Our overall goal is to establish a new methodology for quantifying changes in brain state in single subjects, a paradigm for clinical applications in assessing the effects of a drug or for following the progression of disease and the response to therapy. The method builds on several developments during the previous period of support related to quantitative fMRI methods to measure cerebral blood flow (CBF) and the cerebral metabolic rate of oxygen (CMRO2): the development of an alternative approach to calibration in the calibrated BOLD method that does not require inhalation of special gas mixtures;a series of studies showing that the BOLD response alone is relatively insensitive for detecting a change in brain state that leads to a change in the evoked physiological response to a standard stimulus;and a particular example study of caffeine effects showing that quantitative fMRI methods are able to detect substantial changes in both baseline and activation responses of CBF and CMRO2 that were essentially undetected by BOLD alone. Based on this work we propose that a set of four metrics, reflecting baseline CBF and CMRO2 and their responses to a standard stimulus (analogous to a 'stress test'), can be acquired noninvasively and without requiring special gas mixtures in ~20 min. The goal of the project is to establish a basis for clinical applications of this approach by testing the ability of these metrics to track brain state changes in individual subjects.
Aim 1 will test that the new approach to calibration based on measuring the relaxation rate R2'in the baseline state gives essentially the same required information as the standard hypercapnia challenge for quantifying the CMRO2 response to a stimulus.
Aim 2 will test the reproducibility of the four metrics in a healthy population in both back to back test and in studies ~1 month apart.
Aim 3 is a blinded test case of the ability of these metrics to detect changes in brain state due to caffeine on an individual basis. This work will establish the sensitivity and reliability of these metrics for following brain state changes in individual subjecs as a basis for future focused clinical applications in assessing drug effects (e.g., identifying responders, or quantifying the effect on disease), for determining the progression of disease, or for assessing the effect of therapy.

Public Health Relevance

Functional magnetic resonance imaging (fMRI) has not yet achieved its initial promise as a tool for monitoring the human brain in clinical applications. Thi project will test a new quantitative fMRI approach for measuring changes in the physiological state of the brain (blood flow and oxygen metabolism) in individual patients. If successful, this method will be useful for assessing the effects of a drug or following the progression of disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Medical Imaging Study Section (MEDI)
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Babcock, Debra J
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University of California San Diego
Schools of Medicine
La Jolla
United States
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Buxton, Richard B (2016) Beyond BOLD correlations: A more quantitative approach for investigating brain networks. J Cereb Blood Flow Metab 36:461-2
Guo, Jia; Buxton, Richard B; Wong, Eric C (2016) Wedge-shaped slice-selective adiabatic inversion pulse for controlling temporal width of bolus in pulsed arterial spin labeling. Magn Reson Med 76:838-47
Simon, Aaron B; Dubowitz, David J; Blockley, Nicholas P et al. (2016) A novel Bayesian approach to accounting for uncertainty in fMRI-derived estimates of cerebral oxygen metabolism fluctuations. Neuroimage 129:198-213
Wang, Kang; Smith, Zachary M; Buxton, Richard B et al. (2015) Acetazolamide during acute hypoxia improves tissue oxygenation in the human brain. J Appl Physiol (1985) 119:1494-500
Simon, Aaron B; Buxton, Richard B (2015) Understanding the dynamic relationship between cerebral blood flow and the BOLD signal: Implications for quantitative functional MRI. Neuroimage 116:158-67
Blockley, Nicholas P; Griffeth, Valerie E M; Simon, Aaron B et al. (2015) Calibrating the BOLD response without administering gases: comparison of hypercapnia calibration with calibration using an asymmetric spin echo. Neuroimage 104:423-9
Griffeth, Valerie E M; Simon, Aaron B; Buxton, Richard B (2015) The coupling of cerebral blood flow and oxygen metabolism with brain activation is similar for simple and complex stimuli in human primary visual cortex. Neuroimage 104:156-62
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
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
Buxton, Richard B (2013) The physics of functional magnetic resonance imaging (fMRI). Rep Prog Phys 76:096601

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