Respiratory challenge MRI: practical aspects

Respiratory challenge MRI is the modification of arterial oxygen (PaO2) and/or carbon dioxide (PaCO2) concentration to induce a change in cerebral function or metabolism which is then measured by MRI. Alterations in arterial gas concentrations can lead to profound changes in cerebral haemodynamics which can be studied using a variety of MRI sequences. Whilst such experiments may provide a wealth of information, conducting them can be complex and challenging. In this paper we review the rationale for respiratory challenge MRI including the effects of oxygen and carbon dioxide on the cerebral circulation. We also discuss the planning, equipment, monitoring and techniques that have been used to undertake these experiments. We finally propose some recommendations in this evolving area for conducting these experiments to enhance data quality and comparison between techniques

Quantification of the BOLD response via blood gas modulations

This thesis is intended to contribute to a quantitative understanding of the blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal in order to increase its clinical potential. Here, the vascular, neuronal and physical processes which combine to give a resulting BOLD signal are investigated using respiratory challenges. The effect of isocapnic hyperoxia on vascular responses is investigated at 7 Tesla. No significant change was found in resting-state cerebral blood flow (CBF), resting-state cerebral blood volume (CBV) and task-evoked CBF. This challenges a previously held idea that hyperoxia is vasoconstrictive. The effect of isocapnic hyperoxia on neuronal oscillations was assessed with magnetoencephalography (MEG). Whilst a significant reduction in oscillatory power is reported in the occipital lobe, the change is significantly smaller than the global reduction previously measured with hypercapnia. These findings suggest that hyperoxia is an ideal tool for calibrated BOLD fMRI. The relationship between the change in blood oxygenation and change in transverse relaxation plays a key role in calibrated BOLD fMRI. However, previous measurements have been confounded by a change in CBV. Here, the relationship was found to be sub-linear across 1.5, 3 and 7 Tesla. Previous results which suggest a supralinear relationship at 1.5/3 Tesla and a linear relationship at 7 Tesla, are attributed to the relative contribution of intravascular/extravascular signals and their dependence on field strength, blood oxygenation and echo time. Finally, a comparison of single and multiphase ASL is made at 7 Tesla, with a modified Look-locker EPI sequence presented which allows simultaneous measurement of CBF and transit time, whilst increasing the available BOLD signal. This could have important implications for hypercapnia calibrated BOLD fMRI, where choice of ASL sequence may affect the estimated change in CMRO2. Furthermore, it provides a framework for future cerebral haemodynamic studies where simultaneous measurements are required

Quantification of the BOLD response via blood gas modulations

This thesis is intended to contribute to a quantitative understanding of the blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal in order to increase its clinical potential. Here, the vascular, neuronal and physical processes which combine to give a resulting BOLD signal are investigated using respiratory challenges. The effect of isocapnic hyperoxia on vascular responses is investigated at 7 Tesla. No significant change was found in resting-state cerebral blood flow (CBF), resting-state cerebral blood volume (CBV) and task-evoked CBF. This challenges a previously held idea that hyperoxia is vasoconstrictive. The effect of isocapnic hyperoxia on neuronal oscillations was assessed with magnetoencephalography (MEG). Whilst a significant reduction in oscillatory power is reported in the occipital lobe, the change is significantly smaller than the global reduction previously measured with hypercapnia. These findings suggest that hyperoxia is an ideal tool for calibrated BOLD fMRI. The relationship between the change in blood oxygenation and change in transverse relaxation plays a key role in calibrated BOLD fMRI. However, previous measurements have been confounded by a change in CBV. Here, the relationship was found to be sub-linear across 1.5, 3 and 7 Tesla. Previous results which suggest a supralinear relationship at 1.5/3 Tesla and a linear relationship at 7 Tesla, are attributed to the relative contribution of intravascular/extravascular signals and their dependence on field strength, blood oxygenation and echo time. Finally, a comparison of single and multiphase ASL is made at 7 Tesla, with a modified Look-locker EPI sequence presented which allows simultaneous measurement of CBF and transit time, whilst increasing the available BOLD signal. This could have important implications for hypercapnia calibrated BOLD fMRI, where choice of ASL sequence may affect the estimated change in CMRO2. Furthermore, it provides a framework for future cerebral haemodynamic studies where simultaneous measurements are required

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