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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS036722-14
Application #
8695773
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Babcock, Debra J
Project Start
1998-02-20
Project End
2018-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
14
Fiscal Year
2014
Total Cost
$339,063
Indirect Cost
$120,313
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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