Jaime J. Castrellon

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

Abstract 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 [18 F]fallypride, was significantly reduced in physically active adults compared to less active adults.

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

Abstract 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.

Younger and older adults’ collaborative recall of shared and unshared emotional pictures

Although a group of people working together recalls more items than any one individual, they recall fewer unique items than the same number of people working apart whose responses are combined. This is known as collaborative inhibition, and it is a robust effect that occurs for both younger and older adults. However, almost all previous studies documenting collaborative inhibition have used stimuli that were neutral in emotional valence, low in arousal, and studied by all group members. In the current experiments, we tested the impact of picture-stimuli valence, picture-stimuli arousal, and information distribution in modulating the magnitude of collaborative inhibition. We included both younger and older adults because there are age differences in how people remember emotional pictures that could modulate any effects of emotion on collaborative inhibition. Results revealed that when information was shared (i.e., studied by all group members), there were robust collaborative inhibition effects for both neutral and emotional stimuli for both younger and older adults. However, when information was unshared (i.e., studied by only a single group member), these effects were attenuated. Together, these results provide mixed support for the retrieval strategy disruption account of collaborative inhibition. Supporting the retrieval strategy disruption account, unshared study information was less susceptible to collaborative inhibition than shared study information. Contradicting the retrieval strategy disruption account, emotional valence and arousal did not modulate the magnitude of collaborative inhibition despite the fact that participants clustered the emotional, but not neutral, information together in memory.

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 [18F]fallypride in two samples of healthy human adults (combined N=132). After accounting for regional differences in overall radioligand binding, estimated percent declines 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 (e.g., temporal cortex, putamen) 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 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) and one meta-analytic (Study 2: N=307), 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 significantly associated with time, probability, or physical effort discounting of monetary rewards in healthy humans. 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 like Parkinson’s Disease, obesity, and ADHD 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 larger 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 baseline DA function and decision making in healthy individuals. We show that individual differences in dopamine D2 receptor availability are not related to monetary discounting of time, probability, or physical effort in healthy individuals. By contrast, we suggest that psychopathology accounts for observed inconsistencies in the relationship between measures of dopamine function and reward discounting behavior. Author Note Some of the results reported in this manuscript were presented in a poster at the Society for Neuroeconomics (2017). JLC is now in the Department of Psychological and Brain Sciences at Washington University in St. Louis. JSY is now in the Department of Neurological Surgery at University of California, San Francisco. Data Data and code used in the manuscript can be viewed and downloaded from OSF: https://osf.io/htq56/

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

Abstract 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.

Individual differences in dopamine D 2 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.

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.