New Advances in Susceptibility Weighted MRI to Determine Physiological Parameters

Die Magnetresonanztomographie bietet die Möglichkeit der Bestimmung des Blutoxygenierungsgrades kleiner venöser Gefäße und damit lokaler Hirnareale mit Hilfe einer Multiecho-Gradientenecho-Sequenz. Mit dieser Sequenz kann der Signalzerfall in einem Voxel, welches von einer einzelnen Vene bzw. von Blutkapillaren durchzogen ist, bestimmt werden. Der Signalzerfall ist charakteristisch für die von der Vene oder den Kapillaren erzeugten Feldinhomogenitäten, so dass sich Aussagen über den Blutoxygenierungsgrad und Blutvolumenanteil treffen lassen. Durch Fitten simulierter Signalverläufe an gemessene Phantom- und Probandendaten konnte gezeigt werden, dass es mit der hier vorgestellten Methode möglich ist, den venösen Blutoxygenierungsgrad zu quantifizieren. Weiterhin konnte eine durch gezielte Modulation des zerebralen Blutflusses hervorgerufene Änderung der Blutoxygenierung in vivo nachgewiesen werden. Die Erweiterung des Modells eines einzelnen Gefäßes auf ein Gefäßnetzwerk diente als Grundlage zur theoretischen Beschreibung der Blutkapillaren, die das Hirngewebe durchziehen und mit Sauerstoff versorgen. Dieses Netzwerkmodel konnte in Phantomexperimenten verifiziert werden. Dagegen zeigte sich bei einer Probandenmessung, dass es nicht möglich ist einzig anhand des gemessenen Signalverlaufs valide Werte für die Blutoxygenierung und den Blutvolumenanteil eindeutig zu bestimmen. Die hohe Korrelation zwischen beiden Parametern bewirkt, dass mehrere Paare von Oxygenierungs- und Volumenwerten passende Signalkurven liefern. Eine unabhängige Quantifizierung oder Abschätzung des venösen Blutvolumens kann hier helfen eindeutige Oxygenierungswerte zu erhalten. Im Rahmen der vorliegenden Dissertation konnte das Signalverhalten von suszeptibilitätssensitiven Messungen in der Magnetresonanztomographie genauer untersucht und eine Methode zur nicht-invasiven Bestimmung der venösen Blutoxygenierung an einzelnen Gefäßen entwickelt werden. Erste in vivo Ergebnisse des Gefäßnetzwerkes verdeutlichen, dass für eine genaue Quantifizierung der Blutoxygenierung weitere Parameter, wie das Blutvolumen, unabhängig bestimmt werden müssen. Dennoch ist es möglich, die Methode am einzelnen Blutgefäß zur besseren Charakterisierung von Pathologien sowie physiologischen Änderungen, z.B. bei der funktionellen Magnetresonanztomographie, einzusetzen.Magnetic resonance imaging allows to determine the blood oxygenation level of small venous vessels or the blood capillary network by evaluating the magnetic resonance signal acquired with multi-echo gradient-echo sequences. The signal formation of a voxel traversed by a vein or interspersed with capillaries shows a characteristic decay or modulation as a function of time from which the blood oxygenation and blood volume fraction can be derived. It could be demonstrated in phantom measurements that the signal of a single vessel traversed voxel correctly matched the calculations of numerical signal simulation. By fitting the signal simulation to in vivo measurements of cerebral venous vessels, vessel size and venous blood oxygenation was determined quantitatively. Furthermore, it was possible to detect and to quantify a physiologically induced change in cerebral venous blood oxygenation. To describe the signal of the blood capillary network in normal brain matter, an extension of the single vessel model to a vessel network was applied. This network model was also validated in phantom experiments. As a result of these investigations it was found that the two parameters describing the network, the blood volume fraction and blood oxygenation level, are correlated to each other and can not be separated without additional information by simply fitting the signal simulation to the measurement. This finding was of special importance in the initial in vivo measurements conducted in the present work. Where, independent blood volume determination may help to further validate the quantified blood oxygenation level. In the present work a non-invasive method was developed to quantify cerebral blood oxygenation levels in single veins. This was possible by investigating the signal evolution of susceptibility sensitive magnetic resonance imaging. The initial result of the vessel network signal reveals, that for obtaining a valid blood oxygenation level, the volume fraction has to be further determined by an independent measurement. Nevertheless, is has been demonstrated that the quantification of the blood oxygenation level in single venous vessels is possible and can be applied in clinical diagnosis for better characterization of cerebral pathologies or in physiological investigations, like in functional magnetic resonance imaging

Imaging the Effects of Oxygen Saturation Changes in Voluntary Apnea and Hyperventilation on Susceptibility-Weighted Imaging

BACKGROUND AND PURPOSE: Cerebrovascular oxygenation changes during respiratory challenges have clinically important implications for brain function, including cerebral autoregulation and the rate of brain metabolism. SWI is sensitive to venous oxygenation level by exploitation of the magnetic susceptibility of deoxygenated blood. We assessed cerebral venous blood oxygenation changes during simple voluntary breath-holding (apnea) and hyperventilation by use of SWI at 3T. MATERIALS AND METHODS: We performed SWI scans (3T; acquisition time of 1 minute, 28 seconds; centered on the anterior commissure and the posterior commissure) on 10 healthy male volunteers during baseline breathing as well as during simple voluntary hyperventilation and apnea challenges. The hyperventilation and apnea tasks were separated by a 5-minute resting period. SWI venograms were generated, and the signal changes on SWI before and after the respiratory stress tasks were compared by means of a paired Student t test. RESULTS: Changes in venous vasculature visibility caused by the respiratory challenges were directly visualized on the SWI venograms. The venogram segmentation results showed that voluntary apnea decreased the mean venous blood voxel number by 1.6% (P < .0001), and hyperventilation increased the mean venous blood voxel number by 2.7% (P < .0001). These results can be explained by blood CO2 changes secondary to the respiratory challenges, which can alter cerebrovascular tone and cerebral blood flow and ultimately affect venous oxygen levels. CONCLUSIONS: These results highlight the sensitivity of SWI to simple and noninvasive respiratory challenges and its potential utility in assessing cerebral hemodynamics and vasomotor responses

Imaging the Effects of Oxygen Saturation Changes in Voluntary Apnea and Hyperventilation on Susceptibility-Weighted Imaging

ABSTRACT BACKGROUND AND PURPOSE: Cerebrovascular oxygenation changes during respiratory challenges have clinically important implications for brain function, including cerebral autoregulation and the rate of brain metabolism. SWI is sensitive to venous oxygenation level by exploitation of the magnetic susceptibility of deoxygenated blood. We assessed cerebral venous blood oxygenation changes during simple voluntary breath-holding (apnea) and hyperventilation by use of SWI at 3T

Physiological effect of caffeine in neurological studies based on Susceptibility Weighted Imaging (SWI)

Introdução – O presente estudo avaliou o efeito da cafeína no valor da razão contraste ruído (CNR) em imagens SWI. Objetivos – Avaliar o efeito da cafeína qualitativamente e quantificado pelo cálculo do valor CNR em imagens de magnitude e MIP para as estruturas: veia cerebral interna, seio sagital superior, tórcula e artéria cerebral média. Metodologia – A população do estudo incluiu 24 voluntários saudáveis que estiveram pelo menos 24h privados da ingestão de cafeína. Adquiriram-se imagens SWI antes e após a ingestão de 100ml de café. Os voluntários foram subdivididos em quatro grupos de seis indivíduos/grupo e avaliados separadamente após decorrido um intervalo de tempo diferente para cada grupo (15, 25, 30 ou 45min pós-cafeína). Utilizou-se um scanner Siemens Avanto 1,5 T com bobine standard de crânio e os parâmetros: T2* GRE 3D de alta resolução no plano axial, TR=49; TE=40; FA=15; FOV=187x230; matriz=221x320. O processamento de imagem foi efetuado no software OsiriX® e a análise estatística no GraphPadPrism®. Resultados e Discussão – As alterações de sinal e diferenças de contraste predominaram nas estruturas venosas e não foram significantes na substância branca, LCR e artéria cerebral média. Os valores CNR pré-cafeína diferiram significativamente do pós-cafeína nas imagens de magnitude e MIP na veia cerebral interna e nas imagens de magnitude do seio sagital superior e da tórcula (p<0,0001). Não se verificaram diferenças significativas entre os grupos avaliados nos diferentes tempos pós-cafeína. Conclusões – Especulamos que a cafeína possa vir a ser usada como agente de contraste nas imagens SWI barato, eficaz e de fácil administração.ABSTRACT: Introduction – The present study investigates the effect of caffeine on contrast-to-noise ratio (CNR) in SWI images. Purpose – Data analyses included qualitative and quantitative measures, specifically the CNR pre and post-ingestion, in magnitude and MIP images. The structures evaluated were internal cerebral vein, superior sagital sinus, torcula, and middle cerebral artery. Methodology – Twenty-four healthy volunteers were enrolled in the study. All the volunteers were caffeine-free for 24h prior to the test. SWI images were acquired before caffeine ingestion and post-ingestion of 100 ml of coffee. The volunteers were divided into four groups of six subjects and evaluated sequentially (15, 25, 30 and 45min after caffeine). High-resolution T2* weighted 3D GRE (SWI) sequence was acquired on the axial plane on a 1.5 T (Siemens Avanto) whole body scanner using the manufacturer’s standard head coil and the following parameters: TR=49; TE=40; FA=15; FOV=187x230; matrix=221x320. Statistics were performed with GraphPad Prism® and image analysis with Osirix®. Results and Discussion – We verified that signal alterations and contrast differences were predominant in venous structures and not significant in white matter, CSF and middle cerebral artery. The CNR values between pre and post-caffeine ingestion in magnitude and MIP images in internal cerebral vein (p<0.0001) and in magnitude images of superior sagittal sinus and tórcula showed significant differences CNR. There were no significant differences between groups evaluated at different times after the ingestion of caffeine. Conclusion – We speculate that caffeine can be used as a cost-effective, safe and easy to administrate contrast agent on SWI images

MRT-Untersuchungen zum Einfluss von Koffein auf die zerebrale Physiologie mit Hilfe der suszeptibilitätsgewichteten Bildgebung (SWI)

Die Suszeptibilitätsgewichtete Bildgebung (SWI) ist eine neuartige Methode der Magnetresonanztomographie (MRT), die in der Lage ist, Änderungen der Blutoxygenierung in Venen zu detektieren. Koffein als Vasokonstriktor führt dazu, dass der zerebrale Blutfluss sinkt, was zu einer Senkung des Sauerstoffgehalts in den Venen führt. Daraus resultiert ein Verlust des Blood-Level-Dependent(BOLD)-Signals. Ziel dieser Arbeit war es, sowohl den Zeitverlauf und die Magnitude der relativen BOLD-Signaländerung nach Koffeingabe zu detektieren, als auch die Änderung der Blutoxygenierung mit Hilfe der SWI nichtinvasiv ermittelt werden. Auch der Einfluss von Koffein auf funktionelle MRT-Studien und die klinische Anwendung von Koffein und SWI waren von Interesse. Für die Untersuchung der Änderung des SWI-Signals in Abhängigkeit von Koffeinkonsum und Feldstärke wurde bei koffeinkonsumierenden und -abstinenten Probanden der BOLD-Signalverlauf nach einer Koffeingabe von 200mg bei einer Feldstärke von 1,5T für etwa 1 h beobachtet. Ein Teil der Probanden wurden erneut bei halbierter und geviertelter Dosis gemessen. Ein Proband wurde mit 200mg bei einer Magnetfeldstärke von 1,5 T, 3T und 7T untersucht. Die Änderung der Blutoxygenierung wurde aus Bilddaten und dem Hämatokrit berechnet. Für die fMRT-Studien wurden zwei Probanden vor und nach Koffeingabe einem visuellen Stimulus ausgesetzt. Es konnte gezeigt werden, dass die SWI in Abhängigkeit vom Koffeinkonsum eine signifikant höhere Signaländerung bei koffeinabstinenten Probanden zeigte. Die Variationen von Koffeindosis und Feldstärke zeigten keinen signifikanten Unterschied, vielmehr war die SWI in der Lage, minimale Änderungen in der Gefäßarchitektur, die durch eine geringe Koffeindosis von 50mg hervorgerufen werden können, zu detektieren. Die Veränderung der Blutoxygenierung und der SWI-Signaländerung korrelierten miteinander. In der fMRT zeigte sich eine Änderung der Dynamik des Aktivierungsmusters

A robust multi-scale approach to quantitative susceptibility mapping

Quantitative Susceptibility Mapping (QSM), best known as a surrogate for tissue iron content, is becoming a highly relevant MRI contrast for monitoring cellular and vascular status in aging, addiction, traumatic brain injury and, in general, a wide range of neurological disorders. In this study we present a new Bayesian QSM algorithm, named Multi-Scale Dipole Inversion (MSDI), which builds on the nonlinear Morphology-Enabled Dipole Inversion (nMEDI) framework, incorporating three additional features: (i) improved implementation of Laplace's equation to reduce the influence of background fields through variable harmonic filtering and subsequent deconvolution, (ii) improved error control through dynamic phase-reliability compensation across spatial scales, and (iii) scalewise use of the morphological prior. More generally, this new pre-conditioned QSM formalism aims to reduce the impact of dipole-incompatible fields and measurement errors such as flow effects, poor signal-to-noise ratio or other data inconsistencies that can lead to streaking and shadowing artefacts. In terms of performance, MSDI is the first algorithm to rank in the top-10 for all metrics evaluated in the 2016 QSM Reconstruction Challenge. It also demonstrated lower variance than nMEDI and more stable behaviour in scan-rescan reproducibility experiments for different MRI acquisitions at 3 and 7 Tesla. In the present work, we also explored new forms of susceptibility MRI contrast making explicit use of the differential information across spatial scales. Specifically, we show MSDI-derived examples of: (i) enhanced anatomical detail with susceptibility inversions from short-range dipole fields (hereby referred to as High-Pass Susceptibility Mapping or HPSM), (ii) high specificity to venous-blood susceptibilities for highly regularised HPSM (making a case for MSDI-based Venography or VenoMSDI), (iii) improved tissue specificity (and possibly statistical conditioning) for Macroscopic-Vessel Suppressed Susceptibility Mapping (MVSSM), and (iv) high spatial specificity and definition for HPSM-based Susceptibility-Weighted Imaging (HPSM-SWI) and related intensity projections

Promoters of cerebral small vessel integrity for cognitive disorder prevention

The unique metabolic demands of the brain point to the critical nature of cerebral small vessel integrity for overall brain and cognitive health. Given the lack of any disease-modifying treatments, new avenues for Alzheimer’s disease (AD) prevention and treatment are urgently needed. This dissertation takes a population neuroscience approach to examine potential promoters of cerebral small vessel integrity for cognitive disorder prevention. Existing methods of evaluating cerebral small vessel integrity focus on neuroimaging markers distal to small vessel disease and fail to evaluate the vessels themselves. To address this limitation, I developed a method using 7T susceptibility-weighted imaging (SWI) magnetic resonance imaging (MRI) for direct small vein measurement in older adults; I examined associations with potential small vessel integrity promoters cross-sectionally and found that the APOE*4 allele was associated with small vein tortuosity. In my second paper, a randomized controlled trial, I found that increasing physical activity and brain-derived neurotrophic factor late in life may improve cerebral small vein health profiles as measured by 7T SWI. In an era when multimorbidity is common among older adults, interactions involving vascular and cardiometabolic risk factors (VCMRF) are critical to evaluate in order to effectively target preventions and treatments—the promise of precision medicine. I evaluated associations of interactions of interest with incident dementia and cognitive impairment in a large population-based cohort with 10 years of follow-up. I found that the risk of all-cause dementia conferred by stroke was even greater among those with congestive heart failure; the beneficial effects of alcohol consumption on overall cognitive performance varied by stroke history; and in exploratory results, the detrimental effect of age on AD dementia risk was lower among those who walked more. Taken together, my findings point to physical activity and VCMRF reduction as potential strategies to promote cerebral small vessel integrity for cognitive disorder prevention and suggest that growth factors such as brain-derived neurotrophic factor should be evaluated further. These strategies for prevention could reduce late-life cognitive disorder prevalence as well as attendant disability and costs, goals of great public health significance

The pathophysiology of CADASIL: studies in a Scottish cohort

Since identification that mutations in NOTCH3 are responsible for cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) in the early 1990s, there has been extensive characterisation of the clinical and radiological features of the disease. However therapeutic interventions remain elusive, partly due to a limited understanding of the vascular pathophysiology and how it leads to the development of strokes, cognitive decline and disability. The apparent rarity and heterogenous natural history of CADASIL potentially make conducting any longitudinal or therapeutic trials difficult. The role of disease biomarkers is therefore of some interest. This thesis focuses on vascular function in CADASIL and how it may relate to clinical and radiological markers of disease. Establishing the prevalence of CADASIL in the West of Scotland was important to assess the impact of the disease, and how feasible a trial would be. A mutation prevalence of 10.7 per 100,000 was demonstrated, suggesting significant under diagnosis of the disease across much of Scotland. Cerebral hypoperfusion is thought to be important in CADASIL, and it has been shown that vascular abnormalities precede the development of brain pathology in mouse models. Investigation of vascular function in patients, both in the brain and systemically, requires less invasive measures. Arterial spin labelling magnetic resonance imaging (MRI) and transcranial Doppler ultrasound (TCD) can both be used to obtain non-invasive and quantifiable indices of vascular function. Monitoring patients with MRI whilst they receive different concentrations of inspired oxygen and carbon dioxide can provide information on brain function, and I reviewed the practicalities of this technique in order to guide the design of the studies in this thesis. 22 CADASIL patients were recruited to a longitudinal study. Testing included peripheral vascular assessment, assessment of disability, neurological dysfunction, mood and cognition. A CO2 reactivity challenge during both TCD and arterial spin labelling MRI, and detailed MRI sequences were obtained. I was able to demonstrate that vasoreactivity was associated with the number of lacunes and brain atrophy, as were carotid intima-media thickness, vessel stiffness, and age. Patients with greater disability, higher depressive symptoms and poorer processing speed showed a tendency to worse cerebral vasoreactivity but numbers were small. This observation suggests vasoreactivity may have potential as a therapeutic target, or a biomarker. I then wished to establish if arterial spin labelling MRI was useful for assessing change in cerebral blood flow in CADASIL patients. Cortical grey matter showed the highest blood flow, mean (SD), 55 (10) ml/100g/min and blood flow was significantly lower within hyperintensities (19 (4) ml/100g/min; p <0.001). Over one year, blood flow in both grey matter (mean -7 (10) %; p = 0.028) and deep white matter (-8 (13) %; p = 0.036) declined significantly. Cerebrovascular reactivity did not change over one year. I then investigated whether baseline vascular markers were able to predict change in radiological or neuropsychological measures of disease. Changes in brain volume, lacunes, microbleeds and normalised subcortical hyperintensity volume (increase of 0.8%) were shown over one year. Baseline vascular parameters were not able to predict these changes, or those in neuropsychological testing. NOTCH3 is found throughout the body and a systemic vasculopathy has been seen particularly affecting resistance vessels. Gluteal biopsies were obtained from 20 CADASIL patients, and ex vivo myography investigated the response to vasoactive agents. Evidence of impairment in both vasodilation and vasoconstriction was shown. The addition of antioxidants improved endothelium-dependent relaxation, indicating a role for oxidative stress in CADASIL pathology. Myography measures were not related to in vivo measures in the sub-group of patients who had taken part in both studies. The small vessels affected in CADASIL are unable to be imaged by conventional MR imaging so I aimed to establish which vessels might be responsible for lacunes with use of a microangiographic template overlaid onto brain images registered to a standard brain template. This showed most lacunes are small and associated with tertiary arterioles. On the basis of this thesis, it is concluded that vascular dysfunction plays an important role in the pathophysiology of CADASIL, and further assessment of vascular measures in longitudinal studies is needed. Arterial spin labelling MRI should be used as it is a reliable, non-invasive modality that can measure change over one year. Furthermore conventional cardiovascular risk factor prevention should be undertaken in CADASIL patients to delay the deleterious effects of the disease

Traumatic Brain Injury Induced Cerebral Blood Flow Changes - A Potential Role For Caffeine

Traumatic brain injury (TBI) is a global health problem with significant socio-economic costs. Closed head TBIs are one of the major causes of physical disability and cognitive disorder in young adults and a leading cause of death in children. Alteration in cerebral blood flow due to an impaired autoregulation is one of the most common consequences of TBI. However, studies related to understanding the temporal changes in CBF following TBI in experimental models are limited. The few available studies report acute reduction in CBF following TBI; knowledge related to CBF changes at sub-acute periods extending to 7 days after TBI is still not known. Furthermore, reduction in CBF has been associated with unfavorable neurological outcome and can render the brain vulnerable to secondary damage. However, thus far no effective interventions that can restore or have shown the potential to restore are available. A few available studies have demonstrated that caffeine acts as a neuroprotectant in several neurological disorders acting through diverse mechanisms. It has been postulated that caffeine may offer neuroprotection by restoring or maintaining adequate CBF following TBI. Thus, studying these CBF changes following TBI and its potential modulation by caffeine pre-treatment forms the central theme of this research. We investigated the CBF changes in male Sprague Dawley rats at 4hrs, 24 hrs, 3 days and 7 days following closed head injury, with and without caffeine (chronic and acute) pretreatment. TBI was induced using the Marmarou impact acceleration device (2 m height, 450 g weight). Rats subjected to TBI showed reduced regional and global CBF at 4hrs and 7 days following TBI. In contrast, rats that underwent chronic caffeine (1.5 g/L) pretreatment for 3 weeks did not show apparent changes in regional and global CBF following TBI, indicating a potential benefit after TBI. Acute caffeine treatment (150 mg/kg, i.p. injection 30 minutes before TBI) showed significant reductions in CBF at 4 hrs post-TBI, further deteriorating the cerebral perfusion. Furthermore, chronic caffeine pretreated rats demonstrated significantly reduced surface righting duration following TBI, compared to acute caffeine treated rats subjected to TBI and rats subjected to TBI without caffeine treatment. Therefore, chronic caffeine treatment may be beneficial in offering a degree of neuroprotection against TBI. This study was able to support the hypothesis that chronic caffeine can restore or optimize CBF following TBI and this optimization may be related to the ensuring positive outcomes such as reduced surface righting duration. This may form the stepping stone for further studies on beneficial effects of caffeine in TBI

Characterisation of the Haemodynamic Response Function (HRF) in the neonatal brain using functional MRI

Background: Preterm birth is associated with a marked increase in the risk of later neurodevelopmental impairment. With the incidence rising, novel tools are needed to provide an improved understanding of the underlying pathology and better prognostic information. Functional Magnetic Resonance Imaging (fMRI) with Blood Oxygen Level Dependent (BOLD) contrast has the potential to add greatly to the knowledge gained through traditional MRI techniques. However, it has been rarely used with neonatal subjects due to difficulties in application and inconsistent results. Central to this is uncertainity regarding the effects of early brain development on the Haemodynamic Response Function (HRF), knowledge of which is fundamental to fMRI methodology and analysis. Hypotheses: (1) Well localised and positive BOLD functional responses can be identified in the neonatal brain. (2) The morphology of the neonatal HRF differs significantly during early human development. (3) The application of an age-appropriate HRF will improve the identification of functional responses in neonatal fMRI studies. Methods: To test these hypotheses, a systematic fMRI study of neonatal subjects was carried out using a custom made somatosensory stimulus, and an adapted study design and analysis pipeline. The neonatal HRF was then characterised using an event related study design. The potential future application of the findings was then tested in a series of small experiments. Results: Well localised and positive BOLD functional responses were identified in neonatal subjects, with a maturational tendency towards an increasingly complex pattern of activation. A positive amplitude HRF was identified in neonatal subjects, with a maturational trend of a decreasing time-to-peak and increasing positive peak amplitude. Application of the empirical HRF significantly improved the precision of analysis in further fMRI studies. Conclusions: fMRI can be used to study functional activity in the neonatal brain, and may provide vital new information about both development and pathology