PET/SPECT: Functional Imaging Beyond Flow

Vision Research 41 (2001) 1277–1281 www.elsevier.com/locate/visres

PET/SPECT: functional imaging beyond ﬂow Adriaan A. Lammertsma *

PET Centre, Uni6ersity Hospital, Vrije Uni6ersiteit, PO Box 7057, 1022 MB Amsterdam, The Netherlands

Received 10 May 2000; received in revised form 22 September 2000

Abstract

In this review, ﬁrst principles of positron emission tomography (PET) and single photon emission tomography (SPECT) are discussed together with the relative strengths and weaknesses of both techniques. With both modalities it is possible to image and, especially with PET, to measure regional tissue function, the particular function being interrogated depending on the actual tracer being used. In the second part, the use of PET for neuroactivation studies is presented, illustrated with some key examples from the literature using both perfusion and metabolism tracers. It is argued that the future of PET (and SPECT) neuroactivation studies lies in the use of ligands. Possible approaches for performing ligand activation studies are discussed. © 2001 Elsevier Science Ltd. All rights reserved.

Keywords: Functional imaging; Positron emission tomography; Single photon emission tomography

1. Introduction measured. These include blood flow (perfusion), blood volume (vascularity), oxygen utilisation, glucose At present, there is such an interest in neuroactiva- metabolism, pre- and post-synaptic receptor density tion studies that the term ‘functional imaging’ is often and affinity, neurotransmitter release, enzyme activity, equated with imaging the change in cerebral activity drug delivery and uptake, gene expression, etc. This following the presentation of a stimulus. This terminol- flexibility is a result of the fact that, in principle, nearly ogy is probably, at least in part, due to the use of the all biological molecules can be labelled with positron term ‘functional MRI’ (fMRI), which is used to distin- emitters such as carbon-11, nitrogen-13 and oxygen-15. guish it from ‘standard (structural) MRI’. However, for In addition, fluorine-18 is often used as a substitute of two of the first techniques being able to image neuroac- hydrogen, which itself does not have an isotope suitable tivation tomographically, positron emission tomogra- for in-vivo use. phy (PET) and single photon emission tomography Apart from flexibility, PET is also characterised by (SPECT), the use of the term ‘functional imaging’ the ability to measure regional tissue tracer concentra- solely for imaging flow and/or oxygenation changes is a tions with high degrees of accuracy and sensitivity. This severe underestimation of their potential. is based on the decay characteristics of positron emitters. In tissue, the emission of a positron effectively results in the simultaneous emission of two gamma 2. Positron emission tomography rays, each with a fixed energy of 511 keV. These two annihilation photons are emitted in opposite directions PET is a tomographic imaging technique that allows and are recorded by coincidence detection (i.e. simulta- for accurate non-invasive in-vivo measurements of a neous detection by two opposing detectors). These two whole range of regional tissue functions in man. By detectors define the line of response along which the using different tracers, a multitude of physiological, original annihilation took place. In other words, no biochemical and pharmacokinetic parameters can be lead collimators are needed, thereby providing for opti- mal sensitivity. As the total path length of both annihilation photons together is also known, accurate * Tel.: +31-20-444-4214; fax: +31-20-444-3090. correction for tissue attenuation can be made using a E-mail address: [email protected] (A.A. Lammertsma). separate transmission scan.

At present, PET represents the most selective and 4. Neuroactivation studies sensitive (pico- to nano-molar range) method for measuring molecular pathways and interactions in vivo Functional brain imaging using radioactive inert (Jones, 1996). Apart from its capacity to provide new gases was pioneered by Lassen and coworkers in the pathophysiological information on human disease, PET late 1950s. A few years later, a quantitative method for is also important for the objective assessment of thera- the determination of regional cerebral blood flow was peutic efficacy and plays an ever increasing role in the described (Ingvar & Lassen, 1961). The method was development of new drugs (Comar, 1995). Finally, in developed further to a tomographic technique using those cases where it is difficult to determine whether a SPECT and Xe-133. This method was subsequently change is due to progression of disease or to side-effects applied to initial investigations of the visual system in of (chronic) medication, studies can be performed in normal controls (Henriksen, Paulson, & Lassen, 1981). animal models of disease (Lammertsma et al., 1995). During the 1970s, PET emerged as an accurate method for measuring regional cerebral blood flow and metabolism. In the early 1980s, studies were performed 3. Single photon emission tomography to demonstrate regional changes in both perfusion and metabolism following a stimulus. Initially, analysis con- SPECT differs from PET in that use is made of sisted of subtracting a stimulus from a baseline image. gamma (single photon) emitters. This mode of detection Later, sophisticated statistical packages (e.g. Statistical suffers from a number of disadvantages compared with Parametric Mapping) were developed (Friston et al., PET. Firstly, when a detector registers an event, there is 1995). These packages are now in regular use not only no information about the direction of the incoming for PET, but also for fMRI studies. The early studies photon. To obtain positional information, use is made clearly demonstrated two important issues. Firstly, the of lead collimators. The collimator guarantees that only change in perfusion was associated with a similar photons from a predefined direction are accepted. The change in glucose metabolism, but there was an uncou- lead collimator, however, results in a significant reduc- pling with oxygen utilisation, which increased to a tion in sensitivity. Further disadvantages are that both much smaller extent (Fox & Raichle, 1986). Even now, sensitivity and spatial resolution are position-depen- the mechanism of this uncoupling is a matter of debate. dent, that is they both decrease with increasing depth in Secondly, it was realised early on that control of the the body. As the path length through tissue is not stimulus was of vital importance for interpreting sig- known, attenuation correction methods are more cum- nals. A classical example was the difference in activa- bersome than in PET. Finally, there are no single tion seen in normal controls and professional musicians photon emitting isotopes of the basic biological ele- when listening to a piece of music (Mazziotta, Phelps, ments. Therefore, use is made of radionuclides, such as Carson, & Kuhl, 1982). Tc-99m, that are uncommon to the human body. The Measurement of glucose metabolism using 18FDG fate of a tracer labelled with Tc-99m is not necessarily can be useful in assessing whether a certain treatment the same as that of the native molecule, resulting in has had any effect on global and regional metabolism. potential interpretation problems. For example, there It can also be used for comparing patients with normal are no satisfactory SPECT tracers for oxygen and controls and for comparing different conditions in the glucose metabolism (PET tracers can be used with same subject as images with a high statistical quality SPECT, but are not ideal due to the relatively high can be acquired. The relatively long half-life of fluorine- energy of the annihilation photons). 18 (2 h) precludes repeat measurements in one scan- Of course, SPECT also has some advantages. Firstly, ning session and results in a somewhat higher radiation both equipment and radionuclides are readily available burden to the subject. Similar drawbacks apply to in every nuclear medicine department. Radionuclides studies with SPECT flow tracers. Nevertheless, usually have such a long half-life that they can be metabolic studies using 18FDG have significantly con- bought commercially or can be eluted from a generator. tributed to the development of neuroactivation studies This is in contrast to PET where, due to the (very) short in PET. Mapping of visual cortex metabolism following half-life, radionuclides usually have to be produced visual stimulation was one of the first studies to be with an on-site cyclotron. In other words, SPECT is reported in this new field of research (Phelps, Kuhl, & much cheaper and, therefore, more widely available Mazziotta, 1981; see Fig. 1). than PET. A potentially important advantage of The method of choice for repeat measurements in the 15 SPECT receptor ligands is that, in general, specific same subject is the use of H2 O due to its short half-life activities are much higher than those obtained with of 2 min. Initially, studies were performed in a quanti- carbon-11 ligands, which cannot be made carrier-free. tative manner, i.e. regional cerebral blood flow (CBF) This can have consequences for low-density receptor was measured on a pixel-by-pixel level. Quantification studies. of perfusion, however, requires measurement of the A.A. Lammertsma / Vision Research 41 (2001) 1277–1281 1279 input function (i.e. arterial cannulation; Lammertsma et al., 1990), which is cumbersome, especially in normal controls. A detailed knowledge of the tracer kinetics of 15 H2 O indicated that studies could also be performed on a qualitative basis, as there was a predictable relation- 15 ship between uptake of H2 O and actual perfusion. It should be noted, however, that ‘qualitative’ activation studies require reproducible tracer injections (i.e. tim- ing, duration, volume), preferably using an infusion pump. In addition, similar to most other ‘functional imaging’ techniques, it is not possible to detect any global changes with this qualitative implementation. If there is any suspicion of global changes, then a full quantitative study is recommended. Fig. 2. Results of one of the first studies targeting specialised areas of 15 With regard to the visual system, the first activation the visual cortex. In this study, H2 O was used to measure regional 15 cerebral blood flow. The original legend was as follows: Parametric study using H2 O was reported in 1984. In this study, it and statistical scans at the level of striate and inferior occipital cortices. (a) Parametric image of regional cerebral blood flow (rCBF) during colour activation. The level of striate cortex is 1.2 cm above the AC–PC line and that of the inferior occipital cortex 1.7 cm below it. (b) Map of perturbation (variance). This was calculated from the pixel-by-pixel grey value variance across all six scans divided by the difference in grey values between the two rest scans (a reflection of noise). To reduce noise, each scan was smoothed using a low-pass filter of side length 5 pixels (i.e. 10.25 mm). (c) t-statistic map showing the significance of any difference between colour and grey activated scans. In order to remove variance due to changes in global blood flow, the original scans have been normalised to a total brain blood flow of 50 ml/100 ml/min. As the study was designed to look for an area maximally responsive to colour but not to grey, a one-tailed t-test was used. (d) Map of the covariance of grey values across all six scans with the grey values of a reference pixel located in the striate cortex. In all scans, white and red represent the greatest activity/significance/covariance, and blue the least (reproduced with permission from Lueck et al., 1989).

was demonstrated that the increase in regional cerebral blood flow within the visual cortex depended on the rate of the visual stimulus given (Fox & Raichle, 1984). It took some time before studies were reported in which specialised areas of the visual cortex were targeted directly by appropriate stimulus design, the first one localising the human colour area (Lueck et al., 1989; Fig. 1. Results of one of the first studies on regional activation of see Fig. 2). Since then, numerous studies have been cerebral activity following a visual stimulus. In this study, 18FDG was published, interrogating the visual system in detail (see, used to measure regional cerebral glucose metabolism. The original for example, Watson, 2000 for a review). legend was as follows: (A) Sketches from actual brain slices at In recent years, there has been a shift from PET to approximately the level of the cross-sectional tomographic images (4.4, 3.6, and 2.8 cm above the orbito-meatal plane). The blackened fMRI activation studies. This is, at least in part, due to areas at the posterior of the brain indicate the approximate location the need to administer radioactivity in PET. Although of the primary (PVC) and associative (AVC) visual cortices. (B) studies should, whenever possible, be performed with When the eyes are closed and patched, the tissue metabolic rate is fMRI, there remains a place for PET, namely in those relatively low. (C) Stimulation by white light. The increasing glucose instances where a stimulus cannot easily be repeated metabolic rate appears as increasing shades of grey, with black being the highest. Note the higher metabolic rate of the PVC and AVC such as in some psychiatric conditions. (arrows) when the subject is being visually stimulated. The border The future of PET activation studies, however, lies in zone between the posterior parietal cortex and the Broadmann area ligands. Ligand studies usually require approximately 1 19 of the AVC is also apparent when its metabolic rate is decreased h (Cunningham & Lammertsma, 1995), and it is in the unstimulated state. (D) Metabolic response of the visual cortex to the viewing of a complex visual scene (reproduced with permission difficult to repeat measurements within the same ses- from Phelps et al., 1981). sion. One possibility is to perform two separate studies 1280 A.A. Lammertsma / Vision Research 41 (2001) 1277–1281

Fig. 3. Parametric images of a human [11C]raclopride study through a transaxial plane at the level of the striatum. The left image represents the parameter R1, which is the ratio of local (i.e. pixel) delivery of tracer and delivery to the reference tissue (in this case, cerebellum). The right image represents binding potential BP, which Fig. 5. Region of interest data from basal ganglia () and cerebellum is related to the density of available receptors and the afﬁnity of ( ) single bolus plus infusion administration of [11C]raclopride. The binding of the ligand to the receptor. Raclopride is an antagonist of priming bolus is used to achieve a steady-state [11C]raclopride level in the D2 receptor, and the right image clearly shows a high concentra- tissue more rapidly. At 40 min, equilibrium has been reached, and the tion of D2 receptors in the striatum. It should be noted that both concentration is much higher in the receptor-rich basal ganglia com- images are parametric images, each one being a single image repre- pared with the receptor free cerebellum. At 40 min, 0.4 mg/kg of senting the magnitude of a (different) functional entity on a pixel-by- amphetamine was administered intravenously, producing displace- pixel level. The images were generated from a dynamic data ment of raclopride (from the receptors, i.e. from the basal ganglia, acquisition sequence (i.e. multiple scans over time) by applying a but not from the cerebellum) due to competition with increased tracer kinetic model to each pixel (reproduced with permission from dopamine released in response to the amphetamine challenge. The Gunn et al., 1997). magnitude of the activation can now be estimated from the change in basal ganglia-to-cerebellum ratio (reproduced with permission from Carson et al., 1997).

under different conditions. As it is now possible to generate functional images of receptor binding parameters (Gunn, Lammertsma, Hume, & Cunningham, 1997; see Fig. 3), previously mentioned statistical packages can be applied to these images, thereby directly detecting changes in binding on a pixel-by-pixel level (Koepp et al., 1998; see Fig. 4). If studies need to be performed in a single session, activation can only be detected as a displacement of the expected tissue time- activity curve, i.e. at a certain point in time, the ligand is displaced from the receptor by competition from an increased level of endogenous neurotransmitter that has been released as a result of the activation. Although initial attempts have been made (Friston et al., 1997), analysis of these studies still requires a significant mod- elling and statistical effort. A very promising technique is the so-called bolus-plus-infusion method, in which first a bolus of the ligand is given, followed by a Fig. 4. Results of one of the first receptor activation studies. In this study, eight volunteers underwent two [11C]raclopride studies, one constant infusion (Carson et al., 1997). The purpose of under baseline conditions and one whilst playing a video game. The the bolus is to achieve steady-state tissue (i.e. receptor) volunteers received a reward for each game level achieved. Illustrated tracer concentrations as quickly as possible. Any release are those regions of the brain in which there was a statistically of endogenous neurotransmitter will then result in a significant correlation between reduced [11C]raclopride BP and task performance. This correlation was found to be more pronounced in different steady state, which can be assessed on a the ventral striatum. In the upper row, transverse and coronal glass pixel-by-pixel level. Presently, there is some experience brain views are shown, highlighting voxels with a significant inverse with carbon-11-labelled raclopride for assessing phar- correlation of [11C]raclopride BP with the highest performance level macologically induced dopamine release (see Fig. 5). reached. In the bottom row, results of a statistical parametric map- Clearly, much work still needs to be done with respect ping (SPM) analysis of the data are superimposed on representative transaxial MRI brain slices. Note, that this study made use of the to understanding observed changes (Laruelle, 2000) and method presented in the previous figure (figure kindly provided by Dr in assessing whether changes due to smaller (e.g. cogni- Grasby, MRC Cyclotron Unit, Hammersmith Hospital, London). tive) stimuli are large enough to be detected. If success- A.A. Lammertsma / Vision Research 41 (2001) 1277–1281 1281 ful, however, results will be much more specific than using a simplified reference region model. NeuroImage, 6, 279– present PET or fMRI activation studies, which are 287. based on an indirect change in blood flow. Here, Henriksen, L., Paulson, O. B., & Lassen, N. A. (1981). Visual cortex activation recorded by dynamic computed tomography of inhaled SPECT could also play a more prominent role as the xenon 133. European Journal of Nuclear Medicine, 6, 487–489. steady-state technique is ideally tailored for the slower Ingvar, D. H., & Lassen, N. A. (1961). Quantitative determinations SPECT scanners. of regional cerebral blood flow in man. Lancet, 2, 806. Jones, T. (1996). The role of positron emission tomography within the spectrum of medical imaging. European Journal of Nuclear Medicine, 23, 207–211. References Koepp, M. J., Gunn, R. N., Lawrence, A. D., Cunningham, V. J., Dagher, A., Jones, T., Brooks, D. J., Bench, C. J., & Grasby, P. Carson, R. E., Breier, A., de Bartolomeis, A., Saunders, R. C., Su, T. M. (1998). Evidence for striatal dopamine release during a video P., Schmall, B., Der, M. G., Pickar, D., & Eckelman, W. C. game. Nature, 393, 266–268. (1997). Quantification of amphetamine-induced changes in Lammertsma, A. A., Cunningham, V. J., Deiber, M. P., Heather, J. 11 [ C]raclopride binding with continuous infusion. Journal of Cere- D., Bloomfield, P. M., Nutt, J., Frackowiak, R. S. J., & Jones, T. bral Blood Flow and Metabolism, 17, 437–447. (1990). Combination of dynamic and integral methods for gener- Comar, D. (1995). PET for drug de6elopment and e6aluation. Dor- ating reproducible functional CBF images. Journal of Cerebral drecht: Kluwer Academic. Blood Flow and Metabolism, 10, 675–686. Cunningham, V. J., & Lammertsma, A. A. (1995). Radioligand Lammertsma, A. A., Hume, S. P., Myers, R., Ashworth, S., studies in brain: kinetic analysis of PET data. Medicinal Chem- Bloomfield, P. M., Rajeswaran, S., Spinks, T., & Jones, T. (1995). istry Research, 5,79–96. PET scanners for small animals. Journal of Nuclear Medicine, 36, Fox, P. T., & Raichle, M. E. (1984). Stimulus rate dependance of 2391–2392. regional cerebral blood flow in human striate cortex demonstrated by positron emission tomography. Journal of Neurophysiology, 51, Laruelle, M. (2000). Imaging synaptic neurotransmission with in vivo 1109–1120. binding competition techniques: a critical review. Journal of Cere- Fox, P. T., & Raichle, M. E. (1986). Focal physiological uncoupling bral Blood Flow and Metabolism, 20, 423–451. of cerebral blood flow and oxidative metabolism during so- Lueck, C. J., Zeki, S., Friston, K. J., Deiber, M. P., Cope, P., matosensory stimulation in human subjects. Proceedings of the Cunningham, V. J., Lammertsma, A. A., Kennard, C., & Frack- National Academy of Sciences USA, 83, 1140–1144. owiak, R. S. J. (1989). The colour centre in the cerebral cortex of Friston, K. J., Holmes, A. P., Worsley, K. J., Poline, J. P., Frith, C. man. Nature, 340, 386–389. D., & Frackowiak, R. S. J. (1995). Statistical parametric maps in Mazziotta, J. C., Phelps, M. E., Carson, R. E., & Kuhl, D. E. (1982). functional imaging: A general linear approach. Human Brain Tomographic mapping of human cerebral metabolism: auditory Mapping, 2, 189–210. stimulation. Neurology, 32, 921–937. Friston, K. J., Malizia, A. L., Wilson, S., Cunningham, V. J., Jones, Phelps, M. E., Kuhl, D. E., & Mazziotta, J. C. (1981). Metabolic T., & Nutt, D. J. (1997). Analysis of dynamic radioligand dis- mapping of the brain’s response to visual stimulation: studies in placement or ‘activation’ studies. Journal of Cerebral Blood Flow man. Science, 211, 1445–1448. and Metabolism, 17,80–93. Watson, J. D. G. (2000). The human visual system. In A. W. Toga, Gunn, R. N., Lammertsma, A. A., Hume, S. P., & Cunningham, V. & J. C. Mazziotta, Brain Mapping: The Systems (pp. 263–289). J. (1997). Parametric imaging of ligand–receptor binding in PET San Diego, CA: Academic Press.