This thesis describes experiments to measure the ventilatory response to hypoxia at a constant (isocapnic) level of CO2 (HVR) in 18 subjects. So as to provide a complete picture of the autonomic responses, middle cerebral artery velocity, a surrogate for cerebral blood flow (CBF), as well as finger plethysmography blood pressure (BP) were also measured. Ventilatory responses have been previously described only in terms of an acute peak followed by a decline. However, rather than a single type of response, I found four types categorized as: Decline, Double, Plateau, or No response. The Double pattern, characterized by a second peak of response was the most common, yet is described here for the first time. These patterns are also characteristic of the CBF and BP responses. Furthermore the temporal correlations between these brainstem-controlled responses are also reported here for the first time.

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.

This thesis describes experiments to measure the ventilatory response to hypoxia at a constant (isocapnic) level of CO2 (HVR) in 18 subjects. So as to provide a complete picture of the autonomic responses, middle cerebral artery velocity, a surrogate for cerebral blood flow (CBF), as well as finger plethysmography blood pressure (BP) were also measured. Ventilatory responses have been previously described only in terms of an acute peak followed by a decline. However, rather than a single type of response, I found four types categorized as: Decline, Double, Plateau, or No response. The Double pattern, characterized by a second peak of response was the most common, yet is described here for the first time. These patterns are also characteristic of the CBF and BP responses. Furthermore the temporal correlations between these brainstem-controlled responses are also reported here for the first time.

Heat stress and dehydration pose a severe challenge to physiological function and the capability to perform physical work. There is, however, limited knowledge on the regional haemodynamic and metabolic responses to strenuous exercise in environmentally stressful conditions. The primary aim of this thesis was to examine whether dehydration and heat stress compromise brain, muscle and systemic blood flow and metabolism, and whether depressed brain and muscle oxygen delivery underpin reduced exercise capacity during graded incremental and prolonged exercise. This thesis makes an original contribution to the knowledge by showing for the first time that dehydration markedly accelerates the decline in cerebral blood flow during maximal incremental (Chapter 4) and prolonged sub-maximal exercise (Chapter 5) in the heat. Cerebral metabolism, however, is preserved by compensatory increases in substrate extraction. Falling carbon dioxide tension underpinned the decline in CBF. However, a distinct regional distribution of blood flow across the head was observed, suggesting that different mechanisms are responsible for the regulation of regional blood flow within the head. A reduced cerebral metabolism is therefore an unlikely factor explaining the compromised exercise capacity in physiologically stressful hot environments. Rather, restrictions in active muscle blood flow and oxygen supply, which are not apparent during sub-maximal exercise, may explain the reduced maximal aerobic power in heat stressed conditions. For the first time we have manipulated skin and core temperature to show that combined internal and skin hyperthermia reduces maximal aerobic power in association with restrictions in limb, brain and systemic blood flow and skeletal muscle metabolism (Chapter 6). Overall, the findings of the present thesis provide novel information on how circulatory limitations across contracting skeletal muscle, brain and systemic tissues and organs might underpin the impairment in exercise capacity in physiologically taxing environments evoking significant dehydration and hyperthermia.

The structural integrity of the white matter is required for neuronal communication within the brain which is essential for normal cognitive function. Post-mortem and clinical imaging studies of elderly individuals have demonstrated that white matter integrity is weakened with increasing age which is proposed to underlie age-related cognitive decline. Whilst the exact mechanisms are unknown it is thought that modest age-related reductions in cerebral blood flow, termed chronic cerebral hypoperfusion, may contribute to white matter disruption and impaired cognition with ageing. Investigating the effects of white matter integrity in humans is limited as it is difficult to definitively ascertain a cause and effect relationship. Indeed, elderly individuals with cerebral hypoperfusion often have co-existing disease such as hypertension thus the effects of hypoperfusion in isolation cannot be determined. This has led to the development of a mouse model of chronic cerebral hypoperfusion which provides the opportunity to directly assess whether cerebral hypoperfusion results in disruption to white matter and cognitive impairment. This is achieved by applying small wire coils around both common carotid arteries of the mouse resulting in a global reduction in cerebral blood flow. Importantly the extent of blood flow reduction is dependent on the internal diameter of the coils meaning that differing severities of hypoperfusion can be studied. Previous studies using this model have demonstrated diffuse white matter pathology in white matter tracts including the corpus callosum, internal capsule and optic tract following 1 month of hypoperfusion which is accompanied by impaired spatial working memory. This thesis sought to test the hypothesis that chronic cerebral hypoperfusion would influence the structural integrity of nodal and paranodal domains of myelinated axons of the white matter and result in decreased numbers of oligodendroglial cells. It was additionally hypothesised that treatment with the anti-inflammatory and antioxidant drug dimethyl fumarate (DMF) would ameliorate structural and functional alterations to white matter following hypoperfusion. Aim 1 – To determine the impact of chronic cerebral hypoperfusion on the structural integrity of nodal and paranodal domains of myelinated axons The first aim of this thesis was to investigate the effects of chronic cerebral hypoperfusion on the structural integrity of nodal and paranodal domains of myelinated axons. This was addressed by examining key myelin and axonal proteins found at nodal, paranodal and internodal domains. This revealed significant alterations to the distribution of voltage-gated sodium (Nav1.6) channels at nodes of Ranvier which were differentially altered in response to increasing durations of chronic cerebral hypoperfusion. Specifically an increase in the Nav1.6+ domain length was observed in the corpus callosum following 3 days (p < 0.0001) and 1 month (p < 0.001) of chronic cerebral hypoperfusion but was not significantly different from sham controls following 6 weeks of hypoperfusion (p = 0.066). A significant decrease in Nav1.6 domain length was observed following 3 months of hypoperfusion (p = 0.003). Assessment of paranodal integrity was carried out by measuring nodal gap length and by ultrastructural analysis of paranodal domains. This revealed pronounced alterations to nodal gap length, loss of paranodal septate-like junctions and abnormal morphology of paranodal loops. Furthermore this study revealed a significant loss of myelin associated glycoprotein, a key protein involved in the maintenance of axon-glial integrity, as early as 3 days following the onset of hypoperfusion. A further aim of this study was to examine potential mechanisms underlying the observed alterations to nodal and paranodal domains following cerebral hypoperfusion. It was hypothesised that increased inflammation and accumulation of mitochondria at nodes of Ranvier would be observed following hypoperfusion. The extent of inflammation was assessed by counting numbers of microglia which revealed no significant difference between groups following 3 days of hypoperfusion (p = 0.425) but a significant increase in microglial number was observed following 1 month of hypoperfusion (p = 0.001). In addition, assessment of mitochondrial distribution along myelinated axons revealed decreased numbers of nodes containing mitochondria following 6 weeks of hypoperfusion (p = 0.03) with no difference between groups observed following 3 months (p = 0.742). Taken together the results from this study provide evidence that chronic cerebral hypoperfusion results in dynamic alterations in the localisation of Nav1.6 channels which are accompanied by disruption to paranodal domains and impaired axon-glial integrity. Furthermore microglial number does not appear to mediate nodal and paranodal disruption following 3 days but may contribute to ongoing pathology following 1 month of chronic cerebral hypoperfusion. Aim 2 – To determine the effects of chronic cerebral hypoperfusion on oligodendroglial populations. The second aim of this thesis was to determine the effect of chronic cerebral hypoperfusion on numbers of mature oligodendrocytes and oligodendrocyte precursor cells (OPCs). This revealed a significant decrease in numbers of both populations following 3 days of cerebral hypoperfusion however following 1 month numbers of OPCs were restored and a significant increase in mature oligodendrocyte number was observed. Assessment of OPC proliferation demonstrated low numbers of proliferating cells but revealed that a proportion of newly generated cells had differentiated into mature oligodendrocytes. To determine a potential mechanism involved in OPC differentiation following cerebral hypoperfusion the expression of the GPR17 receptor was examined which has recently been reported to mediate OPC differentiation in response to injury. The results demonstrated decreased expression of GPR17 following 3 days of hypoperfusion (p = 0.007) with no difference between groups observed following 1 month (p = 0.362) indicating that this receptor is not involved in differentiation of OPCs following hypoperfusion. Taken together the results from this study show that mature oligodendrocytes and OPCs are lost early in response to hypoperfusion but that these cells recover over time, highlighting the regenerative capacity of the white matter following cerebral hypoperfusion.Aim 3 – To investigate whether modulation of inflammation and oxidative stress could ameliorate alterations to white matter structure and function following severe chronic cerebral hypoperfusion The third and final aim of this thesis was to determine whether treatment with the anti-inflammatory and antioxidant drug DMF could ameliorate structural and functional alterations to white matter following severe chronic cerebral hypoperfusion. This was achieved by examining myelin and axonal integrity in addition to numbers of oligodendrocytes and OPCs following 7 days of severe chronic cerebral hypoperfusion. This revealed that myelin integrity was significantly decreased in vehicle-treated hypoperfused animals as compared to shams (p = 0.005). However no differences in myelin integrity were observed between sham and hypoperfused mice treated with DMF (p = 0.312). In contrast to the previous study, numbers of oligodendrocytes and OPCs were not altered following severe hypoperfusion however DMF treatment led to significantly increased numbers of oligodendrocytes in sham animals (p = 0.003). Assessment of white matter function using electrophysiology revealed that the conduction velocity of myelinated axons was significantly increased in DMF-treated hypoperfused animals as compared to those treated with vehicle (p = 0.04). Taken together the results of this study demonstrate that modulation of inflammation and oxidative stress may improve structural and functional white matter alterations following chronic cerebral hypoperfusion. Conclusions: The results presented in this thesis demonstrate that chronic cerebral hypoperfusion results in structural alterations to myelinated axons and to oligodendroglial populations within the white matter which are accompanied by impaired spatial working memory. Whilst previous studies using the model have reported that cerebral hypoperfusion results in diffuse white matter pathology, this study has highlighted the vulnerability of nodal and paranodal domains of myelinated axons as regions which are altered early in response to hypoperfusion. Furthermore, characterisation of oligodendroglial populations has revealed that these cells are replaced over time despite ongoing hypoperfusion which demonstrates the regenerative capacity of the white matter following cerebral hypoperfusion. Critically the results presented in this thesis demonstrate that treatment with DMF improved the function of myelinated axons in response to severe reductions in cerebral blood flow and thus may represent an appropriate therapeutic strategy for chronic cerebral hypoperfusion.

No description available.

The ability of the brain to keep a stable and adequate cerebral blood flow (CBF) independently of fluctuations in systemic blood pressure is referred to as cerebral pressure autoregulation (CPA). When the brain is injured by trauma or hemorrhage, this ability may be impaired, leaving the brain vulnerable to events of high or low blood pressure. The aims of this thesis were to study CPA in patients with severe traumatic brain injury (TBI) or subarachnoid hemorrhage (SAH), the relation between CPA and other physiological parameters, and the influence of CPA on outcome. Four retrospective studies are included in the thesis. All patients were treated at the neurointensive care unit, Uppsala University hospital. In paper I, 58 TBI patients were studied. In patients with impaired CPA, cerebral perfusion pressure between 50-60 mm Hg was associated with favorable outcome while CPP &gt; 70 and &gt;80 mm Hg was associated with unfavorable outcome. In patients with intact CPA there was no association between CPP and outcome. In paper II, 107 TBI patients were studied. High CPP was associated with unfavorable outcome in patients with focal injuries. In patients with diffuse injury and impaired CPA, CPP &gt; 70 mm Hg was associated with favorable outcome. In paper III, 47 SAH patients were studied. CBF was measured bedside with Xenon-enhance CT (Xe-CT). Patients with impaired CPA had lower CBF, both in the early (day 0-3) and late (day 4-14) acute phase of the disease. In paper IV, 64 SAH patients were studied. Optimal CPP (CPPopt) was calculated automatically as the level of CPP where CPA works best for the patient, i.e., where PRx is lowest. Patients with actual CPP below their calculated optimum had higher amounts of low-flow regions (CBF &lt; 10 ml/100g/min). The findings in this thesis emphasize the importance of taking CPA into account in the management of TBI and SAH patients, and suggest that treatment should be individualized depending on status of autoregulation. PRx and CPPopt may be used bedside to guide management according to status of autoregulation. In the future CPA-guided management should be tested in prospective studies

Eclampsia is a hypertensive disorder of pregnancy and a leading cause of maternal death. The primary explanation for eclampsia is that it represents a form of hypertensive encephalopathy (HTE) with neurological symptoms including headaches, nausea, vomiting, visual disturbances, and seizures. The etiology of HTE involves an acute increase in arterial blood pressure that exceeds the autoregulatory capacity of the brain leading to forced dilatation of cerebral vessels, decreased cerebrovascular resistance, hyperperfusion, blood-brain barrier (BBB) disruption, and vasogenic cerebral edema formation. Due to the central role of the cerebral circulation in mediating these symptoms, a better understanding of how pregnancy affects the cerebral circulation is important to the treatment and prevention of eclampsia. A central goal of this dissertation was to determine pregnancy’s effect on cerebral blood flow (CBF) autoregulation, edema formation, and BBB permeability during acute hypertension. Women with eclampsia often seize at lower blood pressures than HTE patients. We hypothesized that pregnancy may predispose the brain to eclampsia by lowering the pressure of autoregulatory breakthrough and enhancing cerebral edema formation. Using an in vivo model of HTE, we found that the pressure of autoregulatory breakthrough was not different between nonpregnant (NP) and late-pregnant (LP) rats; however, cerebral edema formation was significantly increased only in LP animals. Nitric oxide synthase inhibition significantly increased the upper limit of autoregulation in both NP and LP animals and attenuated cerebral edema formation in LP animals. BBB permeability during acute hypertension was not different between these groups. Magnesium sulfate (MgSO4) is widely used to treat eclampsia despite an unclear mechanism of action. A second goal of this dissertation was to determine the cerebrovascular effects of MgSO4 during pregnancy. Specifically, we investigated the effect of MgSO4 on in vitro resistance artery vasodilation and in vivo BBB permeability during acute hypertension. We hypothesized that dilation to MgSO4 would be greater in mesenteric than cerebral vessels. MgSO4 elicited concentration-dependent vasodilation in all arteries, as determined by measuring lumen diameter of isolated and pressurized arteries, however, mesenteric arteries were considerably more sensitive than cerebral arteries. In addition, there was no effect of pregnancy on MgSO4 sensitivity in mesenteric arteries, whereas pregnancy decreased sensitivity to MgSO4 in cerebral arteries. We further hypothesized that MgSO4 would decrease BBB disruption during acute hypertension, thereby protecting the brain in eclampsia. Using an in vivo model of HTE, we showed that MgSO4 treatment decreased BBB permeability during acute hypertension in LP rats, with the greatest effect observed in the posterior cerebrum. In conclusion, this dissertation determined CBF autoregulation and cerebral edema formation during pregnancy, and also the effect of MgSO4 on cerebral resistance artery vasodilation and BBB permeability during acute hypertension in LP rats. Although pregnancy did not influence autoregulatory breakthrough, cerebral edema formation was enhanced in LP animals and this may potentiate neurological symptoms in eclampsia. In addition, MgSO4-induced cerebral vasodilation is likely not a primary mechanism of eclampsia treatment, rather MgSO4 may limit edema formation by attenuating BBB permeability during hypertension.

Intracranial pressure (ICP) is an important monitoring modality in the clinical management of several neurological diseases carrying the risk of fatal intracranial hypertension. However, this parameter is not always considered due to its invasive assessment. In this scenario, a non-invasive estimation of ICP (nICP) may be essential, and indeed it has become a Holy Grail in Clinical Neurosciences: extensively searched, albeit never found. This thesis is devoted to the assessment, applications and development of transcranial Doppler (TCD)-based non-invasive methods for ICP and cerebral perfusion pressure (CPP) monitoring. The thesis is divided into three sections: I) The accuracy of existing TCD-based nICP estimators in various scenarios of varying ICP (traumatic brain injury, rise of ICP during plateau waves, and rise in ICP induced by infusion of cerebrospinal fluid during infusion test). The estimators of nICP consisted of a mathematical black box model, methods based on non-invasive CPP, and a method based on TCD pulsatility index. II) The feasibility of the best performing nICP estimator in clinical practice, including patients with closed TBI and brain midline shift, patients with acute liver failure during liver transplant surgery, and patients during non-neurosurgical surgery in the beach chair position. III) The description and assessment of a novel methodology for non-invasive assessment of cerebral perfusion pressure (nCPP) based on spectral arterial blood volume accounting. As main results, TCD-based non-invasive methods could replicate changes in direct ICP across time confidently, and could provide reasonable accuracy in comparison to the standard invasive techniques. Furthermore, in feasibility studies, nICP in association with other TCD physiological parameters provided a comprehensive interpretation of cerebral haemodynamics in conditions presenting impairment of cerebral blood flow circulation. The new method of nCPP estimation could identify changes in CPP across time reliably in conditions of decreasing and increasing CPP. These findings support the use of TCD-based nICP methods in a variety of clinical conditions requiring management of ICP and brain perfusion. More importantly, the low costs associated with nICP methods, since TCD is a widely available medical device, could contribute to its widespread use as a reliable alternative for ICP monitoring in everyday clinical practice.

The Circle of Willis (CoW) is a ring-like arterial structure forming the major anastomotic connection between arterial supply systems in the brain, and is responsible for the distribution of oxygenated blood throughout the cerebral mass. Among the general population, only approximately 50% have a complete CoW, where absent or hypoplastic vessels are common among a multitude of possible anatomical variations, reducing the degree to which blood may be rerouted. While an individual with one of these variations may under normal circumstances suffer no ill effects, there are certain pathological conditions which can present a risk to the person's health and increase the possibility of suffering an ischaemic stroke when compounded with an anatomical variation. This body of work presents techniques for generating 3D models of the cerebral vasculature using magnetic resonance imaging (MRI) and performing computational fluid dynamics (CFD) simulations in order to simulate the flow patterns throughout a circle of Willis. Incorporated with the simulations is a mathematical model of the cerebral autoregulation mechanism, simulating the ability of the smaller arteries and arterioles in the brain to either constrict or dilate in response to alterations in cerebral blood flow, thereby altering the cerebrovascular resistance of each major brain territory and regulating the amount of blood flow within a physiological range of cerebral perfusion pressure. The CFD simulations have the ability to predict the amount of collateral flow rerouted via the communicating arteries in response to a stenosis or occlusion, and the major objective of this study has been the investigation of how anatomical variations of the circle of Willis affect the capacity to provide this collateral flow. Initial work began with the development of three idealized models of common anatomical variations, created using computer aided design software (CAD) and based on the results of MRI scans. The research then shifted to developing a technique whereby patient specific models of the circle of Willis could be directly segmented from the MRI data. As a result of this shift, an interactive GUI-based tool was developed for the processing of the MRI datasets, allowing for rapid data enhancement and creation of a surface topology representing the arterial wall of the circle of Willis, suitable for a CFD simulation. The results of both sets of simulations illustrate that there exist a number of variables associated with a patients circle of Willis geometry, such as cerebral blood flow and combinations and degrees of stenosis, implying that the initial goal of drawing generalized conclusions was perhaps flawed. Instead, a crucial outcome of this body of work is that the future research should be directed toward extending the physiological complexity of both the geometry and the autoregulation model, with the intention of a patient specific application rather than producing large datasets with which to make broad generalizations.