It is easy to think that things were better back in the "good old days". But it was not so long ago that the diagnosis of many diseases required explorative surgery to look inside the body. In a large part of the world, many of these invasive and highly risky practices have now become obsolete – thanks to the development of clinical tomography systems that provide cross-sectional images of the body. In fact, the enormous impact of tomography on human wellbeing has led to several pioneers in the field of tomography being awarded Nobel prizes.

Recently, dedicated tomographic devices for imaging small living animals with extremely high resolution have become commercially available. These devices can replace invasive research procedures such as animal slicing and tissue dissection. They also make it easier to carry out fast dynamic studies and follow-up experiments in which live animals are followed over many months, abilities that not only speed up and refine biomedical research, but also enable us to reduce the number of animals required for certain experiments.

Functional imaging

Alongside tomographic imaging of the body’s structure and anatomy, using X-ray computed tomography (CT) and magnetic resonance imaging (MRI), molecular imaging of a living animal can provide important information on how its body is functioning. To perform this "functional imaging", radio-labelled molecules (or tracers) can be used, for example, with nuclear imaging techniques such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT). PET or SPECT scans provide detailed 3D images consisting of 3D pixels called “voxels”. The intensity of a voxel in a SPECT or PET image indicates the amount of tracer molecule in that voxel. So by determining the average intensity in groups of voxels that correspond spatially to a certain organ or tissue, one can accurately quantify the tracer uptake in the region of interest.

Tracer molecules are typically designed to accumulate specifically in a certain type of tissue or cell. For example, a tracer may bind to receptors in particular tumour cells, to certain types of neurons in the brain or to specific heart-muscle cells. In this way, molecular imaging can reveal the status and existence of certain cell types in tiny regions of the body, or show the location and dynamics of molecules such as pharmaceuticals. This helps scientists to answer important research questions such as “Does the (labelled) pharmaceutical reach the tumour or enter the brain? Where does it accumulate? And for how long?”.

PET and SPECT are also prominent clinical techniques, and often the same tracers that are used in humans are also applied in small-animal studies. Likewise, new SPECT and PET tracers developed for small animals can often be translated relatively easily for use in humans because they rely on the emission of gamma radiation with high enough energy to have a high probability of escaping the human body.

SPECT/PET cardiac scan

Nuclear imaging has a wide range of (bio)medical applications. For instance, one important application of SPECT is imaging of the heart. Here, tracers are available that can image tissue blood flow, the supply of nerves, cell death in oxygen-depleted tissue, and tissue viability in a diseased heart muscle. As SPECT allows a combination of multiple tracers, more than one of these processes can be visualized in a single scan. Another example is the use of SPECT to visualize the highly localized response of the skeleton to different mechanical stresses, caused by micro-fractures, arthritis or the spread of cancer to the bone, for example. For PET, one prominent application is the use of radio-labelled glucose to detect tumours and observe their early response to chemotherapy or other treatments.

Dedicated small-animal systems

PET and SPECT systems used for clinical purposes provide image resolution in the order of 4 mm and 10 mm, respectively. This makes them unsuitable for imaging a small animal such as a mouse or rat (the most commonly studied animals), which are several orders of magnitude smaller than a human. Over the past few decades, it has taken much effort by many research groups to overcome the various challenges of building the dedicated small-animal SPECT and PET devices that are available today. Nowadays, SPECT systems offering quarter-millimetre resolution are being developed (Ivashchenko et al. 2013 Eur. J. Nucl. Med. Mol. Imaging EANM Abstracts 2013), as well as PET systems with sub-millimetre resolution (see, for example). The high performance of today’s scanners is based on advanced mathematical modelling (Phys. Med. Biol. 52 2567), the development of dedicated detectors (J. Nucl. Med. 53 167) and the use of statistical reconstruction algorithms (Phys. Med. Biol. 46 1835).

Imaging of both SPECT and PET tracers requires the detection of high-energy gamma rays. SPECT tracers emit single gamma photons upon decay, and small-animal SPECT relies on pinhole imaging to determine the directions of the emitted photons. High resolution and sufficient signal strength can be obtained with multiple pinholes. Pinholes placed close to a region of tracer activity will magnify the projections of that activity distribution onto the detectors, thereby enabling even conventional gamma detectors with low resolution to produce high-resolution SPECT images.

Most PET devices need to detect two simultaneously emitted gamma rays travelling in (almost) opposite directions that result from PET tracer decay. Since magnification is not applied here, such coincidence detection relies on the use of advanced high-resolution detectors with sufficient time resolution. These also need to provide ways to prevent parallax errors in the thick detectors needed to stop the high-energy photons.

SPECT, PET, CT and MRI provide differing and complementary information, therefore it can be beneficial to combine images from the different modalities. In fact, SPECT or PET are usually combined with CT in a single imaging device, and sometimes also with MRI. The main reason for this is that CT and MRI provide the 3D anatomical reference required to localize the tracer accumulation provided by 3D SPECT or PET images.

Accurate spatial registration of different images requires that the coordinates of voxels in the different modalities are known exactly. Recently, a device that can perform SPECT and PET simultaneously was introduced by MILabs of the Netherlands. This scanner, VECTor/CT, can achieve a resolution of 0.5 mm for SPECT tracers, and less than 0.75 mm for PET tracers. In this way, many different processes can be visualized and correlated in any location in the body.

What is next?

The most important parameters for SPECT and PET imaging are sensitivity to gamma rays, temporal resolution and image resolution. Today, PET can achieve a spatial resolution of 0.75 mm. Very high temporal resolutions can also be reached by larger PET scanners that can contain an entire mouse in the field-of-view. The main challenge for PET now is to improve the detector resolution by reducing parallax errors while preserving high sensitivity. The latest generation SPECT scanners have spatial resolutions of 0.25 mm over the entire mouse, which can be readily improved by using better detectors or even by restricting the field-of-view on existing scanners. Efforts are also ongoing to integrate nuclear systems with MRI to obtain simultaneous PET/MRI (Nature Med. 14 459) or SPECT/MRI, and it is a tremendous challenge to minimize image degradation of the individual integrated modalities.

• This article originally appeared in the Physics World Focus on Medical Imaging.

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