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Physiology 19: 168-175, 2004; doi:10.1152/physiol.00016.2004
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Physiology, Vol. 19, No. 4, 168-175, August 2004
© 2004 Int. Union Physiol. Sci./Am. Physiol. Soc.

EMERGING TECHNOLOGIES

Mouse MRI: Concepts and Applications in Physiology

Robia G. Pautler

Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030
rpautler{at}bcm.tmc.edu


   Abstract
 
The purpose of this review is to provide an introduction to the rapidly expanding field of mouse magnetic resonance imaging (MRI). It is by no means meant to be all-inclusive but rather to provide a brief introduction to the basics of MRI theory, provide some insight into the basic experiments that can be performed in mice by using MRI, and bring to light some factors to consider when planning a mouse MRI experiment.


   Introduction
Top
 Introduction
Basic mouse MRI experiments
 Conclusion
 References
 
In the biological sciences, many studies using mouse models are limited by the inability to gather anatomical and physiological information noninvasively in a longitudinal manner. Invasive imaging modalities such as 2-photon microscopy that provide images of a very high spatial resolution are limited by a depth resolution of a few hundred microns into the mouse. Clearly, there is a great need in mouse research for imaging modalities that can provide in vivo, noninvasive anatomical and physiological information that can be collected in three dimensions at a high spatial and temporal resolution.

Magnetic resonance imaging (MRI) is a very attractive noninvasive imaging modality because it does not rely on ionizing radiation and offers a spatial resolution of tens of microns, exhibiting clear advantages over other imaging methodologies such as positron emission tomography (PET) or X-rays. Additionally, images can be acquired relatively quickly. Compared with traditional histological techniques, which are quite time consuming (taking several days to weeks), MRI images can be acquired in three-dimensional data sets with a very accurate depiction of a sample in a relatively short amount of time (a few hours). Most importantly, images can be acquired in vivo, allowing for the longitudinal acquisition of anatomical and physiological information from the same subject.

With the advent of stronger magnetic fields that allow for better signal-to-noise ratios in MRI images as well as the development of stronger gradients that currently push the spatial resolution of MRI images to that of 10–50 µm, it is clear that MRI technology has advanced to a level that is now capable of providing insights into mouse phenotyping that have not been previously possible.

Most of the MRI imaging that occurs in biological research is centered on signal from hydrogen (1H) because of its proportionally large natural abundance in biological systems as well as the associated large magnetic moment (4, 25). To understand where the signal in 1H-MRI comes from, the basic anatomy of the atom needs to be revisited.

An atom consists of a nucleus that is surrounded by orbiting electrons. Within the nucleus of a hydrogen atom is a positively charged proton. In addition to having a positive charge, it is important to note that protons are also spinning. According to the fundamental principles of electromagnetism, a charged particle that is moving induces a magnetic field. Hence, it is perhaps easiest to conceptualize these protons as tiny magnets or "spins" (4, 25).

In a sample containing hydrogen located on the laboratory benchtop, the orientation of the spins will be random (FIGURE 1AGo, step 1). However, when the same sample is placed in an external magnetic field (B0), a small excess of the spins will align with B0 (FIGURE 1AGo, step 2). The spins aligned in the same direction as B0 will combine, resulting in a net magnetization vector (NMV) that precesses around B0 at a specified frequency, {omega} (FIGURE 1AGo, steps 3 and 4). This plane is referred to as the longitudinal plane (4, 25).



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  		FIGURE 1. Basic description of magnetic resonance imaging (MRI)
A: steps in the MRI process. B: contrast arising from different T1 and T2 values. In a T1-weighted MRI image, tissues with a shorter T1 will have a higher signal intensity than tissues with a longer T1. T1-weighted contrast agents such as Gd-DTPA or Mn2+ shorten the T1 of tissue H2O, resulting in an increase in signal intensity in the tissues where the contrast agent has accumulated. Adapted from Ref. 25.

 
Associated with the MRI nuclei of interest (in this case the proton) is a constant known as the gyromagnetic ratio ({gamma}) that is directly proportional to the precessional frequency. The {gamma} for hydrogen is 42.58 MHz/T, and typical values for B0 range from 1.5 T to as high as 14 T.* The precessional frequency, {omega}, is represented by the Larmour equation:


Protons precess at a frequency that falls into the radio frequency (RF) range. If an RF pulse is applied to this precessing NMV and at 90° to the NMV, the NMV will absorb energy, change direction, and subsequently precess in the transverse plane (FIGURE 1AGo, step 5). For the duration of the RF pulse, the NMV will remain in the transverse plane (4, 25). The application of an RF pulse is known as "excitation."

Once the pulse is turned off, the NMV will recover or "relax" back to the longitudinal plane and once again precess around the main magnetic field. This recovery process along the longitudinal plane is known as spin-lattice relaxation (T1), and the decay along the transverse plane is known as spin-spin relaxation (T2) (FIGURE 1AGo, step 6). T1 recovery is due to nuclei giving up energy to the surrounding environment, whereas T2 decay is due to nuclei exchanging energy with other nuclei (4, 25).

A receiver coil placed in the transverse plane can detect the NMV. When the coherent NMV in the transverse plane cuts across this coil, a voltage is induced in the coil. This is the MRI signal. The timing between RF pulses is known as the repetition time (TR), and the timing from the RF pulse to the acquisition of the signal induced in the coil is known as the echo time (TE) (4, 25).

If the NMV of every tissue type recovered to the original position around B0 at the same rate, it would be impossible to discern the contrast between the different tissue types, because all tissues would consequently have uniform signal intensity. Contrast in MRI images arises from the fact that different tissue types can relax at different rates (i.e., have different T1 and T2 values) (FIGURE 1BGo). The standard and easiest example is to compare fat and water. Fat is quite simply comprised of hydrogen and carbon, whereas water is made up of hydrogen bonded to oxygen. Fat has a very slow molecular tumbling relative to water that causes the recovery of the NMV to be faster (short T1), whereas water has a high molecular mobility that yields a less-efficient recovery of the NMV (long T1) (4, 25).

In addition to inherent tissue contrast, there are exogenous agents that can be applied to tissues or organ systems that cause significant alterations in the local T1 and/or T2 that ultimately result in an alteration of the local magnetic field. These agents are called MRI contrast agents and, depending on the type of agent used, can cause either positive (increased signal intensity) or negative (decreased signal intensity) contrast enhancement in MRI images of tissues or organs where the agent has accumulated (4, 25). Some examples of MRI contrast agents include chelated gadolinium (Gd3+), manganese (Mn2+), and iron (Fe3+).


   Basic mouse MRI experiments
Top
 Introduction
 Basic mouse MRI experiments
Conclusion
 References
 
There are three basic types of mouse MRI experiments. These include anatomical and dynamic MRI acquisitions in addition to a specialized field of MRI imaging known as molecular imaging. Some examples of these different types of imaging are summarized in TABLE 1Go.


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  		TABLE 1. Some different types of experiments that can be performed using MRI
 
Anatomical MRI image acquisitions are relatively straightforward in that high-resolution scans can be acquired to determine the volume or surface area of a specific tissue or organ or the orientation of fibers within an organ (FIGURE 2Go). The typical anatomical MRI experiment consists of selecting the imaging sequence and parameters that will provide optimal signal intensity and contrast within the tissues/organs of interest, acquiring the MRI data, and then using postprocessing software to measure signal intensities or color segment regions of interest and to calculate surface areas or volumes.



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  		FIGURE 2. Anatomical image of the mouse heart from a fast spin-echo imaging sequence
This image was cardiac and respiratory gated to minimize artifacts due to the motion of the beating heart as well as respiration and was acquired on an 11.7 T Bruker Avance system.

 
Additionally, the T1 and T2 of the tissues can be measured, because these values can change during a disease state (5, 18). These two measurements are acquired separately. Typically, an "inversion recovery sequence" is chosen to measure the T1 with a long TR and varying inversion times (TI) (4, 25). For measuring T2, a series of images is acquired with a long TR and a varying TE (4, 25). After the data are collected, either a T1 or T2 map can be generated that gives a color-coded representation of the varying T1 or T2 values within the tissue/organ of interest.

Some examples of anatomical mouse MRI imaging include the determination of tissue/organ or tumor sizes and monitoring changes over time. For example, Susumu Mori’s group (30) has elegantly monitored central nervous system changes by using MRI in the developing mouse embryo. Additional uses of anatomical mouse MRI include mapping neuronal connections by measuring the diffusion of water along axonal pathways, detecting atherosclerotic plaque in major vessels, and discovering changes in T2 due to neuritic plaque formation in mouse models of Alzheimer’s disease (22, 27, 31).

Dynamic MRI experiments, as the name implies, involve the monitoring of a structure over time and determining any ensuing changes that occur during this time course. Dynamic MRI can entail the monitoring of the normal activity of a system or can monitor anatomical and physiological changes in response to a stimuli or disease state.

Perhaps one of the best-known forms of dynamic MRI experiments is that of functional MRI (fMRI). fMRI typically refers to the monitoring of changes in blood flow. Quite commonly, blood oxygen level detection (BOLD) imaging is used in fMRI studies (4). Increased blood flow has been correlated with increases in neuronal activation, reflective of local field potentials (4, 19). BOLD relies on changes in blood flow, blood volume, and the oxygenation state of blood to alter the MRI signal (4). Fast imaging sequences such as echo-planar imaging (EPI) or fast gradient echo imaging sequences are used in BOLD fMRI studies (4).

Additionally, fast imaging sequences can be used in dynamic MRI studies to monitor the inflow or uptake of contrast agents. For example, contrast agents can be used to determine changes in vascular permeability of tumors, providing an assessment of the first-pass dynamics of the agent to assess muscle injury, determine renal perfusion and function, etc. (FIGURE 3Go) (12, 23, 28). Furthermore, organs that exhibit a lot of movement such as the heart or the gastrointestinal tract can be imaged by using fast imaging sequences [e.g., fast low-angle shot (FLASH) or ultrafast, low-angle, rapid acquisition and relaxation enhancement (UFLARE)] and can offer information such as blood flow dynamics, calcium influx, ventricular volumes throughout the cardiac cycle, contractility, gut motility, or bolus volume (10, 26). Gating the image acquisition to the cardiac or respiratory cycle contributes significantly toward the reduction of motion artifacts within the image.



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  		FIGURE 3. MRI in a severe combined immunodeficiency mouse bearing an orthotopic human pancreatic tumor (arrows) 15 days after injection of CAPAN-2 cells into the tail of the pancreas
T1-weighted images without Gd-DTPA (T1 contrast agent) (A) and with Gd-DTPA (B and C) are shown. Note that the kidneys also exhibit enhancement due to the processing of the contrast agent for excretion. Adapted from Grimm et al., Int J Cancer, Copyright 2003 John Wiley & Sons (7).

 
Molecular imaging is an emerging field of MRI imaging that oftentimes uses engineered contrast agents to monitor changes in anatomy or physiology. Additionally, the magnetic labeling of transplanted cells to monitor the progression of cell mobilization falls into this category. The field is rapidly expanding and is making progress as a robust field of study. Some examples of molecular imaging include monitoring apoptosis by magnetically labeling the C2 domain of synaptotagmin I, which binds to plasma membranes of apoptotic cells (32). Additionally, Wadghiri et al. (24) have magnetically labeled the Aß 1–40 peptide that is known to bind to amyloid precursor protein (APP) and have been able to discern AD plaques in transgenic mice overexpressing APP (FIGURE 4Go). Some general issues with engineered contrast agents, however, are being able to target the agent, obtaining enough contrast from the agent, toxicity issues, and being able to turn the agent "on/off."



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  		FIGURE 4. MRI detection of Alzheimer’s disease plaques by using an engineered contrast agent
Aß plaques were detected with ex vivo µMRI after injection of Gd-DTPA-Aß 1–40 with mannitol. A 6-mo-old control mouse (A) and APP/PS1-transgenic mouse (B) are shown. Both brains were extracted and prepared for imaging 6 h after carotid injection of Gd-DTPA-Aß 1–40 with 15% mannitol. Note the obvious matching of many larger plaques (arrows) between µMRI (B) and immunohistochemistry (C). Adapted from Ref. 24.

 

   Conclusion
Top
 Introduction
 Basic mouse MRI experiments
 Conclusion
References
 
The future of MRI in biomedical research will depend on providing current and future investigators with a basic foundation in MRI and will bring to light factors to consider when planning a mouse MRI experiment, thereby allowing this imaging modality to be used as a tool to help accelerate the analysis and understanding of the vast, growing number of mouse models of disease and behaviors (TABLE 2Go; see next page). MRI has rapidly evolved, and the time is suitable to bridge the gap between the existing technology and hypothesis-driven applications in murine-based biomedical research.


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  		TABLE 2. General outline for planning a mouse MRI experiment, including some sample imaging sequences

 


   Acknowledgments
 
Jeannette Kunz, Dave Sweatt, Susan Hamilton, Rita Schack, Lingyun Hu, Gene Pautler, Angelique Louie, and T. Pautler are all gratefully acknowledged for their advice in the preparation of this manuscript.


   Footnotes
 
* As B0 increases, the signal-to-noise ratio will improve. For mouse MRI imaging, it is best to minimally have a B0 of at least 4.7 T and preferably at least 7.0 T. Incidentally, horizontal scanners are preferable to vertical scanners for the obvious reason that it is easier to lay the animal prone rather than have it suspended by its teeth. Back


   References
Top
 Introduction
 Basic mouse MRI experiments
 Conclusion
 References
 

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