Lateralization and gender differences in the dopaminergic response to unpredictable reward in the human ventral striatum

Abstract

Electrophysiological studies have shown that mesostriatal dopamine (DA) neurons increase activity in response to unpredicted rewards. With respect to other functions of the mesostriatal dopaminergic system, dopamine's actions show prominent laterality effects. Whether changes in DA transmission elicited by rewards also are lateralized, however, has not been investigated. Using [¹¹C]raclopride-PET to assess the striatal DA response to unpredictable monetary rewards, we hypothesized that such rewards would induce an asymmetric reduction in [¹¹C]raclopride binding in the ventral striatum, reflecting lateralization of endogenous dopamine release. In 24 healthy volunteers, differences in the regional D₂/₃ receptor binding potential (ΔBP) between an unpredictable reward condition and a sensorimotor control condition were measured using the bolus-plus-constant-infusion [¹¹C]raclopride method. During the reward condition subjects randomly received monetary awards while performing a 'slot-machine' task. The ΔBP between conditions was assessed in striatal regions-of-interest and compared between left and right sides. We found a significant condition × lateralization interaction in the ventral striatum. A significant reduction in binding potential (BP(ND) ) in the reward condition vs. the control condition was found only in the right ventral striatum, and the ΔBP was greater in the right than the left ventral striatum. Unexpectedly, these laterality effects appeared to be partly accounted for by gender differences, as our data showed a significant bilateral BP(ND) reduction in women while in men the reduction reached significance only in the right ventral striatum. These data suggest that DA release in response to unpredictable reward is lateralized in the human ventral striatum, particularly in males.

Figure 1. Illustration of the experimental task

A. Illustration of a sensorimotor and a rewarded trial. During each trial, subjects were presented four distinct pictures (apple, grape, cherry, bell) presented in a “slot-machine” motif. Subjects were asked to choose one of the four with a button press on a four-button response box using their right hand. This response was followed by a 500 msec delay. In the rewarded trials a one dollar bill appeared for 1,000 msec and subjects heard the characteristic sound of an opening cash-register door. These monetary gains were provided in a pseudo-randomized order with an average of one reward per every fourth trial. In the sensorimotor control trials, subjects instead were presented a meaningless symbol accompanied by a “click” sound on every fourth trial. After receiving the trial outcome subjects were presented their running total of earnings for 1,000 msec. Displaying the actual balance account prevented rapid discounting of the rewards presented. At the end of each trial subjects viewed a blank screen for 1,000 msec. During the reward task subjects were unaware of which trial or picture would lead to the receipt of a reward, except that the same picture could not provide a reward in two consecutive trials. Subjects thus were instructed not to select the same picture more than twice in a row (selection of the same picture twice-in-a-row led to interruption of the task, and the task continued only after another picture was selected). B. Timeline of the experiment. Subjects rested for the initial 20 min to allow [¹¹C]raclopride to approach equilibrium. During the subsequent 24.6±2.0 min subjects performed the sensorimotor control task. Beginning 50 min after the start of the [¹¹C]raclopride infusion, subjects performed the monetary reward condition for 24.1±1.7 min. The timing of the tasks relative to scanning was based upon previous optimization studies for PET-[¹¹C]raclopride imaging using the bolus plus constant infusion approach (Watabe et al. 2000; Garraux et al. 2007).

Figure 2

Decay-corrected, tissue radioactivity concentrations across time obtained using PET in the predefined regions-of-interest within the right (A) and left hemispheres (B), with indication of the time epochs in which PET data were analyzed to reflect the sensorimotor (darker shading) and reward conditions (lighter shading). The timing of the image acquisition for each task condition was optimized for PET-[¹¹C]raclopride imaging studies applying the bolus plus constant infusion approach by Watabe et al. (2000). Abbreviations: Bq - becquerels; VS - ventral striatum; DPU - dorsal putamen; MCA - middle caudate; DCA - dorsal caudate. SM: sensorimotor condition. RW: reward condition.

Figure 3

Location of the MRI-based regions-of-interest (ROIs) defined a priori in the putamen, caudate and anteroventral striatum (after Drevets et al 2001). Regional PET measures were extracted using from each ROI and compared between conditions. Abbreviations: DPU: dorsal putamen; DCA: dorsal caudate, AVS: anteroventral striatum.

Figure 4. Reward-related changes in regional binding potentials for [¹¹C]-raclopride

A. Plot of mean percent of change in binding potential (ΔBP) in the regions of interest analyses (ROI). The mean ΔBP value was significant in the right ventral striatum and we found a non-significant trend in the left middle caudate and left dorsal caudate (table 1). A significant laterality difference was evident in the ventral striatum. Abbreviations: VS - ventral striatum; DPU - dorsal putamen; MCA - middle caudate; DCA - dorsal caudate. * p< 0.01, ** p< 0.005, * trend 0.05 < p< 0.1 B–D. Statistical parametric maps of voxel t-values corresponding to the reduction in BP_ND in the monetary reward task condition versus the sensorimotor control condition. This analysis was conducted post hoc to more precisely locate the areas of greatest effect size, so all voxels for which p<.01 are displayed. Results are shown superimposed on a T1-weighted MRI image (provided within SPM software) on horizontal slices situated parallel to a plane containing both the anterior and posterior commissures, located 5 mm below (z = −5), at (z = 0) or 8 mm above (z=8) this reference plane in B, C, and D, respectively. The coordinates for the peak voxel t-values are provided in table 3. The right side is toward the page bottom. Abbreviations: acc – accumbens area (in ventral striatum); caud – caudate nucleus, put - putamen

Figure 5

Individual raclopride binding potential (BP) values in the sensorimotor and the reward tasks in the A. right and B. left ventral striatum.

Figure 6

Plot of the mean percent change in binding potential (ΔBP) in regions where significant gender differences were found. Women showed greater ΔBP values than men in the right and left dorsal putamen and showed a nonsigificant trend toward higher ΔBP values in the left ventral striatum. Considered separately, the mean ΔBP in the left ventral striatum as well as in the right and left dorsal putamen was significant in women only. Right-left differences in ΔBP were significant in the ventral striatum only in men (p<0.001). * p< 0.05, ** p< 0.01, * trend