The dopaminergic basis of human behaviors: a review of molecular imaging studies (2009)

This systematic review describes human molecular imaging studies which have investigated alterations in extracellular DA levels during performance of behavioral tasks. Whilst heterogeneity in experimental methods limits meta-analysis, we describe the advantages and limitations of different methodological approaches. Interpretation of experimental results may be limited by regional cerebral blood flow (rCBF) changes, head movement and choice of control conditions. We revisit our original study of striatal DA release during video-game playing (Koepp et al., 1998) to illustrate the potentially confounding influences of head movement and alterations in rCBF. Changes in [¹¹C]raclopride binding may be detected in extrastriatal as well as striatal brain regions – however we review evidence which suggests that extrastriatal changes may not be clearly interpreted in terms of DA release. Whilst several investigations have detected increases in striatal extracellular DA concentrations during task components such as motor learning and execution, reward-related processes, stress and cognitive performance, the presence of potentially biasing factors should be carefully considered (and, where possible, accounted for) when designing and interpreting future studies.

Relationship between extracellular dopamine levels and D2 radiotracer binding

A somewhat counterintuitive finding from PET studies of task-induced DA release is that the magnitude of change detected in many studies is similar to that observed following administration of psychostimulants such as amphetamine. Microdialysis studies in rats have shown that non-pharmacological stimuli, such as transfer to a novel environment, increase DA levels in the ventral striatum (nucleus accumbens), to an order of approximately 20% (Neigh et al., 2001), whilst amphetamine administration may increase extracellular DA levels by around ~1500% (e.g. (Schiffer et al., 2006). Dual microdialysis and PET studies have demonstrated that the ratio of magnitude of change in extracellular DA to the magnitude of change in [¹¹C]raclopride binding varies according to the stimulus applied (Breier et al., 1997; Schiffer et al., 2006; Tsukada et al., 1999). D₂ antagonist radiotracer displacement generally does not exceed about 40-50% (Kortekaas et al., 2004; Laruelle 2000a). At a basic level, this ceiling effect relates to the fact that there are a limited number of D₂ receptors in the striatum.

In vitro studies of D₂ receptors reveal the existence of intraconvertable high (D_2high) and low (D_2low) affinity states for agonist binding; the D_2high state is regarded as the functional state due to G-protein coupling (Sibley et al., 1982). Whilst antagonists have equal affinity at both receptor states, agonists have greater affinity for the D_2high (1-10 nM) than the D_2low state (0.7-1.5 μM) (Freedman et al., 1994; Richfield et al., 1989; Seeman et al., 2003; Sibley et al., 1982; Sokoloff et al., 1990; Sokoloff et al., 1992). Based on this in vitro data and in vivo estimates of baseline D₂ occupancy by DA and the proportion of receptors in the high affinity state, models have been proposed which attempt to explain the ceiling effect in D₂ PET data (Laruelle 2000a; Narendran et al., 2004). These models estimate that the proportion of D₂ antagonist radiotracer binding susceptible to competition by DA is ~38%.

Recently, D_2/3 agonist radiotracers have been developed in the hope that they may be more sensitive than D_2/3 antagonist radiotracers in detecting fluctuations in DA, as a greater degree of competition will occur at the same site (Cumming et al., 2002; Hwang et al., 2000; Mukherjee et al., 2000; Mukherjee et al., 2004; Shi et al., 2004; Wilson et al., 2005; Zijlstra et al., 1993) Increased sensitivity of D_2/3 agonist radiotracers to changes in extracellular DA has yet to be confirmed in man; an initial study exploring the sensitivity of the D_2/3 agonist radiotracer [¹¹C]PHNO to amphetamine-induced changes in DA showed a sensitivity which was similar or, at most, only marginally greater than that previously observed with [¹¹C]raclopride (Willeit et al., 2008).

The relationship between D_2/3 radiotracer binding and extracellular DA levels may also reflect agonist-dependent receptor internalization (Goggi et al., 2007; Laruelle 2000a; Sun et al., 2003) and/or D₂ monomer-dimer equilibrium (Logan et al., 2001a). As will be discussed in more detail below, the kinetics of changes in extracellular DA relative to D_2/3 radiotracer kinetics may also be important in determining the degree of change in radiotracer binding potential (Morris et al., 2007; Yoder et al., 2004). Therefore whilst changes in BP of D_2/3 radiotracers such as [¹¹C]raclopride clearly show a dose-dependent relationship with extracellular DA levels, the nature of this relationship is complex and linearity may vary according to the type of stimulus applied.

Competition may be predominantly extrasynaptic

Throughout the D_2/3 PET literature it is often assumed that most D_2/3 receptors are synaptic and D_2/3 radiotracer PET therefore measures synaptic DA transmission. However, this interpretation must be reconsidered as several studies show that the location of D_2/3 receptors, and also DATs, is predominantly extrasynaptic (Ciliax et al., 1995; Cragg et al., 2004; Hersch et al., 1995; Sesack et al., 1994; Yung et al., 1995; Zoli et al., 1998). This is accordant with the well accepted view that DA acts via volume transmission in the striatum (Fuxe et al., 2007; Zoli et al., 1998). After phasic release, DA may diffuse several microns from the release site (Gonon et al., 2000; Peters et al., 2000; Venton et al., 2003); a distance far larger than the width of the synaptic cleft (about 0.5 μm) (Groves et al., 1994; Pickel et al., 1981). DA concentrations within the synaptic cleft may transiently rise to 1.6 mM (Garris et al., 1994), and recorded extrasynaptic DA concentrations arising from natural DA transients or following electrical stimulus pulses in rodents range from ~ 0.2-1 μM (Garris et al., 1994; Gonon 1997; Robinson et al., 2001; Robinson et al., 2002; Venton et al., 2003).

Recent models of DA striatal transmission predict that activation of D_2high receptors after release of a single DA vesicle may occur at a maximum effective radius of diffusion of up to 7 μm, whereas concentrations of 1 μM, capable of binding low affinity receptors, are associated with a maximum effective radius of <2 μm; both values far exceed the dimensions of the synaptic cleft (Cragg et al., 2004; Rice et al., 2008). Further analysis shows that, for D_2high receptors, DA released from one synapse may influence receptors (whether intra- or extra-synaptic) in the vicinity of 20-100 DA synapses within this radius (Cragg et al., 2004; Rice et al., 2008). These kinetic analyses have resulted in the proposal of a new model of striatal DA synapses (Rice et al., 2008), which accounts for significant spill over of DA to the extrasynaptic space and the predominant activation of extrasynaptic over intrasynaptic D₂ receptors. Although this model requires further evaluation, it would appear that extrasynaptic receptors play a significant if not predominant role in the binding and displacement D_2/3 radiotracers in the striatum.

Competition may occur within anatomically distinct striatal subdivisions

The striatum is commonly divided into three anatomical subdivisions; the caudate nucleus, putamen and ventral striatum. Whilst the dorsal striatum (neostriatum) includes the major proportion of the caudate nucleus and putamen, the ventral striatum is composed of the nucleus accumbens, part of the olfactory tubercle and the most ventromedial portions of the caudate and putamen. The dorsal striatum primarily receives DA fibres from the substantia nigra, whilst the origin of DA input to the ventral striatum lies principally in the ventral tegmental area (VTA). DA neurons are innervated by glutamatergic afferents from cortical areas, which modulate DA release at the cell body and terminal level (Cheramy et al., 1986; Karreman et al., 1996; Leviel et al., 1990; Murase et al., 1993; Taber et al., 1993; Taber et al., 1995). Cortical inputs to the striatum are topographically organised, forming parallel cortico-striatal-thalamo-cortical loops (Alexander et al., 1986). These loops are organized along a dorsolateral to ventromedial gradient, which may functionally relate to motor, cognitive and reward processes (Haber et al., 2000). Generally speaking, anatomical studies in non-human primates show that the motor and premotor cortices project to the putamen (Flaherty et al., 1994), whilst the head of the caudate receives input from the prefrontal cortex (Selemon et al., 1985) and the ventral striatum receives projections from the orbital and medial frontal cortex (Kunishio et al., 1994).

These anatomical subdivisions have also been conceptualized as ‘functional subdivisions’ (sensorimotor, associative and limbic) for PET image analysis (Martinez et al., 2003). This model should be viewed as probabilistic rather than exclusive due to significant overlap (Martinez et al., 2003) and as delineation may also be limited by scanner resolution and partial volume effects (Drevets et al., 2001; Mawlawi et al., 2001). The most convincing evidence that PET can detect changes in DA release in functionally discrete areas of the striatum is provided in the repetitive transcranial magnetic stimulation (rTMS) studies of Strafella and colleagues (Strafella et al., 2001; Strafella et al., 2003; Strafella et al., 2005). Stimulation of the mid-dorsolateral PFC caused a selective decrease in [¹¹C]raclopride binding in the head of the caudate nucleus (Strafella et al., 2001). The opposite pattern was observed when the motor cortex was stimulated; decreases in [¹¹C]raclopride binding were observed in the putamen but not other striatal areas (Strafella et al., 2003; Strafella et al., 2005). These findings are in accordance with anatomical studies of cortico-striatal projections in primates (Flaherty et al., 1994; Kunishio et al., 1994; Selemon et al., 1985) and suggest that spatially distinct areas of increased DA release as imaged with PET may be functionally related to the discrete behavioral process under investigation.

Choice of radioligand

Currently, D_2/3 receptor binding in the striatum is normally quantified using either the PET radioligand [¹¹C]raclopride, or the single photon emission tomography (SPET) radioligands [¹²³I]IBZM and [¹²³I]epidepride. These D₂ antagonist radiotracers are readily displaceable by increases or decreases in endogenous DA (Endres et al., 1998; Laruelle 2000a). Other D₂ antagonist radiotracers such as spiperone and D1 radiotracers are not readily vulnerable to changes in extracellular DA due to factors such as receptor internalisation (Laruelle 2000a), monomer-dimer formation (Logan et al., 2001b) or tracer kinetics (Morris et al., 2007) as mentioned above. Recent images obtained with the newly developed D_2/3 agonist radiotracer [¹¹C]PHNO demonstrate higher binding in the ventral portion of the striatum and globus pallidus compared to [¹¹C]raclopride (Willeit et al., 2006), which may be attributable to a higher affinity of [¹¹C]PHNO for D₃ over D₂ receptors (Narendran et al., 2006). Although not yet confirmed in human volunteers, [¹¹C]PHNO may therefore offer some particular advantage in assessing changes in DA release in the ventral aspect of the striatum, as DA also has higher affinity for the D₃ over D₂ receptor subtype (Sokoloff et al., 1990). As addressed in detail below, in order to measure extrastriatal D₂ receptor availability and possibly extrastriatal DA release, high affinity antagonist radiotracers such as [¹¹C]FLB457 and [¹⁸F]fallypride are required (Aalto et al., 2005; Montgomery et al., 2007; Riccardi et al., 2006a; Riccardi et al., 2006b; Slifstein et al., 2004).

Changes in cerebral blood flow

In developing these methodologies a major consideration has been the influences that task-induced changes in blood flow may exert on the estimation of D_2/3 radiotracer binding potential. Using hyperventilation to decrease regional cerebral blood flow (rCBF) via vasoconstriction, an [¹¹C]raclopride scan in a single subject showed an apparent decrease in both the distribution volume and transport of the radiotracer to the brain (K₁) (Logan et al., 1994) suggesting that radiotracer delivery may be altered by changes in rCBF. The SRTM returns a similar parameter, R₁-the delivery of the radiotracer to the striatum relative to the cerebellum (Lammertsma et al., 1996b). Hence, using both the Logan graphical analysis and SRTM methods, rCBF effects are theoretically distinguishable from changes in neurotransmitter release – however, these measures are often not reported. These R₁ or K₁ measures are limited in that transient changes in blood flow during the scanning period, which may also produce artifactual results, are not estimated (Laruelle 2000b).

In the original [11C]raclopride PET study of video-game playing, reductions in R1 were observed during the activation condition, in addition to the observed decreases in BP (Koepp et al., 1998). These changes in R1 did not correlate with changes in BPND and it was concluded that the observed decrease in R1 may have been due to relatively greater increases in rCBF in the cerebellum compared to the striatum whilst playing the game. This was subsequently confirmed when cerebral blood flow during the task was measured using H2−150 PET (Koepp et al., 2000).

Figure 1A shows the rCBF values measured in the dorsal and ventral striatum and cerebellum during the rest and task periods. During the task period, the largest increases (mean 29%) in rCBF occurred in the cerebellum. Smaller increases in rCBF occurred in the striatal regions during the task period (dorsal striatum 16%; ventral striatum 10%; caudate 9%). Dividing rCBF values in the dorsal and striatal ROIs by that obtained in the cerebellum gives a measure equivalent to R₁ (CBF_(ROI/CB)). As shown in Figure 1B, CBF_(ROI/CB) was reduced by ~10% in the dorsal striatum, and ~15% in the ventral striatum during the task relative to the baseline condition. These figures are therefore consistent with the changes in R₁ that were detected in the original [¹¹C]raclopride PET investigation, where R₁ decreased by a mean 13% in the dorsal striatum and 14% in the ventral striatum (Koepp et al., 1998). The question was therefore to what extent could these changes in flow could contribute to the apparent decreases in the estimates of striatal [¹¹C]raclopride BP_ND.

  

Figure 1

Regional cerebral blood flow during performance of a videogame

Simulations performed by Dagher et al., (1998) of the single dynamic scan displacement approach have shown that if k₂ (the efflux rate constant) is increased more than K₁, the resulting changes in radiotracer binding are indistinguishable from changes that would result from increased release of DA, potentially resulting in false positive results. However, it can be shown under the assumptions of the Renkin-Crone model with passive transport of a solute between capillary plasma and tissue, that changes in either blood flow rate or the permeability surface product (PS product) for the solute would affect both K₁ and k₂ equally, so that an apparent change in the estimated BP_ND is unlikely under steady state conditions. Simulations performed for validation of the displacement methods have demonstrated that when K₁ and k₂ are increased equally, no significant effects on radiotracer binding are detected (Pappata et al. 2002; Alpert et al. 2003). However, increases in rCBF during the washout period when radiotracer concentration in the blood is minimal will primarily affect efflux and not influx, and it is likely that an increase in rCBF either in the striatum or in the reference region, on commencing the task during the washout period, would lead to biased estimations of BP_ND.

Returning to the video game example, Koepp et al. (2000) concluded that since the mean values of CBF in each of the regions were relatively constant during rest and activation periods, use of SRTM was unlikely to induce a bias in the estimated BPs. This conclusion is supported by simulations of the video game experiments taking into account the actual fluctuations for flow and their variation during rest and activated conditions as reported in Figure 1A. In brief, an arterial plasma parent input function for a bolus [¹¹C]raclopride scan was taken from the study of Lammertsma et al. (1996) together with the mean values for the rate constants (K₁, k₂) describing the fit of cerebellum to a one tissue compartmental model with a plasma input function, as reported by Farde et al. (1989). Equivalent mean PS products were calculated for cerebellum from the mean values for blood flow under rest and activated conditions given in Table 1A, according to the Renkin-Crone model;

PS = −F.log(1 − K₁/F), where F is the plasma flow rate assuming an haematocrit of 0.4.

It was assumed that the total volume of distribution for [¹¹C]raclopride in cerebellum did not change between rest and task conditions. Values for the PS products and equivalent rate constants for dorsal and ventral striatum were then derived from the mean blood flow under rest conditions (Figure 1A), together with estimates of R₁ and BP relative to cerebellum reported by Koepp et al. (1998) under resting conditions. It was then possible to construct individual time activity curves (TACs) for cerebellum under baseline and test conditions and for striatal regions under baseline conditions taking into account the individual fluctuations in blood flow over the scanning periods. It was also assumed that PS products varied in proportion to flow so as to exaggerate the possible effects of the small fluctuations in blood flow during the scans. Striatal TACs were simulated under test conditions either assuming a decrease in BP as reported by Koepp et al., 1998 or with no change in BP. Estimates of BP were then estimated using the STRM, as in Koepp et al., (1998) which takes no account of bias induced by fluctuations in blood flow. These simulations showed that under the above assumptions there was no confounding effect due to fluctuations in flow; the mean apparent BP_ND for ventral striatum would have changed from a baseline value of 2.231 to 2.238 due to blood flow changes alone as opposed to 1.918 given a task induced change in the true BP_ND. The corresponding vales for dorsal striatum were 2.407, 2.412 and 2.213.

In the present case, a blood flow effect on the apparent changes in BP_ND was therefore unlikely, due to the task being initiated prior to scan start and relative constancy of blood flow within each scan. However variations in blood flow during a single scan would result in an underestimation of BP_ND had the task been started within the washout period following a single bolus injection and we consider this factor of significant concern in displacement approaches to quantifying changes in DA release. The method least influenced by local or global changes in rCBF is the bolus infusion (BI) approach; once secular equilibrium has been established, the constant levels of the radiotracer in the plasma avoid any confounding effects of blood flow on specific binding values (Carson et al., 1993; Carson et al., 1997; Carson 2000; Endres et al., 1997; Endres et al., 1998). We therefore consider BI radiotracer administration the optimal choice of available methodology when the influences of concurrent changes in rCBF during the scan period are of concern.

Head movement

Head movement may be especially problematic in behavioral studies where volunteers are required to make a verbal or motor response (Montgomery et al., 2006a). Movement during the scan can markedly reduce the effective scanner resolution (Green et al., 1994) and may lead to inaccurate measurement of BP. Although uncorrected head movement will affect BP measurements obtained using all analysis methods, this may be of particular importance in displacement studies, as it is conceivable that head movement may consistently occur on commencement of the activation task and lead to false positive changes in BP (Dagher et al., 1998). Voxel-wise analysis methods (see below) may also be particularly sensitive to head movement effects, as the binding of [¹¹C]raclopride is much higher in striatal regions compared to the adjacent extrastriatal areas (Zald et al., 2004).

Head movement may be reduced during the scan using restraints such as thermoplastic face masks, as employed by Ouchi et al., (2002) during a motor task and de la Fuente-Fernandez et al., (2001; 2002) in examination of the placebo effect. However, thermoplastic face masks may be uncomfortable for volunteers and previous comparative studies have shown that, although head movement may be considerably reduced, it is not eliminated (Green et al., 1994; Ruttimann et al., 1995). An alternative or complementary approach is to correct effects of head movement post hoc, using frame-by-frame (FBF) realignment. Typical FBF realignment techniques align all frames to either an initial or later frame selected on the basis of a high signal-to-noise ratio (Mawlawi et al., 2001; Woods et al., 1992; Woods et al., 1993). The FBF realignment technique is limited by poor statistical quality of data acquired in later frames and an inability to correct for head-movement within frames (which may be up to 10 minutes long) (Montgomery et al., 2006b). In addition, these methods assume that radiotracer distribution is similar in early and late frames; this is not the case following bolus radiotracer administration, which can lead to false positive results (Dagher et al., 1998). To reduce the influence of radiotracer redistribution producing erroneous alignments, the non-attenuation corrected image can be used instead; these images have a higher scalp signal which provides more information for the realignment program to work with (Montgomery et al., 2006a). In addition, denoising using wavelets can be applied to decrease errors introduced by poor signal to noise ratios (Mawlawi et al., 2001; Turkheimer et al., 1999). Recent [¹¹C]raclopride bolus studies of task-induced DA release published by Dagher and colleagues (Hakyemez et al., 2008; Soliman et al., 2008; Zald et al., 2004) use a novel realignment process (Perruchot et al., 2004). Here, brain regions, following automated segmentation from individual MRI images, are assigned generic time-activity curves on the basis of previous data. The frames acquired during the experimental scans are then automatically realigned to target volumes using a realignment algorithm. New methods, such as the use of motion tracking software and movement correction during re-binning of list-mode data, are under development and show superior test-retest reliability (Montgomery et al., 2006b). This approach has only been used in one study of task-related DA release to date (Sawamoto et al., 2008) and may be of particular value in this context as improved reliability of data will increase ability to detect small changes in DA release.

To illustrate the importance of appropriate head-movement correction, we again revisit our original [¹¹C]raclopride bolus video-game data (Koepp et al., 1998). In the original analysis, head movement, although minimized using an orthopedic collar and head support, was not corrected for. Furthermore, striatal ROI were threshold-defined using a fixed-threshold of 40% of the image maximum. This may also produce artifacts; if systematic increases in regional volume (due to head movement) occur under the activation compared to rest condition, the measured activity will decrease which may lead to false-positive results. To illustrate the bias introduced by these approaches, we compared the original data with that obtained through re-analysis with anatomically-defined ROI and FBF realignment.

To obtain anatomically-defined striatal and cerebellar ROIs we used the criteria described by Mawlawi et al., (2001) to define dorsal and ventral striata on a magnetic resonance scan positioned in Montreal Neurological Institute (MNI) space. An [¹¹C]raclopride template was constructed in MNI space (Meyer et al., 1999) using an average image of 8 scans obtained in healthy control subjects. This template was then spatially transformed into individual PET space and the resulting transformation parameters were used to transform the striatal ROI into individual space. We then combined analysis in re-defined ROIs with head movement correction using FBF-realignment. Non-attenuation corrected dynamic images were denoised using a level 2, order 64 Battle Lemarie wavelet (Battle 1987; Turkheimer et al., 1999). Frames were realigned to a single frame which had a high signal to noise ratio, using a mutual information algorithm (Studholme et al., 1996) and the transformation parameters were then applied to the corresponding attenuation corrected dynamic images. This procedure was applied to all frames to generate a FBF-corrected dynamic image.

Table 2 presents the regional BP values obtained in the original analysis (Koepp et al., 1998) and those obtained following ROI redefinition with subsequent FBF realignment. In the original study, repeated measures ANOVA revealed a significant effect of playing the video game (F₍₁₎=7.72; p <0.01), that was particularly marked in the ventral striatum (see Table 2). Following ROI redefinition, ANOVA showed only a trend-level effect of playing the video game (F₍₁₎ = 3.64; p=0.10) and a significant effect of region (F₍₃₎=90.98; p<0.01). In common with our previous results, but of a smaller magnitude, post hoc t-tests did reveal a significant reduction in BP in the right ventral striatum during the video game condition (t₍₇₎=4.94; p=0.01; mean −7.3%), although this effect only reached trend level significance in the left ventral striatum (t₍₇₎=2.10; p=0.07; mean −4.7%). Whilst in our original data BP in all areas correlated with task performance (Koepp et al., 1998), when ROI were re-defined there were no correlations between performance and change in BP. Following ROI definition and FBF realignment, ANOVA showed a significant overall effect of condition (F₍₁₎ = 7.44; p=0.03) and region (F₍₃₎ = 22.23; p=0.01). However, the magnitudes of change were much smaller (see Table 2) and t-tests did not reveal any significant changes in individual dorsal or ventral striatal regions.

  

Table 2

[11C]raclopride binding potential values obtained by re-analysis

Although we did not observe significant changes in ROI size, or correlations between ROI size and performance during the scan, the diminished experimental effects observed when non-threshold ROI were used in the re-analysis suggests that head movement may have biased our published results. This conclusion is further strengthened by the observation that when FBF re-analysis was applied, the significance of magnitude of changes detected was further diminished. Thus, we cannot overstate the importance of appropriate head movement correction methods for analysis of task-induced DA release using [¹¹C]raclopride PET. Head movement correction is also of particular importance in studies of pharmacologically-evoked DA release when the pharmacological challenge may be associated with behavioral activation (e.g. amphetamine).

Dopamine kinetics and timing

A more important factor may be the shape and timing of the DA release curve in comparison to the radiotracer time-activity curve. Graphical analysis following bolus administration of [18F]-N-methylspiroperidol showed that change in uptake rate is maximal for large DA peaks and slow DA clearance (Logan et al., 1991). Similar results have been obtained for the dual condition, single scan BI approach; changes in specific binding following amphetamine challenge correlate with both the height of the DA pulse (nM) and the DA clearance rate (min⁻¹), and tightest correlations are obtained when the change in specific binding is correlated against the integral of the DA pulse (μM·min) (Endres et al., 1997). It is unclear at present whether DA curves obtained under all physiological stimuli will be sufficient to produce significant radiotracer displacement using this technique.

Simulations performed by Morris and colleagues (1995) for the paired bolus approach suggest that BP changes may be maximized when the activation task is performed over a long time period, and commenced on or before radiotracer administration. Similar results were obtained by Logan et al., (1991), where the largest change in [18F]-N-methylspiroperidol uptake rate occurred when the task commenced simultaneously with radiotracer injection, a finding also replicated in [¹¹C]raclopride simulations of Endres et al., (1998). Yoder et al., (2004) have further demonstrated that the change in BP can be markedly affected by the timing of DA response in relation to the timing of [¹¹C]raclopride concentration following bolus administration, an interaction termed ‘Effective Weighted Availability’ (EWA). Here, greater changes in BP were detected if the onset of the DA response occurred just before [¹¹C]raclopride administration (Yoder et al., 2004). Furthermore, the magnitude of change in BP reflected not only the magnitude of DA release (area under the curve) but also differences in DA temporal kinetics (i.e. the gradient of the DA release curve), with blunt curves producing larger changes in BP for a given amount of DA released (Yoder et al., 2004). When using the paired bolus approach, it is therefore recommended that tasks start just prior to radiotracer administration and continue for a significant duration of the scan.

Pharmacological enhancement of dopamine release

An interesting strategy to increase detection of task-induced changes in DA release is the use of DA re-uptake inhibitors such as methylphenidate (MP), which has been used with some success (Volkow et al., 2002b; Volkow et al., 2004). As MP inhibits the re-uptake of released DA to the presynaptic terminal through dopamine transporters, released DA accumulates thus producing a greater magnitude of change in [¹¹C]raclopride binding (Volkow et al., 2002a). However, small but significant differences between four combinations of conditions (placebo or MP plus control or activation) are required in order for clear additive effects to be observed, meaning this approach has been difficult to validate; ideally dose-response studies of re-uptake inhibition are required. In addition, variable absorption of oral MP will introduce some noise into these measurements. Care is also required as DA reuptake inhibitors may also produce additional effects on regional blood flow, or on DA release via action on other neurotransmitter systems. Nonetheless, DA reuptake inhibition may theoretically be a useful ‘pharmacological enhancement maneuver’ for imaging task-induced DA release.

Voxel-based analysis

Differences in BP between control and activation conditions may also be determined using parametric analysis. Standard voxel-wise analysis can be carried out using statistical parametric mapping (SPM) software (Friston et al., 1995); (http://www.fil.ion.ucl.ac.uk/spm/). A further approach is the voxel-wise statistical method of Aston et al., (2000), currently available for data obtained using paired bolus scans. Different to the usual SPM approach, the method of Aston et al., (2000), uses residuals of the least squares fit of the kinetic model to estimate the standard deviation of BP measurements at each voxel from the noise of dynamic data. These standard deviations are then used to estimate the t statistic at each voxel and, in proportion to the number of time-frames in the dynamic data, the degrees of freedom (df) are thereby greatly increased. Simulations showed that statistical sensitivity to detect changes in BP was greatly enhanced; indeed changes could be detected in single subjects across experimental conditions in simulated data (Aston et al., 2000). When considering what is currently known about the neuroanatomy of the striatum (see above), it would seem prudent that voxel-based approaches are presented alongside ROI-based analyses.

Motor performance and sequential motor learning

Several studies have shown that D_2/3 radiotracer BP in the dorsal striatum decreases when subjects perform repetitive limb movements during the scan; paradigms include a hand-writing task, foot extension/flexion and simple finger movements (Badgaiyan et al., 2003; Goerendt et al., 2003; Lappin et al., 2008; Lappin et al., 2009; Larisch et al., 1999; Ouchi et al., 2002; Schommartz et al., 2000). These decreases in BP have been reported following [¹²³I]IBZM SPET (Larisch et al., 1999; Schommartz et al., 2000), paired bolus [¹¹C]raclopride PET (Goerendt et al., 2003; Lappin et al., 2009; Ouchi et al., 2002) or[¹¹C]raclopride bolus displacement (Badgaiyan et al., 2003) methodologies. The only study to report negative results administered [¹¹C]raclopride after completion of a motor task (treadmill running) (Wang et al., 2000), suggesting that there may be a requirement for ongoing DA release in the presence of the radiotracer in order for significant effects to be observed. The positive study of Schommartz et al., (2000) was the first study of task-induced DA release to employ a non-resting control condition; [¹²³I]IBZM binding in a handwriting task was compared to that in a reading task, thought to involve an equivalent cognitive load but without the motor requirements. As detailed in Table 3, this approach has since been adopted in a number of studies.

Some evidence suggests that DA release may also mediate motor learning. Widespread reductions in striatal [¹¹C]raclopride binding have recently been reported during a finger sequence learning task using a single bolus plus constant infusion paradigm (Garraux et al., 2007), although as the control condition was not matched for motor output, DA release associated with motor learning could not be dissociated from that associated with motor performance. Use of motor control conditions to investigate changes in DA which may specifically relate to motor learning have been employed in two studies by Badgaiyan and colleagues (Badgaiyan et al., 2007; Badgaiyan et al., 2008). Here, both implicit and explicit learning of complex motor sequences, relative to a motor control condition, increased [¹¹C]raclopride displacement in the caudate and putamen (Badgaiyan et al., 2007; Badgaiyan et al., 2008). However, as these studies used a [¹¹C]raclopride single bolus displacement paradigm, confounding effects of blood flow changes cannot be excluded (see above). We have recently compared DA release during motor sequence learning and motor sequence execution within subjects using paired bolus [¹¹C]raclopride scans (Lappin et al., 2009), and did not find any significant differences in [¹¹C]raclopride between sequence learning and execution, although both conditions significantly decreased [¹¹C]raclopride binding in the sensorimotor and associative striatum compared to resting baseline values. This result therefore questions the extent to which motor and cognitive tasks components may be separated in terms of DA release in striatal subdivisions.

Reward-related processes

11C-raclopride PET studies have investigated the role of striatal DA in several aspects of reward in humans. With respect to reward consumption, Small et al., 2003 have shown that decreases in [¹¹C]raclopride BP occur in the dorsal caudate and dorsal putamen, following consumption of a ‘favorite meal’ just prior to scanning (Small et al., 2003). In this study, the feeding-induced decreases in [¹¹C]raclopride BP, which were observed in previously food-deprived subjects, were correlated with subjective ratings of pleasantness, hunger and satiety.

Studies in experimental animals reveal that the relationship between reward and striatal DA levels is complex. Whilst microdialysis studies demonstrate that lever pressing for natural reinforcers, such as food, increases striatal DA release (e.g. Hernandez et al., 1988), further research indicates that it is the requirement for operant responding (lever pressing), rather than the presence of the reward itself, which is associated with increased DA (Salamone et al., 1994; Sokolowski et al., 1998). This is mirrored in human studies of DA release; decreased striatal 11C-raclopride BP is observed during an active (Zald et al., 2004) but not a passive (Hakyemez et al., 2007) reward task. Decreases in [¹¹C]raclopride BP in the ventral and dorsal striatum have also recently been detected in Parkinsonian patients during a gambling task requiring active responses (Steeves et al., 2009). Interestingly, in the ventral striatum, the change in [¹¹C]raclopride BP was greater in patients with a pathological gambling disorder than control patients, whilst baseline D2/3 receptor availability was lower (Steeves et al., 2009). This is accordant with animal research suggesting that low D2/3 receptor availability may mediate vulnerability to addiction (Dalley et al., 2007), and that aspects of addiction may be mediated through sensitized DA release (Robinson and Berridge, 2000; Volkow et al., 2006).

In animals, as a cue becomes paired with a reward during Pavlovian conditioning, increases in DA neuron firing rate become more tuned to the reward-predicting cue than to the reward itself (Schultz 1998), so that increases in striatal DA release occur on cue presentation (Kiyatkin et al., 1996; Phillips et al., 2003). Recently, cue-induced DA release has been investigated using a delayed monetary incentive task (Schott et al., 2008). In comparison to a neutral control condition (designed to minimize sensorimotor and cognitive differences between conditions), decreases in [¹¹C]raclopride BP were observed in the left ventral striatum (nucleus accumbens). Volkow et al., (Volkow et al., 2002b; Volkow et al., 2006) have investigated cue-induced DA release in food-deprived or cocaine-addicted volunteers. In food-deprived subjects, food-associated cues did not significantly alter [¹¹C]raclopride BP in the striatum, except when combined with methylphenidate (Volkow et al., 2002b). However, in cocaine-addicted volunteers, drug-associated cues delivered via a video of the simulated purchase, preparation and smoking of crack cocaine produced significant decreases in dorsal striatal [¹¹C]raclopride BP. These changes correlated with self-reports of craving and may relate to habitual aspects of compulsive drug taking (Volkow et al., 2006). Together, these results are consistent with the hypothesis that reward anticipation and reinforcement learning may relate to DA responses in the ventral striatum, but that DA process linked to habitual behaviors in addiction are mediated by more dorsal striatal regions (Porrino et al., 2004).

There is some evidence that, in clinical disorders, drug placebos can also act as reward-predicting cues, in that placebo administration may lead to expectation of clinical benefits, such as pain relief, which function as rewards (de la Fuente-Fernandez et al., 2004). Placebo-induced DA release across the striatum has been observed in Parkinson’s Disease patients following administration of saline in place of apomorphine (de la Fuente-Fernandez et al., 2001; de la Fuente-Fernandez et al., 2002) and during sham rTMS (Strafella et al., 2006). In the apomorphine study, the change in [¹¹C]raclopride binding in the dorsal striatum correlated with the amount of clinical benefit reported following placebo administration (de la Fuente-Fernandez et al., 2001; de la Fuente-Fernandez et al., 2002; de la Fuente-Fernandez et al., 2004) and a similar but non-significant trend was observed following rTMS (Strafella et al., 2006). Although only observed using voxel-wise and not ROI analysis, a similar result in the ventral striatum has recently been suggested following administration of a placebo for glucose in fasted men (Haltia et al., 2008). These studies, performed by different groups, both utilized paired bolus scans. Increased extracellular DA in the striatum in response to placebo administration has also been observed in analgesia studies using BI methodology; [¹¹C]raclopride BP decreased in the placebo condition both during the expectation of pain (Scott et al., 2007a), and during the delivery of the painful stimulus (Scott et al., 2008). Here, the DA release in the ventral striatum appeared to be particularly associated with the placebo response (Scott et al., 2007a; Scott et al., 2008). Decreased [¹¹C]raclopride BP may also be particularly apparent in the ventral striatum when placebo tablets are administered in place of psychostimulant drugs; when placebo tablets, identical to the previously administered amphetamine tablets, were given in an environmental setting previously paired with amphetamine administration, marked decreases in [¹¹C]raclopride binding in the ventral striatum were detected (23%) (Boileau et al., 2007).

In the novel [¹¹C]raclopride displacement method of Pappata et al., (2002,) significant [¹¹C]raclopride displacement in the ventral striatum occurred in an unexpected monetary gain condition (Pappata et al., 2002). Using a carefully designed study with an appropriate sensorimotor control condition and an established [¹¹C]raclopride modeling technique, it has been demonstrated that unpredictable monetary rewards increase DA levels in the medial left caudate nucleus (Zald et al., 2004). As stated above, in accordance with microdialysis studies of operant responding in animals (Salamone et al., 1994), this increase in DA appears dependent on the requirement for subjects to make a behavioral response, as no increase in DA was seen during a passive reward task (Hakyemez et al., 2008). Interestingly, during both active and passive reward tasks, increases in [¹¹C]raclopride binding were detected in the putamen, indicating decreases in DA release, possibly due to withholding of expected rewards (Hakyemez et al., 2008; Zald et al., 2004). Similarly, when alcohol predicting cues were presented whilst subjects were in the scanner, but alcohol was not given until after the scan had finished, increases in [¹¹C]raclopride binding were observed in the right ventral striatum (Yoder et al., 2009). Increases in [¹¹C]raclopride binding have also been observed in the dorsal striatum of fasted men administered placebo for glucose (Haltia et al., 2008). Although unclear at present, these results may relate to decreases in DA neuronal firing which have been observed in animals when expected rewards are omitted (‘negative prediction error’) (Schultz, 1997; Schultz, 1998) and an altered balance between the potentially opposing effects (Grace, 1991) of phasic DA release and the level of tonic (population) dopaminergic activity on [¹¹C]raclopride binding (Hakyemez et al., 2008). Whilst interesting, substantial work in experimental animals investigating changes in striatal [¹¹C]raclopride binding in relation to tonic and phasic DA neuron firing, and under different reward paradigms in awake animals (Patel et al., 2008), is required before these effects can be clearly interpreted.

The animal literature on DA release in reward and reinforcement presents a complex picture, and the precise role of DA in different divisions of the striatum in reward and reinforcement learning is still under debate (Salamone 2007). Whilst these PET studies provide compelling evidence for DA release in the human striatum across several reward paradigms, the direction, magnitude and regional selectivity of these responses likely depends on factors such as reward / reinforcement contingencies and predictability, conditioning and habit formation, as is the case in the animal literature.

Psychological and pain stress

In animals, cortical and striatal DA release increases following exposure to stressors such as chronic restraint, foot or tail-shock (Abercrombie et al., 1989; Imperato et al., 1991; Sorg et al., 1991). Stress is believed to be an important factor in the development of disorders such as schizophrenia and depression, and this association may be mediated by molecular alterations in DA systems (Butzlaff et al., 1998; Howes et al., 2004; Thompson et al., 2004; Walker et al., 1997). The striatal DA response to stress using [¹¹C]raclopride PET has been investigated using arithmetic tasks as psychological stressors (Montgomery et al., 2006a; Pruessner et al., 2004; Soliman et al., 2008), and pain stress (Scott et al., 2006; Scott et al., 2007b). The experimental design employed in two studies by the same group (Pruessner et al., 2004; Soliman et al., 2008) used an arithmetic task which was performed in-front of a study investigator, who regularly gave negative verbal feedback. This design is thought to particularly induce psychosocial stress. In the stress condition decreases in [¹¹C]raclopride binding were apparent and these were particularly notable in the ventral striatum. Interestingly, the decreases in [¹¹C]raclopride binding were only apparent in vulnerable individuals (those reporting low maternal care or scoring highly on a negative schizotypy scale). Under a different arithmetic task, but relative to a matched control condition and using dual condition BI [¹¹C]raclopride administration, we were unable to detect any stress-induced DA release (Montgomery et al., 2006a). This difference may be because the task may not have loaded quite so highly on psychosocial stress, or may relate to the fact that only a small proportion of these volunteers reported low maternal care. In similarity to this, the bolus study of Volkow et al., (2004), performed in individuals who were not selected on the basis of stress vulnerability, showed no difference in [¹¹C]raclopride binding during an arithmetic task, except in the presence of methylphenidate. Therefore, the vulnerability of the subjects, and the degree to which tasks load on psychosocial stress (in addition to the cognitive challenge of the arithmetic task) may be important in eliciting DA release.

The use of painful stimuli as stressors may cause a large DA response. Using BI methodology, large decreases in [¹¹C]raclopride BP occurred across the striatum on administration of hypertonic saline to the masseter muscle (Scott et al., 2006; Scott et al., 2007b). Interestingly, whilst changes in dorsal striatal areas were particularly associated with pain ratings, those in the ventral striatum correlated with a negative affective state and fear ratings (Scott et al., 2006). These data indicate that striatal DA release in the human brain may occur in response to aversive (Scott et al., 2006; Scott et al., 2007b) as well as rewarding (Hakyemez et al., 2008; Small et al., 2003; Volkow et al., 2006; Zald et al., 2004) stimuli.

Cognitive tasks and states

Functional MRI and rCBF studies reveal striatal activation during performance of several cognitive tasks, including spatial planning, spatial working memory and set-shifting (Dagher et al., 1999; Mehta et al., 2003; Monchi et al., 2001; Monchi et al., 2006b; Owen et al., 1996; Owen 2004; Rogers et al., 2000). Although less work has been performed in this area, dopaminergic contributions to some aspects of cognitive functioning have been investigated using PET. In particular, decreases in [¹¹C]raclopride BP were observed when planning a set shift (Monchi et al., 2006a), and during spatial planning (Lappin et al., 2009) and spatial working memory tasks (Sawamoto et al., 2008). Whilst decreases in [¹¹C]raclopride BP were detected compared to non-resting control conditions in the investigations of Monchi et al., 2006a and Sawamoto et al., 2008; in the spatial planning investigation of Lappin et al., (2009) the cognitive components of the task could not be clearly separated from motor components. Interesting, the results from all these studies suggest that effects may be greatest in the caudate, which would be in accordance with predictions from striatal anatomy (Alexander et al., 1986; Haber et al., 2000) and the functional subdivision model (Martinez et al., 2003) which suggest that DA in the caudate (associative striatum) may particularly modulate cognitive functions.

Finally, some evidence suggests that [¹¹C]raclopride BP values may also vary according to the internal cognitive state of the individual when no behavioral output is required. Yoga-Nidra mediation is associated with decreases in BP in the ventral striatum (Kjaer et al., 2002) and a small study suggested volunteer uncertainty of the experimental procedure (whether or not alcohol would be infused) also alters baseline BP (Yoder et al., 2008). Whilst further confirmation is required, this latter study, together with those of psychological stress in vulnerable individuals (Pruessner et al., 2004; Soliman et al., 2008) may illustrate the importance of carefully controlled experimental conditions during PET investigations of DA release.

The authors would like to thank Prof. Alain Dagher (Montreal Neurological Institute, McGill University, Montreal, Canada) and Dr Stephanie Cragg (University of Oxford, UK) for their valuable input to this manuscript.

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