Ian D. Driver

An improved method for acquiring cerebrovascular reactivity maps

This study aims to improve the method used to produce cerebrovascular reactivity (CVR) maps by MRI. Previous methods have used a standard boxcar presentation of carbon dioxide (CO2). Here this is replaced with a sinusoidally modulated CO2 stimulus. This allowed the use of Fourier analysis techniques to measure both the amplitude and phase delay of the BOLD CVR response, and hence characterize the arrival sequence of blood to different regions of the brain. This characterization revealed statistically significant relative delays between regions of the brain (ANOVA < 0.0001). In addition, post hoc comparison showed that the frontal (P < 0.001) and parietal (P = 0.004) lobes reacted earlier than the occipital lobe. Magn Reson Med, 2011.

The effect of hypercapnia on resting and stimulus induced MEG signals.

The effect of hypercapnia (an increase in CO(2) concentration in the blood) on the functional magnetic resonance imaging (fMRI) blood oxygenation level dependent (BOLD) haemodynamic response has been well characterised and is commonly used for BOLD calibration. However, relatively little is known of the effect of hypercapnia on the electrical brain processes that underlie the BOLD response. Here, we investigate the effect of hypercapnia on resting and stimulus induced changes in neural oscillations using a feed-forward low gas flow system to deliver a reliable and repeatable level of hypercapnia. Magnetoencephalography (MEG) is used in conjunction with beamformer source localisation algorithms to non-invasively image changes in oscillatory amplitude. At rest, we find robust oscillatory power loss in the alpha (8Hz-13Hz), beta (13Hz-30Hz) and low gamma (30Hz-50Hz) frequency bands in response to hypercapnia. Further, we show that the spatial signature of this power loss differs across frequency bands, with the largest effect being observed for the beta band in sensorimotor cortices. We also measure changes in oscillatory activity induced by visual and motor events, and the effect of hypercapnia on these changes; whilst the percentage change in oscillatory activity on activation was largely unaffected by hypercapnia, the absolute change in oscillatory amplitude differed between normocapnia and hypercapnia. This work supports invasive recordings made in animals, and the results have potential implications for calibrated BOLD studies.

Calibrated BOLD using direct measurement of changes in venous oxygenation

Calibration of the BOLD signal is potentially of great value in providing a closer measure of the underlying changes in brain function related to neuronal activity than the BOLD signal alone, but current approaches rely on an assumed relationship between cerebral blood volume (CBV) and cerebral blood flow (CBF). This is poorly characterised in humans and does not reflect the predominantly venous nature of BOLD contrast, whilst this relationship may vary across brain regions and depend on the structure of the local vascular bed. This work demonstrates a new approach to BOLD calibration which does not require an assumption about the relationship between cerebral blood volume and cerebral blood flow. This method involves repeating the same stimulus both at normoxia and hyperoxia, using hyperoxic BOLD contrast to estimate the relative changes in venous blood oxygenation and venous CBV. To do this the effect of hyperoxia on venous blood oxygenation has to be calculated, which requires an estimate of basal oxygen extraction fraction, and this can be estimated from the phase as an alternative to using a literature estimate. Additional measurement of the relative change in CBF, combined with the blood oxygenation change can be used to calculate the relative change in CMRO2 due to the stimulus. CMRO2 changes of 18 ± 8% in response to a motor task were measured without requiring the assumption of a CBV/CBF coupling relationship, and are in agreement with previous approaches.

The change in cerebrovascular reactivity between 3 T and 7 T measured using graded hypercapnia.

Mapping cerebrovascular reactivity (CVR) to hypercapnia is important both clinically and for improved understanding of the haemodynamic properties of the BOLD effect. In this work, BOLD/R2 CVR was investigated by using a device which provided small, repeatable and stable steps in PETCO2, whilst maintaining a steady PETO2 level. Significant CVR was observed in both grey and white matter at both 3 and 7 T, whilst an approximately linear relationship found between R2 CVR and field strength has implications for BOLD models and calibration. Grey matter R2 CVR was 0.066+/-0.004 s(-1) mm Hg(-1) at 3 T and 0.141+/-0.008 s(-1) mm Hg(-1) at 7 T. White matter R2 CVR was 0.021+/-0.003 s(-1) mm Hg(-1) at 3 T and 0.040+/-0.007 s(-1) mm Hg(-1) at 7 T.

Measuring venous blood volume changes during activation using hyperoxia.

This study describes a novel method for measuring relative changes in venous cerebral blood volume (CBVv) using hyperoxia as a contrast agent. This method exploits the extravascular BOLD effect and its dependency on both task-related activation induced changes in venous blood oxygenation and changes due to breathing an oxygen enriched gas mixture. Changes in CBVv on activation can be estimated by comparing the change in transverse relaxation rate, R2*, due to hyperoxia in both baseline and activation states. Furthermore these measurements can be converted into a measure of the percentage change in CBVv. Experiments were performed to measure changes in a CBVv-weighted signal in response to a simple motor task. Both positive and negative changes in CBVv-weighted signal were detected in the positively activated BOLD region.

The Central Vein Sign in Multiple Sclerosis Lesions Is Present Irrespective of the T2* Sequence at 3 T.

Previous T2*‐weighted magnetic resonance imaging (MRI) studies have used white matter lesion (WML) central veins to distinguish multiple sclerosis (MS) from its mimics. To be clinically applicable, the “central vein sign” needs to be detectable across different T2* sequences. Our objective was to determine if the central vein sign is reliably present in MS and absent in patients with ischemic small vessel disease (SVD) across different T2* sequences at 3T MRI.

Arterial CO2 fluctuations modulate neuronal rhythmicity: implications for MEG and fMRI studies of resting state networks

A fast emerging technique for studying human resting state networks (RSNs) is based on spontaneous temporal fluctuations in neuronal oscillatory power, as measured by magnetoencephalography. However, it has been demonstrated recently that this power is sensitive to modulations in arterial CO2 concentration. Arterial CO2 can be modulated by natural fluctuations in breathing pattern, as might typically occur during the acquisition of an RSN experiment. Here, we demonstrate for the first time the fine-scale dependence of neuronal oscillatory power on arterial CO2 concentration, showing that reductions in alpha, beta, and gamma power are observed with even very mild levels of hypercapnia (increased arterial CO2). We use a graded hypercapnia paradigm and participant feedback to rule out a sensory cause, suggesting a predominantly physiological origin. Furthermore, we demonstrate that natural fluctuations in arterial CO2, without administration of inspired CO2, are of a sufficient level to influence neuronal oscillatory power significantly in the delta-, alpha-, beta-, and gamma-frequency bands. A more thorough understanding of the relationship between physiological factors and cortical rhythmicity is required. In light of these findings, existing results, paradigms, and analysis techniques for the study of resting-state brain data should be revisited. SIGNIFICANCE STATEMENT In this study, we show for the first time that neuronal oscillatory power is intimately linked to arterial CO2 concentration down to the fine-scale modulations that occur during spontaneous breathing. We extend these results to demonstrate a correlation between neuronal oscillatory power and spontaneous arterial CO2 fluctuations in awake humans at rest. This work identifies a need for studies investigating resting-state networks in the human brain to measure and account for the impact of spontaneous changes in arterial CO2 on the neuronal signals of interest. Changes in breathing pattern that are time locked to task performance could also lead to confounding effects on neuronal oscillatory power when considering the electrophysiological response to functional stimulation.

The absolute CBF response to activation is preserved during elevated perfusion: Implications for neurovascular coupling measures

Functional magnetic resonance imaging (fMRI) techniques in which the blood oxygenation level dependent (BOLD) and cerebral blood flow (CBF) response to a neural stimulus are measured, can be used to estimate the fractional increase in the cerebral metabolic rate of oxygen consumption (CMRO2) that accompanies evoked neural activity. A measure of neurovascular coupling is obtained from the ratio of fractional CBF and CMRO2 responses, defined as n, with the implicit assumption that relative rather than absolute changes in CBF and CMRO2 adequately characterise the flow-metabolism response to neural activity. The coupling parameter n is important in terms of its effect on the BOLD response, and as potential insight into the flow-metabolism relationship in both normal and pathological brain function. In 10 healthy human subjects, BOLD and CBF responses were measured to test the effect of baseline perfusion (modulated by a hypercapnia challenge) on the coupling parameter n during graded visual stimulation. A dual-echo pulsed arterial spin labelling (PASL) sequence provided absolute quantification of CBF in baseline and active states as well as relative BOLD signal changes, which were used to estimate CMRO2 responses to the graded visual stimulus. The absolute CBF response to the visual stimuli were constant across different baseline CBF levels, meaning the fractional CBF responses were reduced at the hyperperfused baseline state. For the graded visual stimuli, values of n were significantly reduced during hypercapnia induced hyperperfusion. Assuming the evoked neural responses to the visual stimuli are the same for both baseline CBF states, this result has implications for fMRI studies that aim to measure neurovascular coupling using relative changes in CBF. The coupling parameter n is sensitive to baseline CBF, which would confound its interpretation in fMRI studies where there may be significant differences in baseline perfusion between groups. The absolute change in CBF, as opposed to the change relative to baseline, may more closely match the underlying increase in neural activity in response to a stimulus.

The effect of isocapnic hyperoxia on neurophysiology as measured with MRI and MEG.

The physiological effect of hyperoxia has been poorly characterize d, with studies reporting conflicting results on the role of hyperoxia as a vasoconstrictor. It is not clear whether hyperoxia is the primary contributor to vasoconstriction or whether induced changes in CO2 that commonly accompany hyperoxia are a factor. As calibrated BOLD fMRI based on hyperoxia becomes more widely used, it is essential to understand the effects of oxygen on resting cerebral physiology. This study used a RespirAct™ system to deliver a repeatable isocapnic hyperoxia stimulus to investigate the independent effect of O2 on cerebral physiology, removing any potential confounds related to altered CO2. T1-independent Phase Contrast MRI was used to demonstrate that isocapnic hyperoxia has no significant effect on carotid blood flow (normoxia 201 ± 11 ml/min, -0.3% ± 0.8% change during hyperoxia, p = 0.8), while Look Locker ASL was used to demonstrate that there is no significant change in arterial cerebral blood volume (normoxia 1.3% ± 0.4%, -0.5 ± 5% change during hyperoxia). These are in contrast to significant changes in carotid blood flow observed for hypercapnia (6.8% ± 1.5%/mm Hg CO2). In addition, magnetoencephalography provided a method to monitor the effect of isocapnic hyperoxia on neuronal oscillatory power. In response to hyperoxia, a significant focal decrease in oscillatory power was observed across the alpha, beta and low gamma bands in the occipital lobe, compared to a more global significant decrease on hypercapnia. This work suggests that isocapnic hyperoxia provides a more reliable stimulus than hypercapnia for calibrated BOLD, and that previous reports of vasoconstriction during hyperoxia probably reflect the effects of hyperoxia-induced changes in CO2. However, hyperoxia does induce changes in oscillatory power consistent with an increase in vigilance, but these changes are smaller than those observed under hypercapnia. The effect of this change in neural activity on calibrated BOLD using hyperoxia or combined hyperoxia and hypercapnia needs further investigation.

Global intravascular and local hyperoxia contrast phase-based blood oxygenation measurements

The measurement of venous cerebral blood oxygenation (Yv) has potential applications in the study of patient groups where oxygen extraction and/or metabolism are compromised. It is also useful for fMRI studies to assess the stimulus-induced changes in Yv, particularly since basal Yv partially accounts for inter-subject variation in the haemodynamic response to a stimulus. A range of MRI-based methods of measuring Yv have been developed recently. Here, we use a method based on the change in phase in the MR image arising from the field perturbation caused by deoxygenated haemoglobin in veins. We build on the existing phase based approach (Method I), where Yv is measured in a large vein (such as the superior sagittal sinus) based on the field shift inside the vein with assumptions as to the veins shape and orientation. We demonstrate two novel modifications which address limitations of this method. The first modification (Method II), maps the actual form of the vein, rather than assume a given shape and orientation. The second modification (Method III) uses the intra and perivascular phase change in response to a known change in Yv on hyperoxia to measure normoxic Yv in smaller veins. Method III can be applied to veins whose shape, size and orientation are not accurately known, thus allowing more localised measures of venous oxygenation. Results demonstrate that the use of an overly fine spatial filter caused an overestimation in Yv for Method I, whilst the measurement of Yv using Method II was less sensitive to this bias, giving Yv = 0.62 ± 0.03. Method III was applied to mapping of Yv in local veins across the brain, yielding a distribution of values with a mode of Yv = 0.661 ± 0.008.