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Hypoxia (decreased tissue oxygen levels) has long been considered as a possible mechanism of alcohol-induced developmental deficits, yet research has not conclusively disproved this hypothesis, nor has it provided substantial evidence for a mechanism of developmental alcohol insults involving hypoxia. Previous research has shown that moderate acute doses of alcohol does not induce hypoxemia (decreased arterial oxygen levels), yet these same studies have shown that this same alcohol exposure does transiently decrease cerebral blood flow (CBF). This is significant because although developmental alcohol exposure did not result in hypoxemia, the decreases in CBF seen in these previous studies may induce hypoxia within the brain. Unfortunately, these experiments were only performed after acute doses of alcohol, so it is unknown if a more chronic or repeated alcohol exposure paradigm would have similar effects. The present study examined blood flow in the sheep fetus after repeated alcohol exposure in a bingelike paradigm throughout the third trimester. Additionally, this study examined the fetal neurovascular response to a subsequent infusion of alcohol after the repeated alcohol exposure. This latter experiment was designed to examine the hypothesis that alcohol exposure throughout the third trimester affects the normal responsiveness of the neurovasculature to alcohol (compared to previous research demonstrating acute alcohol-induced decreases in CBF). The results from the present experiments indicate that although few regions were significant, the majority of the regions (especially the brain regions) exhibited a trend for increases in blood flows after alcohol exposure. This phenomenon was especially prominent in the group receiving the lower dose of alcohol. Additionally, the data from this study demonstrated that after repeated alcohol exposures the near-term sheep fetus did not respond to a subsequent dose of alcohol in a similar manner seen in previous experiments when the acute alcohol exposure was administered in alcohol naïve animals. After the final alcohol exposure the subjects in this study had either no effect in terms of blood flow or an increase in CBF. This is opposite to previous observations which demonstrated reduced blood flow in numerous brain regions. The present experiments suggest that alcohol does not induce fetal hypoxia, but does negatively affect the normal neurovascular response to alcohol. This latter phenomenon could have negative consequences on future development of the brain.

With the aging population on the rise, the prevalence of heart failure is expected to increase in the coming years. Heart failure is independently correlated with cognitive decline and has a negative impact on quality of life, morbidity and mortality. Reduced cardiac output (Q) and cerebral blood flow (CBF) are proposed mechanistic links between heart failure and cognitive decline; however, reports are limited to the supine position and the response to an everyday upright posture is unknown. The purpose of this thesis was to primarily investigate the CBF response to a common upright seated position encountered in daily life in heart failure patients compared to healthy age- and sex-matched controls. Furthermore, we sought to determine whether cognitive performance or cognitive-activated hemodynamics were posture-dependent in the heart failure group. The secondary objective of this thesis was to be inclusive to patients that represent those encountered in clinical practice???specifically to include patients with higher left ventricular ejection fractions (LVEF) and atrial fibrillation with co-existing heart failure. Our findings confirmed greater cognitive impairments and a low supine CBF and Q in heart failure compared to controls and importantly, for the first time, a greater reduction in CBF with an upright seated position compared to healthy age- and sex- matched controls. When a cognitive task was performed supine and seated, performance outcomes were independent of posture in heart failure patients. However, mean flow velocity through the middle cerebral artery (MFV_MCA) increased less in response to the cognitive task seated. With regard to our secondary objectives, the results suggest that those with higher LVEF are equally at risk for cognitive decline and cerebral hypoperfusion due to a low Q. Furthermore, high variability in Q and MFV_MCA were detected in association with the beat-to-beat variation inherent to atrial fibrillation and suggest that this may be an underappreciated pathway to cognitive impairments in this sub-group. Together, these results suggest that upright cerebral hypoperfusion throughout the day may contribute to cognitive decline in heart failure and create a basis for further work to be done with larger sample sizes. Moreover, cerebral hypoperfusion with higher LVEF and the blood flow variation in atrial fibrillation represent important pathways contributing to cognitive decline in these under investigated sub-groups.

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Little is known of the temporal cerebral blood flow response to a chemical stimulus consisting of increased PCO2 measured over time. Currently, there is only one study suggesting multiple phases in the CBF-CO2 response. Time constants of middle cerebral artery blood velocity (MCAV) response to a change in PETCO2 have been reported to be between 3 and 99.4 s. We studied the MCAV response in 28 subjects (10 females) to a sustained +10 mmHg above baseline (10 min) acute increase of PETCO2. We found that there were three distinct MCAV response patterns among subjects. Additionally, the responses of males and females differed. These studies suggest that there are multiple overlapping mechanisms controlling the chemoresponse of cerebral blood vessels and that these mechanisms may differ between men and women.