Electron Paramagnetic Resonance Imaging

Magnetic resonance comes in two types: nuclear magnetic resonance and electron paramagnetic resonance. In Chapter 18 of the 4th edition of Intermediate Physics for Medicine and Biology, Russ Hobbie and I write

Two kinds of spin measurements have biological importance. One is associated with electron magnetic moments and the other with the magnetic moments of nuclei. Most neutral atoms in their ground state have no magnetic moment due to the electrons. Exceptions are the transition elements that exhibit paramagnetism. Free radicals, which are often of biological interest, have an unpaired electron and therefore have a magnetic moment. In most cases this magnetic moment is due almost entirely to the spin of the unpaired electron.

Magnetic resonance imaging is based on the magnetic moments of atomic nuclei in the patient. The total angular momentum and magnetic moment of an atomic nucleus are due to the spins of the protons and neutrons, as well as any orbital angular momentum they have inside the nucleus. Table 18.1 lists the spin and gyromagnetic ratio of the electron and some nuclei of biological interest.

The key insight from Table 18.1 is that the Larmor frequency for an electron in a magnetic field is about a thousand times higher than for a proton. Therefore, MRI works at radio frequencies, whereas EPR imaging is at microwave frequencies. Can electron paramagnetic resonance be used to make images like nuclear magnetic resonance can? I should know the answer to this question, because I hold two patents about a “Pulsed Low Frequency EPR Spectrometer and Imager” (U.S. Patents 5,387,867 and 5,502,386)!

I’m not particularly humble, so when I tell you that I didn’t contribute much to developing the EPR imaging technique described in these patents, you should believe me. The lead scientist on the project, carried out at the National Institutes of Health in the mid 1990s, was John Bourg. John was focused intensely on developing an EPR imager. Just as with magnetic resonance imaging, his proposed device needed strong magnetic field gradients to map spatial position to precession frequency. My job was to design and build the coils to produce these gradients. The gradients would need to be strong, so the coils would get hot and would have to be water cooled. I worked on this with my former boss Seth Goldstein, who was a mechanical engineer and therefore know what he was doing in this design project. Suffice to say, the coils never were built, and from my point of view all that came out of the project was those two patents (which have never yielded a dime of royalties, at least that I know of). This project was probably the closest I ever have come to doing true mechanical engineering, even though I was a member of the Mechanical Engineering Section when I worked in the Biomedical Engineering and Instrumentation Program at NIH.

One of our collaborators, Sankaran Subramanian, continued to work on this project for years after I left NIH. In a paper in Magnetic Resonance Insights, Subramanian describes his work in “Dancing With The Electrons: Time-Domain and CW In Vivo EPR Imaging” (Volume 2, Pages 43–74, 2011). Below is an excerpt from the introduction of his article, with references removed. It provides an overview of the advantages and disadvantages of EPR imaging compared to MRI.

Magnetic resonance spectroscopy, in general, deals with the precessional frequency of magnetic nuclei, such as ¹H, ¹³C, ¹⁹F, ³¹P, etc. and that of unpaired electrons in free radicals and systems with one or more unpaired electrons when placed in a uniform magnetic field. The phenomena of nuclear induction and electron resonance were discovered more or less at the same time, and have become two of the most widely practiced spectroscopic techniques. The finite dimensional spin space of magnetic nuclei makes it possible to quantum mechanically precisely predict how the nuclear spin systems will behave in a magnetic field in presence of radiofrequency fields. On the other hand, the complex and rather diffuse wave functions of the unpaired electron which get further influenced by the magnetic vector potential make it a real challenge to predict the precise behavior of electron resonance systems. The subtle variations in the precessional frequencies brought about by changes in the electronic environment of the magnetic nuclei in NMR and that of the unpaired electrons in EPR make the two techniques widely practiced and very useful in the structural elucidation of complex biomolecules. It was discovered subsequently that the presence of linear field gradients enabled precise spatial registration of nuclear spins which led to the development of imaging of the distribution of magnetic nuclei establishing an important non-invasive medical imaging modality of water-rich soft tissues in living systems with its naturally abundant presence of protons. Nuclear Magnetic Resonance Imaging, popularly known as MRI, is now a well-known and indispensable tool in diagnostic radiology. …

The entirely analogous field of electron paramagnetic (spin) resonance (EPR or ESR) that deals with unpaired electron systems developed as a structural tool much more rapidly with the intricate spectra of free radicals and metal complexes providing an abundance of precise structural information on molecules, that would otherwise be impossible to unravel. The spectroscopic practice of EPR traditionally started in the microwave region of the electromagnetic spectrum and was essentially a physicist’s tool to study magnetic properties and the structure of paramagnetic solid state materials, crystal defects (color centers), etc. Later, chemists started using EPR to unravel the structure of organic free radicals and paramagnetic transition metal and lanthanide complexes. Early EPR instrumentation closely followed the development of radar systems during the Second World War and was operating in the X-band region of the electromagnetic spectrum (~9 GHz). Pulsed EPR methods developed somewhat later due to the requirement of ultra fast switches and electronic data acquisition systems that can cope with three orders of magnitude faster dynamics of the electrons, compared to that of protons. The absence of relatively long-lived free radicals of detectable range of concentration in living systems made in vivo EPR imaging not practical. It became essential that one has to introduce relatively stable biocompatible free radicals as probes into the living system in order to image their distribution. Further the commonly practiced X-band EPR frequency is not useful for interrogating reasonable size of aqueous systems due lack of penetration. Frequencies below L-band (1–2 GHz) are needed for sufficient penetration and one has to employ either water soluble spin probes that can be introduced into the living system (via intramuscular or intravenous infusion) or solid particulate free radicals that can be implanted in vivo. Early imaging attempts were entirely in the CW mode at L-band frequencies (1–2 GHz) on small objects. For addressing objects such a laboratory mouse, rat etc., it became necessary to lower the frequency down to radiofrequency (200–500 MHz). With CW EPR imaging, the imaging approach is one of generating projections in presence of static field gradients and reconstructing the image via filtered back-projection as in X-ray CT or positron emission tomography (PET). Most spin probes used for small animal in vivo imaging get metabolically and/or renally cleared within a short time and hence there is need to speed up the imaging process. Further, the very fast dynamics, with relaxation times on the order of microseconds of common stable spin probes such as nitroxides, until recently, precluded the use of pulsed methods that are in vogue in MRI.

As a postscript, Seth Goldstein retired from NIH and now creates kinetic sculpture. Watch some of these creative devices here.

Cobalt-60

In Chapter 16 of the 4th edition of Intermediate Physics for Medicine and Biology, Russ Hobbie and I mention the radioactive isotope cobalt-60. Three times—in the captions of Figs. 16.13, 16.15, and 16.46—we show data obtained using ⁶⁰Co radiation. So, what is a cobalt-60 radiation source, and why is it important?

In Radiation Oncology: A Physicist’s-Eye View, Michael Goitein discusses this once-prevalent but now little-used tool for generating therapeutic photons.

Radioactive isotopes are one source of radiation, and the ⁶⁰Co therapy machine takes advantage of this. A highly active source of ⁶⁰Co is placed in a heavy lead shield which has an aperture through which the photons produced in the decay of ⁶⁰Co can escape to provide the therapeutic beam. The whole is then usually mounted on a rotating gantry so that the beam can be directed at the patient from any angle. ⁶⁰Co therapy machines are little used these days, except in areas of the world where the supply of electricity and/or repair service are problematic. I mention these machines because they are unusual in that their photon beam is near mono-energetic. It consists primarily of γ-rays of 1.17 and 1.33 MeV energy – which are close enough together that one can think of the radiation as consisting of 1.25 MeV primary photons. However, photons interacting with the shielding around the ⁶⁰Co source produce lower energy secondary photons which lower the effective energy of the beam somewhat.

The Gamma Knife is a device that uses hundreds of collimated cobalt sources to deliver radiation to a cancer from many directions. It was once state-of-the-art, but now has be largely superseded by other techniques. Most modern radiation sources are produced using a linear accelerator, and have energies over a range from a few up to ten MeV. However, cobalt sources are used still in many developing countries (see a recent point/counterpoint article debating if this is a good or bad situation).

Cobalt-60’s 5.3-year half-life makes it notorious as a candidate for a dirty bomb, in which radioactive fallout poses a greater risk than the explosion. Isotopes with much shorter half-lives decay away quickly and therefore produce intense but short-lived doses of radiation. Isotopes with much longer half-lives decay so slowly that they give off little radiation. ⁶⁰Co’s intermediate half-life means that it lasts long enough and produces enough radiation that it could contaminate a region for years, creating a Dr. Strangelove-like doomsday device.

Fortunately, dirty bombs remain hypothetical. However, cobalt sources have a real potential for causing radiation exposure if not handled properly. Here is an excerpt from an International Atomic Energy Agency (IAEA) report about one radiological accident.

A serious radiological accident occurred in Samut Prakarn, Thailand, in late January and early February 2000 when a disused 60 Co teletherapy head was partially dismantled, taken from an unsecured storage location and sold as scrap metal. Individuals who took the housing apart and later transported the device to a junkyard were exposed to radiation from the source. At the junkyard the device was further disassembled and the unrecognized source fell out, exposing workers there. The accident came to the attention of the relevant national authority when physicians who examined several individuals suspected the possibility of radiation exposure from an unsecured source and reported this suspicion. Altogether, ten people received high doses from the source. Three of those people, all workers at the junkyard, died within two months of the accident as a consequence of their exposure.

The Immortal Life of Henrietta Lacks

The Immortal Life
of Henrietta Lacks,
by Rebecca Skloot.

For Christmas I received a portable CD player to replace one that was broken, so I am now back in business listening to audio books while walking my dog Suki. This week I finished The Immortal Life of Henrietta Lacks by Rebecca Skloot. The book explains how a biopsy from a fatal tumor led to the most famous cell line used in medical research: HeLa.

HeLa cells are grown in cell culture. Russ Hobbie and I describe cell culture experiments in the 4th edition of Intermediate Physics for Medicine and Biology, when discussing the biological effects of radiation.

16.10.1 Cell Culture Experiments

Cell-culture studies are the simplest conceptually. A known number of cells are harvested from a stock culture and placed on nutrient medium in plastic dishes. The dishes are then irradiated with a variety of doses including zero as a control. After a fixed incubation period the cells that survived have grown into visible colonies that are stained and counted. Measurements for many absorbed doses give survival curves such as those in Fig. 16.32. These curves are difficult to measure for very small surviving fractions, because of the small number of colonies that remain.

Russ and I don’t mention HeLa cells in IPMB, but they played a key role in establishing how cells respond to radiation. For instance, Terasima and Tolmach measured “Variations in Several Responses of HeLa Cells to X-Irradiation during the Division Cycle” (Biophysical Journal, Volume 3, Pages 11–33, 1963), and found that “survival (colony-forming ability) is maximal when cells are irradiated in the early post-mitotic (G1) and the pre-mitotic (G2) phases of the cycle, and minimal in the mitotic (M) and late G1 or early DNA synthetic (S) phases.” Russ and I discuss these observations in Section 16.10.2 about Chromosome Damage

“Even though radiation damage can occur at any time in the cell cycle (albeit with different sensitivity), one looks for chromosome damage during the next M phase, when the DNA is in the form of visible chromosomes.”

Skloot’s book not only explains HeLa cells and their role in medicine but also describes the life and death of Henrietta Lacks (1920-1951). Her cervical cancer was treated at Johns Hopkins University by a primitive type of brachytherapy (see Section 17.15 of IPMB) in which tubes of radium where placed near the tumor for several days. The treatment failed and Lacks soon died from her aggressive cancer, but not before researcher George Gey obtained a biopsy and used it to create the first immortal human cell line.

The Immortal Life of Henrietta Lacks is about more than just HeLa cells and Henrietta. It also describes the story of how the Lacks family—and in particular Henrietta’s daughter Deborah—learned about and coped with the existence of HeLa cells. In addition, it is a first-person account of how Skloot came to know and gain the trust of the Lacks family. Finally, it is a case study in medical ethics, exploring the use of human tissues in research, the growing role of informed consent in human studies, and the privacy of medical records. The public’s perception of medical research and the view of those doing the research can be quite different. In 2013, the National Institutes of Health and the Lacks family reached an understanding about sharing genomic data from HeLa cells. With part of the income from her book, Skloot established the Henrietta Lacks Foundation to support the Lacks family.

It looks like Suki and I are again enjoying audio books on our walks (for example, see here and here). At least I am; I’m not sure what Suki thinks about it. I hope all the books are all this good.

 Listen to Rebecca Skloot discuss The Immortal Life of Henrietta Lacks.

The Electric Potential of a Rectangular Sheet of Charge

My idea of a great physics problem is one that is complicated enough so that it is not trivial, yet simple enough that it can be solved analytically. An example can be found in Sec. 6.3 of the 4th edition of Intermediate Physics for Medicine and Biology.

If one considers a rectangular sheet of charge lying in the xy plane of width 2c and length 2b, as shown in Fig. 6.10, it is possible to calculate exactly the E field along the z axis…. The result is

This is plotted in Fig. 6.11 for c = 1 m, b = 100 m. Close to the sheet (z much less than 1) the field is constant, as it is for an infinite sheet of charge. Far away compared to 1 m but close compared to 100 m, the field is proportional to 1/r as with a line charge. Far away compared to 100 m, the field is proportional to 1/r², as from a point charge.

What I like most about this example is that you can take limits of the expression to illustrate the different cases. Russ Hobbie and I leave this as a task for the reader in Problem 8. It is not difficult. All you need is the value of the inverse tangent for a large argument (π/2), and its Taylor’s series, tan^-1(x) = x –x³/3 + ^…. Often expressions like these will show simple behavior in two limits, when some variable is either very large or very small. But this example illustrates intuitive behavior in three limits. How lovely. I wish I could take credit for this example, but it was present in earlier editions of IPMB, on which Russ was the sole author. Nicely done, Russ.

Usually the electric potential, a scalar, is easier to calculate than is the electric field, a vector. This led me to wonder what electric potential is produced by this same rectangle of charge. I imagine the expression for the potential everywhere is extremely complicated, but I would be satisfied with an expression for the potential along the z axis, like in Eq. 6.10 for the electric field. We should be able to find the potential in one of two ways. We could either integrate the electric field along z, or solve for the potential directly by integrating 1/r over the entire sheet. I tried both ways, with no luck. I ground to a halt trying to integrate inverse tangent with a complicated argument. When solving directly, I was able to integrate over y successfully but then got stuck trying to integrate an inverse hyperbolic sine function with an argument that is a complicated function of x. So, I’m left with Eq. 6.10, an elegant expression for the electric field involving an inverse tangent, but no analytical expression for the electric potential.

I was concerned that I might be missing something obvious, so I checked my favorite references: Griffiths’ Introduction to Electrodynamics and Jackson’s infamous Classical Electrodynamics. Neither of these authors solve the problem, even for a square sheet.

As a last resort, I turn to you, dear readers. Does anyone out there—I always assume there is someone out there reading this—know of an analytic expression for the electric potential along the z axis caused by a rectangular sheet of charge, centered at the origin and oriented in the xy plane? If you do, please share it with me. (Warning: I suspect such an expression does not exist.) If you send me one, the first thing I plan to do is to differentiate it with respect to z, and see if I get Eq. 6.10.

This will be fun.

Triplet Production

In the 4th edition of Intermediate Physics for Medicine and Biology, Russ Hobbie and I describe how x rays interact with tissue by pair production.

A photon with energy above 1.02 MeV can produce a particle–antiparticle pair: a negative electron and a positive electron or positron… Since the rest energy (m_ec²) of an electron or positron is 0.51 MeV, pair production is energetically impossible for photons below 2m_ec² = 1.02 MeV.


One can show, using hν₀ = pc for the photon, that momentum [p] is not conserved by the positron and electron if [the conservation of energy] is satisfied. However, pair production always takes place in the Coulomb field of another particle (usually a nucleus) that recoils to conserve momentum. The nucleus has a large mass, so its kinetic energy p²/2m is small…

Then we discuss a related process: triplet production.

Pair production with excitation or ionization of the recoil atom can take place at energies that are only slightly higher than the threshold [2m_ec²]; however, the cross section does not become appreciable until the incident photon energy exceeds 4m_ec² = 2.04 MeV, the threshold for pair production in which a free electron (rather than a nucleus) recoils to conserve momentum. Because ionization and free-electron pair production are (γ, e⁻e⁻e⁺) processes, this is usually called triplet production.” 

Spacetime Physics,
by Taylor and Wheeler.

Where does the factor of four in “4m_ec²” come from? To answer that question, we must know more about special relativity than is presented in IPMB. We know already that the energy of a photon is hν and the momentum is hν/c, where ν is the frequency, h is Planck’s constant, and c is the speed of light. What we need in addition is that the energy of an electron with rest mass m_e is γm_ec², and its momentum is βγm_ec, where β is the ratio of the electron’s speed to the speed of light, β = v/c, and γ = 1/sqrt(1−β²). The factors of β and, especially, γ may look odd, but they are common in special relativity. To learn how they arise, read the marvelous book Spacetime Physics by Edwin Taylor and John Archibald Wheeler. Assume a photon with energy hν interacts with an electron at rest (β = 0, γ = 1). Furthermore (and this is not obvious), assume that after the collision the original electron and the new electron-positron pair all move in the direction of the original photon, and travel at the same speed. The conservation of energy requires

hν + m_ec² = 3γm_ec²,

and conservation of momentum implies

hν/c = 3βγm_ec .

The rest is algebra. Eliminate hν and you find that 3γβ + 1 = 3γ. Then use γ = 1/sqrt(1−β²) to find that β = 4/5 and γ = 5/3. (I love how the Pythagorean triple 3, 4, 5 arises in triplet production). Then conservation of energy or conservation of momentum implies hν = 4m_ec². Now you know the origin of that mysterious factor of four.

The paper “Pair and Triplet Production Revisited for the Radiologist” by Ralph Raymond (American Journal of Roentgenology, Volume 114, Pages 639–644, 1972) provides additional details. To learn about special relativity, I recommend either Spacetime Physics (their Sec. 8.5 analyzes triplet production) or Space and Time in Special Relativity by one of the best writers of physics, N. David Mermin. I hear Mermin’s recent book It’s About Time is also good, but I haven’t read it yet.