Investigation of the neurovascular coupling in positive and negative BOLD responses in human brain at 7T

Decreases in stimulus-dependent blood oxygenation level dependent (BOLD) signal and their underlying neurovascular origins have recently gained considerable interest. In this study a multi-echo, BOLD-corrected vascular space occupancy (VASO) functional magnetic resonance imaging (fMRI) technique was used to investigate neurovascular responses during stimuli that elicit positive and negative BOLD responses in human brain at 7 T. Stimulus-induced BOLD, cerebral blood volume (CBV), and cerebral blood flow (CBF) changes were measured and analyzed in ‘arterial’ and ‘venous’ blood compartments in macro- and microvasculature. We found that the overall interplay of mean CBV, CBF and BOLD responses is similar for tasks inducing positive and negative BOLD responses. Some aspects of the neurovascular coupling however, such as the temporal response, cortical depth dependence, and the weighting between ‘arterial’ and ‘venous’ contributions, are significantly different for the different task conditions. Namely, while for excitatory tasks the BOLD response peaks at the cortical surface, and the CBV change is similar in cortex and pial vasculature, inhibitory tasks are associated with a maximum negative BOLD response in deeper layers, with CBV showing strong constriction of surface arteries and a faster return to baseline. The different interplays of CBV, CBF and BOLD during excitatory and inhibitory responses suggests different underlying hemodynamic mechanisms

Cortical lamina-dependent blood volume changes in human brain at 7T

Cortical layer-dependent high (sub-millimeter) resolution functional magnetic resonance imaging (fMRI) in human or animal brain can be used to address questions regarding the functioning of cortical circuits, such as the effect of different afferent and efferent connectivities on activity in specific cortical layers. The sensitivity of gradient echo (GE) blood oxygenation level-dependent (BOLD) responses to large draining veins reduces its local specificity and can render the interpretation of the underlying laminar neural activity impossible. The application of the more spatially specific cerebral blood volume (CBV)-based fMRI in humans has been hindered by the low sensitivity of the noninvasive modalities available. Here, a vascular space occupancy (VASO) variant, adapted for use at high field, is further optimized to capture layer-dependent activity changes in human motor cortex at sub-millimeter resolution. Acquired activation maps and cortical profiles show that the VASO signal peaks in gray matter at 0.8–1.6 mm depth, and deeper compared to the superficial and vein-dominated GE-BOLD responses. Validation of the VASO signal change versus well-established iron-oxide contrast agent based fMRI methods in animals showed the same cortical profiles of CBV change, after normalization for lamina-dependent baseline CBV. In order to evaluate its potential of revealing small lamina-dependent signal differences due to modulations of the input-output characteristics, layer-dependent VASO responses were investigated in the ipsilateral hemisphere during unilateral finger tapping. Positive activation in ipsilateral primary motor cortex and negative activation in ipsilateral primary sensory cortex were observed. This feature is only visible in high-resolution fMRI where opposing sides of a sulcus can be investigated independently because of a lack of partial volume effects. Based on the results presented here, we conclude that VASO offers good reproducibility, high sensitivity and lower sensitivity than GE-BOLD to changes in larger vessels, making it a valuable tool for layer-dependent fMRI studies in humans

Cortical depth dependent functional responses in humans at 7T: improved specificity with 3D GRASE

Ultra high fields (7T and above) allow functional imaging with high contrast-to-noise ratios and improved spatial resolution. This, along with improved hardware and imaging techniques, allow investigating columnar and laminar functional responses. Using gradient-echo (GE) (T2* weighted) based sequences, layer specific responses have been recorded from human (and animal) primary visual areas. However, their increased sensitivity to large surface veins potentially clouds detecting and interpreting layer specific responses. Conversely, spin-echo (SE) (T2 weighted) sequences are less sensitive to large veins and have been used to map cortical columns in humans. T2 weighted 3D GRASE with inner volume selection provides high isotropic resolution over extended volumes, overcoming some of the many technical limitations of conventional 2D SE-EPI, whereby making layer specific investigations feasible. Further, the demonstration of columnar level specificity with 3D GRASE, despite contributions from both stimulated echoes and conventional T2 contrast, has made it an attractive alternative over 2D SE-EPI. Here, we assess the spatial specificity of cortical depth dependent 3D GRASE functional responses in human V1 and hMT by comparing it to GE responses. In doing so we demonstrate that 3D GRASE is less sensitive to contributions from large veins in superficial layers, while showing increased specificity (functional tuning) throughout the cortex compared to GE

Functional Imaging of Autonomic Regulation: Methods and Key Findings.

Central nervous system processing of autonomic function involves a network of regions throughout the brain which can be visualized and measured with neuroimaging techniques, notably functional magnetic resonance imaging (fMRI). The development of fMRI procedures has both confirmed and extended earlier findings from animal models, and human stroke and lesion studies. Assessments with fMRI can elucidate interactions between different central sites in regulating normal autonomic patterning, and demonstrate how disturbed systems can interact to produce aberrant regulation during autonomic challenges. Understanding autonomic dysfunction in various illnesses reveals mechanisms that potentially lead to interventions in the impairments. The objectives here are to: (1) describe the fMRI neuroimaging methodology for assessment of autonomic neural control, (2) outline the widespread, lateralized distribution of function in autonomic sites in the normal brain which includes structures from the neocortex through the medulla and cerebellum, (3) illustrate the importance of the time course of neural changes when coordinating responses, and how those patterns are impacted in conditions of sleep-disordered breathing, and (4) highlight opportunities for future research studies with emerging methodologies. Methodological considerations specific to autonomic testing include timing of challenges relative to the underlying fMRI signal, spatial resolution sufficient to identify autonomic brainstem nuclei, blood pressure, and blood oxygenation influences on the fMRI signal, and the sustained timing, often measured in minutes of challenge periods and recovery. Key findings include the lateralized nature of autonomic organization, which is reminiscent of asymmetric motor, sensory, and language pathways. Testing brain function during autonomic challenges demonstrate closely-integrated timing of responses in connected brain areas during autonomic challenges, and the involvement with brain regions mediating postural and motoric actions, including respiration, and cardiac output. The study of pathological processes associated with autonomic disruption shows susceptibilities of different brain structures to altered timing of neural function, notably in sleep disordered breathing, such as obstructive sleep apnea and congenital central hypoventilation syndrome. The cerebellum, in particular, serves coordination roles for vestibular stimuli and blood pressure changes, and shows both injury and substantially altered timing of responses to pressor challenges in sleep-disordered breathing conditions. The insights into central autonomic processing provided by neuroimaging have assisted understanding of such regulation, and may lead to new treatment options for conditions with disrupted autonomic function

Applicability of Quantitative Functional MRI Techniques for Studies of Brain Function at Ultra-High Magnetic Field

This thesis describes the development, implementation and application of various quantitative functional magnetic resonance imaging (fMRI) approaches at ultra-high magnetic field including the assessment with regards to applicability and reproducibility. Functional MRI (fMRI) commonly uses the blood oxygenation level dependent (BOLD) contrast to detect functionally induced changes in the oxy-deoxyhaemoglobin composition of blood which reflect cerebral neural activity. As these blood oxygenation changes do not only occur at the activation site but also downstream in the draining veins, the spatial specificity of the BOLD signal is limited. Therefore, the focus has moved towards more quantitative fMRI approaches such as arterial spin labelling (ASL), vascular space occupancy (VASO) or calibrated fMRI which measure quantifiable physiologically and physically relevant parameters such as cerebral blood flow (CBF), cerebral blood volume (CBV) or cerebral metabolic rate of oxygen (CMRO2), respectively. In this thesis a novel MRI technique was introduced which allowed the simultaneous acquisition of multiple physiological parameters in order to beneficially utilise their spatial and temporal characteristics. The advantages of ultra-high magnetic field were utilised to achieve higher signal-to-noise and contrast-to-noise ratios compared to lower field strengths. This technique was successfully used to study the spatial and temporal characteristics of CBV, CBF and BOLD in the visual cortex. This technique is the first one that allows simultaneous acquisition of CBV, CBF and BOLD weighted fMRI signals in the human brain at 7 Tesla. Additionally, this thesis presented a calibrated fMRI technique which allowed the quantitative estimation of changes in cerebral oxygen metabolism at ultra-high field. CMRO2 reflects the amount of thermodynamic work due to neural activity and is therefore a significant physical measure in neuroscience. The calibrated fMRI approach presented in this thesis was optimised for the use at ultra-high field by adjusting the MRI parameters as well as implementing a specifically designed radio-frequency (RF) pulse. A biophysical model was used to calibrate the fMRI data based on the simultaneous acquisition of BOLD and CBF weighted MRI signals during a gas-breathing challenge. The reproducibility was assessed across multiple brain regions and compared to that of various physiologically relevant parameters. The results indicate that the degree of intra-subject variation for calibrated fMRI is lower than for the classic BOLD contrast or ASL. Consequently, calibrated fMRI is a viable alternative to classic fMRI contrasts with regards to spatial specificity as well as functional reproducibility. This calibrated fMRI approach was also compared to a novel direct calibration technique which relies on complete venous oxygenation saturation during the calibration scan via a gas-breathing challenge. This thesis introduced several reliable quantitative fMRI approaches at 7 Tesla and the results presented are a step forward to the wider application of quantitative fMRI.:1 Introduction 3 2 Background to Functional Magnetic Resonance Imaging 7 2.1 Magnetic Resonance 7 2.1.1 Quantum Mechanics 7 2.1.2 The Classical Point of View 10 2.1.3 Radio Frequency Pulses 12 2.1.4 Relaxation Effects 13 2.1.5 The Bloch Equations 15 2.2 Magnetic Resonance Imaging 16 2.2.1 Data Acquisition 16 2.2.2 Image Formation 17 2.2.2.1 Slice Selection 17 2.2.2.2 Frequency Encoding 18 2.2.2.3 Phase Encoding 19 2.2.2.4 Mathematics of Image Formation 20 2.2.2.5 Signal Formation 22 2.3 Advanced Imaging Methods 24 2.3.1 Echo-Planar Imaging (EPI) 24 2.3.2 Partial Fourier Acquisition 25 2.3.3 Generalised Autocalibrating Partially Parallel Acquisition (GRAPPA) 25 2.3.4 Inversion Recovery (IR) 26 2.3.5 Adiabatic Inversion 26 2.3.5.1 Hyperbolic Secant (HS) RF pulses 28 2.3.5.2 Time Resampled Frequency Offset Corrected Inversion (tr-FOCI) RF Pulses 28 2.4 Physiological Background 29 2.4.1 Neuronal Activity 30 2.4.2 Energy Metabolism 31 2.4.3 Physiological Changes During Brain Activation 32 2.4.4 The BOLD Contrast 34 2.4.5 Disadvantages of the BOLD Contrast 35 2.5 Arterial Spin Labelling (ASL) 35 2.5.1 Pulsed Arterial Spin Labelling 37 2.5.2 Arterial Spin Labelling at Ultra-High Field 41 2.6 Vascular Space Occupancy (VASO) 42 2.6.1 VASO at Ultra-High Field 44 2.6.2 Slice-Saturation Slab-Inversion (SS-SI) VASO 45 2.7 Calibrated Functional Magnetic Resonance Imaging 47 2.7.1 The Davis Model 47 2.7.2 The Chiarelli Model 50 2.7.3 The Generalised Calibration Model (GCM) 52 3 Materials and Methods 53 3.1 Scanner Setup 53 3.2 Gas Delivery and Physiological Monitoring System 53 3.3 MRI Sequence Developments 55 3.3.1 Tr-FOCI Adiabatic Inversion 55 3.3.2 Optimisation of the PASL FAIR QUIPSSII Sequence Parameters 60 3.3.3 Multi-TE Multi-TI EPI 64 4 Experiment I: Comparison of Direct and Modelled fMRI Calibration 68 4.1 Background Information 68 4.2 Methods 69 4.2.1 Experimental Design 69 4.2.2 Visuo-Motor Task 70 4.2.3 Gas Manipulations 71 4.2.4 Scanning Parameters 71 4.2.5 Data Analysis 72 4.2.6 M-value Modelling 72 4.2.7 Direct M-Value Estimation 73 4.3 Results 74 4.4 Discussion 79 4.4.1 M-value Estimation 79 4.4.2 BOLD Time Courses 82 4.4.3 M-Maps and Single Subject Analysis 82 4.4.4 Effects on CMRO2 Estimation 83 4.4.5 Technical Limitations and Implications for Calibrated fMRI 84 4.5 Conclusion 89 5 Experiment II: Reproducibility of BOLD, ASL and Calibrated fMRI 90 5.1 Background Information 90 5.2 Methods 91 5.2.1 Experimental Design 91 5.2.2 Data Analysis 91 5.2.3 Reproducibility 93 5.2.4 Learning and Habituation Effects 95 5.3 Results 95 5.4 Discussion 101 5.4.1 Breathing Manipulations 102 5.4.2 Functional Reproducibility 107 5.4.3 Habituation Effects on Reproducibility 109 5.4.4 Technical Considerations for Calibrated fMRI 110 5.5 Conclusion 112 6 Experiment III: Simultaneous Acquisition of BOLD, ASL and VASO Signals 113 6.1 Background Information 113 6.2 Methods 114 6.2.1 SS-SI VASO Signal Acquisition 114 6.2.2 ASL and BOLD Signal Acquisition 114 6.2.3 Experimental Design 114 6.2.4 Data Analysis 115 6.3 Results 115 6.4 Discussion 116 6.5 Conclusion 120 7 Conclusion and Outlook 12

Simultaneous acquisition of cerebral blood volume-, blood flow-, and blood oxygenation-weighted MRI signals at ultra-high magnetic field

Purpose Yang et al. proposed an MRI technique for the simultaneous acquisition of cerebral blood volume (CBV), cerebral blood flow (CBF), and blood oxygenation level-dependent (BOLD)-weighted MRI signals (9). The purpose of this study was to develop modified version of the Yang sequence, which utilizes the advantages of 7 Tesla, leading to a robust and reliable MRI sequence. MethodsThe inversion recovery-based MR pulse sequence introduced here involves slice-saturation slab-inversion vascular space occupancy (SI-SS-VASO) MRI, double echo planar imaging readouts for arterial spin labeling, and VASO in order to correct for BOLD contamination, and a separate BOLD acquisition to minimize inversion effects on the BOLD signal. A standard visual stimulus block design was used to evaluate the spatial and temporal characteristics of CBV-, CBF-, and BOLD-weighted images. ResultsThe high signal-to-noise ratio and spatial resolution of this method leads to robust activation maps. This technique enables the investigation of the differential spatial specificity and temporal characteristics of the different modalities. ConclusionThe pulse sequence could be a powerful tool for studies of neurovascular coupling, hemodynamic response, or calibrated BOLD. Magn Reson Med 74:513-517, 2015

Interpreting BOLD: towards a dialogue between cognitive and cellular neuroscience

Cognitive neuroscience depends on the use of blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to probe brain function. Although commonly used as a surrogate measure of neuronal activity, BOLD signals actually reflect changes in brain blood oxygenation. Understanding the mechanisms linking neuronal activity to vascular perfusion is, therefore, critical in interpreting BOLD. Advances in cellular neuroscience demonstrating differences in this neurovascular relationship in different brain regions, conditions or pathologies are often not accounted for when interpreting BOLD. Meanwhile, within cognitive neuroscience, increasing use of high magnetic field strengths and the development of model-based tasks and analyses have broadened the capability of BOLD signals to inform us about the underlying neuronal activity, but these methods are less well understood by cellular neuroscientists. In 2016, a Royal Society Theo Murphy Meeting brought scientists from the two communities together to discuss these issues. Here we consolidate the main conclusions arising from that meeting. We discuss areas of consensus about what BOLD fMRI can tell us about underlying neuronal activity, and how advanced modelling techniques have improved our ability to use and interpret BOLD. We also highlight areas of controversy in understanding BOLD and suggest research directions required to resolve these issues