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Magnetic Resonance as a Tool for Pharmaco-Imaging

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Pharmaco-Imaging in Drug and Biologics Development

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 8))

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Abstract

Imaging technologies in the nonclinical laboratory have been greatly bolstered by the ever-improving methods available with magnetic resonance (MR) imaging. Small animal systems have been growing in capability even while becoming more amenable to use by biologists, revolutionizing how we can study pathophysiology and follow a drug or biologic therapy. MR’s ability to characterize many anatomical and physiological processes, based on their underlying influence on tissue magnetization properties, has led, for example, to discoveries in the psychopharmacology of attention deficit and cognitive drug therapies and in recording changes of oxygenation, blood flow and vessel permeability in acute studies, or the chronic remodeling of tissue water diffusion following therapy. This is a short and clearly abbreviated discussion of the applications of MRI in the nonclinical (and clinical) drug development laboratory, and it is meant to introduce the reader to the concepts and how this specific imaging modality likely offers the most versatile of all imaging modalities as well as being one with very high resolution.

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Notes

  1. 1.

    Refer to Wechsler Intelligence Scale for Children http://www.pearsonassessments.com/HAIWEB/Cultures/en-us/Productdetail.htm?Pid=015-8979-044.

Abbreviations

ADC:

Apparent diffusion coefficient—the diffusion of molecules in tissues is modulated by many mechanisms that restrict or impose tortuosity around obstacles and such as blood flow in small vessels or cerebrospinal fluid in ventricles and other contributions to MR signal attenuation. Images are “weighted” by the “apparent” diffusion processes. Note that the ADC concept has been extremely successful in tumor biology to demonstrate necrosis, especially for clinical applications. The basic ADC approach has been challenged recently, as new, more comprehensive models of diffusion in biological tissues have been introduced. Also, the rADC, or relative ADC, is a ratio of lesions to control brain ROIs

B 0 :

Static main magnetic field provided by the MR system magnet

B 1 :

Secondary magnetic field perpendicular to B 0 transiently created during an experiment by the system’s radiofrequency coils and gradient sets

BOLD:

Blood oxygen level dependent (a particular contrast mechanism)

Chemical shift:

The resonant frequency of nuclei in some chemical environment relative to those in a standard environment (e.g., the protons of benzene)

CNR:

Contrast-to-noise ratio—the CNR is directly linked to statistical measures such as the t-values, but it does not depend on the number of points or runs as do the t-values; in fMRI it is made up of the functional signal change and the temporal signal change as the average signal change (task related) over the non-task-related variability over time (time-series noise)

FT:

Fourier Transform—a mathematical treatment of the FID or echo signal from a modern pulsed MR experiment to convert the recorded time-domain data into usable spatial frequency-domain data and hence images; an MR image consists of a matrix of pixels based on the number of lines filed in “K-space” (phase matrix) and the number of data points in each line (frequency matrix)

FID:

Free induction decay—the signal observed during the process of relaxation that follows an excitation of nuclei induced by a pulse of radiofrequency energy

FOV:

Field of view—physical dimensions of the imaged volume

fMRI:

Functional magnetic resonance imaging—generally for cerebral blood flow

Gradient:

A (relatively small) magnetic field that increases in strength with distance from the center of the image; these are created transiently by pulses from the gradient coils to impart the magnetic spins with frequency and phase information to facilitate image formation

K-space:

A spatial frequency domain where information on the frequencies of a signal and where it comes from (on the gradient) in the patient is located; this information is in radians per cm; often called the chest of drawers for how the data is stored

NMR:

Nuclear magnetic resonance—general term for the analytical chemistry of chemical shift analysis and the former term of MR as “NMR imaging”

phMRI:

Physiologic or pharmacologic imaging using MRI

Pulse sequences:

A programmed sequence of magnetic field pulses and time delays from the radiofrequency coil and the gradient set during the imaging experiment which manipulate the spin behavior of nuclei; changes to the induction and relaxation can be exploited to reveal properties of the tissue of interest

Relaxation:

Process by which a population of excited (high-energy) nuclei give up RF energy and return to their ground (low-energy) state. This emitted energy is detected to form the images

Relaxivity:

The ability of magnetic compounds to increase the relaxation rates of the surrounding water proton spins. Relaxivity is used to improve the contrast of the image and to study tissue-specific areas where the contrast agent better diffuses; view http://www.youtube.com/watch?v=Osx8Ced9Eyw

RF:

Radiofrequency—the resonant frequency of protons at commonly used magnetic field strengths is in the radiofrequency range, e.g., 64 MHz at 1.5 Tesla

SNR:

Signal-to-noise ratio

T1 :

Longitudinal relaxation occurs when a population of excited nuclei give up their extra energy to the surrounding electronic environment; the time constant “T1” (63 % of the longitudinal magnetization to recover) for this process is also known as the “spin–lattice” relaxation time constant. T1 values are typically on the order of a second

T2 :

Transverse relaxation occurs when a population of excited nuclei exchange energy with their neighbors; the time constant “T2” (63 % of the longitudinal magnetization to recover) for this process is also known as the “spin–spin relaxation” time constant. In biological tissues T2 values are typically on the order of tenths of a second

T2*:

The observed decay of the FID signal following the RF excitation pulse; it is faster than T2 as it is the combination of the T2 decay superimposed on dephasing phenomena such as magnetic field inhomogeneity

Tesla:

One weber per meter squared; the SI unit of magnetic field strength

TOF:

Time of flight—flowing nuclei present in a slice of interest which has an excitation pulse applied; more or less signal is recovered depending on their velocity; useful in magnetic resonance angiography

A full listing of definitions is available at

http://cis.rit.edu/htbooks/mri/gloss.html (8 pages of glossary terms)

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Authors and Affiliations

  1. BRMoyer & Associates, LLC, 23 Hawk Drive, Bedford, NH, 03110, USA

    Brian R. Moyer M.S. (Pharm), M.S. (Tox), C.N.M.T.

  2. Health and Human Services (HHS), Office of the Assistant Secretary for Preparedness and Response (ASPR), Biomedical Advanced Research and Development Authority (BARDA), Washington, DC, 20201, USA

    Tom C.-C. Hu Ph.D., M.B.A.

  3. Nuclear and Radiological Engineering/Medical Physics Program, George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, North Avenue, Atlanta, GA, 30332, USA

    Tom C.-C. Hu Ph.D., M.B.A.

  4. Department of Biomedical Imaging, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA

    Simon Williams D.Phil.

  5. NIH Mouse Imaging Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive, B1D-69, Bethesda, MD, 20892, USA

    H. Douglas Morris Ph.D.

Authors
  1. Brian R. Moyer M.S. (Pharm), M.S. (Tox), C.N.M.T.
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  2. Tom C.-C. Hu Ph.D., M.B.A.
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  3. Simon Williams D.Phil.
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  4. H. Douglas Morris Ph.D.
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Correspondence to Brian R. Moyer M.S. (Pharm), M.S. (Tox), C.N.M.T. .

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Editors and Affiliations

  1. BRMoyer & Associates, LLC, Bedford, New Hampshire, USA

    Brian R. Moyer

  2. Covidien, Hazelwood, Missouri, USA

    Narayan P.S. Cheruvu

  3. Health and Human Services Office of the Asst Secretary of Preparedness and Response (ASPR), Biomedical Advanced Research and Development Authority (BARDA), Washington, District of Columbia, USA

    Tom C.-C. Hu

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© 2014 American Association of Pharmaceutical Scientists

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Moyer, B.R., Hu, T.CC., Williams, S., Morris, H.D. (2014). Magnetic Resonance as a Tool for Pharmaco-Imaging. In: Moyer, B., Cheruvu, N., Hu, TC. (eds) Pharmaco-Imaging in Drug and Biologics Development. AAPS Advances in the Pharmaceutical Sciences Series, vol 8. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8247-5_11

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