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«David G. Bennett June 2007 Approved: Christopher H. Sotak, Ph.D. Major Advisor Professor Department of Biomedical Engineering Worcester Polytechnic ...»

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Osmotic- and Stroke-Induced Blood-Brain Barrier Disruption

Detected by Manganese-Enhanced Magnetic Resonance


A dissertation submitted to the faculty of

Worcester Polytechnic Institute

in partial fulfillment of the requirements for the degree of Doctor of Philosophy in

Biomedical Engineering


David G. Bennett

June 2007


Christopher H. Sotak, Ph.D.

Major Advisor


Department of Biomedical Engineering

Worcester Polytechnic Institute George D. Pins, Ph.D. Karl G. Helmer, Ph.D.

Associate Professor A. A. Martinos Center for Biomedical Imaging Department of Biomedical Engineering Charlestown, Massachusetts Worcester Polytechnic Institute Yitzhak Mendelson, Ph.D. Peter Grigg, Ph.D.

Professor and Interim Head Professor Department of Biomedical Engineering Department of Physiology Worcester Polytechnic Institute University of Massachusetts Medical School


As I look back on my time at WPI it is apparent that I owe a debt of gratitude to several individuals who assisted me in good times and bad. First and foremost, I am thankful for having the support of my wonderful wife Alexia and close friends of ours. Alexia is a woman of seemingly infinite patience and love. She stood steadfast by my side during summer weekend imaging trials, periods of frustration, and months of writing. Alexia’s support and encouragement helped make this work possible. Thank you for everything my love. I love you.

My start to a career in MRI began with the generous support of TJ and Maura McCartney back in 1994. Maura, you started me on this career path with your generous assistance and I wish I could celebrate and thank you in person now. You truly came to me at a decisive time in my life and for this I am humbly grateful. My memory of you is crystal clear and my affections have not changed over the years since your passing. I hope to see you again. May God bless you.

I am very thankful for having been a part of Prof. Christopher Sotak’s lab. Through his wealth of scientific knowledge and demand for scientific rigor Chris provides a rich research environment that is demanding yet open to new ideas. Chris, you are well aware of my successes and failures and through each of these I have grown as a person and as a scientist. I sincerely thank you for your efforts in steering me towards success. As another member of Chris’ lab during my time at WPI, Dr. Karl Helmer was a key resource for scientific and personal advice.

Karl, since your parting from the lab I have missed our discussions, both scientific and political!

Thank you for all forms of your support during my time at WPI.

I very much enjoyed the time I spent with Dr. Yitzhak Mendelson, both in the classroom and in informal discussions. Dr. Mendelson’s friendly demeanor made it easy to talk about graduate student life in general and he provided perspective from someone with a background similar to mine. Dr. Nils Henninger and James Bouley provided invaluable surgical assistance during my experiments. Nils, your scientific skepticism was most appreciated and motivated me further towards experimental rigor. And Nils please remember, it’s manganese, not magnesium! I thank you very much for everything and I am glad to consider you both a friend.

I am grateful for the efforts of my dissertation committee members; Drs. Chris Sotak, Karl Helmer, Yitzhak Mendelson, Peter Grigg, and George Pins. I appreciate their time spent reading my dissertation and attending committee meetings. I also appreciate their suggestions during my defense discussion and I will strive to reach their level of scientific achievement and personal success.

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ABSTRACT Manganese (Mn2+) has recently gained acceptance as a magnetic resonance imaging (MRI) contrast agent useful for generating contrast in the functioning brain. The paramagnetic properties of Mn2+, combined with the cell’s affinity for Mn2+ via voltage-gated calcium channels, makes Mn2+ sensitive to cellular activity in the brain. Compared with indirect measures of brain function, such as blood oxygenation level dependent (BOLD) functional MRI, manganese-enhanced MRI (MEMRI) can provide a direct means to visualize brain activity.

MEMRI of the brain typically involves osmotic opening of the blood-brain barrier (BBB) to deliver Mn2+ into the interstitial space prior to initiation of a specific neuronal stimulus. This method assumes that the BBB-disruption process itself does not induce any apparent stimuli or cause tissue damage that might obscure any subsequent experimental observations. However, this assumption is often incorrect and can lead to misleading results for particular types of MRI applications.

One aspect of these studies focused on characterizing the confounding effects of the BBBopening process on MRI measurements typically employed to characterize functional activity or disease in the brain (Chapters 4 and 5). The apparent diffusion coefficient (ADC) of tissue water was found to decrease (relative to the undisrupted contralateral hemisphere) following BBB opening, obscuring similar ADC changes associated with ischemic brain tissue following stroke. Brain regions exhibiting reduced ADC values following osmotic BBB disruption also experienced permanent tissue damage, as validated by histological measures in the same vicinity of the brain.

Non-specific MEMRI-signal enhancement was also observed under similar conditions and was found to be correlated to regions with BBB opening as verified by Evans Blue histological staining.

vi In this case, MEMRI may prove to be a useful alternative for monitoring BBB-permeability changes in vivo.

MEMRI was also investigated as a method for visualizing regions of BBB damage following ischemic brain injury (Chapter 6). BBB disruption following stroke has been investigated using gadolinium-based MRI contrast agents (e.g., Gd-DTPA). However, as an extracellular MRI contrast agent, Gd-DTPA is not expected to provide information regarding cell viability or function as part of MR image contrast enhancement. By comparison, brain regions with ischemia-induced BBB damage, and blood-flow levels sufficient to deliver Mn2+, show MEMRI-signal enhancement that correlates to regions with tissue damage as verified by histological staining. This approach should allow us to better understand the factors responsible for ischemia-induced BBB damage.

Furthermore, MEMRI should be a useful tool for monitoring therapeutic interventions that might mitigate the damage associated with BBB disruption following stroke.


Basic Principles of MRI

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1.0 Basic Physical Principles of Nuclear Magnetic Resonance

1.1 Introduction This chapter is an introduction to the basic theory of magnetic resonance imaging (MRI). The topics covered include the MR theory and methods that pertain specifically to the research described in this dissertation. The MR theory is discussed at a depth that should provide a basic understanding of spin-echo, gradient echo, echo-planar and diffusion-weighted MR imaging.

1.2 Electromagnetic Wave Theory The electromagnetic wave is of fundamental importance for the generation of a magnetic resonance image. A brief discussion of the basic components of an electromagnetic wave, the electric and magnetic field, and what portions of the wave are important to magnetic resonance imaging (MRI) are presented here.

1.2.1 The Electric and Magnetic Field Generation of the electric and magnetic field by charged particles The concept of a ‘field’ can be described with a common force that surrounds us: gravity. To every point in space we can assign a vector g that represents the force F exerted on some mass m by earth’s gravity. The gravitational field is then written as g = F/m. In a similar fashion we can talk of a vector E that represents the force F that a positive electric charge q experiences when placed near a charged rod. The electric field is then described as E = F/q. The direction of the vector E is the same as F; it is the direction the stationary positively-charged particle would accelerate towards the rod.

The electric field, therefore, is representing the force of one electrically-charged particle on another.

Can it then be said that the magnetic field is a representation of a magnetically-charged particle on Basic Principles of MRI 2 another? The answer to date is no, i.e., there are no known magnetic charges. It is the moving electrical charge that generates a magnetic field.

Properties of the Magnetic Field A charged particle moving in the presence of a magnetic field B does not experience acceleration but can have its direction changed. The magnetic field deflects a moving charge by a force FB maximally when the charged particle is moving perpendicular to the direction of the magnetic field: FB = qvBsin(θ) where θ is the angle between the direction of the moving particle and the direction of the magnetic field, q is the measure of electric charge, and v is the velocity of the charge. The measure of magnetic field strength is the newton / (ampere * meter) or more simply and more commonly referred to as the Tesla (1 T = 1 N/(A * M) ) (1). As reference a small toy magnet (refrigerator magnet) has a magnetic field strength of ~ 10-2 T, the magnetic field at the surface of the earth is ~ 10-4 T and a clinical MRI scanner is at 1.5 T. Figure 1.1 shows an example of the magnetic-field profile of a bar magnet.

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1.2.2 Generation of an Electromagnetic Wave Electric and magnetic fields can be generated by point charges and bar magnets, respectively, as discussed in the previous section. What is required to generate a magnetic resonance image is a propagating magnetic field (which moves in a direction perpendicular to the main magnetic field of the MRI scanner). A convenient way to generate a relatively small and switchable magnetic field is by passing an electric current through a small loop of wire that surrounds the sample we are interested in imaging. The small loop of wire and the circuit that completes it is referred to as a LC oscillator.

Induced Magnetic Field in Wire Loop For a single loop of wire carrying a current I, a fairly homogenous magnetic field is generated near

the center of the loop as shown in Figure 1-2:

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The LC Oscillator The electric charge and current in the LC oscillator circuit fluctuates at a particular frequency given by ω = 1/√LC where L and C are the inductance and capacitance values in the circuit. The oscillation frequency of the LC circuit is more commonly named the resonant frequency. For MRI applications the frequency of oscillation of the magnetic field needed for MR signal generation is in the radiofrequency (RF) range. Therefore, the ‘coil’ (or coils) used to generate MR images are commonly referred to as RF coils. When an LC oscillator (or resonator) is used to acquire images in a 2 Tesla MR scanner, the resonant frequency of the LC circuit must be tuned to 2 Tesla * 42.57 MegaHertz/ Tesla (MHz/T) or ~ 85 MHz. The special constant, 42.57 MHz/T, will be discussed later in this chapter.

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Figure 1-3: LC oscillator circuit. The capacitor shown is adjustable to allow the user to tune the coil to an exact frequency (the resonant frequency of the coil can change due to stray capacitance values in the sample among several other variables). The inductor shown is a single loop of copper wire. In this form the RF coil is referred to as a ‘surface coil’.

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within the diameter of the coil. The transfer of energy from the coil to the tissue (sample) of interest (via the magnetic field produced by the coil) is the primary goal of the LC oscillator and all RF coils used for MRI. Water molecules within the tissue of interest become ‘excited’ by the magnetic energy produced by the coil. The means by which the tissue becomes excited is the subject of the next section.

1.3 Nuclear Energy States

Atomic structure and angular momentum Atomic structure is defined by an atom’s nuclear configuration and its orbiting electron(s).

The nucleus of the atom consists of protons (charge = +e, where e is the charge of an electron:

-1.60 x 10Coulomb) and neutrons (charge = 0); both of which are referred to as nucleons. The electron(s) that orbit(s) the nucleus are each negatively charged and possess both spin and orbital angular momentum. The angular momentum associated with a charged particle generates a magnetic field (referred to as the magnetic dipole moment or MDM) which is a vector quantity with both magnitude and direction. The magnetic field associated with electrons is referred to as the electron MDM. Since nuclei can also possess spin and orbital angular momentum and are positively charged, the associated magnetic field is referred to as the nuclear MDM. For MRI, the MDM of the 1H isotope of hydrogen is simply that associated with the single proton in the nucleus (Figure 1-4). The proton MDM is the fundamental physical property that is exploited to generate an MR image.

Basic Principles of MRI 6

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µ Figure 1-4: Single proton (1H isotope of hydrogen) showing the angular momentum vector (P) and the antiparallel nuclear MDM (µ) vector that is created by the moving positive charge associated with the proton.

A convenient way to represent the relationship between the nuclear MDM and its angular momentum is to consider the ratio of the two quantities. This ratio is referred to as the magnetogyric (or gyromagnetic) ratio and is written as γ = µ/P = -(e/2me), where e and me are the charge and mass of the proton, respectively, when considering the 1H isotope of hydrogen.

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