Individual Differences in Dopamine Are Associated with Reward Discounting in Clinical Groups But Not in Healthy Adults.

Some people are more willing to make immediate, risky, or costly reward-focused choices than others, which has been hypothesized to be associated with individual differences in dopamine (DA) function. In two studies using PET imaging, one empirical (Study 1: N = 144 males and females across 3 samples) and one meta-analytic (Study 2: N = 307 across 12 samples), we sought to characterize associations between individual differences in DA and time, probability, and physical effort discounting in human adults. Study 1 demonstrated that individual differences in DA D2-like receptors were not associated with time or probability discounting of monetary rewards in healthy humans, and associations with physical effort discounting were inconsistent across adults of different ages. Meta-analytic results for temporal discounting corroborated our empirical finding for minimal effect of DA measures on discounting in healthy individuals but suggested that associations between individual differences in DA and reward discounting depend on clinical features. Addictions were characterized by negative correlations between DA and discounting, but other clinical conditions, such as Parkinson's disease, obesity, and attention-deficit/hyperactivity disorder, were characterized by positive correlations between DA and discounting. Together, the results suggest that trait differences in discounting in healthy adults do not appear to be strongly associated with individual differences in D2-like receptors. The difference in meta-analytic correlation effects between healthy controls and individuals with psychopathology suggests that individual difference findings related to DA and reward discounting in clinical samples may not be reliably generalized to healthy controls, and vice versa.SIGNIFICANCE STATEMENT Decisions to forgo large rewards for smaller ones due to increasing time delays, uncertainty, or physical effort have been linked to differences in dopamine (DA) function, which is disrupted in some forms of psychopathology. It remains unclear whether alterations in DA function associated with psychopathology also extend to explaining associations between DA function and decision making in healthy individuals. We show that individual differences in DA D2 receptor availability are not consistently related to monetary discounting of time, probability, or physical effort in healthy individuals across a broad age range. By contrast, we suggest that psychopathology accounts for observed inconsistencies in the relationship between measures of DA function and reward discounting behavior.

Differential regional decline in dopamine receptor availability across adulthood: Linear and nonlinear effects of age.

Theories of adult brain development, based on neuropsychological test results and structural neuroimaging, suggest differential rates of age-related change in function across cortical and subcortical sub-regions. However, it remains unclear if these trends also extend to the aging dopamine system. Here we examined cross-sectional adult age differences in estimates of D2-like receptor binding potential across several cortical and subcortical brain regions using PET imaging and the radiotracer [18 F]Fallypride in two samples of healthy human adults (combined N = 132). After accounting for regional differences in overall radioligand binding, estimated percent difference in receptor binding potential by decade (linear effects) were highest in most temporal and frontal cortical regions (~6-16% per decade), moderate in parahippocampal gyrus, pregenual frontal cortex, fusiform gyrus, caudate, putamen, thalamus, and amygdala (~3-5%), and weakest in subcallosal frontal cortex, ventral striatum, pallidum, and hippocampus (~0-2%). Some regions showed linear effects of age while many showed curvilinear effects such that binding potential declined from young adulthood to middle age and then was relatively stable until old age. Overall, these data indicate that the rate and pattern of decline in D2 receptor availability is regionally heterogeneous. However, the differences across regions were challenging to organize within existing theories of brain development and did not show the same pattern of regional change that has been observed in gray matter volume, white matter integrity, or cognitive performance. This variation suggests that existing theories of adult brain development may need to be modified to better account for the spatial dynamics of dopaminergic system aging.

Individual differences in dopamine D2 receptor availability correlate with reward valuation.

Reward valuation, which underlies all value-based decision-making, has been associated with dopamine function in many studies of nonhuman animals, but there is relatively less direct evidence for an association in humans. Here, we measured dopamine D2 receptor (DRD2) availability in vivo in humans to examine relations between individual differences in dopamine receptor availability and neural activity associated with a measure of reward valuation, expected value (i.e., the product of reward magnitude and the probability of obtaining the reward). Fourteen healthy adult subjects underwent PET with [18F]fallypride, a radiotracer with strong affinity for DRD2, and fMRI (on a separate day) while performing a reward valuation task. [18F]fallypride binding potential, reflecting DRD2 availability, in the midbrain correlated positively with neural activity associated with expected value, specifically in the left ventral striatum/caudate. The present results provide in vivo evidence from humans showing midbrain dopamine characteristics are associated with reward valuation.

Reduced effects of age on dopamine D2 receptor levels in physically active adults.

Physical activity has been shown to ameliorate dopaminergic degeneration in non-human animal models. However, the effects of regular physical activity on normal age-related changes in dopamine function in humans are unknown. Here we present cross-sectional data from forty-four healthy human subjects between 23 and 80 years old, showing that typical age-related dopamine D2 receptor loss, assessed with PET [18F]fallypride, was significantly reduced in physically active adults compared to less active adults.

Associations between dopamine D2 receptor availability and BMI depend on age.

OBJECTIVE: The dopamine D2/3 receptor subtypes (DRD2/3) are the most widely studied neurotransmitter biomarker in research on obesity, but results to date have been inconsistent, have typically involved small samples, and have rarely accounted for subjects' ages despite the large impact of age on DRD2/3 levels. We aimed to clarify the relation between DRD2/3 availability and BMI by examining this association in a large sample of subjects with BMI spanning the continuum from underweight to extremely obese. SUBJECTS: 130 healthy subjects between 18 and 81years old underwent PET with [18F]fallypride, a high affinity DRD2/3 ligand. RESULTS: As expected, DRD2/3 availability declined with age. Critically, age significantly interacted with DRD2/3 availability in predicting BMI in the midbrain and striatal regions (caudate, putamen, and ventral striatum). Among subjects under 30years old, BMI was not associated with DRD2/3 availability. By contrast, among subjects over 30years old, BMI was positively associated with DRD2/3 availability in the midbrain, putamen, and ventral striatum. CONCLUSION: The present results are incompatible with the prominent dopaminergic hypofunction hypothesis that proposes that a reduction in DRD2/3 availability is associated with increased BMI, and highlights the importance of age in assessing correlates of DRD2/3 function.

Modulation of impulsivity and reward sensitivity in intertemporal choice by striatal and midbrain dopamine synthesis in healthy adults.

Converging evidence links individual differences in mesolimbic and mesocortical dopamine (DA) to variation in the tendency to choose immediate rewards ("Now") over larger, delayed rewards ("Later"), or "Now bias." However, to date, no study of healthy young adults has evaluated the relationship between Now bias and DA with positron emission tomography (PET). Sixteen healthy adults (ages 24-34 yr; 50% women) completed a delay-discounting task that quantified aspects of intertemporal reward choice, including Now bias and reward magnitude sensitivity. Participants also underwent PET scanning with 6-[(18)F]fluoro-l-m-tyrosine (FMT), a radiotracer that measures DA synthesis capacity. Lower putamen FMT signal predicted elevated Now bias, a more rapidly declining discount rate with increasing delay time, and reduced willingness to accept low-interest-rate delayed rewards. In contrast, lower FMT signal in the midbrain predicted greater sensitivity to increasing magnitude of the Later reward. These data demonstrate that intertemporal reward choice in healthy humans varies with region-specific measures of DA processing, with regionally distinct associations with sensitivity to delay and to reward magnitude.

Genotype status of the dopamine-related catechol-O-methyltransferase (COMT) gene corresponds with desirability of "unhealthy" foods.

The role of dopamine is extensively documented in weight regulation and food intake in both animal models and humans. Yet the role of dopamine has not been well studied in individual differences for food desirability. Genotype status of the dopamine-related catechol-O-methyltransferase (COMT) gene has been shown to influence dopamine levels, with greater COMT enzymatic activity in val/val individuals corresponding to greater degradation of dopamine. Decreased dopamine has been associated with poorer cognitive control and diminished goal-directed behavior in various behavioral paradigms. Additionally, dopaminergic-rich regions such as the frontal cortex and dorsal striatum have been shown to be important for supporting food-related decision-making. However, the role of dopamine, as assessed by COMT genotype status, in food desirability has not been fully explored. Therefore, we utilized an individual's COMT genotype status (n = 61) and investigated food desirability based on self-rated "healthy" and "unhealthy" food perceptions. Here we found val/val individuals (n = 19) have greater desirability for self-rated "unhealthy" food items, but not self-rated "healthy" food items, as compared to val/met (n = 24) and met/met (n = 18) individuals (p < 0.005). Utilizing an objective health measure for the food items, we also found val/val and val/met individuals have greater desirability for objectively defined "unhealthy" food items, as compared to met/met individuals (p < 0.01). This work further substantiates the role of dopamine in food-related behaviors and more specifically in relationship to food desirability for "unhealthy" food items.

Dopamine and the cognitive downside of a promised bonus.

It is often assumed that the promise of a monetary bonus improves cognitive control. We show that in fact appetitive motivation can also impair cognitive control, depending on baseline levels of dopamine-synthesis capacity in the striatum. These data not only demonstrate that appetitive motivation can have paradoxical detrimental effects for cognitive control but also provide a mechanistic account of these effects.

Dopamine supports coupling of attention-related networks.

Attentional processing has been associated with the dorsal attention, default mode, and frontoparietal control networks. The dorsal attention network is involved in externally focused attention whereas the default mode network is involved in internally directed attention. The frontoparietal control network has been proposed to mediate the transition between external and internal attention by coupling its activity to either the dorsal attention network or the default mode network, depending on the attentional demand. Dopamine is hypothesized to modulate attention and has been linked to the integrity of these three attention-related networks. We used PET with 6-[(18)F]fluoro-L-m-tyrosine to quantify dopamine synthesis capacity in vivo and fMRI to acquire stimulus-independent brain activity in cognitively healthy human subjects. We found that in the resting state where internal cognition dominates, dopamine enhances the coupling between the frontoparietal control network and the default mode network while reducing the coupling between the frontoparietal control network and the dorsal attention network. These results add a neurochemical perspective to the role of network interaction in modulating attention.

Genetic effects on behavior are mediated by neurotransmitters and large-scale neural networks.

Claims of gene-behavior associations are complex and sometimes difficult to replicate because these relationships involve many downstream endogenous and environmental processes that mediate genetic effects. Knowing these mediating processes is critical to understanding the links between genes and behavior and how these factors differ between people. We identified and characterized the effects of a gene on neurochemistry and neural networks to elucidate the mechanism, at the systems level, whereby genes influence cognition. Catechol-O-methyltransferase (COMT) degrades dopamine in the prefrontal cortex (PFC) and is polymorphic with alleles differing in enzymatic activity. We found that COMT genotype determined dopamine synthesis, such that individuals with greater COMT activity synthesized more dopamine. Dopamine synthesis in the midbrain and ventral striatum affected functional connectivity in the default mode network, likely through the mesocorticolimbic pathway, in an inverted-U pattern with greater functional connectivity in medial PFC associated with intermediate levels of COMT activity and dopamine. Greater functional connectivity correlated with greater deactivation during performance of a set-shifting task that engaged the PFC. Greater deactivation was in turn associated with better performance. The integration of these results yields a model whereby COMT affects prefrontal function by a mechanism involving dopaminergic modulation of the default mode network. The model features the well-known inverted-U function between dopamine and performance and supports the hypothesis that dopamine and the default mode network shift attentional resources to influence prefrontal cognition.

Striatal dopamine influences the default mode network to affect shifting between object features.

Cognitive flexibility or the ability to change behavior in response to external cues is conceptualized as two processes: one for shifting between perceptual features of objects and another for shifting between the abstract rules governing the selection of these objects. Object and rule shifts are believed to engage distinct anatomical structures and functional processes. Dopamine activity has been associated with cognitive flexibility, but patients with dopaminergic deficits are not impaired on all tasks assessing cognitive flexibility, suggesting that dopamine may have different roles in the shifting of objects and rules. The goals of this study were to identify brain regions supporting object and rule shifts and to examine the role of dopamine in modulating these two forms of cognitive flexibility. Sixteen young, healthy volunteers underwent fMRI while performing a set-shift task designed to differentiate shifting between object features from shifting between abstract task rules. Participants also underwent PET with 6-[¹8F]-fluoro-l-m-tyrosine (FMT), a radiotracer measuring dopamine synthesis capacity. Shifts of abstract rules were not associated with activation in any brain region, and FMT uptake did not correlate with rule shift performance. Shifting between object features deactivated the medial PFC and the posterior cingulate and activated the lateral PFC, posterior parietal areas, and the striatum. FMT signal in the striatum correlated negatively with object shift performance and deactivation in the medial PFC, a component of the default mode network, suggesting that dopamine influences object shifts via modulation of activity in the default mode network.

Mesolimbic dopamine D2 receptors and neural representations of subjective value.

The process by which the value of delayed rewards is discounted varies from person to person. It has been suggested that these individual differences in subjective valuation of delayed rewards are supported by mesolimbic dopamine D2-like receptors (D2Rs) in the ventral striatum. However, no study to date has documented an association between direct measures of dopamine receptors and neural representations of subjective value in humans. Here, we examined whether individual differences in D2R availability were related to neural subjective value signals during decision making. Human participants completed a monetary delay discounting task during an fMRI scan and on a separate visit completed a PET scan with the high affinity D2R tracer [18 F]fallypride. Region-of-interest analyses revealed that D2R availability in the ventral striatum was positively correlated with subjective value-related activity in the ventromedial prefrontal cortex and midbrain but not with choice behavior. Whole-brain analyses revealed a positive correlation between ventral striatum D2R availability and subjective value-related activity in the left inferior frontal gyrus and superior insula. These findings identify a link between a direct measure of mesolimbic dopamine function and subjective value representation in humans and suggest a mechanism by which individuals vary in neural representation of discounted subjective value.

Partial-volume correction increases estimated dopamine D2-like receptor binding potential and reduces adult age differences.

The relatively modest spatial resolution of positron emission tomography (PET) increases the likelihood of partial volume effects such that binding potential (BPND) may be underestimated. Given structural grey matter losses across adulthood, partial volume effects may be even more problematic in older age leading to overestimation of adult age differences. Here we examined the effects of partial volume correction (PVC) in two studies from different sites using different high-affinity D2-like radioligands (18 F-Fallypride, 11C-FLB457) and different PET camera resolutions (∼5 mm, 2.5 mm). Results across both data sets revealed that PVC increased estimated BPND and reduced, though did not eliminate, age effects on BPND. As expected, the effects of PVC were smaller in higher compared to lower resolution data. Analyses using uncorrected data that controlled for grey matter volume in each region of interest approximated PVC corrected data for some but not all regions. Overall, the findings suggest that PVC increases estimated BPND in general and reduces adult age differences especially when using lower resolution cameras. The findings suggest that the past 30 years of research on dopamine receptor availability, for which very few studies use PVC, may overestimate effects of aging on dopamine receptor availability.

Lack of consistent sex differences in D-amphetamine-induced dopamine release measured with [18F]fallypride PET.

RATIONALE: Sex differences in the dopaminergic response to psychostimulants could have implications for drug abuse risk and other psychopathology involving the dopamine system, but human data are limited and mixed. OBJECTIVES: Here, we sought to investigate sex differences in dopamine release after oral D-amphetamine administration. METHODS: We used [18F]fallypride positron emission tomography (PET) to measure the change in dopamine D2/3 receptor availability (%ΔBPND, an index of dopamine release) between placebo and D-amphetamine sessions in two independent datasets containing a total of 39 females (on either hormonal birth control n = 18, postmenopausal n = 10, or studied in the first 10 days of their menstrual cycle n = 11) and 37 males. RESULTS: Using both a priori anatomical regions of interest based on previous findings and voxelwise analyses, we failed to consistently detect broad sex differences in D-amphetamine-induced dopamine release. Nevertheless, there was limited evidence for greater right ventral striatal dopamine release in young adult males relative to similarly aged females, but this was not consistently observed across samples. Plasma estradiol did not correlate with dopamine release and this measure did not differ in females on and off hormonal birth control. CONCLUSIONS: While our finding in young adults from one dataset of greater %ΔBPND in males is partially consistent with a previously published study on sex differences in D-amphetamine-induced dopamine release, our data do not support the presence of consistent widespread sex differences in this measure of dopamine release.

Reproducibility of the correlative triad among aging, dopamine receptor availability, and cognition.

The evidence that dopamine function mediates the association between aging and cognition is one of the most cited findings in the cognitive neuroscience of aging. However, few and relatively small studies have directly examined these associations. Here we examined correlations among adult age, dopamine D2-like receptor (D2R) availability, and cognition in two cross-sectional studies of healthy human adults. Participants completed a short cognitive test battery and, on a separate day, a PET scan with either the high-affinity D2R tracer [18F]Fallypride (Study 1) or [11C]FLB457 (Study 2). Digit span, a measure of short-term memory maintenance and working memory, was the only cognitive test for which dopamine D2R availability partially mediated the age effect on cognition. In Study 1, age was negatively correlated with digit span. Striatal D2R availability was positively correlated with digit span controlling for age. The age effect on digit span was smaller when controlling for striatal D2R availability. Although other cognitive measures used here have individually been associated with age and D2R availability in prior studies, we found no consistent evidence for significant associations between low D2R availability and low cognitive performance on these measures. These results at best only partially supported the correlative triad of age, dopamine D2R availability, and cognition. While a wealth of other research in human and nonhuman animals demonstrates that dopamine makes critical contributions to cognition, the present studies suggest caution in interpreting PET findings as evidence that dopamine D2R loss is a primary cause of broad age-related declines in fluid cognition. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Subjective value representations during effort, probability and time discounting across adulthood.

Every day, humans make countless decisions that require the integration of information about potential benefits (i.e. rewards) with other decision features (i.e. effort required, probability of an outcome or time delays). Here, we examine the overlap and dissociation of behavioral preferences and neural representations of subjective value in the context of three different decision features (physical effort, probability and time delays) in a healthy adult life span sample. While undergoing functional neuroimaging, participants (N = 75) made incentive compatible choices between a smaller monetary reward with lower physical effort, higher probability, or a shorter time delay versus a larger monetary reward with higher physical effort, lower probability, or a longer time delay. Behavioral preferences were estimated from observed choices, and subjective values were computed using individual hyperbolic discount functions. We found that discount rates were uncorrelated across tasks. Despite this apparent behavioral dissociation between preferences, we found overlapping subjective value-related activity in the medial prefrontal cortex across all three tasks. We found no consistent evidence for age differences in either preferences or the neural representations of subjective value across adulthood. These results suggest that while the tolerance of decision features is behaviorally dissociable, subjective value signals share a common representation across adulthood.

FTO affects food cravings and interacts with age to influence age-related decline in food cravings.

The fat mass and obesity associated gene (FTO) was the first gene identified by genome-wide association studies to correlate with higher body mass index (BMI) and increased odds of obesity. FTO remains the locus with the largest and most replicated effect on body weight, but the mechanism whereby FTO affects body weight and the development of obesity is not fully understood. Here we tested whether FTO is associated with differences in food cravings and a key aspect of dopamine function that has been hypothesized to influence food reward mechanisms. Moreover, as food cravings and dopamine function are known to decline with age, we explored effects of age on relations between FTO and food cravings and dopamine function. Seven-eight healthy subjects between 22 and 83years old completed the Food Cravings Questionnaire and underwent genotyping for FTO rs9939609, the first FTO single nucleotide polymorphism associated with obesity. Compared to TT homozygotes, individuals carrying the obesity-susceptible A allele had higher total food cravings, which correlated with higher BMI. Additionally, food cravings declined with age, but this age effect differed across variants of FTO rs9939609: while TT homozygotes showed the typical age-related decline in food cravings, there was no such decline among A carriers. All subjects were scanned with [18F]fallypride PET to assess a recent proposal that at the neurochemical level FTO alters dopamine D2-like receptor (DRD2) function to influence food reward related mechanisms. However, we observed no evidence of FTO effects on DRD2 availability.

Ventral striatal dopamine transporter availability is associated with lower trait motor impulsivity in healthy adults.

Impulsivity is a transdiagnostic feature of a range of externalizing psychiatric disorders. Preclinical work links reduced ventral striatal dopamine transporter (DAT) availability with heightened impulsivity and novelty seeking. However, there is a lack of human data investigating the relationship between DAT availability, particularly in subregions of the striatum, and the personality traits of impulsivity and novelty seeking. Here we collected PET measures of DAT availability (BPND) using the tracer 18F-FE-PE2I in 47 healthy adult subjects and examined relations between BPND in striatum, including its subregions: caudate, putamen, and ventral striatum (VS), and trait impulsivity (Barratt Impulsiveness Scale: BIS-11) and novelty seeking (Tridimensional Personality Questionnaire: TPQ-NS), controlling for age and sex. DAT BPND in each striatal subregion showed nominal negative associations with total BIS-11 but not TPQ-NS. At the subscale level, VS DAT BPND was significantly associated with BIS-11 motor impulsivity (e.g., taking actions without thinking) after correction for multiple comparisons. VS DAT BPND explained 13.2% of the variance in motor impulsivity. Our data demonstrate that DAT availability in VS is negatively related to impulsivity and suggest a particular influence of DAT regulation of dopamine signaling in VS on acting without deliberation (BIS motor impulsivity). While needing replication, these data converge with models of ventral striatal functions that emphasize its role as a key interface linking motivation to action.

Spontaneous Eye Blink Rate (EBR) Is Uncorrelated with Dopamine D2 Receptor Availability and Unmodulated by Dopamine Agonism in Healthy Adults.

Spontaneous eye blink rate (EBR) has been proposed as a noninvasive, inexpensive marker of dopamine functioning. Support for a relation between EBR and dopamine function comes from observations that EBR is altered in populations with dopamine dysfunction and EBR changes under a dopaminergic manipulation. However, the evidence across the literature is inconsistent and incomplete. A direct correlation between EBR and dopamine function has so far been observed only in nonhuman animals. Given significant interest in using EBR as a proxy for dopamine function, this study aimed to verify a direct association in healthy, human adults. Here we measured EBR in healthy human subjects whose dopamine D2 receptor (DRD2) availability was assessed with positron emission tomography (PET)-[18F]fallypride to examine the predictive power of EBR for DRD2 availability. Effects of the dopamine agonist bromocriptine on EBR also were examined to determine the responsiveness of EBR to dopaminergic stimulation and, in light of the hypothesized inverted-U profile of dopamine effects, the role of DRD2 availability in EBR responsivity to bromocriptine. Results from 20 subjects (age 33.6 ± 7.6 years, 9F) showed no relation between EBR and DRD2 availability. EBR also was not responsive to dopaminergic stimulation by bromocriptine, and individual differences in DRD2 availability did not modulate EBR responsivity to bromocriptine. Given that EBR is hypothesized to be particularly sensitive to DRD2 function, these findings suggest caution in using EBR as a proxy for dopamine function in healthy humans.

Variability in paralimbic dopamine signaling correlates with subjective responses to d-amphetamine.

Subjective responses to psychostimulants vary, the basis of which is poorly understood, especially in relation to possible cortical contributions. Here, we tested for relationships between participants' positive subjective responses to oral d-amphetamine (dAMPH) versus placebo and variability in striatal and extrastriatal dopamine (DA) receptor availability and release, measured via positron emission tomography (PET) with the radiotracer (18)F-fallypride. Analyses focused on 35 healthy adult participants showing positive subjective effects to dAMPH measured via the Drug Effects Questionnaire (DEQ) Feel, Like, High, and Want More subscales (Responders), and were repeated after inclusion of 11 subjects who lacked subjective responses. Associations between peak DEQ subscale ratings and both baseline (18)F-fallypride binding potential (BPnd; an index of D2/D3 receptor availability) and the percentage change in BPnd post dAMPH (%ΔBPnd; a measure of DA release) were assessed. Baseline BPnd in ventromedial prefrontal cortex (vmPFC) predicted the peak level of High reported following dAMPH. Furthermore, %ΔBPnd in vmPFC positively correlated with DEQ Want More ratings. DEQ Want More was also positively correlated with %ΔBPnd in right ventral striatum and left insula. This work indicates that characteristics of DA functioning in vmPFC, a cortical area implicated in subjective valuation, are associated with both subjective high and incentive (wanting) responses. The observation that insula %ΔBPnd was associated with drug wanting converges with evidence suggesting its role in drug craving. These findings highlight the importance of variability in DA signaling in specific paralimbic cortical regions in dAMPH's subjective response, which may confer risk for abusing psychostimulants.