Multiparametric measurement of cerebral physiology using calibrated fMRI

The ultimate goal of calibrated fMRI is the quantitative imaging of oxygen metabolism (CMRO2), and this has been the focus of numerous methods and approaches. However, one underappreciated aspect of this quest is that in the drive to measure CMRO2, many other physiological parameters of interest are often acquired along the way. This can significantly increase the value of the dataset, providing greater information that is clinically relevant, or detail that can disambiguate the cause of signal variations. This can also be somewhat of a double-edged sword: calibrated fMRI experiments combine multiple parameters into a physiological model that requires multiple steps, thereby providing more opportunity for error propagation and increasing the noise and error of the final derived values. As with all measurements, there is a trade-off between imaging time, spatial resolution, coverage, and accuracy. In this review, we provide a brief overview of the benefits and pitfalls of extracting multiparametric measurements of cerebral physiology through calibrated fMRI experiments

Direct Estimation of Evoked Hemoglobin Changes by Multimodality Fusion Imaging

In the last two decades, both diffuse optical tomography (DOT) and blood oxygen level dependent (BOLD)-based functional magnetic resonance imaging (fMRI) methods have been developed as noninvasive tools for imaging evoked cerebral hemodynamic changes in studies of brain activity. Although these two technologies measure functional contrast from similar physiological sources, i.e., changes in hemoglobin levels, these two modalities are based on distinct physical and biophysical principles leading to both limitations and strengths to each method. In this work, we describe a unified linear model to combine the complimentary spatial, temporal, and spectroscopic resolutions of concurrently measured optical tomography and fMRI signals. Using numerical simulations, we demonstrate that concurrent optical and BOLD measurements can be used to create cross-calibrated estimates of absolute micromolar deoxyhemoglobin changes. We apply this new analysis tool to experimental data acquired simultaneously with both DOT and BOLD imaging during a motor task, demonstrate the ability to more robustly estimate hemoglobin changes in comparison to DOT alone, and show how this approach can provide cross-calibrated estimates of hemoglobin changes. Using this multimodal method, we estimate the calibration of the 3tesla BOLD signal to be −0.55%±0.40% signal change per micromolar change of deoxyhemoglobin

Quantifying the Microvascular Origin of BOLD-fMRI from First Principles with Two-Photon Microscopy and an Oxygen-Sensitive Nanoprobe

The blood oxygenation level-dependent (BOLD) contrast is widely used in functional magnetic resonance imaging (fMRI) studies aimed at investigating neuronal activity. However, the BOLD signal reflects changes in blood volume and oxygenation rather than neuronal activity per se. Therefore, understanding the transformation of microscopic vascular behavior into macroscopic BOLD signals is at the foundation of physiologically informed noninvasive neuroimaging. Here, we use oxygen-sensitive two-photon microscopy to measure the BOLD-relevant microvascular physiology occurring within a typical rodent fMRI voxel and predict the BOLD signal from first principles using those measurements. The predictive power of the approach is illustrated by quantifying variations in the BOLD signal induced by the morphological folding of the human cortex. This framework is then used to quantify the contribution of individual vascular compartments and other factors to the BOLD signal for different magnet strengths and pulse sequences.National Institutes of Health (U.S.) (Grant P41RR14075)National Institutes of Health (U.S.) (Grant R01NS067050)National Institutes of Health (U.S.) (Grant R01NS057198)National Institutes of Health (U.S.) (Grant R01EB000790)American Heart Association (Grant 11SDG7600037)Advanced Multimodal NeuroImaging Training Program (R90DA023427

Can Blood Oxygenation Level Dependent Functional Magnetic Resonance Imaging Be Used Accurately to Compare Older and Younger Populations? A Mini Literature Review

A wealth of research has investigated the aging brain using blood oxygenation level dependent functional MRI [Blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI)]. However, many studies do not consider the aging of the cerebrovascular system, which can influence the BOLD signal independently from neural activity, limiting what can be inferred when comparing age groups. Here, we discuss the ways in which the aging neurovascular system can impact BOLD fMRI, the consequences for age-group comparisons and possible strategies for mitigation. While BOLD fMRI is a valuable tool in this context, this review highlights the importance of consideration of vascular confounds

Multimodality imaging and mathematical modelling of drug delivery to glioblastomas

MAJC would like to thank the Isaac Newton Institute for Mathematical Sciences for its hospitality during the programme “Coupling Geometric PDEs with Physics for Cell Morphology, Motility and Pattern Formation” supported by EPSRC Grant Number EP/K032208/1.Patients diagnosed with glioblastoma, an aggressive brain tumour, have a poor prognosis, with a median overall survival of less than 15 months. Vasculature within these tumours is typically abnormal, with increased tortuosity, dilation and disorganization and they typically exhibit a disrupted blood brain barrier. Although it has been hypothesized that the “normalization” of the vasculature resulting from anti-angiogenic therapies could improve drug delivery through improved blood flow, there is also evidence that suggests that the restoration of blood brain barrier integrity might limit the delivery of therapeutic agents and hence their effectiveness. In this paper we apply mathematical models of blood flow, vascular permeability and diffusion within the tumour microenvironment to investigate the effect of these competing factors on drug delivery. Preliminary results from the modelling indicate that all three physiological parameters investigated – flow rate, vessel permeability, and tissue diffusion coefficient – interact nonlinearly to produce the observed average drug concentration in the microenvironment.PostprintPeer reviewe

Biophysical modeling of hemodynamic-based neuroimaging techniques

Thesis (Ph. D. in Medical Engineering and Medical Physics)--Harvard-MIT Program in Health Sciences and Technology, 2013.Cataloged from PDF version of thesis.Includes bibliographical references (pages 163-182).Two different hemodynamic-based neuroimaging techniques were studied in this work. Near-Infrared Spectroscopy (NIRS) is a promising technique to measure cerebral hemodynamics in a clinical setting due to its potential for continuous monitoring. However, the presence of strong systemic interference in the signal significantly limits our ability to recover the hemodynamic response without averaging tens of trials. Developing a new methodology to clean the NIRS signal from systemic interference and isolate the cortical signal would therefore significantly increase our ability to recover the hemodynamic response opening the door for clinical NIRS studies such as epilepsy. Toward this goal, a new method based on multi-distance measurements and state-space modeling was developed and further optimized to remove systemic physiological oscillations contaminating the NIRS signal. Furthermore, the cortical and pial contributions to the NIRS signal were quantified using a new multimodal regression analysis. Functional Magnetic Resonance Imaging (fMRI) based on the Blood Oxygenation Level Dependent (BOLD) response has become the method of choice for exploring brain function, and yet the physiological basis of this technique is still poorly understood. Despite the effort, a detailed and validated model relating the signal measured to the physiological changes occurring in the cortical tissue is still lacking. Modeling the BOLD signal is challenging because of the difficulty to take into account the complex morphology of the cortical microvasculature, the distribution of oxygen in those microvessels and its dynamics during neuronal activation. Here, we overcome this difficulty by performing Monte Carlo simulations over real microvascular networks and oxygen distributions measured in vivo on rodents, at rest and during forepaw stimulation, using two-photon microscopy. Our model reveals for the first time the specific contribution of individual vascular compartment to the BOLD signal, for different field strengths and different cortical orientations. Our model makes a new prediction: the amplitude of the BOLD signal produced by a given physiological change during neuronal activation depends on the spatial orientation of the cortical region in the MRI scanner. This occurs because veins are preferentially oriented either perpendicular or parallel to the cortical surface in the gray matter.by Louis Gagnon.Ph.D.in Medical Engineering and Medical Physic

Astroglial Control of Respiratory Rhythm Generating Circuits

Astrocytes, the most numerous glial cells of the central nervous system, are well known to provide neuronal circuits with essential structural and metabolic support. There is also evidence that astrocytes may modulate the activities of neuronal circuits controlling motor rhythms including those of the brainstem’s preBötzinger complex (preBötC) that generates the rhythm of breathing in mammals. However, the extent and mechanisms of active astroglial control of the respiratory rhythm-generating circuits remain unknown. The morphological features of astrocytes in this critical brainstem region are also unknown. In this dissertation, viral gene transfer approaches designed to block or activate astroglial signaling pathways were used to determine the role of preBötC astrocytes in the control of breathing using in vitro and in vivo experimental models. Computer-aided morphometric analyses were used to investigate the structural features of brainstem astrocytes potentially contributing to their functional role. The results from these complementary, multi-faceted experiments show that (i) morphologically, preBötC astrocytes are larger, have more branches, and longer processes when compared to astrocytes residing in other regions of the brainstem; (ii) in conscious adult rats, blockade of vesicular release mechanisms or ATP-mediated signaling in preBötC astrocytes by virally-induced bilateral expression of either the light chain of tetanus toxin (TeLC), the dominant-negative SNARE proteins (dnSNARE), or a potent ectonucleotidase – transmembrane prostatic acid phosphatase – results in a significant reduction of resting respiratory frequency and frequency of sighs, augmented breaths that engage preBötC circuits to increase inspiratory effort; (iii) hypoxic- and CO2-induced ventilatory responses are significantly reduced when vesicular release mechanisms in preBötC astrocytes are blocked; (iv) activation of preBötC astrocytes expressing Gq-coupled Designer Receptor Exclusively Activated by Designer Drug is associated with higher frequency of both normal inspirations and sighs; (v) blockade of vesicular release mechanisms (expression of TeLC or dnSNARE) in preBötC astrocytes is associated with a dramatic reduction of exercise capacity. These data suggest that astroglial mechanisms involving exocytotic vesicular release of signaling molecules (gliotransmitters), provides tonic excitatory drive to the inspiratory rhythm-generating circuits of the preBötC and contributes to the generation of sighs. The role of preBötC astrocytes in central nervous mechanisms controlling breathing becomes especially important in conditions of metabolic stress requiring homeostatic adjustments of breathing such as systemic hypoxia, hypercapnia, and exercise, when enhanced respiratory efforts are critical to support physiological and behavioral demands of the body