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The ability to exercise for more than a short period requires energy to be supplied by using oxygen (aerobic energy supply). How quickly we can supply energy depends on how much oxygen we can deliver to muscles. Similarly, delivery of oxygen (O2 del) to the brain is important as brief, transient disruptions can cause nausea or fainting. Therefore, regulation of O2 del so that the O2 supply matches the metabolic requirement (O2 del matching metabolic demand) is essential to exercise tolerance and brain function. O2 del to the brain is often researched in response to orthostatic stress, however little is known about vascular responses protecting O2 del. In muscle, use of a forearm exercise model is common as measuring O2 del is difficult in other exercise modalities. Unfortunately, it is also difficult to measure/test metabolism in the forearm. Hence, measuring O2 del response to exercise at a known metabolic intensity is difficult. Purpose: To investigate O2 del matching metabolic demand in the following manner: 1) develop a repeatable and reliable critical power (CP, highest sustainable rate of aerobic metabolism) test for the forearm exercise model 2) discover if individual differences in O2 del account for differences in forearm CP (fCP) 3) determine if fCP is sensitive to changes in O2 del 4) characterize cerebral vascular response to an orthostatic challenge Methods: Echo and Doppler ultrasound measured blood flow through the brachial artery. Venous blood samples were used to measure hemoglobin and O2 content for calculations of O2 del and consumption. Middle cerebral blood velocity measured via transcranial Doppler ultrasound. Blood pressure was measured using finger photoplethysmography. Results: 1) fCP can be accurately estimated from a maximal effort handgripping test 2) Inter-individual differences in O2 del account for most of the variance in fCP 3) fCP is sensitive to changes in O2 del 4) cerebral vascular responses blunt cerebral hypoperfusion in response to initial orthostatic hypotension. Conclusions: CP is an exercise characteristic of aerobic metabolism which is dependent on and sensitive to O2 del. Therefore, fCP can be used in the forearm exercise model to research O2 del-metabolism matching. / Thesis (Ph.D, Kinesiology & Health Studies) -- Queen's University, 2013-01-04 15:04:44.391

Introduction Retinal vascular reactivity is impaired in patients with diabetes and is thought to be involved in the onset and progression of diabetic retinopathy (DR). Previous studies that have utilized hyperoxia to assess retinal vascular reactivity have been limited due to confounding factors associated with the administration of oxygen and have used a variety of different instruments to measure retinal blood flow. The influence of blood glucose at the time of blood flow assessment has also not been systemically investigated. The specific aims of each Chapter are as follows: Chapter 3: To compare three systems used to administer hyperoxia to human subjects. Chapter 4: To quantify the magnitude and timeline of change of retinal hemodynamic parameters induced by an isocapnic hyperoxic stimulus. Chapters 5, 6 and 7: To quantify the magnitude of change of retinal hemodynamic parameters induced by hyperoxia, hyperglycemia and combined hyperoxia / hyperglycemia, respectively, in groups of diabetic patients with no clinically visible, and mild-to-moderate, DR and in age-matched subjects without diabetes. Methods Chapter 3: Subjects breathed air followed by oxygen, or oxygen plus carbon dioxide using a non-rebreathing system, or air followed by oxygen using a sequential rebreathing system. The magnitude of change and variability of CO2 concentrations was compared between systems. Chapter 4: Baseline retinal blood flow data was acquired while the subjects breathed air using a sequential rebreathing system. An isocapnic hyperoxic stimulus was initiated and maintained for 20 minutes. Air was then re-administered for 10 minutes. Retinal blood flow measurements were acquired every minute over the course of the study. The magnitude of change of each hemodynamic parameter was determined by fitting individual data with a sigmoidal function. For Chapter 5, 6 and 7 diabetic patients with no clinically visible, and mild-to-moderate, DR were stratified into groups based upon their retinopathy status. Age-matched non-diabetic subjects were recruited as controls. Baseline retinal blood flow data was acquired while subjects breathed air. Retinal blood flow measurements were then acquired after exposure to (a) hyperoxia, (b) hyperglycemia and (c) combined hyperoxic / hyperglycemic stimuli. Change in hemodynamic parameters was compared between groups and correlated with objective measures of retinal edema. Results Chapter 3: The difference in group mean end-tidal CO2 levels between baseline and hyperoxia was significant for oxygen administration using a non-rebreathing system. The sequential rebreathing technique resulted in a significantly lower variability of individual CO2 levels than either of the other techniques. Chapter 4: An ~11% decrease of diameter, ~36% decrease of velocity and ~48% decrease of blood flow was observed in response to isocapnic hyperoxia in young, healthy subjects. A response time of 2.30??0.53 minutes and 2.62??0.54 minutes was observed for diameter and velocity, respectively. Chapter 5: Retinal blood velocity, flow, and WSR significantly decreased in response to isocapnic hyperoxia in all groups. The magnitude of the reduction of blood flow was significantly reduced with increasing severity of retinopathy. There was a significant relationship between baseline objective edema index values and retinal vascular reactivity. Chapter 6: A significant change in blood glucose level was observed for all groups. No significant change in any hemodynamic parameter was found in patients with diabetes and in age-matched subjects without diabetes. Chapter 7: Retinal blood velocity and flow significantly decreased in all groups in response to combined hyperoxic / hyperglycemic provocation. The vascular reactivity response was not significantly different across the groups. Conclusions Chapter 3: Control of CO2 is necessary to attain standardized, reproducible hyperoxic stimuli for the assessment of retinal vascular reactivity. Chapter 4: Arteriolar retinal vascular reactivity to isocapnic hyperoxic provocation occurs within a maximum of 4 minutes. Although there was a trend for diameter to respond before velocity, the response characteristics were not significantly different between diameter and velocity. Different response characteristics of the retinal vasculature to transmural pressure mediated autoregulation as opposed to metabolic mediated vascular reactivity are suggested. Chapter 5: The vascular reactivity response in terms of the reduction of blood flow relative to baseline was significant in all groups but the magnitude of the change in flow was significantly reduced with increasing severity of retinopathy. A loss of retinal vascular reactivity is indicated in patients with moderate DR without clinically evident diabetic macular edema (DME), and in patients with DME. Chapter 6: Unaltered retinal arteriolar blood flow was found 1 hour after glucose ingestion in patients with diabetes and in age-matched subjects without diabetes. These results do not support the theory that retinal blood flow is affected by an acute increase of blood glucose in diabetic patients and in subjects without diabetes. Chapter 7: The vascular reactivity response to a combined hyperoxic / hyperglycemic provocation produced a pronounced reduction in blood flow. Unlike the response to hyperoxia alone, the vascular reactivity response was not significantly different across the groups. This suggests that hyperglycemia may influence the retinal vascular reactivity response to hyperoxia.

The phase-encoded method of NMR flow imaging is examined in detail. The motion of isochromatic groups in the direction of suitably balanced magnetic field gradients will give a phase change in the NMR signal directly proportional to the velocity, acceleration, or higher derivative of position, dependent upon the form of the field gradient. If a simple bipolar pulse is used then the phase change, for isochromats moving with constant velocity, will be proportional to the velocity. If two such pulses are placed back to back then the phase change is proportional to the acceleration. The motion of isochromats in the magnetic field gradients used for imaging will also cause phase changes. These effects are considered, and simple methods of reducing them presented. Phase errors due to main field inhomogeneity are shown to be eliminated by a simple phase difference technique. In this two image data sets having different flow sensitivities are obtained, and the phase difference between them calculated. Velocity images were obtained using this technique, both by the manipulation of the frequency-encoding and selection gradients, and by the insertion of bipolar pulses in the imaging sequence. Acceleration images were also produced by adding double bipolar pulses to the imaging sequence. Both spin-echo and field-echo sequences were used. Field-echo sequences were shown to be superior for high velocities, particularly when the direction of flow is through the slice, otherwise spin-echo sequences were preferred. The Fourier imaging of velocity is also examined, and images presented. This technique is only considered to be useful for projective imaging, where it is shown to have an SNR advantage over established methods. Using two specially designed phantoms the accuracy of all these techniques is shown to be within 5%.

Hypothermia has been shown to provide protective benefits to the brain after head trauma. Current treatment methods employ full body hypothermia which can lead to further associated complications, such as a compromised immune system. Alternatively, cooling the brain individually can provide the same benefits whilst minimising the risks associated. Unfortunately, the feasibility of this is still uncertain due to the invasiveness of measuring cerebral temperatures directly and the unavailability of brain temperature maps. Mathematical modelling provides an important alternative avenue for predicting the outcome of hypothermic procedures, such as scalp cooling. However, these tend to rely on Pennes Bioheat Equation which simplifies the blood flow within the system as a single perfusion term. This removes any directional thermal advection which could play an important part in biological heat transfer. In this thesis, an alternative method is developed, tested, and proposed where the full cerebral circulatory system is modelled using vascular channels embedded in a porous tissue simulating the blood vessels and capillaries, respectively. This is dubbed the vascular porous (VaPor) method. This dissertation tests and discusses the feasibility of inducing hypothermia by cooling the scalp using the VaPor model. Initially, the blood vessels were modelled in 3D to fully capture the effects of flow, however, this was deemed computationally inefficient and difficult to manipulate so was subsequently replaced with a system of 1-Dimensional line segments. Temperatures produced from this method conform to expected ranges of values and agree with available data from studies in rat brains. It was observed that core brain temperatures can be impacted by scalp cooling but only with a large number of generated vessels. This is due to the tortuous nature of the vasculature which is not captured by the porous media alone. Various input parameters are also tested to ensure the validity of results from this model. One tested parameter that did not agree with in-vivo results was the measurement of tissue perfusion which appeared to be grossly exaggerated by the VaPor model, although conservation of mass was conserved at each stage. This was investigated further by simulating tracer transport in the cerebral domain in the same manner that in-vivo measurements use. While in-vivo measurements and the predictions by tracer transport produce perfusion values of the same order of magnitude, a full quantitative match cannot be expected because of the differences in the measurement techniques used. Various approximations that can be imposed to resolve this are discussed. The versatility of the VaPor model was explored by simulating a variety of applications relevant to cerebral cooling. The inclusion of counter-current flow within the porous domain showed similar results to trials performed with dense vascular trees. Trials on the scale of a neonatal brain showed that hypothermia could be achieved from scalp cooling alone contrary to previous models. The transient response of scalp cooling was explored as well as the thermal response after simulating an ischemic stroke. All results demonstrated that, due to the inclusion of directional flow, scalp cooling has a larger impact on cerebral temperatures than seen with previous bioheat models.

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