Seong-Gi Kim - US grants

The functional mapping of brain activity based on perfusion changes were demonstrated using a technique (FAIR) based on slice selective and non-selective inversion pulses and EPI data acquisition: FAIR technique has been developed to determine relative CBF changes and signal changes due to finger opposition on the order of 50%, were documented. An important feature of the FAIR technique is that macrovascular and microvascular flow effects can be differentiated and this was experimentally demonstrated. FAIR technique was also applied to quantify CBF changes. We have reported this technique initially in the last year's report. In the past year, functional maps obtained with fair were extensively compared with BOLD based maps and the functional mapping capability of the modality was validated.

technology /technique development; male; female; mental disorders; magnetic resonance imaging; nervous system; human subject; biomedical resource;

Mechanistic issues in BOLD based fMRI were further examined by comparing BOLD images with perfusion change measurements, demonstrating that in gray matter areas in the visual cortex, absolute and relative CBF changes in humans during photic stimulation were 31 1 11 SD ml/100 g tissue/min and 43 1 16 SD% (n = 12), respectively, while the relative oxygen consumption change was close to zero. These findings were in agreement with previous results using positron emission tomography.

9907842


Kamil Ugurbil

This grant involves funds for the purchase of a 7 Tesla/90cm bore NMR imaging/spectroscopy instrument for the Center for Magnetic Resonance Research (CMRR) at the University of Minnesota. Only recently has it been possible to develop the necessary instrumentation and methodology, explore the potential and establish the advantages of the higher fields to extract complementary functional and biochemical information. A significant part of that work was realized at the CMRR. The 7T/90 system will enable a major lead in these developments and provide a mechanism by which this unique instrumentation, spin-physics methodology and expertise are available to researchers in the USA and elsewhere.

Unraveling the mysteries of the human brain represents one of the great challenges of modern biology. Recently, developed functional magnetic resonance imaging (fMRI) has provided a unique capability towards meeting this challenge. Further developments to improve sensitivity, spatial specificity and spatial resolution and extend the methodology to temporally resolved true single event related studies require higher neuronal activation and significant increases in the magnitude of the inherently weak signal changes that are used in fMRI. In going to 7 Tesla, these combined gains are expected to catapult this methodology to a level that is significantly beyond what is currently available. Equally important are recent efforts relying on detection of key intracellular bioenergetics and neuronal activity. However, additional gains in sensitivity and spectral resolution available at 7T are needed to make a significant impact on the biological problem.

DESCRIPTION (Verbatim from the Applicant's Abstract): Understanding the origin and the limitations of the signal intensity changes detected by functional magnetic resonance imaging (fMRI) is critical for full utilization of the capabilities of this technique. This in turn requires an in-depth examination of the physiological basis of fMRI signals. The most commonly used fMRI technique, based on blood oxygenation level dependent (BOLD) effect, is complex and depends on alterations in cerebral metabolic rate of oxygen consumption (CNM02), cerebral blood flow (CBF), and cerebral blood volume (CBV) in response to increased neuronal activity. Contribution of these metabolic and hemodynamic parameters to BOLD is expected to depend on vascular dimensions and geometry as well as experimental parameters such as static magnetic field and spatial resolution. Our understanding of these relationships remains largely qualitative, derives from modeling efforts, and requires additional experimental evaluation. This application aims to bring together expertise in spin-physics, BOLD modeling, and physiology, together with methods utilizing magnetic resonance (MR) imaging and spectroscopy, and different magnetic field strengths (going from 4.7 Tesla to 9.4 Tesla), to focus on investigating the spatiodynamics of vascular and metabolic basis of fMRI signal changes in a well-established animal model. The hypotheses to be tested are: 1) During steady state conditions, regional changes in CMR02 Can be calculated from BOLD and CBF data; and 2) Dynamically, the CMR02 change during neuronal activity is constant except for a transition period in the seconds domain at the onset and the termination of the neuronal stimulation, and the temporal characteristics of the BOLD response is determined by the temporal behavior of CBF and CBV.

Orderly representation of the physical environment in the form of "cortical maps" is a prominent feature of the mammalian brain. In particular, in the primary visual cortex, neurons with similar response properties are clustered into respective iso-functional domains. Spatial layout, development, and function of cortical maps have been studied extensively using a variety of techniques in the past. Despite their enormous success, the use of the traditional mapping techniques is hampered by practical constraints: lack of sufficient field of view (intra- and extracellular recordings); impossibility of in vivo mapping (2-deoxyglucose); and loss of depth information (optical imaging). The rapid development of functional Magnetic Resonance Imaging (fMRI) raises the possibilities to map the functional architecture of the living brain without such limitations. The crucial question is, however, whether the spatial resolution of fMRI is ultimately sufficient to label the computational "scaffold" of the brain's functional architecture: that of columns and maps. Based on our preliminary data, we hypothesize that columnar- and layer-specific functional activity in the cortex can be imaged using hemodynamic magnetic resonance contrasts under ultra high magnetic fields (at 9.4 Tesla). It will be exciting to explore the potentials of this novel technique to elucidate the structure, function, and maps in animals and humans.

DESCRIPTION (Verbatim from Applicant's Abstract): Blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) provides a critical tool to the medical and scientific communities. Despite the indispensable role of the BOLD fMRI technique in mapping human brain function, MRI cannot be readily used to map sub‑millimeter functional structures such as cortical columns due to its relatively broad point spread function, which extends beyond the neuronally active area. It has been proposed, however, that a BOLD signal decrease, which precedes the positive BOLD signal change, can be used to improve the spatial specificity of fMRI. This early negative BOLD signal (sometimes referred to as the "dip") is presumably induced by an early localized increase in oxygen consumption rate without a commensurate localized cerebral blood flow (CBF) increase. Recently, by using the early negative BOLD signal, mapping of functional columns in the cat visual cortex has been successfully achieved in our laboratory. However, the existence of the dip in other species is highly controversial. Further, the negative BOLD signal change observed so far is small and transient, thus its utility to columnar resolution fMRI is limited. Therefore, to fully utilize the dip for functional imaging, it is imperative to understand the biophysical and physiological sources of the early negative BOLD signal change. In this application, we aim to elucidate the origin of the early negative BOLD signal and determine the spatial specificity of fMRI techniques. This will be accomplished by using a well‑established feline orientation column model at an ultra‑high field of 9.4 Tesla. The hypotheses to be tested are: 1.) The source of the early negative BOLD signal change is an early oxygen consumption increase followed by a delayed CBF increase. 2.) The magnitude and dynamics of the early negative BOLD signal are heavily influenced by changes in CBF during increased neural activity. 3.) Columnar structures can be mapped using the CBF response as well as the early negative BOLD signal. The long‑term goal is to improve the spatial resolution of fMRI, so that it will ultimately yield the capability of mapping columnar structures in both animals and humans non‑invasively. Further insight into functional columnar organization in animals and humans will greatly facilitate our basic understanding of the structure, development and plasticity of cortical maps.

DESCRIPTION (provided by applicant): The primary aim of this proposal is to establish a 9.4 Tesla 31 cm bore size magnetic resonance (MR) instrument at the University of Pittsburgh. The high resolution and high sensitivity of this instrument will significantly enhance our ability to perform state-of-art MR imaging research on small to medium sized animals and it will be particularly valuable to the rapidly expanding suite of studies on non-human primates. This proposed system will be used by nine investigators (7 major and 2 minor users) from the University of Pittsburgh, Carnegie Mellon University, and Allegheny General Hospital. The research areas of nine users include advance of functional and physiological MR imaging techniques as well as applications of these methodologies to normal brain function and physiology, trauma, stroke, ischemia, and organ transplantation research. This 9.4T system will be housed in a new imaging facility of approximately 10,000 sq. ft., which also includes a 3T Siemens human and non-human primate MR system and a physiology laboratory. The new imaging facility has the infrastructure and personnel to operate and maintain the proposed instrument. The University of Pittsburgh has made major commitments to establishing a 9.4T imaging laboratory by providing three year operating cost, all necessary auxiliary equipment for animal MR research, and necessary computer facilities. Combining MR imaging and conventional physiology research in a synergistic fashion, the new imaging facility with the proposed 9.4T MR system will play a central role in biomedical MR research.

[unreadable] DESCRIPTION (provided by applicant): [unreadable] [unreadable] Hemodynamic-based brain-mapping techniques, including functional magnetic resonance imaging (fMRI), are widely used for clinical and basic neuroscience research. However, the exact relationship between neural activity and the hemodynamic response with regard to spatial extent and amplitude is not yet clear. A few studies have examined this issue with the most widely used fMRI technique, which is based on blood oxygenation level dependent (BOLD) image contrast. However, the BOLD effect has a complex mechanism that depends on alterations in cerebral metabolic rate of oxygen (CMR02), cerebral blood flow (CBF), and cerebral blood volume (CBV) in response to increased neuronal activity. More importantly, the spatial specificity of the conventional BOLD signal is hampered by contributions from large draining vessels, which can be a few centimeters from neuronally active sites. Further, BOLD contrast depends on vascular dimensions and geometry, as well as imaging techniques (e.g., gradient-echo, spin-echo) and experimental parameters (e.g., static magnetic field strength, echo time). Thus, a correlation between neural activity and the BOLD effect found in one experimental condition cannot be easily generalized to other conditions. Therefore, we propose to determine (i) the spatial correspondence between neural activity and tissue-specific CBF-based fMRI devoid of large vascular contributions and (ii) the quantitative relationship between neural activity and CBF, which is independent of magnetic field strength and imaging parameters. We will investigate these issues using the well-established cat orientation column model, which has been extensively investigated with single-unit recording, 2-deoxyglucose (2-DG) autoradiography, and optical imaging, and which has already been implemented in the PI's laboratory. Since individual orientation columns are separated by a) 1- 1.4 mm, it is an ideal model for our proposed studies.

Abstract Not Provided.

Abstract Not Provided.

[unreadable] DESCRIPTION (provided by applicant): Understanding the relationship between neural activity and functional magnetic resonance imaging (fMRI) signals is critical for pinpointing sites of neural activity and for determining strength of neural activity. The most extensively-used fMRI technique is based on blood oxygenation level dependent (BOLD) images whose contrast depends on alterations in the cerebral metabolic rate of oxygen (CMRO2), cerebral blood flow (CBF), and cerebral blood volume (CBV) in response to increased neuronal activity. BOLD contrast also depends on the choice of many experimental variables, such as imaging technique (e.g., gradient-echo, spin-echo), static magnetic field strength, and echo time. Consequently, the relationship between neural activity and the BOLD effect found for one experimental condition cannot be easily generalized to other conditions. Therefore, fMRI based on a single physiological parameter, such as CBF or CBV, is preferable due to the independence of magnetic field and other experimental variables. The long-term goal of our investigations is to determine the spatial, temporal and magnitude relationships between neural activity and perfusion changes. In the last grant period (7/1/2002-present), we demonstrated that CBF and CBV responses induced by increased neural activity are relatively specific to sites of neural activity. The highest CBF and CBV responses occur within layer 4 in the somatosensory cortex and visual cortex, and within orientation-selective columns in the visual cortex. However, both the source of non-specific perfusion signals from neurally-inactive cortical columns and the quantitative relationship between neural activity and perfusion response at submillimeter resolution are unclear. In this competitive renewal application, we aim to pursue our examination of the neural correlates of perfusion-based signal changes at ultra-high field (9.4 Tesla) using the well-established animal model, which has been extensively investigated with electrophysiology, 2-deoxyglucose autoradiography, and optical imaging. Since CBV responses are closely correlated with CBF responses, functional CBV changes can be converted into CBF changes and vice versa. The CBV-weighted fMRI technique with exogenous contrast agent is more sensitive than CBF-weighted fMRI; so our proposed studies will focus on CBV-weighted fMRI. We also aim to evaluate CBV-weighted techniques that can be applied to human studies. Our proposed studies will provide insight into the size of a vascular functional unit, and consequently could provide a limit to ultimately achievable spatial localization by all hemodynamic-based mapping techniques, including fMRI, H215O-based positron emission tomography, and intrinsic optical imaging. [unreadable] [unreadable] [unreadable]

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