presence of maximal (12.4 Â 5.1 versus 10.3 Â 3.2, p = 0.04), and at the end of the exercise stress test (6.9 Â 3.6 versus 5.02 Â 1.77, p = 0.01). L-glutamine in nutraceutical doses is recommended for use to practitioners of physical activity and not hemodynamic features.

The purpose of this study was to determine if α1- adrenergic receptor blockade alters the hemodynamic response to exercise in young (<25 yr) male adult borderline hypertensives differently than in young normotensives. Five hypertensive (HTN, MAP>105 mmHg) and 7 normotensive (NTN, MAP<95 mmHg) college-age males underwent two 30 min bouts of cycle ergometry exercise at 50% V02Pk in a warm (25°C, 50% rh) environment; one bout occurred followed α1-receptor blockade with prazosin (HTN-α, NTN-α) and the other following placebo administration (HTN-p, NTN-p). At rest, HTN-p exhibited an elevated cardiac output (Q, p=.024) and MAP (p=.007). Resting Q was similar for HTN-α and NTN-α. Resting heart rate (HR) was elevated more in HTN-α than NTNα (p=.013) and not different for placebo. Resting and exercise forearm blood flows were similar between groups and altered similarly with prazosin. Exercise resulted in greater (p=.035) Q for HTN vs NTN (HTN-u > NTN-α; HTN-p = NTN-p). HR was higher (p=.043) with prazosin for both groups. Regardless of drug treatment, MAP was stable for NTN while it declined after 10 min of exercise in HTN. Rectal temperatures rose above baseline after 10 min. since Q was similar between groups with placebo but not with α1- blockade, and FBF, MAP, and HR were similarly altered between drug trials, it was concluded that young male hypertensives have an elevated blood pressure due to an elevated Q. In this group, α1-blockade may reduce Q by reducing central venous return.
Ph. D.

Cardiovascular activities may increase the brain blood flow improving neuronal activities leading to improved cognition. Consequently, the effects of an acute bout of moderate intensity aerobic exercise on brain hemodynamics and its correlation with cognitive color-word Stroop task performance were tested. The Stroop tasks were congruent (color matches word) and incongruent (color does not match word). Prefrontal (PFC) and motor cortex (MC) blood flow was recorded by fNIRS (functional near-infrared spectroscopy) while the subject was performing the Stroop tasks before and after the 30 minutes of exercise or equivalent time of rest controls (checking for practice effects). Ninety human subjects of age 24± 6, 20 ADHD (attention-deficit hyper-activity disorder), 27 High-BMI (>25), 29 males were recruited. Reaction time ‘RT' decreased (p<0.05) after exercise for both the congruent (12%) and incongruent (10%) Stroop tasks, compared to 8% with practice alone. Accuracy did not change after practice or exercise. HR changes after exercise correlated (p<0.05) with better accuracy and faster RT for the incongruent Stroop task. In general, a metabolic lag occurred in the neuronal deoxy- hemoglobin (Hb) signals behind the systemic oxy-Hb signals. PFC showed the highest effect sizes of Stroop task-responsive systemic hemodynamic changes compared to baseline irrespective of rest or exercise. Yet, PFC showed most significant (p<0.001) neuronal hemodynamic changes between the before and after exercise sessions, and these changes were opposite for right and left PFC, and opposite for congruent and incongruent Stroop tasks. Correlating the RT and mistakes with hemodynamics for both the Stroop tasks revealed that, after exercise, neuronal hemodynamic changes occurred at both PFC and MC associated with faster RT (p<0.05), and systemic hemodynamic responses occurred at PFC correlated (p<0.05) with mistakes. Overall, it was concluded that exercise changed the neuronal hemodynamic changes affecting speed; however, neuronal metabolic changes did not occur sufficiently to help improve accuracy in all subjects.

Mechanical forces are known to be important in various physiological and pathological processes, including the development of atherosclerosis. In particular it is believed that abnormal shear stress, transduced by the vascular endothelium, is particularly important in promoting atherogenesis. However, it is still unclear to what extent the precise details of the mechanical environment to which the vascular endothelium is subjected affect its response. Therefore, a novel flow-bioreactor system has been developed which is capable of subjecting endothelial cells cultured in vitro to various mechanical parameters at similar levels to those applied in vivo. The fluid dynamics within the flow-bioreactor system has been analysed computationally to accurately quantify the mechanical forces experienced by cells cultured within the flow-bioreactor system, and a validation of the computational model used has been performed to ensure the accuracy of the results of the computational fluid dynamics analysis. The flow bioreactor system has been used to subject human endothelial cells to physiologically realistic mechanical forces for up to 24 hours. The cells were shown to realign in the direction of the shear stress and elongate in response to the application of WSS, consistent with the results shown both in other mechanical models and in vivo. A computational image processing programme has been developed to accurately quantify the morphology of cells. Quantitative analysis using this programme showed that the degree of realignment and elongation was significantly dependent on the local cell density. The enabling technologies developed during this project may help with future work aimed at elucidating the features of the mechanical environment which are important in promoting or suppressing atherogenesis.

The technique of functional magnetic resonance imaging (fMRI) is rapidly developing from one of technical interest to wide clinical application. fMRI exploits the fact that brain neural activity produces a change in blood oxygenation level dependent (BOLD) response which is recorded at each point in the brain. In a typical experiment, a subject is given a stimulus or cognitive task, and the statistical question is to relate it to the BOLD response, usually via a linear model. The BOLD response is not instantaneous; it is delayed and smoothed by about 6 seconds. In this thesis we propose a rapid method of estimating and making inference about this delay. Our method is compared to other alternatives, and validated on an fMRI data set from an experiment in pain perception.

The postural control-cognition dual-task literature has demonstrated greater postural stability through the examination of multiple kinetic and kinematic measures. Recently, sample entropy (SampEn) and wavelet discrete transform have supported the claim of automaticity, as higher SampEn values and a shift toward higher contribution from automatic sensory systems have been demonstrated in dual-task settings. In order to understand the cortical component of postural control, functional near-infrared spectroscopy (fNIRS) has been used to identify cortical activation under postural control conditions. However, the neural correlates of automatic postural behaviour have yet to be fully investigated. Therefore, the purpose of this study is to confirm the presence of automatic postural control through static and dynamic measurements, and to investigate the prefrontal cortex activation (PFC) when concurrently performing quiet standing and auditory cognitive tasks. Eighteen healthy young adults (21,4 ± 3,96yo), 12 females and 6 males, with no balance deficits were recruited. Participants were instructed to either quietly stand on a force platform (SM), perform three cognitive tasks while seated (SC) and perform a combination of SM and SC concurrently (DT). Results revealed automatic postural control as evidenced by lower area and standard deviation of center-of-pressure in DT conditions. As for SampEn and the wavelet analysis, greater values and a shift from vision to the cerebellum contribution were demonstrated in DT conditions. For the DNS task, a trend toward significantly lower right hemisphere PFC activation compared to left hemisphere activation in DT was evidenced, which potentially reiterate the presence of automaticity. Therefore, as demonstrated by this experiment, the simultaneous performance of a difficult cognitive task and posture yields automatic postural behaviour, and provides insight into the neural correlates of automaticity.

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2011.
Cataloged from PDF version of thesis.
Includes bibliographical references (p. 68-74).
Near-Infrared Spectroscopy (NIRS) allows the recovery of the hemodynamic response associated with evoked brain activity. The signal is contaminated with systemic physiological interference which occurs in the superficial layers of the head as well as in the brain tissue. The back-reflection geometry of the measurement makes the DOI signal strongly contaminated by systemic interference occurring in the superficial layers. A recent development has been the use of signals from small source-detector separation (1 cm) optodes as regressors. Since those additional measurements are mainly sensitive to superficial layers in adult humans, they help in removing the systemic interference present in longer separation measurements (3 cm). Encouraged by those findings, we developed a dynamic estimation procedure to remove global interference using small optode separations and to estimate simultaneously the hemodynamic response. The algorithm was tested by recovering a simulated synthetic hemodynamic response added over baseline DOI data acquired from 6 human subjects at rest. The performance of the algorithm was quantified by the Pearson R2 coefficient and the mean square error (MSE) between the recovered and the simulated hemodynamic responses. Our dynamic estimator was also compared with a static estimator and the traditional adaptive filtering method. We observed a significant improvement (two-tailed paired t-test, p < 0.05) in both HbO and HbR recovery using our Kalman filter dynamic estimator compared to the traditional adaptive filter, the static estimator and the standard GLM technique. We then show that the systemic interference occurring in the superficial layers of the human head is inhomogeneous across the surface of the scalp. As a result, the improvement obtained by using a short separation optode decreases as the relative distance between the short and the long measurement is increased. NIRS data was acquired on 6 human subjects both at rest and during a motor task consisting of finger tapping. The effect of distance between the short and the long channel was first quantified by recovering a synthetic hemodynamic response added over the resting-state data. The effect was also observed in the functional data collected during the finger tapping task. Together, these results suggest that the short separation measurement must be located as close as 1.5 cm from the standard NIRS channel in order to provide an improvement which is of practical use. In this case, the improvement in Contrast-to-Noise Ratio (CNR) compared to a standard GLM procedure without using any small separation optode reached 50% for HbO and 100% for HbR. Using small separations located farther than 2 cm away resulted in mild or negligible improvements only.
by Louis Gagnon.
S.M.

Purpose. The purpose of this thesis was to investigate the nonthermoregulatory control of cutaneous vascular conductance (CVC) and sweating during recovery from exercise-induced hyperthermia as well as to determine possible sex-related differences during the recovery period. It was hypothesized that an active and passive recovery would maintain mean arterial pressure (MAP), CVC and sweat rate at higher levels than an inactive recovery and result in a faster rate of esophageal temperature (Tes) decay. It was also hypothesized that changes in MAP, CVC and sweat rate would be sex dependent. Methods. Eighteen participants (9 males, 9 females) were rendered hyperthermic by exercise (i.e. Tes = 39.5°C) and recovered in one of three recovery modalities for 60-min: (1) active, (2) inactive or (3) passive. Tes, CVC, sweat rate, cardiac output, stroke volume, heart rate, total peripheral resistance, and MAP were recorded at baseline and 2, 5, 12, 20 and every 10-min until the end of recovery. Results. Both active and passive recoveries were equally effective in maintaining MAP, CVC and sweat rate at greater levels compared with an inactive recovery (p ≤ 0.05). A significantly lower Tes was subsequently observed during passive recovery at 20-min and for the rest of recovery compared to the active mode (p ≤ 0.05). Sex did not affect any of the measured variables at any time point during any recovery mode, with the exception of sweat rate which was significantly higher in males throughout the recovery period (p ≤ 0.05). Conclusion. We conclude that despite an important thermal drive, nonthermal input remains an important influence in the modulation of postexercise heat loss responses. Further, action of the muscle pump/mechanoreceptors is the main nonthermal determinant in the postexercise modulation of MAP, CVC and sweat rate irrespective of sex.

Thesis (Ph.D.)--Tufts University, 2004.
Adviser: David A. Boas. Submitted to the Dept. of Electrical Engineering. Includes bibliographical references (leaves 407-416). Access restricted to members of the Tufts University community. Also available via the World Wide Web;

Thesis (Ph. D.)--University of Florida, 2001.
Title from first page of PDF file. Document formatted into pages; contains xi, 132 p.; also contains graphics. Vita. Includes bibliographical references (p. 120-130).

Thesis (Ph. D.)--Harvard-MIT Program in Health Sciences and Technology, 2012.
Cataloged from PDF version of thesis.
Includes bibliographical references (p. 109-144).
The incidence of autism spectrum disorders (ASD) has risen alarmingly in the United States, and is now thought to affect approximately 1 in 110 live births. Early diagnosis and intervention is the only treatment proven effective in cases of autism, however the behavioral tests currently available cannot make this diagnosis until at least two years of age. A lack of normal attention to faces and abnormal face processing is a cognitive deficit common to nearly all individuals with autism spectrum disorder, and this deficit is likely present from a very early age. The primary goal of this dissertation is therefore to characterize the specific neural response of face processing in infants with near-infrared spectroscopy (NIRS), and to then apply these measures to the study of abnormal face processing in infants at high risk for autism. In order to achieve these objectives, the work described herein aims to: 1) characterize the hemodynamic response to faces in normal infants at six months of age as measured by the Hitachi ETG-4000 functional Near-Infrared Spectroscopy (fNIRS) system; 2) Simultaneously measure orbitofrontal hemodynamic responses to social/emotional engagement and the response to faces in infants at high risk for autism as compared to low risk controls; and 3) Utilize a novel method of condition-related component selection and classification to identify waveforms associated with face and emotion processing in 6-7-month-old infants at high risk for ASD, and matched low-risk controls. Our results indicate similarities of response waveforms, but differences in both the spatial distribution, magnitude, and timing of oxy-hemoglobin and deoxy-hemoglobin responses between groups. Our findings represent the first identification of neuroimaging markers of a functional endophenotype at six months of age that may be associated with high risk of ASD. These results support a model of altered frontal lobe structure through evidence of altered hemodynamic response and/or functional activity in the high risk infant group, and these changes may, in turn, contribute to the development of ASD in specific individuals.
by Sharon Elizabeth Fox.
Ph.D.

Master of Science
Department of Kinesiology
Bradley J. Behnke
Given the critical role of tumor O₂ delivery on patient prognosis and the rise in preclinical exercise-oncology studies, we investigated tumor and host-tissue blood flow at rest and during exercise as well as vascular reactivity using a rat prostate cancer model grown in two transplantation sites. Methods. In male COP/CrCrl rats, blood flow (via radiolabeled microspheres) to prostate tumors (R3327-MatLyLu cells injected in the left flank (ectopic) or ventral prostate (orthotopic)) and host-tissue was measured at rest and during a bout of mild-intensity exercise. Alpha-adrenergic vasoconstriction to norepinephrine (NE: 10⁻⁹ to 10⁻⁴ M) was determined in arterioles perforating the tumors and host-tissue. To determine host-tissue exercise hyperemia in healthy tissue, a sham-operated group was included. Results. Blood flow was lower at rest and during exercise in ectopic tumors and host-tissue (subcutaneous adipose) versus the orthotopic tumor and host-tissue (prostate). During exercise, blood flow to the ectopic tumor significantly decreased by 25 ± 5%, whereas flow to the orthotopic tumor increased by 181 ± 30%. Maximal vasoconstriction to NE was not different between arterioles from either tumor location. However, there was a significantly higher peak vasoconstriction to NE in subcutaneous adipose arterioles (92 ± 7%) versus prostate arterioles (55 ± 7%). Establishment of the tumor did not alter host-tissue blood flow from either location at rest or during exercise. Conclusion. These data demonstrate blood flow in tumors is dependent on host-tissue hemodynamics and that the location of the tumor may critically affect how exercise impacts the tumor microenvironment and treatment outcomes.

Neurovascular coupling (NVC), or functional hyperemia, is a term used to describe the increases in local cerebral blood flow (CBF) seen in areas of increased neuronal activity. Serotonin (5-HT) released from afferents of the dorsal raphe nucleus (DRN) is one neuromodulator thought to induce such a functional hyperemic response. However, the mechanisms underlying this response are largely unexplored. Here, we have attempted to identify in vivo the neuronal and glial mediators involved in the increases in cortical CBF observed during stimulations of the DRN. Electrical stimulation of the DRN was found to induce an approximately 30% bilateral increase in CBF in the somatosensory cortex. Selective depletion of 5-HT nerve terminals resulted in almost complete elimination of this evoked CBF increase (PCPA, -66%, p<0.01). Similarly, cortical noradrenergic denervation also largely eliminated this response (DSP-4, -80%, p<0.01). The bilateral increase in CBF was found to be unaltered by blockade of NMDA receptors (with MK-801) and 5-HT-2A receptors (with ketanserine). However, the evoked CBF response was decreased by blockade of GABA-A receptors (picrotoxin, -45%, p<0.05), nonselective α-adrenergic receptor antagonist (phentolamine, -45%, p<0.05) and nonselective β-adrenergic receptor blocker (propranolol, -55%, p<0.05) and had a trend towards a decrease, albeit not significant, upon blockade of group I metabotropic glutamate receptors (mGluR1 and 5; MPEP+ LY LY367385). The hyperemic response was found to also be reduced after selective inhibition of the epoxygenation reactions catalyzed by specific CYP450 isozymes (MS-PPOH, -42%, p<0.05). This was the first study of its kind to clarify not only the influence of the noradrenergic system on evoked CBF increases to DRN electrical stimulation, but also to begin to characterize the cortical mediators involved in this response. These results demonstrate that the hyperemic response seen after electrical stimulation of the DRN depends heavily upon interactions between the serotonergic and the noradrenergic systems, and also largely on GABA interneurons and metabolically active astrocytes.
Neurovasculaire couplage est un terme utilisé pour décrire les augmentations du débit sanguin cérébral local (CBF) vus dans les domaines de l'activité neuronale accrue. La sérotonine (5-HT) a publié des afférences du noyau dorsal du raphé (DRN) est un neuromodulateur pensé pour induire une telle réponse fonctionnelle hyperémique. Cependant, les mécanismes sous-jacents de cette réponse sont largement inexploré. Ici, nous avons tenté d'identifier in vivo les médiateurs neuronales et gliales impliquées dans l'augmentation de la corticale CBF observées lors de stimulations de la DRN. La stimulation électrique du DRN a été trouvé pour induire une augmentation d'environ 30% bilatérale dans CBF dans le cortex somatosensoriel. Déplétion sélective des terminaisons nerveuses 5-HT a entraîné l'élimination presque complète de cette augmentation a évoqué CBF (PCPA, -66%, p<0,01). De même, la dénervation noradrénergique corticale aussi largement éliminé cette réponse (DSP-4, -80%, p<0,01). L'augmentation bilatérale dans CBF a été jugée non modifiée par le blocage des récepteurs NMDA (MK-801) et 5-HT-2A récepteurs (avec ketanserine). Cependant, la réponse évoquée CBF a été diminué par le blocage des récepteurs GABA-A (picrotoxin, -45%, p<0,05), antagoniste des récepteurs α non sélectif-adrénergique (phentolamine, -45%, p<0,05) et non sélectif des récepteurs β-adrénergiques bloqueur (propranolol, -55%, p<0,05) et a eu une tendance vers une diminution, bien que non significatif, sur le blocus du groupe I récepteurs métabotropiques du glutamate (mGluR1 et 5) (MPEP + LY LY367385). La réponse hyperémique a été trouvé également être réduit après l'inhibition sélective des réactions catalysées par epoxygenation spécifique du CYP450 isozymes (MS-PPOH, -42%, p<0,05). Cette étude était la première de son genre afin de clarifier non seulement l'influence du système noradrénergique sur les augmentations de CBF évoqués à DRN stimulation électrique, mais aussi pour tenter de caractériser le réseau cortical impliqué dans cette réponse. Ces résultats démontrent que la réponse hyperémique observée après stimulation électrique de la DRN dépend fortement des interactions entre la sérotonine et les systèmes noradrénergiques, et aussi en grande partie sur les interneurones GABA et métaboliquement actives astrocytes.

The ability to determine the brain's hemodynamic response without relying on an input function would be an extremely valuable asset in a large number of medical applications, and today, functional Magnetic Resonance Imaging (fMRI) is one of the leading methods in developing a better understanding of the human brain. Assuming the linear timeinvariant model for the observed fMRI response ([1], [2], [4]), this work provides an estimate of the hemodynamic brain response both on a regional and on an individual voxel level, as well as provides an estimate of the input signal that excited the brain's response. The solution to this problem is achieved using the Eigenvector-Based Algorithm for Multichannel Blind Deconvolution (EVAM) ([5], [6]) combined with Independent Component Analysis (ICA) [23]. The resulting estimate of the input signal produced by the proposed method could prove to be a valuable insight into the actual signal that triggered the brain during the experiment, and not the ideal signal that should have triggered it based on experimental observations. Also, contrary to previous works, no prior assumptions regarding the shape or order of the brain's response are made. When compared to non-blind identification algorithms traditionally used in the literature, the results show a significant improvement as the shape of the hemodynamic brain response conforms with current medical understandings. Furthermore, the estimated hemodynamic brain response is then used as a basis to determine active and inactive voxels. Two clustering methods, K-Means Clustering and Correlation-Based Clustering, are compared. Correlation-Based Clustering is found to be superior and is thus used to spatially map the active and inactive voxels. Spatial maps of important brain regions yield promising results where spatial sparseness is not characteristic of the images. Finally, a preliminary comparison between a healthy subject and a subject inflicted with Parkinson's disease yields promising differences, especially in the left primary cortex where very little activation was observed. Interestingly, symptoms of Parkinson's disease are thought to be a result of decreased stimulation of the motor cortex. Although no major medical conclusions can be made due to the risk of incorrectly attributing intersubject variability to differences due to Parkinson's disease, this preliminary comparison shows promising results that encourage future research in this area
Applied Science, Faculty of
Electrical and Computer Engineering, Department of
Graduate

Unwanted and distressing visual imagery is a persistent and emotionally taxing symptom characteristic of several mental illnesses, including depression, schizophrenia, and posttraumatic stress disorder. Intrusive imagery symptoms have been linked to maladaptive memory formation, abnormal visual cortical activity during viewing, gaze pattern deficits, and trait characteristics of mental imagery. Emotional valence of visual stimuli has been shown to alter perceptual processes that influence the direction of attention to visual information, which may result in enhanced attention to suboptimal and generalizable visual properties. This study tested the hypothesis that aberrant gaze patterns to central and peripheral image regions influence the formation of decontextualized visual details which may facilitate involuntary and emotionally negative mental imagery experiences following a stressful or traumatic event. Gaze patterns and hemodynamic response from occipital cortical locations were recorded while healthy participants (N = 39) viewed and imagined scenes with negative or neutral emotional valence. Self-report behavioral assessments of baseline vividness of visual imagery and various cognitive factors were combined with these physiological measures to investigate the potential relationship between visual perception and mental recreation of negative scenes. Results revealed significant effects of task and valence conditions on specific fixation measures and hemodynamic response patterns in ventral visual areas, which interacted with cognitive factors such as imagery vividness and familiarity. Findings further suggest that behaviors observed during mental imagery reveal processes related to representational formation over and above perceptual performance and may be applied to the study of disorders such as PTSD.
Ph. D.

In this thesis, we conduct functional Magnetic Resonance Imaging (fMRI) data analysis with the aim of grouping the brain voxels depending on their responsiveness to a neural task. We mathematically treat the fMRI signals as the convolution of the neural stimulus with the hemodynamic response function (HRF). We first estimate a time series including HRFs for each of the observed fMRI signals from a given set and we cluster them in order to identify the groups of brain voxels. The HRF estimation problem is studied within the Bayesian framework through a blind deconvolution algorithm using MAP approach under completely unsupervised and model-free settings, i.e, stimulus is assumed to be unknown and also no particular shape is assumed for the HRF. Only using a given fMRI signal together with a weak Gaussian prior distribution imposed on HRF favoring &lsquo
smoothness&rsquo
, our method successfully estimates all the components of our framework: the HRF, the stimulus and the noise process. Then, we propose to use a modified version of Hausdorff distance to detect similarities within the space of HRFs, spectrally transform the data using Laplacian Eigenmaps and finally cluster them through EM clustering. According to our simulations, our method proves to be robust to lag, sampling jitter, quadratic drift and AWGN (Additive White Gaussian Noise). In particular, we obtained 100% sensitivity and specificity in terms of detecting active and passive voxels in our real data experiments. To conclude with, we propose a new framework for a mathematical treatment for voxel-based fMRI data analysis and our findings show that even when the HRF is unpredictable due to variability in cognitive processes, one can still obtain very high quality activation detection through the method proposed in this thesis.

Arteries respond to changes in global mechanical parameters (pressure, flow rate, and longitudinal stretching) by remodeling to restore local parameters (circumferential stress, shear stress, and axial strain) to baseline levels. Because a change in a single global parameter results in changes of multiple local parameters, the effects of individual local parameters on remodeling remain unknown. This study uses a novel approach to study remodeling in organ culture based on independent control of local mechanical parameters. The approach is illustrated by studying the effects of circumferential and shear stress on remodeling-related biological markers. Porcine carotid arteries were cultured for three days at a circumferential stress of 50 kPa or 150 kPa or, in separate experiments, a shear stress of 0.75 Pa or 2.25 Pa. At high circumferential stress, matrix synthesis, smooth muscle cell proliferation, and cell death are significantly greater, but matrix metalloproteinase-2 (MMP-2) and pro-MMP-2 activity are significantly less. In contrast, biological markers measured were unaffected by shear stress. Applications of the proposed approach for improved understanding of remodeling, optimizing mechanical conditioning of tissue engineered arteries, and selection of experimentally motivated growth laws are discussed.

Functional Magnetic Resonance Imaging (fMRI) is one of the most popular neuroimaging methods for investigating the activity of the human brain during cognitive tasks. The main objective of the thesis is to identify this underlying brain activation over time, using fMRI signal by detecting active and passive voxels. We performed two sub goals sequentially in order to realize the main objective. First, by using simple, data-driven Fourier Wavelet Regularized Deconvolution (ForWaRD) method, we extracted hemodynamic response function (HRF) which is the information that shows either a voxel is active or passive from fMRI signal. Second, the extracted HRFs of voxels are classified as active and passive using Laplacian Eigenmaps. By this, the active and passive voxels in the brain are identified, and so are the activation areas. The ForWaRD method is directly applied to fMRI signals for the first time. The extraction method is tested on simulated and real block design fMRI signals, contaminated with noise from a time series of real MR images. The output of ForWaRD contains the HRF for each voxel. After HRF extraction, using Laplacian Eigenmaps algorithm, active and passive voxels are classified according to their HRFs. Also with this study, Laplacian Eigenmaps are used for HRF clustering for the first time. With the parameters used in this thesis, the extraction and clustering methods presented here are found to be robust to changes in signal properties. Performance analyses of the underlying methods are explained in terms of sensitivity and specificity metrics. These measurements prove the strength of our presented methods against different kinds of noises and changing signal properties.

Aims: (1) Explore the physiological effect of renal denervation (RDN) (2) Explore the efficacy of distal denervation on blood pressure (BP) reduction in patients undergoing directly observed anti-hypertensive therapy (DOT) to minimise measurement bias (3) Evaluate the 6-month safety of distal denervation Methods: Patients with resistant hypertension were recruited and underwent assessment of drug compliance by assaying urinary drug levels. All subsequent measurements were recorded under DOT. Pre-denervation, office and ambulatory BP were measured, and patients underwent bilateral renal angiography and invasive measurement of aortic and renal arterial pressure and blood flow velocity. RDN was performed using the Symplicity Spyral catheter, denervating in the main renal arteries and each distal branch >3mm diameter. Invasive and non-invasive measurements were repeated 6-months post denervation under DOT. Results: 16 patients underwent denervation (age 63±12 years) with referral office SBP 180±18 mmHg. In total each patient received 22.6±5.0 ablations, 9.3±2.9 ablations in the main trunk and 13.3±4.8 ablations distally. At 6-months follow-up, overall unblinded 24-hour SBP reduction was -5.1±7.5 mmHg (p=0.020), with DBP reduction -3.4±4.9 mmHg (p=0.018). At 6-months follow-up an overall increase in renal blood flow velocity occurred at rest (1.91±3.51cm/s, p=0.04) and under identical sedation states (1.81±3.44 cm/s, p=0.05). Patients with the largest reduction in ambulatory SBP at 6-months had the largest increase in renal blood flow acutely after RDN (R 2=0.60, p < 0.001) and the largest decrease in renal resistance (R2=0.56, p < 0.001). Quantitative vessel angiography showed no significant change in any main or distal renal artery dimensions at 6-months. Conclusion: This unblinded study of distal RDN showed a significant reduction in ambulatory systolic and diastolic BP with no safety concerns at 6-months. These exploratory results suggest that acute changes in renal hemodynamics may be predictive of blood pressure response at 6-months follow-up.

Abstract Cardiac hypertrophy is the primary adaptive mechanism of the heart to increased workload, though when advanced, it becomes a leading predictor for heart failure and sudden death. The growth stimulus elicited by a hemodynamic load is attributable to a combination of mechanical and neurohumoral factors, but the precise roles of individual growth promoting components are still unclear. This study utilized atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) as model genes with which to investigate the involvement and mechanisms of mechanical stress and peptide growth factors in hypertrophic response of cardiac myocytes. The direct effect of mechanical stretch was studied in two different in vitro models of cultured neonatal rat cardiomyocytes. In the first approach, hypo-osmotic swelling -induced stretch increased ANP mRNA levels in atrial cells. In the second model, cyclic mechanical stretch of ventricular cells grown on flexible membranes evoked ANP and BNP gene expression and secretion. The mechanisms of stretch-induced BNP gene expression were studied by measurement of the activities of transcription factors and by utilizing promoter analysis together with site specific mutations. Stretch activated the binding of the transcription factor GATA-4 similarly to pressure overload in vivo. Mutational studies revealed that specific GATA consensus sites on the BNP promoter, in combination with an Nkx-2.5 binding element, were critical for stretch-activated BNP transcription. Importantly, a reduction of GATA-4 protein levels inhibited the stretch-induced hypertrophic response. Both cyclic mechanical stretchin vitro and hemodynamic overload in vivo activated the expression of peptide growth factor bone morphogenetic protein-2 (BMP-2). The effects of BMP-2 closely resembled those of mechanical stretch including the increase in the expressions of ANP and BNP. Furthermore, the BMP antagonist noggin inhibited the effect of stretch on ANP and BNP. Fibroblast growth factor 1 stimulated ANP synthesis and secretion in a protein kinase C dependent manner. In conclusion, this work demonstrates that mechanical stretch per se is sufficient to activate the hypertrophic gene program in cardiac myocytes. This effect seems to be at least partially mediated by the growth factor BMP-2 acting in a paracrine manner. The activation of the GATA-4 transcription factor, in cooperation with a factor binding to the Nkx-2.5 binding element, is essential for mechanical stretch-induced cardiomyocyte hypertrophy
Tiivistelmä Sydämen tärkein mukautumiskeino kohonneeseen työmäärään on sydänlihaksen kasvu. Sydänlihaksen liikakasvu on kuitenkin tärkein sydämen vajaatoiminnan ja äkkikuoleman ennustetekijä. Hemodynaamisen ylikuormituksen kasvua edistävä vaikutus on lukuisten mekaanisten ja neurohumoraalisten tekijöiden summa, jossa kunkin yksittäisen tekijän osuus on vielä epäselvä. Tässä väitöskirjatyössä tutkittiin mekaanisen venytyksen ja peptidikasvutekijöiden osuutta ja vaikutusmekanismeja sydämen liikakasvun synnyssä käyttämällä malligeeneinä sydämen eteispeptidiä (ANP) ja B-tyypin natriureettista peptidiä (BNP). Mekaanisen venytyksen välitöntä vaikutusta tutkittiin vastasyntyneen rotan sydänsoluviljelymalleissa. Osmolaliteetin muutoksella aiheutettu venytys lisäsi ANP:n lähetti-RNA-tasoja eteissoluissa. Venyväpohjaisilla kalvoilla kasvatettujen kammiosolujen syklinen venytys stimuloi ANP:n ja BNP:n geeniekspressiota ja eritystä. BNP:n geenisäätelymekanismeja tutkittiin mittaamalla transkriptiotekijöiden aktiivisuutta sekä geeninsiirtokokeilla hyödyntäen muunneltuja BNP:n geenisäätelyalueita. Venytys lisäsi transkriptiotekijä GATA-4:n sitoutumisaktiivisuutta samaan tapaan kuin painekuormitus koe-eläimillä. Tietyt BNP:n säätelyalueen GATA-sitoutumispaikat yhdessä Nkx-2.5:ttä sitovan elementin kanssa osoittautuivat tärkeiksi venytysvasteen kannalta. GATA-4 -proteiinitasojen vähentäminen esti venytyksen aiheuttamaa kasvuvastetta. Sekä syklinen mekaaninen venytys soluviljelykokeissa että hemodynaaminen ylikuormitus koe-eläimillä lisäsivät peptidikasvutekijä bone morphogenetic protein-2:n (BMP-2) geeniekspressiota. BMP-2:n suorat vaikutukset puolestaan muistuttivat läheisesti mekaanisen venytyksen vaikutusta, ANP:n ja BNP:n lisääntynyt geeniekspressio mukaan lukien. BMP-antagonisti noggin esti lisäksi venytyksen vaikutusta ANP:iin ja BNP:iin. Työssä osoitettiin myös, että fibroblastikasvutekijä 1 stimuloi ANP:n synteesiä ja eritystä proteiinikinaasi C:n välityksellä. Yhteenvetona tulokset osoittavat, että mekaaninen venytys itsessään riittää aktivoimaan sydänlihaksen kasvuun liittyvää geeniohjelmaa. Vasteen välittäjänä näyttää kuitenkin ainakin osittain toimivan paikallisesti tuotettu BMP-2. Edelleen, transkriptiotekijä GATA-4 yhdessä Nkx-2.5 -elementtiin sitoutuvan tekijän kanssa osoittautui välttämättömäksi mekaanisen venytyksen aiheuttamalle kasvuvasteelle

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Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Introdução: A promoção da prática regular de exercícios físicos é uma das principais metas globais de inúmeras sociedades médicas para prevenção e controle de doenças crônicas não transmissíveis, sendo uma das principais terapêuticas para o paciente com hipertensão arterial sistêmica. O exercício físico em piscina aquecida tem surgido como uma potencial alternativa ao exercício físico em solo para a redução da pressão arterial (PA) de pacientes hipertensos. Entretanto, seus efeitos agudos sobre a PA ambulatorial, bem como sobre variáveis hemodinâmicas envolvidas no controle da PA de idosos hipertensos não têm sido investigados. Objetivo: Avaliar os efeitos agudos de uma sessão de exercício físico em piscina aquecida (EPA) versus exercício físico em solo (ES) sobre a PA, rigidez arterial, função endotelial e variabilidade da frequência cardíaca em idosos hipertensos. Metodologia: 15 idosos hipertensos (idade superior a 60 anos) de ambos os sexos, sedentários e em tratamento farmacológico anti-hipertensivo, foram submetidos a uma sessão de EPA, ES e controle sem exercício (CON) em ordem randomizada (2 a 5 dias de intervalo entre as intervenções) e tiveram a PA, rigidez arterial, função endotelial e variabilidade da frequência cardíaca analisadas antes, imediatamente após e 45 minutos após cada intervenção, enquanto que a PA ambulatorial foi analisada durante 24 horas após cada intervenção. As sessões de EPA e ES consistiram de 30 min de exercícios aeróbios com intensidade entre relativamente fácil e ligeiramente cansativo na escala de percepção subjetiva de esforço de Borg, enquanto que a sessão CON consistiu de 30 min de repouso na posição sentada. Resultados: Houve redução da PA (9,9 ± 3,1 mmHg; P < 0,01) 45 min após EPA, mas não após ES e CON, quando comparado aos valores pré-intervenção. A análise da PA ambulatorial demonstrou que apenas a sessão de EPA reduziu (P < 0.05) a PA sistólica 24-h (EPA: 118 ± 3,0 mmHg; ES: 123 ± 3,3 mmHg; CON: 123 ± 3,7 mmHg), de vigília (EPA: 120 ± 3,1 mmHg; ES: 124 ± 3,2 mmHg; CON: 125 ± 3,5 mmHg) e sono (EPA: 114 ± 3,1 mmHg; ES: 120 ± 3,9 mmHg; CON:119 ± 4,3 mmHg), bem como a PA diastólica 24-h (EPA: 72 ± 2,4 mmHg; ES:75 ± 2,9 mmHg; CON: 74 ± 2,9 mmHg) e de vigília (EPA: 74 ± 2,9 mmHg; ES: 77 ± 3,0 mmHg; CON 76 ± 2,9 mmHg), enquanto que a PA diastólica de sono não reduziu após ambas as sessões de exercício. A magnitude de redução da PA após EPA em comparação a sessão CON variou de 4,5 ± 1,3 mmHg (PA diastólica 24-h) à 9,5 ± 3,0 mmHg (PA sistólica de sono), e perdurou de maneira significativa até a 17a hora pós-intervenção, para a PA sistólica e até a 10a hora pós-intervenção, para a PA diastólica. Não houve alteração significativa VOP carótido-femoral, função endotelial e VFC durante as intervenções, bem como entre as intervenções. Conclusão: Apenas a sessão de EPA foi efetiva para reduzir a PA de repouso e ambulatorial, sugerindo que o exercício físico em piscina aquecida pode ter importantes implicações para controle da PA de idosos hipertensos em tratamento farmacológico.
Background: Physical exercise promotion is one of the main global goals of innumerous health and medical societies for preventing and managing non communicable chronic diseases, being one of the main therapeutic for the patient with hypertension. Exercise in heated swimming pool has emerged as a potential alternative to physical exercise on the ground for the reduction of blood pressure (BP) of hypertensive patients, however, its effects on BP and about hemodynamic variables of hypertensive elderly patients have not been investigated. Purpose: Evaluate the acute effects of physical exercise in a heated pool (Hex) versus in land-based (Lb) on pressure, arterial stiffness, endothelial function, and heart rate variability in older hypertensive adults. Methods: 15 hypertensive elderly ( older than 60 years) of both sexes, sedentary and in antihypertensive drug treatment were submitted to a session of Hex, Lb and control without exercise (CON) in random order (2 to 5 days the interval between interventions) and had BP, arterial stiffness, endothelial function and heart rate variability were analyzed before, immediately after and 45 minutes after each intervention, whereas outpatient PA was analyzed for 24 hours after each intervention. The sessions of Hex and Lb consisted of 30 minutes of aerobic exercise with intensity between relatively easy and slightly tiring on the scale of subjective perception of Borg effort, while the CON session consisted of 30 minutes of rest in the sitting position. Results: There was a reduction in BP (9,9 ± 3,1 mmHg; P< 0,01) 45 min after Hex, but not after Lb and CON, when compared to pre-intervention values. Outpatient BP analysis showed that only the Hex session reduced (P < 0.05) systolic BP 24 h (Hex: 118 ± 3,0 mmHg; Lb: 123 ± 3,3 mmHg; CON: 123 ± 3,7 mmHg), daytime systolic (Hex: 120 ± 3,1 mmHg; Lb: 124 ± 3,2 mmHg; CON: 125 ± 3,5 mmHg) and nighttime systolic (Hex: 114 ± 3,1 mmHg; Lb: 120 ± 3,9 mmHg; CON:119 ± 4,3 mmHg), as well as 24-h diastolic BP (Hex: 72 ± 2,4 mmHg; Lb:75 ± 2,9 mmHg; CON: 74 ± 2,9 mmHg) and daytime systolic (Hex: 74 ± 2,9 mmHg; Lb: 77 ± 3,0 mmHg; CON 76 ± 2,9 mmHg), while nighttime diastolic BP did not decrease after both exercise sessions. The magnitude of BP reduction after EPA compared to the CON session ranged from 4.5 ± 1.3 mmHg (24-h diastolic BP ) to 9.5 ± 3.0 mmHg (nighttime systolic BP), and persisted significant difference up to the 17th postoperative hour for systolic BP and up to the 10th postoperative hour for diastolic BP. There was no significant change in carotid-femoral VOP, endothelial function and HRV during interventions, as well as between interventions. Conclusion: Only the Hex session was effective in reducing BP at rest and in the outpatient setting, suggesting that physical exercise in a heated pool may have important implications for BP control of elderly hypertensive patients undergoing pharmacological treatment.
2015/09259-2

[Truncated abstract] A reduction in the force-generating capacity of a muscle is the primary indicator of fatigue and the majority of this force loss is the result of peripheral fatigue. However, there is also evidence that the central nervous system (CNS) does not drive muscles maximally during fatiguing exercise, which has led to the concept of central fatigue. The strongest evidence for this comes from interpolated twitch studies showing that transcranial magnetic stimulation (TMS) during a maximal voluntary contraction can produce an increment in force which becomes greater as fatigue develops. In addition, the silent period (SP) duration increases during a fatiguing exercise, suggesting that there is a buildup of intracortical inhibition that might limit central motor drive. In contrast, motor evoked potential (MEP) amplitude increases during fatigue suggesting an increase in corticomotor excitability during exercise . . . The primary finding was a progressive increase in the fMRI signal during exercise, with a reduction following exercise, and signal changes were observed in all regions. These studies provide evidence that central adaptive processes occur during muscle fatigue and highlight the potential to facilitate these processes with interventional paradigms. The findings indicate the extent of cortical changes during fatigue and suggest that there may also be neurohaemodynamic and/or metabolic components to central adaptive processes. Understanding the central response to muscle fatigue should incorporate mechanisms both of central adaptation and central fatigue.

Functional Magnetic Resonance Imaging (fMRI) is one of the best techniques for neuroimaging and has revolutionized the way to understand the brain functions. It measures the changes in the blood oxygen level-dependent (BOLD) signal which is related to the neuronal activity. Complexity of the data, presence of different types of noises and the massive amount of data makes the fMRI data analysis a challenging one. It demands efficient signal processing and statistical analysis methods.  The inference of the analysis is used by the physicians, neurologists and researchers for better understanding of the brain functions.      The purpose of this study is to design a toolbox for fMRI data analysis. It includes methods to detect the brain activity maps, estimation of the hemodynamic response (HDR) and the connectivity of the brain structures. This toolbox provides methods for detection of activated brain regions measured with Bayesian estimator. Results are compared with the conventional methods such as t-test, ordinary least squares (OLS) and weighted least squares (WLS). Brain activation and HDR are estimated with linear adaptive model and nonlinear method based on radial basis function (RBF) neural network. Nonlinear autoregressive with exogenous inputs (NARX) neural network is developed to model the dynamics of the fMRI data.  This toolbox also provides methods to brain connectivity such as functional connectivity and effective connectivity.  These methods are examined on simulated and real fMRI datasets.

Orientador: José Eduardo Tanus dos Santos
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: Evidências clínicas e experimentais indicam o envolvimento de metaloproteinases da matriz extracelular (MMPs) na patogênese de diversas doenças, incluindo as doenças cardiovasculares. Particularmente, alterações na atividade da MMP-2 parecem desempenhar um importante papel na hipertensão, na insuficiência cardíaca e em outras alterações do sistema cardiovascular. Diversos estudos mostram vários alvos não relacionados à matriz extracelular para a MMP-2, incluindo proteínas intracelulares e mediadores vasoativos. Adicionalmente, diversos trabalhos indicam o envolvimento desta enzima na clivagem proteolítica de receptores ?1- e ?2-adrenérgicos. Embora alguns estudos tenham sugerido que a MMP-2 possa afetar o tônus vascular e prejudicar a função dos ?-adrenoreceptores, nenhum estudo prévio examinou os efeitos hemodinâmicos agudos desta enzima. Nós verificamos os efeitos da MMP-2 recombinante humana (rhMMP-2), administrada por via intravenosa (i.v.), a carneiros anestesiados sob condições basais e durante estimulação ?-adrenérgica com dobutamina. Vinte e seis carneiros machos anestesiados foram utilizados em dois protocolos experimentais. Primeiramente, rhMMP-2 (220 ng.kg-1.min-1 durante 60 min) ou salina foi infundida e nenhuma alteração hemodinâmica foi encontrada. No segundo protocolo, infundiu-se dobutamina (5 ?g.kg-1.min-1, i.v., durante 180 min) ou salina em carneiros que haviam recebido a mesma infusão descrita acima de rhMMP-2 ou salina precedida pelo tratamento com doxiciclina (10 mg.kg-1, i.v., durante 15 min) ou salina. Os níveis plasmáticos e cardíacos de MMP-2 foram avaliados por zimografia e a atividade gelatinolítica foi analisada por espectrofluorimetria. Nós observamos que, enquanto a infusão de rhMMP-2 não aumentou os níveis plasmáticos e cardíacos de MMP-2, produziu um aumento na atividade gelatinolítica do coração, e a doxiciclina preveniu este efeito. A dobutamina reduziu o índice de resistência vascular sistêmico (IRVS) e aumentou o índice cardíaco (IC) e a dP/dtmax no ventrículo esquerdo. Entretanto, a co-infusão de rhMMP-2 e dobutamina foi associada com uma menor redução no IRVS e com menores aumentos no IC e na dP/dtmax induzidos pela dobutamina. O pré-tratamento com doxiciclina impediu estas alterações induzidas pela rhMMP-2 na resposta à dobutamina. Adicionalmente, verificou-se que a rhMMP-2 reduziu a formação de AMP cíclico em cardiomiócitos e que os inibidores de MMPs doxiciclina e ONO-4817 impediram esta redução. Nossos resultados mostram que a rhMMP-2, sob condições basais, não exerce efeitos hemodinâmicos em carneiros. Entretanto, a rhMMP-2, sob estimulação cardíaca, prejudica a resposta cardiovascular induzida pela ativação de receptores ?-adrenérgicos
Abstract: Experimental and clinical evidence indicate the involvement of matrix metalloproteinases (MMPs) in the pathogenesis of many disease conditions, including cardiovascular diseases. Particularly, imbalanced MMP-2 activity apparently plays a critical role in hypertension, heart failure and in other alterations of the cardiovascular system. Various studies show many targets unrelated to the extracellular matrix for MMP-2, including intracellular proteins and vasoactive mediators. Additionally, recent studies indicate the involvement of this enzyme in proteolytic cleavage of 'beta'1- and 'beta'2-adrenoreceptors. Although some studies have suggested that MMP-2 may affect the vascular tone and impair 'beta'-adrenoreceptor function, no previous study has examined the acute hemodynamic effects of this enzyme. We examined the effects of recombinant human MMP-2 (rhMMP-2) administered intravenously (i.v.) to anesthetized lambs at baseline conditions and during ?-adrenergic stimulation with dobutamine. Twenty-six anesthetized male lambs were used in two study protocols. Firstly, rhMMP-2 (220 ng.kg-1.min-1 over 60 min) or vehicle was infused and no significant hemodynamic changes were found. In the second protocol, we infused dobutamine (5 ug.kg-1.min-1, i.v., over 180 min) or saline in lambs that had received the same rhMMP-2 infusion preceded by treatment with doxycycline (10 mg.kg-1, i.v., during 15 min) or saline. Plasma and cardiac MMP-2 levels were assessed by gelatin zymography and gelatinolytic activity was assessed by spectrofluorimetry. We found that, while the infusion of rhMMP-2 did not increase plasma and cardiac MMP-2 levels, it increased cardiac gelatinolytic activity, and doxycycline blunted this effect. Dobutamine decreased systemic vascular resistance index (SVRI) and increased the cardiac index (CI) and left ventricular dP/dtmax. However, co-infusion of rhMMP-2 and dobutamine was associated with lower dobutamine-induced decrease in SVRI and with lower dobutamine-induced increase in CI and dP/dtmax. Pre-treatment with doxyxycline blunted rhMMP-2-induced changes in dobutamine responses. Additionally, we found that rhMMP-2 decreased cyclic AMP levels in cardiomyocytes and that tne inhibitors of MMPs doxyxycline and ONO-4817 prevented this reduction. Our findings show that rhMMP-2, at baseline conditions, exerts no major hemodynamic effects in lambs. However, rhMMP-2, during cardiac stimulation, impairs the responses elicited by activation of 'beta'-adrenoreceptors
Doutorado
Farmacologia
Doutora em Farmacologia

Le cadre neuroconstructiviste du développement cognitif, en considérant la variabilité des contraintes qui agissent dès la conception et façonnent le développement, apparaît pertinent pour considérer l’influence des expériences sensorielles précoces sur le développement neurocomportemental des nouveau-nés prématurés. Ils évoluent dans un environnement particulier et ont une vulnérabilité aux troubles neurodéveloppementaux, auxquels des atypies du traitement tactile et temporel sont associées. L’objectif de ce travail de thèse est d’étudier les compétences tactiles et temporelles des nouveaux nés prématurés, et d’évaluer l’effet de l’environnement précoce sur ces perceptions. La perception tactile passive et la cognition ont été étudié auprès de 61 nouveau-nés prématurés (nés entre 32 et 34SA) à 35 semaines d’âge corrigé. Les réponses d’orientation manuelle lors de stimulations tactiles passives du membre supérieur ont été mesurées lors d'un paradigme d’habituation et de déshabituation (changement de localisation ou pause dans la séquence de stimulation). Les prématurés montrent une réponse d'orientation manuelle aux stimuli, qui diminue lors de la répétition, indépendamment de son emplacement sur le bras. L'habituation est retardée chez les sujets nés le plus tôt, à un petit poids et ayant vécu davantage d’expériences douloureuses. Enfin, les prématurés perçoivent les changements de localisation du stimulus et l'intervalle interstimulus, ce qui suggère un développement prénatal des capacités de traitement temporel. Ces capacités de traitement temporel et leur utilisation pour générer une prédiction sensorielle ont été évaluées au cours d’une seconde étude. 19 nouveau-nés prématurés (nés entre 31 et 32 SA) ont été soumis à une séquence tactile (régulière ou irrégulière) aux âges corrigés de 33 et 35 SA. Les variations de flux sanguin cérébral été mesurées. Aux deux âges corrigés, les stimuli tactiles sont associés à une réponse hémodynamique au sein du cortex somatosensoriel. À 33 semaines d’âge gestationnel corrigé les omissions dans la séquence sont associées à une augmentation du flux sanguin cérébral, qui indique que les prématurés forment des prédictions sensorielles, indépendamment du groupe expérimental. Ce travail de thèse permet de mieux caractériser les capacités de traitement tactile et temporel des nouveau-nés prématurés, qui manquent d’investigations récentes et approfondies. De plus, il apporte des arguments rationnels qui pourraient permettre de proposer des thérapies sensorielles à ces patients, basées sur leurs capacités de perception
The neuroconstructivist theoretical framework of cognitive development, taking into account the variability of the constraints that act from the conception to shape development, is relevant to consider the early influence of sensory experiences on the neurobehavioral development of preterm neonates. They evolve in a particular environment and are vulnerable to neurodevelopmental disorders, to which atypical tactile and temporal processing are associated. The aim of the thesis is to study tactile and temporal abilities in preterm newborns and to evaluate the effect of the early environment on these perceptions. We included 61 preterm neonates (born between 32 and 34 weeks of gestational age (wGA)). At 35 weeks of corrected gestational age, we measured orienting responses (forearm, hand, and fingers movements) during vibrotactile stimulation of their hand and forearm, during a habituation and dishabituation paradigm, the dishabituation being either a location change or a pause in the stimulation sequence. Preterm newborns displayed a manual orienting response to vibrotactile stimuli which significantly decreased when the stimulus was repeated, regardless of the stimulated location on the limb. Habituation was delayed in subjects born at a younger gestational age, smaller birth weight, and having experienced more painful care procedures. Preterm neonates perceived changes in stimulus location and interstimulus time interval, suggesting a prenatal development of temporal processing capacities. These temporal processing abilities and their use to generate sensory prediction are being evaluated in a second study. 19 premature neonates (born between 31 and 32wGA) were presented with a tactile sequence (regular or irregular) at 33 and 35 weeks of corrected GA. Variations in cerebral blood flow were measured. At both corrected GA, tactile stimuli are associated with a hemodynamic response in the primary somatosensory cortex. At 33 weeks of corrected GA, omissions in the sequence are associated with an increase in cerebral blood flow, which indicates that premature neonates form sensory predictions, regardless of their experimental group. This thesis work allows to better characterize the tactile and temporal processing abilities in premature neonates, which lack recent and thorough investigation. In addition, it provides rational arguments that could help to propose sensory therapies to these patients, based on their perceptual abilities