| 1. |
- Birnefeld, Johan, 1989-
(författare)
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Cerebral hemodynamics in stroke, cerebral small vessel disease and pharmacological interventions : a 4D flow MRI study
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background and aim: Current cerebrovascular imaging techniques provide important information on arterial anatomy and structural pathologies, such as stenoses and occlusions, but physicians are left to infer how the blood flow is affected. In addition, the relationship between blood pressure and cerebral blood flow is complex and poorly understood. Increased transmission of cardiac pulsatility to the cerebral microvasculature has been suggested as a causative factor of cerebral small vessel disease (CSVD) but previous research have yielded conflicting results regarding this relationship. 4D flow magnetic resonance imaging (MRI) is a novel and promising technique enabling time-resolved blood flow quantification with whole-brain coverage and relatively short scan times. However, despite its obvious potential, there is not yet an evidence-based application for the use of 4D flow MRI within stroke or CSVD. This dissertation aimed to apply 4D flow MRI to describe blood flow patterns in posterior circulation stroke and cerebral blood flow responses to common pharmacological agents used to alter arterial blood pressure as well as to examine the relationship between cerebral arterial pulsatility and CSVD.Methods and Results: This doctoral dissertation consisted of four papers, referred to by roman numerals. 4D flow MRI and computed tomography angiography (CTA) were applied in 25 patients with acute ischemic stroke in the posterior circulation and a reference population of 15 healthy elderly (paper I). Individual flow profiles were created for each stroke patient and hemodynamic disturbances as well as collateral compensation were described. We show that hemodynamic findings were related to structural findings from CTA.The cross-sectional relationship between cerebral arterial pulsatility (quantified using 4D flow MRI as pulsatility index [PI] and flow volume pulsatility [FVP]) and features of CSVD were examined using regression analysis in 89 patients with acute ischemic stroke (paper II) and a population-based sample of 862 elderly (paper III). Internal carotid artery FVP was associated with increasing white matter hyperintensity (WMH) volume in patients with stroke and TIA (paper II). In addition, increasing middle cerebral artery FVP and PI were associated with worse cognitive function. In the population sample, high FVP and PI were associated with increasing WMH volume, lower brain volume and the presence of lacunes, but not the composite MRI-CSVD (paper III). Among subjects with MRI-CSVD, displaying symptoms consistent with cerebral small vessel disease was associated with higher WMH volume, lower brain volume and active smoking, but not any measure of pulsatility.Eighteen healthy volunteers were administered noradrenaline to increase mean arterial pressure by 20% above baseline, and labetalol to decrease mean arterial pressure to 15% below baseline (paper IV). Cerebral blood flow was measured using phase-contrast MRI at each blood pressure level and compared to baseline. Despite a marked increase in blood pressure, noradrenaline administration caused a reduction in cerebral blood flow and cardiac output. Meanwhile, labetalol administration caused no change in cerebral blood flow but an increased cardiac output.Conclusions: 4D flow MRI can detect hemodynamic disturbances and discriminate between hemodynamic disturbances and normal flow in patients with structural vascular pathologies. This additional information compared to structural imaging alone could potentially be used for prognosis and selection for procedures in clinical care. Cerebral arterial pulsatility is modestly associated with several MRI and clinical features of CSVD but not all. Cerebral arterial pulsatility as the main risk factor of CSVD seems unlikely but its involvement in the pathophysiology cannot be ruled out. Raising the blood pressure with noradrenaline decreases cerebral blood flow and cardiac output without any redistribution from peripheral to cerebral flow. This highlights the pitfalls of using blood pressure as a surrogate for cerebral blood flow and questions the validity of our understanding of cerebral autoregulation. Lowering the blood pressure with labetalol does not affect cerebral blood flow, reassuring its use in clinical routine. 4D flow MRI can be integrated into an in-patient work-up in selected cases of acute ischemic stroke and into the workflow of large epidemiological studies.
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| 2. |
- Dunås, Tora, 1988-
(författare)
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Blood flow assessment in cerebral arteries with 4D flow magnetic resonance imaging : an automatic atlas-based approach
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Disturbed blood flow to the brain has been associated with several neurological diseases, from stroke and vascular diseases to Alzheimer’s and cognitive decline. To determine the cerebral arterial blood flow distribution, measurements are needed in both distal and proximal arteries.4D flow MRI makes it possible to obtain blood flow velocities from a volume covering the entire brain in one single scan. This facilitates more extensive flow investigations, since flow rate assessment in specific arteries can be done during post-processing. The flow rate assessment is still rather laborious and time consuming, especially if the number of arteries of interest is high. In addition, the quality of the measurements relies heavily on the expertise of the investigator.The aim of this thesis was to develop and evaluate an automatic post-processing tool for 4D flow MRI that identifies the main cerebral arteries and calculates their blood flow rate with minimal manual input. Atlas-based labeling of brain tissue is common in toolboxes for analysis of neuroimaging-data, and we hypothesized that a similar approach would be suitable for arterial labeling. We also wanted to investigate how to best separate the arterial lumen from background for calculation of blood flow.Methods: An automatic atlas-based arterial identification method (AAIM) for flow assessment was developed. With atlas-based labeling, voxels are labeled based on their spatial location in MNI-space, a stereotactic coordinate system commonly used for neuroimaging analysis. To evaluate the feasibility of this approach, a probabilistic atlas was created from a set of angiographic images derived from 4D flow MRI. Included arteries were the anterior (ACA), middle (MCA) and posterior (PCA) cerebral arteries, as well as the internal carotid (ICA), vertebral (VA), basilar (BA) and posterior communicating (PCoA) arteries. To identify the arteries in an angiographic image, a vascular skeleton where each branch represented an arterial segment was extracted and labeled according to the atlas. Labeling accuracy of the AAIM was evaluated by visual inspection.Next, the labeling method was adapted for flow measurements by pre-defining desired regions within the atlas. Automatic flow measurements were then compared to measurements at manually identified locations. During the development process, arterial identification was evaluated on four patient cohorts, with and without vascular disease. Finally, three methods for flow quantification using 4D flow MRI: k-means clustering; global thresholding; and local thresholding, were evaluated against a standard reference method.Results: The labeling accuracy on group level was between 96% and 87% for all studies, and close to 100% for ICA and BA. Short arteries (PCoA) and arteries with large individual anatomical variation (VA) were the most challenging. Blood flow measurements at automatically identified locations were highly correlated (r=0.99) with manually positioned measurements, and difference in mean flow was negligible.Both global and local thresholding out-performed k-means clustering, since the threshold value could be optimized to produce a mean difference of zero compared to reference. The local thresholding had the best concordance with the reference method (p=0.009, F-test) and was the only method that did not have a significant correlation between flow difference and flow rate. In summary, with a local threshold of 20%, ICC was 0.97 and the flow rate difference was -0.04 ± 15.1 ml/min, n=308.Conclusion: This thesis work demonstrated that atlas-based labeling was suitable for identification of cerebral arteries, enabling automated processing and flow assessment in 4D flow MRI. Furthermore, the proposed flow rate quantification algorithm reduced some of the most important shortcomings associated with previous methods. This new platform for automatic 4D flow MRI data analysis fills a gap needed for efficient in vivo investigations of arterial blood flow distribution to the entire vascular tree of the brain, and should have important applications to practical use in neurological diseases.
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| 3. |
- Holmgren, Madelene, 1992-
(författare)
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4D flow MRI and modelling to assess cerebral arterial hemodynamics : method development and evaluation, with implementation in patients with symptomatic carotid stenosis
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Blood flow measurements are important for understanding the development of cerebrovascular diseases. With 4D flow magnetic resonance imaging (4D flow MRI), simultaneous velocity measurements are obtained in all cerebral arteries in a scan of about ten minutes. However, 4D flow MRI is a relatively new technique. For usefulness in both clinics and research, detailed knowledge is needed about its accuracy and precision for flow quantification. In patients with stroke or transient ischemic attack (TIA) from a symptomatic carotid stenosis, the stenosis may generate a difference in blood pressure and flow between the left and right cerebral hemispheres. Such a hemispheric pressure difference could be an early marker of to what extent a stenosis is affecting cerebral hemodynamics, which could be useful in the planning of carotid surgery. The overall aim of the thesis was to determine the accuracy of 4D flow MRI to measure cerebral arterial blood flow, and to develop and evaluate an approach combining 4D flow MRI and computational fluid dynamics (CFD) to characterize the cerebral arterial hemodynamics, with implementation in patients with symptomatic carotid stenosis. The thesis is based on four papers, investigating two cohorts.The first cohort consisted of 35 elderly volunteers (mean age 79 years) and was studied in paper I-II. Blood flow rates were measured in nine cerebral arteries with 4D flow MRI and 2D phase-contrast MRI as reference. Three different flow quantification methods for 4D flow MRI were evaluated and optimized: one clustering approach and two threshold-based methods. The proposed new method, based on a locally adapted threshold, outperformed the previously suggested methods in flow rate quantification. For the clustering method, flow rates were systematically underestimated. 4D flow MRI was also evaluated to assess different arterial pulsatility measures, and a Windkessel model was used to estimate reference values for cerebrovascular resistance and cerebral arterial compliance in elderly.The second cohort consisted of 28 stroke and TIA patients (mean age 73 years) with symptomatic carotid stenosis and was studied in paper III-IV. With 4D flow MRI and CFD, the preoperative hemispheric pressure laterality was quantified in the patients. The pressure laterality was compared to hemispheric flow lateralities. Estimating the hemispheric pressure laterality was a promising physiological biomarker for grading the cerebral arterial hemodynamic disturbances in patients with symptomatic carotid stenosis. A CFD model was also developed to predict carotid stump pressure, i.e., the important pressure measured in the clamped carotid artery during surgical removal of the stenosis. The predicted stump pressures were correlated with the pressures measured during surgery. Stump pressure prediction was promising and could be a potential tool in the preoperative planning in order to avoid hypoperfusion during surgery. In summary, post-processing methods were successfully developed and evaluated for accurate assessment of mean and pulsatile cerebral blood flow rates with 4D flow MRI. Thereby, this thesis provided knowledge about possibilities and limitations of how 4D flow MRI can be used with respect to cerebral arterial blood flow rate assessment. By contributing with models combining 4D flow MRI and CFD, specifically developed for analysis of pressure distributions in cerebral arteries, novel methods were proposed for assessing patients with symptomatic carotid stenosis in the planning of carotid surgery.
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| 4. |
- Vikner, Tomas, 1990-
(författare)
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Cerebral arterial pulsatility imaging using 4D flow MRI : methodological development and applications in brain aging
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 4D flow magnetic resonance imaging (MRI) is increasingly recognizedas a versatile tool to assess arterial and venous hemodynamics. Cerebral arterial pulsatility is typically assessed by analyzing flow waveforms over the cardiac cycle, where flow amplitude is a function of cardiac output, central arterial stiffness, and cerebrovascular resistance and compliance. Excessive pulsatility may propagate to the cerebral microcirculation, and constitute a harmful mechanism for the brain. Indeed, imaging studies have linked arterial pulsatility to hippocampus volume, cerebral small vessel disease (SVD), and Alzheimer’s disease (AD). In animal models, elevated pulsatility leads to blood-brain barrier (BBB) leakage, capillary loss, and cognitive decline. However, associations to cerebrovascular lesions and brain function in the spectrum of normal aging are less investigated. Further, previous 4D flow studies have mainly assessed pulsatility in relatively large cerebral arteries. When exploring links to microvascular damage and brain function, more distal measurements, closer to the microcirculation, are desired. This thesis aimed to develop 4D flow MRI post-processing methods to obtain pulsatile waveforms in small, distal cerebral arteries with noisy velocity data and a complex vascular anatomy, and to evaluate pulsatility (primarily assessed by the pulsatility index) in relation to aging, brain function, and other imaging biomarkers of cerebrovascular damage, with particular dedication towards the hippocampus and cerebral SVD. To assess pulsatility in distal cerebral arteries, a post-processing method that automatically samples waveforms from numerous small arteries, to obtain a whole-brain representation of the distal arterial waveform, was developed (Paper I). We demonstrated the importance of averaging flow waveforms along multiple vessel segments to avoid overestimations in the pulsatility index, showed agreement with reference methods, and linked distal arterial pulsatility to age. To explore links to hippocampal function, we evaluated pulsatility in relation to cognition, hemodynamic low-frequency oscillations (LFOs), perfusion, and hippocampus volume (Paper II). We found that higher pulsatility was linked to worse hippocampus-sensitive episodic memory, weaker hippocampal LFOs, and lower whole-brain perfusion. These findings aligned with models suggesting that hippocampal microvessels could be particularly susceptible to pulsatile stress.To inform on SVD pathophysiology, we evaluated 5-year associations among pulsatility, white matter lesions (WMLs) and perivascular space (PVS) dilation, using mixed models, factor analysis, and change score models (Paper III). Lead-lag analyses indicated that, while pulsatility at baseline could not predict WML nor PVS progression, WML and PVS volumes at baseline predicted 5-year pulsatility-increases. These findings indicate that individuals with a higher load of cerebrovascular damage are more prone to see increased pulsatility over time, and suggest that high pulsatility is a manifestation, rather a risk factor, for cerebral SVD. To shed light on the potential role of BBB leakage in aging and SVD, we used dynamic contrast enhanced (DCE) MRI and intravenous gadolinium injections to quantify BBB permeability (Paper IV). We found stepwise increases in permeability from healthy white matter to WMLs, supporting that BBB leakages are implicated in SVD. However, hippocampal BBB permeability was unrelated to age, indicating that this capillary property is maintained in aging. Finally, arterial pulsatility was unrelated to BBB permeability in WMLs and in the hippocampus, providing no evidence of excessive pulsatility as a trigger of BBB leakage. In conclusion, distal arterial pulsatility measurements are reliable when averaging 4D flow waveforms over a large number of vessels. Pulsatility increases with age, and individuals with more cerebrovascular lesions are prone to see larger increases over time. Pulsatility is negatively related to perfusion and hippocampal function. However, the temporal dynamics among the SVD biomarkers, and the absence of pulsatility–permeability associations, challenge the concept of excessive pulsatility as a trigger of microvascular damage. Future studies are needed to understand whether altered cerebral hemodynamics play a causal role in cognitive decline and dementia. Meanwhile, 4D flow hemodynamic parameters could be useful as biomarkers related to vessel properties and cerebrovascular health.
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| 5. |
- Wåhlin, Anders, 1983-
(författare)
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Cerebral blood flow and intracranial pulsatility studied with MRI : measurement, physiological and pathophysiological aspects
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- During each cardiac cycle pulsatile arterial blood inflates the vascular bed of the brain, forcing cerebrospinal fluid (CSF) and venous blood out of the cranium. Excessive arterial pulsatility may be part of a harmful mechanism causing cognitive decline among elderly. Additionally, restricted venous flow from the brain is suggested as the cause of multiple sclerosis. Addressing hypotheses derived from these observations requires accurate and reliable investigational methods. This work focused on assessing the pulsatile waveform of cerebral arterial, venous and CSF flows. The overall aim of this dissertation was to explore cerebral blood flow and intracranial pulsatility using MRI, with respect to measurement, physiological and pathophysiological aspects. Two-dimensional phase contrast magnetic resonance imaging (2D PCMRI) was used to assess the pulsatile waveforms of cerebral arterial, venous and CSF flow. The repeatability was assessed in healthy young subjects. The 2D PCMRI measurements of cerebral arterial, venous and CSF pulsatility were generally repeatable but the pulsatility decreased systematically during the investigation. A method combining 2D PCMRI measurements with invasive CSF infusion tests to determine the magnitude and distribution of compliance within the craniospinal system was developed and applied in a group of healthy elderly. The intracranial space contained approximately two thirds of the total craniospinal compliance. The magnitude of craniospinal compliance was less than suggested in previous studies. The vascular hypothesis for multiple sclerosis was tested. Venous drainage in the internal jugular veins was compared between healthy controls and multiple sclerosis patients using 2D PCMRI. For both groups, a great variability in the internal jugular flow was observed but no pattern specific to multiple sclerosis could be found. Relationships between regional brain volumes and potential biomarkers of intracranial cardiac-related pulsatile stress were assessed in healthy elderly. The biomarkers were extracted from invasive CSF pressure measurements as well as 2D PCMRI acquisitions. The volumes of temporal cortex, frontal cortex and hippocampus were negatively related to the magnitude of cardiac-related intracranial pulsatility. Finally, a potentially improved workflow to assess the volume of arterial pulsatility using time resolved, four-dimensional phase contrast MRI measurements (4D PCMRI) was evaluated. The measurements showed good agreement with 2D PCMRI acquisitions. In conclusion, this work showed that 2D PCMRI is a feasible tool to study the pulsatile waveforms of cerebral blood and CSF flow. Conventional views regarding the magnitude and distribution of craniospinal compliance was challenged, with important implications regarding the understanding of how intracranial vascular pulsatility is absorbed. A first counterpoint to previous near-uniform observations of obstructions in the internal jugular veins in multiple sclerosis was provided. It was demonstrated that large cardiac- related intracranial pulsatility were related to smaller volumes of brain regions that are important in neurodegenerative diseases among elderly. This represents a strong rationale to further investigate the role of excessive intracranial pulsatility in cognitive impairment and dementia. For that work, 4D PCMRI will facilitate an effective analysis of cerebral blood flow and pulsatility.
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| 6. |
- Zackariasson, Peter, 1972-
(författare)
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World Builders : A Study on the Development of a Massively Multiplayer Online Role-Playing Game
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This dissertation is a study of the development of a video game called Anarchy Online. This game was developed by the Funcom company between 1995 and 2001, and is a so-called Massively Multiplayer Online Role-Playing Game (MMORPG). This genre of video games differs from traditional games in that it offers a persistent virtual world that gamers can access at all hours of the night or day. It is also a world where gamers make avatars that play with or against each other. All in all, it is as much a social sphere as a game. The popularity of MMORGPGs has continued to increase, and today there are several million gamers worldwide who participate in these virtual worlds. Because virtual worlds are places where many people socialize, play, and spend a great deal of time, there is a need to form an understanding of them. In this thesis, I am studying how Anarchy Online was produced in order to understand the assumptions behind the rules governing the interaction in this specific virtual world were selected and organized. In doing so, I am using material from two sources: the developers and the game itself. This material was gathered through interviews, documents, and virtual ethnographic observations.Ultimately, games consist of codes; but in order to program the code, they need to be specified by a game content. The analysis shows that the content of the game is defined by the developers’ view of a good society – the belief in a human being’s need for self-actualization and social interaction. The thesis thus concludes with the observation that the need to select the discourses and/or philosophies for content and possible gamers’ actions requires the development of games and virtual worlds such as Anarchy Online to be more than the creation of an entertaining product. Rather, discourses were recreated from the physical world in which the developers live. In the end, gamers are locked into a discoursive prison created by the developers.
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