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Overview
Lab Members
John Detre / Mark Elliott / JiongJiong Wang / Andrew Newberg
About the Core
We are establishing the use of multimodal imaging to assess brain physiology during functional activation and in pathological states, with a focus on cerebrovascular disorders. Two related projects are addressed. We have a longstanding interest in the development and validation of perfusion MRI based on arterial spin labeling (ASL). ASL methods are being optimized for use at high field, and for special populations including children. Because ASL methods are completely noninvasive, they provide a unique means for characterizing cerebral blood flow and metabolism in these populations. Also we are trying to utilize high field ASL techniques to quantify CBF changes during sensorimotor activation, cognitive activation, and pharmacological modulation of cerebral function with caffeine. The coupling between CBF and metabolism under these conditions is being examined with PET scanning following 18FDeoxyglucose administration during task activation within the MRI scanner. This innovative approach will allow, for the first time, concurrent examination of fMRI hemodynamics and glucose metabolism.
Active Research
Arterial Spin Labeled Perfusion MRI
Parenchymal perfusion is an important physiologic parameter in the evaluation and management of a variety of neurologic and psychiatric disorders, most notably cerebrovascular disease. ASL perfusion MRI is a promising and noninvasive technique to measure blood flow by utilizing arterial blood water as an endogenous tracer. During the past decade, methodologies for ASL perfusion imaging have evolved from feasibility studies into practical usage. In this project, we are further pursuing development of ASL including: 1) implementation of pseudo-continuous ASL (pCASL) and 3D acquisition (GRASE) with background suppression (BS) at high magnetic field to acquire whole brain perfusion images within a minute (Snapshot ASL), 2) quantification of transit effects using using flow encoding arterial spin tagging (FEAST) technique, and 3) mapping oxygenation and water permeability using ASL images acquired with multiple TEs and diffusion weighting. The improved ASL methods will be applied for measuring hypoperfusion in adults as well as children with cerebrovascular diseases.
Metabolic Correlates of fMRI
Functional MRI studies rely on changes in cerebral blood flow (CBF) as a surrogate measure of changes in metabolism and neural activity. In various pathological states, and possibly even in some physiological states, there may be an uncoupling between these parameters. Our goal is to develop and test a unique multimodal imaging technique combining functional magnetic resonance imaging (fMRI) during 18Ffluorodeoxyglucose (FDG) infusion and subsequent FDG positron emission tomography (FDG-PET) to measure CBF and glucose metabolism concurrently. This is possible because FDG is trapped in the brain during infusion, and has a sufficiently long halflife to allow imaging to be carried out at a slightly later time. This approach will be developed and initially assessed under three separate conditions that should be associated with varying degrees of coupling between CBF and metabolism: 1) Primary sensorimotor stimulation, 2) A cognitive task, and 3) Pharmacological manipulation of cerebral metabolism with caffeine. Once validated, this approach will be useful for verifying the coupling between CBF and metabolism in a variety of other physiological and pathophysiological states. Immediate applications of this technique at our institution alone include the assessment of brain function during sleep deprivation and recovery of function from stroke.
Vigilance Task Performance of CBF and CMRGIc
Tasks that require sustained attention may provide a unique window into understanding the brain especially during conditions in which there is a decrease in overall brain function such as sleep deprivation. The psychomotor vigilance task (PVT), which was developed at the University of Pennsylvania, has proven to be extremely sensitive to individual vulnerability to performance deficits from sleep loss. The PVT, which has been used to measure psychomotor vigilance in a multitude of recent experiments, and also has the advantage of having no substantial practice effect. While the PVT has been well characterized behaviorally, there have been no imaging studies designed to test the relative changes in CBF or CMRGlc associated with performance of the task. Since it is a continuous performance task, it is well suited to the combined fMRI/PET approach, which only allows a single prolonged condition to be examined at a time. Additional, this task has been shown to produce worsening performance the longer the task is performed during each session (time-ontask/TOT effect). One objective of this project is to evaluate changes in CBF and CMRGlc associated with TOT effect in performance of PVT.
The Effects of Caffeine on CBF andCMRGIc
Caffeine is an intriguing pharmacological probe since it reduces blood flow but appears to enhance wakefulness and performance, especially in sleep deprived states. Since fMRI studies typically depend on changes in blood flow to reflect concomitant changes in cerebral metabolism, caffeine administration is an important probe to help further evaluate a technique that can differentiate CBF and CMRGlc. The ability to differentiate metabolism and blood flow in response to caffeine administration is important for fully evaluating the combined fMRI/PET technique described in this proposal since it contrasts with the coupled CBF and CMRGlc response to visual stimulation. The effects of caffeine administration on cerebral function have demonstrated a mixed response with blood flow decreased in response to vasoconstriction and metabolism increased due to cellular effects. These effects occur rapidly since caffeine is quickly absorbed through the gastrointestinal tract. Studies of the effect of caffeine on cerebral blood flow have typically demonstrated a significant reduction in blood flow as the result of its vasoconstrictive effects. This reduction has been as much as 30% for the entire brain, and regional values have had similar reductions. One report suggested that there was an overall decrease in CBF, but a concomitant increase in glucose metabolism after the administration of caffeine. The mechanisms by which caffeine exerts its stimulant effects have not been fully elucidated. Pharmacological studies have demonstrated that caffeine at the levels reached during normal consumption exerts its action through antagonistic effects at central adenosine (A1 & A2) receptors. Stimulation of adenosine receptors increases potassium conductance, which is a critical determinant of hyperpolarization of neurons and thereby of EEG synchronization and sleepiness. Adenosine also inhibits the release of a number of excitatory neurotransmitters thereby promoting hyperpolarization even further. Adenosine is released by neurons during periods of high brain metabolism such as wakefulness. Adenosine is thus thought to represent an essential element of the sleep homeostasis, and caffeine is believed to interfere with this homeostatic regulation by blocking adenosine receptors.
