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Overview

Lab Members

Rahim Rizi / Mitchell Schnall / William Happer / Masaru Ishii / Punam Saha / Reynold Panettieri / David Lipson / Warren Gefter / Kiarash Emami / J.Hansen-Flaschen / Jiansheng Yu / Rakesh Kumar / Fani Bozkurt / Maxim Itkin

About the Core

The primary focus of the group, functional and metabolic imaging, is on ‘hyperpolarized’ agents, in which specific nuclei are aligned to a degree 104-105 times greater than is possible in ordinary MRI. This leads to tremendous signal-to-noise advantages, which can be used to increase spatial resolution, temporal resolution, or molecular specificity. The techniques are currently in the preclinical stage, but show great promise for noninvasive diagnosis and classification of a variety of disorders at a very early stage.

One set of methods makes use of hyperpolarized helium-3 gas. The nuclei are aligned through an interaction with polarized laser light and then breathed in by the subject. Images of the gas distribution in the lungs and sinuses clearly show pre- and non-symptomatic asthma and emphysema, and are being studied to understand the pathogenesis of those and other diseases. Additional aspects of the images, such as the image intensity decay rate, gas diffusion rate, and gas flow rate can be analyzed to yield details about lung oxygenation, perfusion, and microstructure with unprecedented detail. Our group engages and human and animal studies to establish the techniques in a clinical environment, and study predictive value and correlation to disease progression and treatment.

Another set of techniques makes use of hyperpolarized carbon-13 in a variety of molecules. Although in an earlier research stage, molecular imaging is particularly exciting because of its specificity. A molecular event or transformation may be chosen and isolated in an imaging environment, eventually allowing for disorders to be identified at the earliest and most correctable stage. The techniques used in our group involve spin order transfer from parahydrogen or polarized electrons in free radicals, followed by a series of rapid chemical reactions, purification, and temperature/pH normalization. The work is therefore more focused on device engineering and basic chemistry/physics studies, although we have begun in vivo work with cell culture and animal studies as well.

	Hyperpolarized 3He MRI ventilation scans of a Yorkshire pig along with the corresponding fractional ventilation map.
	Hyperpolarized 13C MRI angiograms of a Yorkshire pig depicting pulmonary blood flow though a coronal slice just posterior to the heart. Images were taken at one-second intervals. 5 ml of hyperpolarized 2-hydroxyethyl propionate, 300 mM solution, was injected into the femoral vein at a rate of 1 ml per second.

Active Research

Physiolgical Lung Function MRI

Due to diagnostic limitations, the pathophysiology of ventilation (V), perfusion (Q), and oxygen alterations in patients with lung disease remain incomplete. The traditional radionuclide method (i.e., V/Q scan) is the ‘gold standard’ of clinical assessment of V/Q mismatch. However, it has low spatial resolution, cannot image cross-sectional views, deposits radiolabeled aerosols in the central airways (causing error), and provides no quantitative data. Single-photon emission computed tomography (SPECT) has a higher resolution, but still higher resolution is essential. Global pulmonary function may be determined by the multiple inert gas elimination technique (MIGET), but this yields no regional information.

We position our efforts to advance the technology of MR-V/Q imaging in the hopes of being able to detect acute and chronic pulmonary diseases. We utilize novel hyperpolarized 3Helium-magnetic resonance imaging (3He-MRI) to assess V/Q and develop methods to obtain a set of physiological parameters of regional ventilation, regional perfusion, regional partial pressure of oxygen, and regional oxygen depletion rate for the complete appreciation of lung function.

Traditionally, pulmonary imaging techniques have focused on anatomic and pathologic descriptions of the lung parenchyma, airways, and vasculature. Functional lung imaging is a relatively recent development that seeks to image physiologic parameters. It has generated considerable interest because of the potential to generate high resolution, regional distributions of functional parameters. These regional measurements can enhance detection of lung pathologies and provide fundamental insights into the pathophysiologic mechanisms of disease.

The central purpose of our investigations is to demonstrate that HP 3He MRI maps of regional physiologic parameters describing lung function (regional ventilation, regional perfusion, regional alveolar partial pressure of oxygen (PAO2), alveolar oxygen depletion rate, and the regional alveolar ventilation/perfusion ratio (VA/Q)) will more accurately detect early functional and structural changes in the lung than existing imaging modalities.

The overall goal of this project is to obtain regional maps of the important functional lung parameters using nuclear magnetic resonance imaging of hyperpolarized 3He gas. Our investigations plan to also refine and characterize a safe, sensitive, regional, truly quantitative, non-invasive, and non-radioactive MR technique that offers the newfound ability to detect early changes in lung function and structure associated with pulmonary diseases, to quantitatively follow the progression of disease, and to immediately ascertain response to therapy.

129Xe MR Technology Development

We have two goals: (1) to improve yields of hyperpolarized 129Xe and increase its nuclear polarization for applications in medicine and other fields, and (2) to carry out exploratory experiments on the use of 129Xe for medical diagnostics. Most biological work with hyperpolarized gases has focused on 3He. The only other noble gas that can be readily polarized, 129Xe, has received relatively little attention because of two factors: (1) The MR signals from 129Xe are substantially smaller than those from 3He; and (2) For in-vivo applications, there has been concern about the anesthetic properties of 129Xe. However, 129Xe has a number of potential advantages over 3He: 129Xe is much more soluble in tissue than 3He, so it is much easier to obtain MR signals from tissue than with 3He; 129Xe exhibits a much larger chemical shift than 3He, and this chemical shift changes for different biological media—e.g., blood plasma, red blood cells, oxygenated and deoxygenated blood, etc; 129Xe comprises 26.44% of the naturally occurring xenon in the earth’s atmosphere, rendering the supply of 129Xe virtually inexhaustible. In contrast, all 3He is produced artificially as radioactive tritium (3H) decays, resulting in a limited supply and substantially higher cost.

Paranasal Sinuses MR Imaging

In this project, we propose to develop a noninvasive imaging method that provides for integrated structural and functional evaluation of the sinuses. This method is based on the magnetic resonance imaging (MRI) of laser-polarized helium-3 (3He) gas. High-resolution three-dimensional (3D) images of the steady-state distribution of the gas will provide a structural assessment of the paranasal sinuses, allowing for direct visualization of airway patency. Moreover dynamic, time-resolved images of gas flow through the sinuses will provide a synchronous functional assessment of ostial patency. These methods must initially be simulated in representative phantom structures. Subsequently, animal experiments may then be conducted to test these hypotheses and to provide in vivo validation through comparison to gold standard methods.

Sinusitis is a significant health problem in the United States, affecting 33 million Americans and resulting in 22-25 million physician visits annually with medical costs estimated at more than $5.8 billion yearly. Sinusitis is a treatable disease and functional endoscopic sinus surgery (FESS) is one of the most common surgical procedures in the United States. Although noninvasive structural imaging techniques such as high-resolution CT have made a positive impact on clinical management, no clinically available functional imaging methods for evaluating paranasal sinus exist. This is in contrast to other organs and systems such as the lungs, kidney, balance system, etc., where functional tests have simplified and clarified treatment strategies. In this project we propose to develop a hyperpolarized 3He MRI technique for evaluating paranasal sinus function. Through collaborative studies these techniques will be used to determine whether physiologic information obtained using 3He MRI can be used to make a positive impact on the management and treatment of chronic sinusitis.

Pulmonary V/Q Co-registration

The ability to compute spatially co-registered images of pulmonary ventilation and perfusion is of great clinical interest. Many pathophysiologic states alter either ventilation (e.g., chronic obstructive pulmonary disease, emphysema) and/or perfusion (pulmonary hypertension, pulmonary embolism). Recently, noninvasive forms of magnetic resonance pulmonary imaging have been developed. Such methods may be used to obtain quantitative images of lung perfusion. However, the accurate calculation of regional V/Q has proven to be very demanding, as it requires information on both alveolar ventilation and perfusion. The combined method for obtaining regional V/Q that has been proposed here is not straightforward. Several issues must first be addressed before these methods can achieve widespread clinical usage. Among them is the issue of co-registration between ventilation and perfusion images in order to achieve spatially matched measures of regional V and Q. A feasible solution of this problem demands pre-segmented object definitions in two images, or at least identification of matching landmarks in the two images. In this project, we develop a method for accurate co-registration of ventilation and perfusion images of the lung.

Accurate measurement of physiological parameters for comprehensive assessment of lung function requires a reliable method for co-registration of lung images obtained from either identical or different imaging methods. Imaging of the regional distribution of pulmonary ventilation (V), pulmonary perfusion (Q), and the resulting ventilation/perfusion ratio (V/Q) provides important insight into the mechanisms of both normal and abnormal physiology. Recently, noninvasive forms of magnetic resonance (MR) pulmonary ventilation and perfusion imaging have been developed. Each of these functional pulmonary imaging methods has been applied independently to a variety of physiological conditions. However, the accurate calculation of a physiological parameter such as regional V/Q is not straightforward, when each of these parameters is evaluated using an independent method. In fact, several issues must first be addressed before these methods can achieve widespread clinical usage. Among them is the issue of co-registration between ventilation and perfusion images, necessary in order to achieve spatially matched measures of regional V and Q.

Likewise, accurate identification of anatomical structure in the sinuses requires co-registration of images. Recently, combined proton and 3He images of the paranasal sinuses have proven to be an extremely important step in obtaining an intimate knowledge of sinus anatomy, a clear understanding of which sinuses are diseased, and of those, which would benefit from intervention techniques. The goal of this project is to develop methods for co-registration of proton and 3He images of the lung and sinuses