Our overall goal is to develop a quantitative understanding of the coupling of blood flow and energy metabolism in the human brain, and to develop quantitative methods for assessing this coupling in health and disease. Functional magnetic resonance imaging (fMRI) has revolutionized the study of the working human brain by providing a sensitive, non-invasive tool for mapping brain activity. The method exploits the sensitivity of the MR signal to local changes in deoxy-hemoglobin content, called the Blood Oxygenation Level Dependent (BOLD) effect. The central physiological phenomenon underlying the BOLD effect is that cerebral blood flow (CBF) increases more than the cerebral metabolic rate of oxygen (CMRO2) during increased brain activity. Yet despite its success as a mapping tool, quantitative interpretation of the magnitude of the BOLD response as a reflection of the magnitude of underlying physiological changes is problematic because of our poor understanding of the variability of CBF/CMRO2 coupling. During the previous period of support we implemented and evaluated a calibrated-BOLD approach, measuring local CBF and BOLD responses to mild hypercapnia in addition to neural activation, to measure the coupling of CBF and CMRO2. Our work highlighted the importance of the CBF/CMRO2 coupling ratio for interpreting BOLD responses across brain regions and in disease, and also demonstrated that the calibrated-BOLD approach provides a powerful tool for quantitatively assessing brain physiology for both basic research and potentially in clinical settings. A central problem for the interpretation of the BOLD response is that we do not know to what degree CBF/CMRO2 coupling varies in the healthy human brain, and the primary goal of this proposal is to determine that variability. Our previous results are consistent with the hypothesis that the CBF/CMRO2 coupling ratio increases for stronger stimuli, which is consistent with current ideas that CBF is driven by the input neural activity to a region while CMRO2 responds to the total energy needs of the full evoked activity. We will test this hypothesis in the healthy human brain with experimental paradigms designed to manipulate the types of neural activity involved and test for a dissociation of the CBF and CMRO2 responses. The proposed experiments exploit contrast sensitivity and temporal frequency tuning effects (Aim 1), adaptation effects (Aim 2), and inhibitory effects and negative BOLD signals (Aims 1 and 3). In addition, we will improve the current calibrated-BOLD methodology by developing a more complete mathematical model for the BOLD response that includes effects of intravascular signal change and arterial blood volume changes, and test an alternative hyperoxia technique for calibration as an alternative to hypercapnia (Aim 4). Completion of these goals will lay a solid physiological foundation for both basic science studies with BOLD-fMRI and clinical applications of fMRI.

Public Health Relevance

A calibrated-fMRI methodology has the potential to provide a quantitative probe of brain physiology by measuring blood flow and oxygen metabolism changes. This tool can serve as a "stress-test" to evaluate brain function for early detection of dysfunction and for monitoring the progression of disease or the response to drugs and therapy. Our goal is to lay the groundwork for these applications by extending and improving the methodology and by gaining a better understanding of how flow and metabolism are coupled in the healthy brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS036722-13
Application #
8221003
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Babcock, Debra J
Project Start
1998-02-20
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
13
Fiscal Year
2012
Total Cost
$386,924
Indirect Cost
$136,488
Name
University of California San Diego
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Buxton, Richard B; Griffeth, Valerie E M; Simon, Aaron B et al. (2014) Variability of the coupling of blood flow and oxygen metabolism responses in the brain: a problem for interpreting BOLD studies but potentially a new window on the underlying neural activity. Front Neurosci 8:139
Simon, Aaron B; Griffeth, Valerie E M; Wong, Eric C et al. (2013) A novel method of combining blood oxygenation and blood flow sensitive magnetic resonance imaging techniques to measure the cerebral blood flow and oxygen metabolism responses to an unknown neural stimulus. PLoS One 8:e54816
Leontiev, Oleg; Buracas, Giedrius T; Liang, Christine et al. (2013) Coupling of cerebral blood flow and oxygen metabolism is conserved for chromatic and luminance stimuli in human visual cortex. Neuroimage 68:221-8
Liang, Christine L; Ances, Beau M; Perthen, Joanna E et al. (2013) Luminance contrast of a visual stimulus modulates the BOLD response more than the cerebral blood flow response in the human brain. Neuroimage 64:104-11
Blockley, Nicholas P; Griffeth, Valerie E M; Germuska, Michael A et al. (2013) An analysis of the use of hyperoxia for measuring venous cerebral blood volume: comparison of the existing method with a new analysis approach. Neuroimage 72:33-40
Moradi, Farshad; Buxton, Richard B (2013) Adaptation of cerebral oxygen metabolism and blood flow and modulation of neurovascular coupling with prolonged stimulation in human visual cortex. Neuroimage 82:182-9
Buxton, Richard B (2013) The physics of functional magnetic resonance imaging (fMRI). Rep Prog Phys 76:096601
Moradi, Farshad; Buracas, Giedrius T; Buxton, Richard B (2012) Attention strongly increases oxygen metabolic response to stimulus in primary visual cortex. Neuroimage 59:601-7
Blockley, Nicholas P; Griffeth, Valerie E M; Buxton, Richard B (2012) A general analysis of calibrated BOLD methodology for measuring CMRO2 responses: comparison of a new approach with existing methods. Neuroimage 60:279-89
Ances, Beau M; Vaida, Florin; Cherner, Mariana et al. (2011) HIV and chronic methamphetamine dependence affect cerebral blood flow. J Neuroimmune Pharmacol 6:409-19

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