Papers by Richard b. Buxton
NeuroImage, Jan 19, 2016
Several techniques have been proposed to estimate relative changes in cerebral metabolic rate of ... more Several techniques have been proposed to estimate relative changes in cerebral metabolic rate of oxygen consumption (CMRO2) by exploiting combined BOLD fMRI and cerebral blood flow data in conjunction with hypercapnic or hyperoxic respiratory challenges. More recently, methods based on respiratory challenges that include both hypercapnia and hyperoxia have been developed to assess absolute CMRO2, an important parameter for understanding brain energetics. In this paper, we empirically optimize a previously presented "original calibration model" relating BOLD and blood flow signals specifically for the estimation of oxygen extraction fraction (OEF) and absolute CMRO2. To do so, we have created a set of synthetic BOLD signals using a detailed BOLD signal model to reproduce experiments incorporating hypercapnic and hyperoxic respiratory challenges at 3T. A wide range of physiological conditions was simulated by varying input parameter values (baseline cerebral blood volume (CB...
Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 2011
Human immunodeficiency virus (HIV) and methamphetamine (METH) dependence are independently associ... more Human immunodeficiency virus (HIV) and methamphetamine (METH) dependence are independently associated with neuronal dysfunction. The coupling between cerebral blood flow (CBF) and neuronal activity is the basis of many task-based functional neuroimaging techniques. We examined the interaction between HIV infection and a previous history of METH dependence on CBF within the lenticular nuclei (LN). Twenty-four HIV-/METH-, eight HIV-/METH+, 24 HIV+/METH-, and 15 HIV+/METH+ participants performed a finger tapping paradigm. A multiple regression analysis of covariance assessed associations and two-way interactions between CBF and HIV serostatus and/or previous history of METH dependence. HIV+ individuals had a trend towards a lower baseline CBF (-10%, p = 0.07) and greater CBF changes for the functional task (+32%, p = 0.01) than HIV- subjects. Individuals with a previous history of METH dependence had a lower baseline CBF (-16%, p = 0.007) and greater CBF changes for a functional task (...
Frontiers in Neuroscience, 2014
NeuroImage, 2012
Top-down attention enhances neural processing, but its effect on metabolic activity in primary vi... more Top-down attention enhances neural processing, but its effect on metabolic activity in primary visual cortex (V1) is unclear. Combined blood flow and oxygenation measurements provide the best tool for investigating modulations of oxidative metabolism. We measured the human V1 response to a peripheral low contrast stimulus using fMRI and found a larger fractional modulation of blood flow with attention compared to the blood oxygenation level dependent (BOLD) response, thus indicating a much larger modulation of oxygen metabolism than was previously thought. These findings point to different aspects of neural activity driving flow and metabolic changes to different degrees. We propose that V1 flow is driven strongly but not exclusively by the initial sensory-driven neural activity, which dominates the response in the unattended condition, while V1 oxygen metabolism is driven strongly by the overall neural activity, which is modulated by top-down signals related to attention.
NeuroImage, 2013
Prolonged visual stimulation results in neurophysiologic and hemodynamic adaptation. However, the... more Prolonged visual stimulation results in neurophysiologic and hemodynamic adaptation. However, the hemodynamic adaptation appears to be small compared to neural adaptation. It is not clear how the cerebral metabolic rate of oxygen (CMRO 2) is affected by adaptation. We measured cerebral blood flow (CBF) and CMRO 2 change in responses to peripheral stimulation either continuously, or intermittently (on/off cycles). A linear system's response to the continuous input should be equal to the sum of the original response to the intermittent input and a version of that response shifted by half a cycle. The CMRO 2 response showed a large non-linearity consistent with adaptation, the CBF response adapted to a lesser degree, and the blood oxygenation level dependent (BOLD) response was nearly linear. The metabolic response was coupled with a larger flow in the continuous condition than in the intermittent condition. Our results suggest that contrast adaptation improves energy economy of visual processing. However BOLD modulations may not accurately represent the underlying metabolic nonlinearity due to modulation of the coupling of blood flow and oxygen metabolism changes. 1 Introduction Prolonged exposure to a stimulus alters how subsequent stimuli are perceived. Adaptation is a form of neural plasticity that is ubiquitous in the sensory systems. Different forms of adaptation are present throughout the visual processing pathway (
NeuroImage, 2013
Hyperoxia is known to cause an increase in the blood oxygenation level dependent (BOLD) signal th... more Hyperoxia is known to cause an increase in the blood oxygenation level dependent (BOLD) signal that is primarily localised to the venous vasculature. This contrast mechanism has been proposed as a way to measure venous cerebral blood volume (CBVv) without the need for more invasive contrast media. In the existing method the analysis modelled the data as a dynamic contrast agent experiment, with the assumption that the BOLD signal of tissue was dominated by intravascular signal. The effects on the accuracy of the method due to extravascular BOLD signal changes, as well as signal modulation by intersubject differences in baseline physiology, such as haematocrit and oxygen extraction fraction, have so far been unexplored. In this study the effect of extravascular signal and intersubject physiological variability was investigated by simulating the hyperoxia CBVv experiment using a detailed BOLD signal model. This analysis revealed substantial uncertainty in the measurement of CBVv using the existing analysis based on dynamic contrast agent experiments. Instead, the modelling showed a simple and direct relationship between the BOLD signal change and CBVv, and an alternative analysis method with much reduced uncertainty was proposed based on this finding. Both methods were tested experimentally, with the new method producing results that are consistent with the limited literature in this area.
The Journal of Infectious Diseases, 2010
We investigated the interactions between human immunodeficiency virus (HIV) infection and aging a... more We investigated the interactions between human immunodeficiency virus (HIV) infection and aging and their effects on brain function demands by means of functional magnetic resonance imaging (fMRI). A multiple-regression model was used to study the association and interaction between fMRI measures, HIV serostatus, and age for 26 HIV-infected subjects and 25 seronegative subjects. Although HIV serostatus and age independently affected fMRI measures, no interaction occurred. Functional brain demands in HIV-positive subjects were equivalent to those of HIV-negative subjects who were 15-20 years older. Frailty parallels between HIV infection and aging could result from continued immunological challenges depleting resources and triggering increased metabolic demands. In the future, fMRI could be a noninvasive biomarker to assess HIV infection in the brain. Biological similarities exist between aging and human immunodeficiency virus (HIV) infection. Both cause a frailty phenotype characterized by generalized decreased physical function caused by enhanced vulnerability to immunological stressors
Frontiers in neuroenergetics, 2010
Functional magnetic resonance imaging is widely used to map patterns of brain activation based on... more Functional magnetic resonance imaging is widely used to map patterns of brain activation based on blood oxygenation level dependent (BOLD) signal changes associated with changes in neural activity. However, because oxygenation changes depend on the relative changes in cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO(2)), a quantitative interpretation of BOLD signals, and also other functional neuroimaging signals related to blood or tissue oxygenation, is fundamentally limited until we better understand brain oxygen metabolism and how it is related to blood flow. However, the positive side of the complexity of oxygenation signals is that when combined with dynamic CBF measurements they potentially provide the best tool currently available for investigating the dynamics of CMRO(2). This review focuses on the problem of interpreting oxygenation-based signals, the challenges involved in measuring CMRO(2) in general, and what is needed to put oxygenation-based estim...
SummarySeveral current functional neuroimaging methods are sensitive to cerebral metabolism and c... more SummarySeveral current functional neuroimaging methods are sensitive to cerebral metabolism and cerebral blood flow (CBF) rather than the underlying neural activity itself. Empirically, the connections between metabolism, flow and neural activity are complex and somewhat counterintuitive: CBF and glycolysis increase more than seems to be needed to provide oxygen and pyruvate for oxidative metabolism, and the oxygen extraction fraction is relatively low in the brain anddecreaseswhen oxygen metabolism increases. This work lays a foundation for the idea that this unexpected pattern of physiological changes is consistent with basic thermodynamic considerations related to metabolism. In the context of this thermodynamic framework, the apparent mismatches in metabolic rates and CBF are related to preserving the entropy change of oxidative metabolism, specifically the O2/CO2ratio in the mitochondria. However, the mechanism supporting this CBF response is likely not due to feedback from a h...
Functional magnetic resonance imaging (fMRI) using the blood oxygenation level dependent (BOLD) s... more Functional magnetic resonance imaging (fMRI) using the blood oxygenation level dependent (BOLD) signal is a standard tool in human neuroscience studies. However, the BOLD signal is physiologically complex, depending on the baseline state of the brain and the balance of changes in blood flow and oxygen metabolism in response to a change in neural activity. Interpretation of the magnitude of the BOLD response is thus problematic; specifically, group differences of the BOLD response to a standard task or stimulus, or a change after administration of a drug, could be due to a change in the neural response, neurovascular coupling, or the baseline state. While changes in oxygen metabolism can serve as a biomarker of neural activity change, reflecting the energy cost of activity, oxygen metabolism cannot be estimated from BOLD measurements alone. Here we used the effects of caffeine as a test case to show that a suite of additional noninvasive measurements, requiring no manipulation of inh...
Quantitative functional magnetic resonance imaging methods make it possible to measure cerebral o... more Quantitative functional magnetic resonance imaging methods make it possible to measure cerebral oxygen metabolism (CMRO2) in the human brain. Current methods require the subject to breathe special gas mixtures (hypercapnia and hyperoxia). We tested a noninvasive suite of methods to measure absolute CMRO2in both baseline and dynamic activation states without the use of special gases: arterial spin labeling (ASL) to measure baseline and activation cerebral blood flow (CBF), with concurrent measurement of the blood oxygenation level dependent (BOLD) signal as a dynamic change in tissue R2*; VSEAN to estimate baseline O2extraction fraction (OEF) from a measurement of venous blood R2, which in combination with the baseline CBF measurement yields an estimate of baseline CMRO2; and FLAIR-GESSE to measure tissue R2′to estimate the scaling parameter needed for calculating the change in CMRO2in response to a stimulus with the calibrated BOLD method. Here we describe results for a study sample...
Philosophical transactions of the Royal Society of London. Series B, Biological sciences, Oct 5, 2016
The computational properties of the human brain arise from an intricate interplay between billion... more The computational properties of the human brain arise from an intricate interplay between billions of neurons connected in complex networks. However, our ability to study these networks in healthy human brain is limited by the necessity to use non-invasive technologies. This is in contrast to animal models where a rich, detailed view of cellular-level brain function with cell-type-specific molecular identity has become available due to recent advances in microscopic optical imaging and genetics. Thus, a central challenge facing neuroscience today is leveraging these mechanistic insights from animal studies to accurately draw physiological inferences from non-invasive signals in humans. On the essential path towards this goal is the development of a detailed 'bottom-up' forward model bridging neuronal activity at the level of cell-type-specific populations to non-invasive imaging signals. The general idea is that specific neuronal cell types have identifiable signatures in th...
eLife, 2016
Identification of the cellular players and molecular messengers that communicate neuronal activit... more Identification of the cellular players and molecular messengers that communicate neuronal activity to the vasculature driving cerebral hemodynamics is important for (1) the basic understanding of cerebrovascular regulation and (2) interpretation of functional Magnetic Resonance Imaging (fMRI) signals. Using a combination of optogenetic stimulation and 2-photon imaging in mice, we demonstrate that selective activation of cortical excitation and inhibition elicits distinct vascular responses and identify the vasoconstrictive mechanism as Neuropeptide Y (NPY) acting on Y1 receptors. The latter implies that task-related negative Blood Oxygenation Level Dependent (BOLD) fMRI signals in the cerebral cortex under normal physiological conditions may be mainly driven by the NPY-positive inhibitory neurons. Further, the NPY-Y1 pathway may offer a potential therapeutic target in cerebrovascular disease.
NeuroImage, Jan 7, 2015
Calibrated BOLD imaging, in which traditional measurements of the BOLD signal are combined with m... more Calibrated BOLD imaging, in which traditional measurements of the BOLD signal are combined with measurements of cerebral blood flow (CBF) within a BOLD biophysical model to estimate changes in oxygen metabolism (CMRO2), has been a valuable tool for untangling the physiological processes associated with neural stimulus-induced BOLD activation. However, to date this technique has largely been applied to the study of essentially steady-state physiological changes (baseline to activation) associated with block-design stimuli, and it is unclear whether this approach may be directly extended to the study of more dynamic, naturalistic experimental designs. In this study we tested an assumption underlying this technique whose validity is critical to the application of calibrated BOLD to the study of more dynamic stimuli, that information about fluctuations in venous cerebral blood volume (CBVv) can be captured indirectly by measuring fluctuations in CBF, making the independent measurement o...
NeuroImage, Jan 15, 2008
Functional magnetic resonance imaging (fMRI) based on blood oxygenation level dependent (BOLD) si... more Functional magnetic resonance imaging (fMRI) based on blood oxygenation level dependent (BOLD) signal changes is a sensitive tool for mapping brain activation, but quantitative interpretation of the BOLD response is problematic. The BOLD response is primarily driven by cerebral blood flow (CBF) changes, but is moderated by M, a scaling parameter reflecting baseline deoxyhemoglobin, and n, the ratio of fractional changes in CBF to cerebral metabolic rate of oxygen consumption (CMRO(2)). We compared M and n between cortical (visual cortex, VC) and subcortical (lentiform nuclei, LN) regions using a quantitative approach based on calibrating the BOLD response with a hypercapnia experiment. Although M was similar in both regions (~5.8%), differences in n (2.21+/-0.03 in VC and 1.58+/-0.03 in LN; Cohen d=1.71) produced substantially weaker (~3.7x) subcortical than cortical BOLD responses relative to CMRO(2) changes. Because of this strong sensitivity to n, BOLD response amplitudes cannot ...
Advances in Neurobiology, 2011
ABSTRACT With the growing recognition of the complexity of neurovascular coupling, research has f... more ABSTRACT With the growing recognition of the complexity of neurovascular coupling, research has focused on the “neurovascular unit”, a close association between neurons, astrocytes and blood vessels. A number of experimental tools have been developed for probing the neurovascular unit in animal models, providing the potential for a much deeper understanding of these fundamental physiological mechanisms. In this chapter, we review some of the available experimental and computational methods and present a multi-level conceptual framework for analyzing and interpreting a wide range of experimental measurements. We then discuss our working hypotheses regarding the regulation of blood flow and neurophysiological correlates of fMRI signals. Finally, we discuss how multimodal imaging, along with valid physiological models, can ultimately be used to obtain quantitative estimates of physiological parameters in health and disease and provide an outlook for the future directions in neurovascular research.
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 25, 2015
The blood oxygenation level-dependent (BOLD) contrast is widely used in functional magnetic reson... more 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 str...
NeuroImage, 2008
Although functional MRI (fMRI) based on blood oxygenation leveldependent (BOLD) signal changes is... more Although functional MRI (fMRI) based on blood oxygenation leveldependent (BOLD) signal changes is a sensitive tool for mapping brain activation, quantitative studies of the physiological effects of pharmacological agents using fMRI alone are difficult to interpret due to the complexities inherent in the BOLD response. Hypercapnia-calibrated BOLD methodology is potentially a more powerful physiological probe of brain function, providing measures of the changes in cerebral blood flow (CBF) and the cerebral metabolic rate of oxygen (CMRO 2 ). In this study, we implemented a quantitative R 2 * approach for assessing the BOLD response to improve the stability of repeated measurements, in combination with the calibrated BOLD method, to examine the CBF and CMRO 2 responses to caffeine ingestion. Ten regular caffeine consumers were imaged before and after a 200-mg caffeine dose. A dual-echo arterial spin labeling technique was used to measure CBF and BOLD responses to visual stimulation, caffeine consumption and mild hypercapnia. For a region of interest defined by CBF activation to the visual stimulus, the results were: hypercapnia increased CBF (+ 46.6%, ± 11.3, mean and standard error), visual stimulation increased both CBF (+ 47.9%, ±2.9) and CMRO 2 (+ 20.7%, ±1.4), and caffeine decreased CBF (-34.5%, ± 2.6) with a non-significant change in CMRO 2 (+5.2%, ± 6.4). The coupling between CBF and CMRO 2 was significantly different in response to visual stimulation compared to caffeine consumption. A calibrated BOLD methodology using R 2 * is a promising approach for evaluating CBF and CMRO 2 changes in response to pharmacological interventions.
Acoustical Imaging, 1995
ABSTRACT Elasticity imaging is based on two processes. The first is the evaluation of the mechani... more ABSTRACT Elasticity imaging is based on two processes. The first is the evaluation of the mechanical response of a stressed tissue using imaging modalities, e.g. ultrasound, magnetic resonance imaging (MRI), computed tomography (CT) scans and Doppler ultrasound. The second step is depiction of the elastic properties of internal tissue structures by mathematical solution of the inverse mechanical problem. The evaluation of elastic properties of tissues has the potential for being an important diagnostic tool in the detection of cancer as well as other injuries and diseases. The success of breast self-examination in conjunction with mammography for detection and continuous monitoring of lesions has resulted in early diagnosis and institution of therapy. Self-examination is based on the manually palpable texture difference of the lesion relative to adjacent tissue and, as such, is limited to lesions located relatively near the skin surface and increased lesion hardness with respect to the surrounding tissue. Imaging of tissue “hardness” should allow more sensitive detection of abnormal structures deeper within tissue. Tissue hardness can actually be quantified in terms of the tissue elastic moduli and may provide good contrast between normal and abnormal tissues based on the large relative variation in shear (or Young’s) elastic modulus.
PloS one, 2013
Simultaneous implementation of magnetic resonance imaging methods for Arterial Spin Labeling (ASL... more Simultaneous implementation of magnetic resonance imaging methods for Arterial Spin Labeling (ASL) and Blood Oxygenation Level Dependent (BOLD) imaging makes it possible to quantitatively measure the changes in cerebral blood flow (CBF) and cerebral oxygen metabolism (CMRO(2)) that occur in response to neural stimuli. To date, however, the range of neural stimuli amenable to quantitative analysis is limited to those that may be presented in a simple block or event related design such that measurements may be repeated and averaged to improve precision. Here we examined the feasibility of using the relationship between cerebral blood flow and the BOLD signal to improve dynamic estimates of blood flow fluctuations as well as to estimate metabolic-hemodynamic coupling under conditions where a stimulus pattern is unknown. We found that by combining the information contained in simultaneously acquired BOLD and ASL signals through a method we term BOLD Constrained Perfusion (BCP) estimatio...
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Papers by Richard b. Buxton