Enhancing dopamine tone modulates global and local cortical perfusion as a function of COMT Val158Met genotype

The cognitive effects of pharmacologically enhancing cortical dopamine (DA) tone are variable across healthy human adults. It has been postulated that individual differences in drug responses are linked to baseline cortical DA activity according to an inverted-U-shaped function. To better understand the effect of divergent starting points along this curve on DA drug responses, researchers have leveraged a common polymorphism (rs4680) in the gene encoding the enzyme catechol-O-methyltransferase (COMT) that gives rise to greater (Met allele) or lesser (Val allele) extracellular levels of cortical DA. Here we examined the extent to which changes in resting cortical perfusion following the administration of two mechanistically-distinct dopaminergic drugs vary by COMT genotype, and thereby track predictions of the inverted-U model. Using arterial spin labeling (ASL) and a double-blind, within-subject design, perfusion was measured in 75 healthy, genotyped participants once each after administration of tolcapone (a COMT inhibitor), bromocriptine (a DA D2/3 agonist), and placebo. COMT genotype and drug interacted such that COMT Val homozygotes exhibited increased prefusion in response to both drugs, whereas Met homozygotes did not. Additionally, tolcapone-related perfusion changes in the right inferior frontal gyrus correlated with altered performance on a task of executive function. No comparable effects were found for a genetic polymorphism (rs1800497) affecting striatal DA system function. Together, these results indicate that both the directionality and magnitude of drug-induced perfusion change provide meaningful information about individual differences in response to enhanced cortical DA tone

Striatal dopamine synthesis and cognitive flexibility differ between hormonal contraceptive users and nonusers

In rodents and nonhuman primates, sex hormones are powerful modulators of dopamine (DA) neurotransmission. Yet less is known about hormonal regulation of the DA system in the human brain. Using positron emission tomography (PET), we address this gap by comparing hormonal contraceptive users and nonusers across multiple aspects of DA function: DA synthesis capacity via the PET radioligand 6-[18F]fluoro-m-tyrosine ([18F]FMT), baseline D2/3 receptor binding potential using [11C]raclopride, and DA release using methylphenidate-paired [11C]raclopride. Participants consisted of 36 healthy women (n = 15 hormonal contraceptive users; n = 21 naturally cycling/non users of hormonal contraception), and men (n = 20) as a comparison group. A behavioral index of cognitive flexibility was assessed prior to PET imaging. Hormonal contraceptive users exhibited greater DA synthesis capacity than NC participants, particularly in dorsal caudate, and greater cognitive flexibility. Furthermore, across individuals, the magnitude of striatal DA synthesis capacity was associated with cognitive flexibility. No group differences were observed in D2/3 receptor binding or DA release. Analyses by sex alone may obscure underlying differences in DA synthesis tied to women\u27s hormone status. Hormonal contraception (in the form of pill, shot, implant, ring, or intrauterine device) is used by ~400 million women worldwide, yet few studies have examined whether chronic hormonal manipulations impact basic properties of the DA system. Findings from this study begin to address this critical gap in women\u27s health

Anticipatory and consummatory pleasure and displeasure in major depressive disorder: An experience sampling study

Pleasure and displeasure can be parsed into anticipatory and consummatory phases. However, research on pleasure and displeasure in major depressive disorder (MDD), a disorder characterized by anhedonia, has largely focused on deficits in the consummatory phase. Moreover, most studies in this area have been laboratory-based, raising the question of how component processes of pleasure and displeasure are experienced in the daily lives of depressed individuals. Using experience sampling, we compared anticipatory and consummatory pleasure and displeasure for daily activities reported by adults with MDD (n=41) and healthy controls (n=39). Participants carried electronic devices for one week and were randomly prompted eight times a day to answer questions about activities to which they most and least looked forward. Compared to healthy controls, MDD participants reported blunted levels of both anticipatory and consummatory pleasure and elevated levels of both anticipatory and consummatory displeasure for daily activities. Independent of MDD status, participants accurately predicted pleasure but overestimated displeasure. These results are the first to provide evidence that, across both anticipatory and consummatory phases, individuals with MDD experience blunted pleasure and elevated displeasure for daily activities. Our findings clarify the disturbances in pleasure and displeasure that characterize MDD and may inform treatment for this debilitating disorder

Effects of dopaminergic drugs on cognitive control processes vary by genotype

Dopamine (DA) has been implicated in modulating multiple cognitive control processes, including the robust maintenance of task sets and memoranda in the face of distractors (cognitive stability) and, conversely, the ability to switch task sets or update the contents of working memory when it is advantageous to do so (cognitive flexibility). In humans, the limited specificity of available pharmacological probes has posed a challenge for understanding the mechanisms by which DA, acting on multiple receptor families across the PFC and striatum, differentially influences these cognitive processes. Using a within-subject, placebo-controlled design, we contrasted the impact of two mechanistically distinct DA drugs, tolcapone (an inhibitor of catechol

Assessing the Efficacy and Safety of a Digital Therapeutic for Symptoms of Depression in Adolescents: Protocol for a Randomized Controlled Trial

BackgroundDepression is a serious, prevalent, recurrent, and undertreated disorder in adolescents. Low levels of treatment seeking and treatment adherence in this age group, combined with a growing national crisis in access to mental health care, have increased efforts to identify effective treatment alternatives for this demographic. Digital health interventions for mental illness can provide cost-effective, engaging, and accessible means of delivering psychotherapy to adolescents. ObjectiveThis protocol describes a virtual randomized controlled trial designed to evaluate the efficacy and safety of a self-guided, mobile app–based implementation of behavioral activation therapy, SparkRx, for the adjunct treatment of symptoms of depression in adolescents. MethodsParticipants are recruited directly through web-based and print advertisements. Following eligibility screening and consenting, participants are randomly assigned to a treatment arm (SparkRx) or a control arm (assessment-enhanced usual care) for 5 weeks. The primary efficacy outcome, total score on the 8-item Patient Health Questionnaire (PHQ-8), is assessed at the end of the 5-week intervention period. Additional participant-reported outcomes are assessed at baseline, the postintervention time point, and 1-month follow-up. The safety of the intervention is assessed by participant report (and legal guardian report, if the participant is younger than 18 years) and by patterns of symptom deterioration on the PHQ-8, as part of a larger clinical safety monitoring protocol. The primary efficacy outcome, total PHQ-8 score at the postintervention time point, will be compared between SparkRx and enhanced usual care arms using mixed effect modeling, with baseline PHQ-8 and current antidepressant medication status included as covariates. Secondary efficacy outcomes, including the proportion of participants exhibiting treatment response, remission, and minimal clinically significant improvement (all derived from total PHQ-8 scores), will be compared between groups using chi-square tests. Symptom severity at 1-month follow-up will also be compared between arms. Planned subgroup analyses will examine the robustness of treatment effects to differences in baseline symptom severity (PHQ-8 score <15 or ≥ 15) and age (younger than 18 years and older than 18 years). The primary safety outcome, the number of psychiatric serious adverse events, will be compared between trial arms using the Fisher exact test. All other adverse events will be presented descriptively. ResultsAs of May 2023, enrollment into the study has concluded; 223 participants were randomized. The analysis of the efficacy and safety data is expected to be completed by Fall 2023. ConclusionsWe hypothesize that the results of this trial will support the efficacy and safety of SparkRx in attenuating symptoms of depression in adolescents. Positive results would more broadly support the prospect of using accessible, scientifically validated, digital therapeutics in the adjunct treatment of mental health disorders in this age range. Trial RegistrationClinicalTrials.gov NCT05462652; https://clinicaltrials.gov/study/NCT05462652 International Registered Report Identifier (IRRID)DERR1-10.2196/4874

Augmenting Frontal Dopamine Tone Enhances Maintenance over Gating Processes in Working Memory.

The contents of working memory must be maintained in the face of distraction, but updated when appropriate. To manage these competing demands of stability and flexibility, maintained representations in working memory are complemented by distinct gating mechanisms that selectively transmit information into and out of memory stores. The operations of such dopamine-dependent gating systems in the midbrain and striatum and their complementary dopamine-dependent memory maintenance operations in the cortex may therefore be dissociable. If true, selective increases in cortical dopamine tone should preferentially enhance maintenance over gating mechanisms. To test this hypothesis, tolcapone, a catechol-O-methyltransferase inhibitor that preferentially increases cortical dopamine tone, was administered in a randomized, double-blind, placebo-controlled, within-subject fashion to 49 participants who completed a hierarchical working memory task that varied maintenance and gating demands. Tolcapone improved performance in a condition with higher maintenance requirements and reduced gating demands, reflected in a reduction in the slope of RTs across the distribution. Resting-state fMRI data demonstrated that the degree to which tolcapone improved performance in individual participants correlated with increased connectivity between a region important for stimulus response mappings (left dorsal premotor cortex) and cortical areas implicated in visual working memory, including the intraparietal sulcus and fusiform gyrus. Together, these results provide evidence that augmenting cortical dopamine tone preferentially improves working memory maintenance