Christopher T. Smith

Ovarian Cycle Effects on Immediate Reward Selection Bias in Humans: A Role for Estradiol

A variety of evidence suggests that, among humans, the individual tendency to choose immediate rewards (“Now”) over larger, delayed rewards (“Later”), or Now bias, varies with frontal dopamine (DA) levels. As cyclic elevations in estradiol (E+) modulate other frontal DA-dependent behaviors, we tested ovarian cycle effects on Now bias, and whether any such effects are E+ mediated. To do so, we quantified Now/Later choice behavior in naturally cycling adult females (n = 87; ages 18–40 years) during both the menstrual phase (MP; cycle day 1–2; low E+), and the follicular phase (FP; cycle day 11–12; high E+). Now bias decreased an average of 3.6% from MP to FP (p = 0.006). Measures of salivary E+ levels at each visit were available in a subsample of participants (n = 34). Participants with a verified E+ rise from MP to FP showed significantly greater decreases in Now bias at mid-cycle (n = 23) than those without a rise (n = 11; p = 0.03); Now bias decreased an average of 10.2% in the E+ rise group but increased an average of 7.9% in the no E+ rise group. The change in Now bias from MP to FP inversely correlated with the change in E+ (ρ = −0.39; p = 0.023), an effect driven by individuals with putatively lower frontal DA based on genotype at the Val158Met polymorphism in the COMT gene. This is the first demonstration that intertemporal choice varies across the ovarian cycle, with Now bias declining at mid-cycle, when fertility peaks. Moreover, our data suggest that the interacting effects of estradiol and frontal DA mediate this cycle effect on decision making.

Comprehensive interrogation of CpG island methylation in the gene encoding COMT, a key estrogen and catecholamine regulator

BackgroundThe catechol-O-methyltransferase (COMT) enzyme has been widely studied due to its multiple roles in neurological functioning, estrogen biology, and methylation metabolic pathways. Numerous studies have investigated variation in the large COMT gene, with the majority focusing on single nucleotide polymorphisms (SNPs). This body of work has linked COMT genetic variation with a vast array of conditions, including several neurobehavioral disorders, pain sensitivity, and multiple human cancers. Based on COMT’s numerous biological roles and recent studies suggesting that methylation of the COMT gene impacts COMT gene expression, we comprehensively interrogated methylation in over 200 CpG dinucleotide sequences spanning the length of the COMT gene.MethodsUsing saliva-derived DNA from a non-clinical sample of human subjects, we tested for associations between COMT CpG methylation and factors reported to interact with COMT genetic effects, including demographic factors and alcohol use. Finally, we tested associations between COMT CpG methylation state and COMT gene expression in breast cancer cell lines. We interrogated >200 CpGs in 13 amplicons spanning the 5’ UTR to the last exon of the CpG dinucleotide-rich COMT gene in n = 48 subjects, n = 11 cell lines and 1 endogenous 18S rRNA control.ResultsWith the exception of the CpG island in the 5’UTR and 1st exon, all other CpG islands were strongly methylated with typical dynamic ranges between 50-90%. In the saliva samples, methylation of multiple COMT loci was associated with socioeconomic status or ethnicity. We found associations between methylation at numerous loci and genotype at the functional Val158Met SNP (rs4680), and most of the correlations between methylation and demographic and alcohol use factors were Val158Met allele-specific. Methylation at several of these loci also associated with COMT gene expression in breast cancer cell lines.ConclusionsWe report the first comprehensive interrogation of COMT methylation. We corroborate previous findings of variation in COMT methylation with gene expression and the Val158Met genotype, and also report novel associations with socioeconomic status (SES) and ethnicity at several methylated loci. These results point to novel mechanisms for COMT regulation, which may have broad therapeutic implications.

Neural systems underlying individual differences in intertemporal decision-making

Excessively choosing immediate over larger future rewards, or delay discounting (DD), associates with multiple clinical conditions. Individual differences in DD likely depend on variations in the activation of and functional interactions between networks, representing possible endophenotypes for associated disorders, including alcohol use disorders (AUDs). Numerous fMRI studies have probed the neural bases of DD, but investigations of large-scale networks remain scant. We addressed this gap by testing whether activation within large-scale networks during Now/Later decision-making predicts individual differences in DD. To do so, we scanned 95 social drinkers (18–40 years old; 50 women) using fMRI during hypothetical choices between small monetary amounts available “today” or larger amounts available later. We identified neural networks engaged during Now/Later choice using independent component analysis and tested the relationship between component activation and degree of DD. The activity of two components during Now/Later choice correlated with individual DD rates: A temporal lobe network positively correlated with DD, whereas a frontoparietal–striatal network negatively correlated with DD. Activation differences between these networks predicted individual differences in DD, and their negative correlation during Now/Later choice suggests functional competition. A generalized psychophysiological interactions analysis confirmed a decrease in their functional connectivity during decision-making. The functional connectivity of these two networks negatively correlates with alcohol-related harm, potentially implicating these networks in AUDs. These findings provide novel insight into the neural underpinnings of individual differences in impulsive decision-making with potential implications for addiction and related disorders in which impulsivity is a defining feature.

Individual differences in timing of peak positive subjective responses to d-amphetamine: Relationship to pharmacokinetics and physiology.

Rate of delivery of psychostimulants has been associated with their positive euphoric effects and potential addiction liability. However, information on individual differences in onset of d-amphetamine’s effects remains scarce. We examined individual differences in the time to peak subjective and physiological effects and the pharmacokinetics/pharmacodynamics of oral d-amphetamine. We considered two independent studies that used different dosing regimens where subjects completed the drug effects questionnaire at multiple time points post d-amphetamine. Based on the observation of distinct individual differences in time course of drug effects questionnaire “feel”, “high”, and “like” ratings (DEQH+L+F) in Study 1, subjects in both studies were categorized as early peak responders (peak within 60 minutes), late peak responders (peak > 60 minutes) or nonresponders; 20–25% of participants were categorized as early peak responders, 50–55% as late peak responders and 20–30% as nonresponders. Physiological (both studies) and plasma d-amphetamine (Study 1) were compared among these groups. Early peak responders exhibited an earlier rise in plasma d-amphetamine levels and more sustained elevation in heart rate compared to late peak responders. The present data illustrate the presence of significant individual differences in the temporal pattern of responses to oral d-amphetamine, which may contribute to heightened abuse potential.

Intertemporal Choice Behavior in Emerging Adults and Adults: Effects of Age Interact with Alcohol Use and Family History Status

Adults with alcohol use disorders (AUDs) show marked immediate reward selection (or “Now”) bias in intertemporal choice tasks. This Now bias persists long into abstinence, suggesting an irreversible consequence of chronic alcohol abuse or a pre-existing AUD intermediate phenotype. However, some data show substantial Now bias among emerging adults (18–25), regardless of drinking behavior, suggesting age-dependent effects on Now bias. The objectives of the present study were to determine (1) whether Now bias is greater among emerging adults relative to adults, (2) whether any such age effect on Now bias is diminished in sub-clinical heavy alcohol users, and (3) whether having a problem drinking first degree relative is independently associated with elevated Now bias. To achieve these objectives, we used an intertemporal choice task to quantify Now bias in n = 237 healthy participants (ages 18–40; 50% female), and a wide range of non-zero alcohol use, based on the Alcohol Use Disorders Identification Test (AUDIT). We found that among non-heavy drinkers, Now bias inversely correlated with age; this relationship was not present among heavy drinkers. We found no significant relationship between AUDIT score and Now bias among emerging adults, but AUDIT scores and Now bias were positively correlated among 26–40 year olds. Additionally, non-heavy drinking adults who reported a problem drinking first degree relative showed greater Now bias compared to those not reporting familial problem drinking. While not definitive, these findings lend support for elevated Now bias in adulthood as an intermediate phenotype for AUDs. Moreover, non-additive effects of age and heavy drinking on Now bias suggest perturbations in largely common neural circuits in both groups.

Genetic polymorphisms regulating dopamine signaling in the frontal cortex interact to affect target detection under high working memory load

Frontal-dependent task performance is typically modulated by dopamine (DA) according to an inverted-U pattern, whereby intermediate levels of DA signaling optimizes performance. Numerous studies implicate trait differences in DA signaling based on differences in the catechol-O-methyltransferase (COMT) gene in executive function task performance. However, little work has investigated genetic variations in DA signaling downstream from COMT. One candidate is the DA- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32), which mediates signaling through the D1-type DA receptor, the dominant DA receptor in the frontal cortex. Using an n-back task, we used signal detection theory to measure performance in a healthy adult population (n = 97) genotyped for single nucleotide polymorphisms in the COMT (rs4680) and DARPP-32 (rs907094) genes. Correct target detection (hits) and false alarms were used to calculate d′ measures for each working memory load (0-, 2-, and 3-back). At the highest load (3-back) only, we observed a significant COMT × DARPP-32 interaction, such that the DARPP-32 T/T genotype enhanced target detection in COMTValVal individuals, but impaired target detection in COMTMet carriers. These findings suggest that enhanced dopaminergic signaling via the DARPP-32 T allele aids target detection in individuals with presumed low frontal DA (COMTValVal) but impairs target detection in those with putatively higher frontal DA levels (COMTMet carriers). Moreover, these data support an inverted-U model with intermediate levels of DA signaling optimizing performance on tasks requiring maintenance of mental representations in working memory.

Nigrostriatal and mesolimbic D2/3 receptor expression in Parkinson's disease patients with compulsive reward-driven behaviors

The nigrostriatal and mesocorticolimbic dopamine networks regulate reward-driven behavior. Regional alterations to mesolimbic dopamine D2/3 receptor expression are described in drug-seeking and addiction disorders. Parkinsons disease (PD) patients are frequently prescribed D2-like dopamine agonist (DAgonist) therapy for motor symptoms, yet a proportion develop clinically significant behavioral addictions characterized by impulsive and compulsive behaviors (ICBs). Until now, changes in D2/3 receptor binding in both striatal and extrastriatal regions have not been concurrently quantified in this population. We identified 35 human PD patients (both male and female) receiving DAgonist therapy, with (n = 17) and without (n = 18) ICBs, matched for age, disease duration, disease severity, and dose of dopamine therapy. In the off-dopamine state, all completed PET imaging with [18F]fallypride, a high affinity D2-like receptor ligand that can measure striatal and extrastriatal D2/3 nondisplaceable binding potential (BPND). Striatal differences between ICB+/ICB− patients localized to the ventral striatum and putamen, where ICB+ subjects had reduced BPND. In this group, self-reported severity of ICB symptoms positively correlated with midbrain D2/3 receptor BPND. Group differences in regional D2/3 BPND relationships were also notable: ICB+ (but not ICB−) patients expressed positive correlations between midbrain and caudate, putamen, globus pallidus, and amygdala BPNDs. These findings support the hypothesis that compulsive behaviors in PD are associated with reduced ventral and dorsal striatal D2/3 expression, similar to changes in comparable behavioral disorders. The data also suggest that relatively preserved ventral midbrain dopaminergic projections throughout nigrostriatal and mesolimbic networks are characteristic of ICB+ patients, and may account for differential DAgonist therapeutic response. SIGNIFICANCE STATEMENT The biologic determinants of compulsive reward-based behaviors have broad clinical relevance, from addiction to neurodegenerative disorders. Here, we address biomolecular distinctions in Parkinsons disease patients with impulsive compulsive behaviors (ICBs). This is the first study to image a large cohort of ICB+ patients using positron emission tomography with [18F]fallypride, allowing quantification of D2/3 receptors throughout the mesocorticolimbic network. We demonstrate widespread differences in dopaminergic networks, including (1) D2-like receptor distinctions in the ventral striatum and putamen, and (2) a preservation of widespread dopaminergic projections emerging from the midbrain, which is associated with the severity of compulsive behaviors. This clearly illustrates the roles of D2/3 receptors and medication effects in maladaptive behaviors, and localizes them specifically to nigrostriatal and extrastriatal regions.

COMT Val158Met Polymorphism Exerts Sex-Dependent Effects on fMRI Measures of Brain Function

Evidence suggests that dopamine levels in the prefrontal cortex (PFC) modulate executive functions. A key regulator of PFC dopamine is catechol-O-methyltransferase (COMT). The activity level of the COMT enzyme are influenced by sex and the Val158Met polymorphism (rs4680) of the COMT gene, with male sex and Val alleles both being associated with higher bulk enzyme activity, and presumably lower PFC dopamine. COMT genotype has not only been associated with individual differences in frontal dopamine-mediated behaviors, but also with variations in neuroimaging measures of brain activity and functional connectivity. In this study, we investigated whether COMT genotype predicts individual differences in neural activity and connectivity, and whether such effects are sex-dependent. We tested 93 healthy adults (48 females), genotyped for the Val158Met polymorphism, in a delay discounting task and at rest during fMRI. Delay discounting behavior was predicted by an interaction of COMT genotype and sex, consistent with a U-shaped relationship with enzyme activity. COMT genotype and sex similarly exhibited U-shaped relationships with individual differences in neural activation, particularly among networks that were most engaged by the task, including the default-mode network. Effects of COMT genotype and sex on functional connectivity during rest were also U-shaped. In contrast, flexible reorganization of network connections across task conditions varied linearly with COMT among both sexes. These data provide insight into the potential influences of COMT-regulated variations in catecholamine levels on brain function, which may represent endophenotypes for disorders of impulsivity.

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/

[ 18 F]fallypride characterization of striatal and extrastriatal D 2/3 receptors in Parkinson's disease

Parkinsons disease (PD) is characterized by widespread degeneration of monoaminergic (especially dopaminergic) networks, manifesting with a number of both motor and non-motor symptoms. Regional alterations to dopamine D2/3 receptors in PD patients are documented in striatal and some extrastriatal areas, and medications that target D2/3 receptors can improve motor and non-motor symptoms. However, data regarding the combined pattern of D2/3 receptor binding in both striatal and extrastriatal regions in PD are limited. We studied 35 PD patients off-medication and 31 age- and sex-matched healthy controls (HCs) using PET imaging with [18F]fallypride, a high affinity D2/3 receptor ligand, to measure striatal and extrastriatal D2/3 nondisplaceable binding potential (BPND). PD patients completed PET imaging in the off medication state, and motor severity was concurrently assessed. Voxel-wise evaluation between groups revealed significant BPND reductions in PD patients in striatal and several extrastriatal regions, including the locus coeruleus and mesotemporal cortex. A region-of-interest (ROI) based approach quantified differences in dopamine D2/3 receptors, where reduced BPND was noted in the globus pallidus, caudate, amygdala, hippocampus, ventral midbrain, and thalamus of PD patients relative to HC subjects. Motor severity positively correlated with D2/3 receptor density in the putamen and globus pallidus. These findings support the hypothesis that abnormal D2/3 expression occurs in regions related to both the motor and non-motor symptoms of PD, including areas richly invested with noradrenergic neurons.