Search

Study Objectives: Many adults without a diagnosed sleep disorder report poor sleep. Recently, there has been a dramatic increase in the use of app-based audio tools to aid sleep by the general public, yet there is a paucity of evidence on whether such tools are efficacious. This study evaluated the feasibility and preliminary efficacy of two categories of audio tools, comprising music and narrated stories, featured on the Unmind app., Methods: We conducted an online, parallel, multi-arm, external pilot randomized controlled trial, with two intervention arms and a waitlist (WL) control group. Participants were working adults who were screened for poor sleep. Feasibility was assessed via objective and self-report measures. Preliminary efficacy was evaluated via self-report measures of sleep disturbance, work productivity, and other mental health outcomes, captured at baseline (t0) and following a 4-week intervention period (t1), and analyzed using mixed effects models with intention-to-treat principles., Results: Three hundred participants were randomized, and 92% were retained at t1. 90.5% of participants completed at least one intervention session. 82.1% reported being "satisfied" or "very satisfied" with their intervention, and 84.3% rated their intervention as "good" or "excellent." The between-group Hedges' g effect size for sleep disturbance was 0.92 [0.63-1.22] and 1.09 [0.80-1.39] for the two interventions compared to the WL group., Conclusions: Both interventions are feasible and acceptable. Preliminary efficacy findings suggest that audio tools designed to aid sleep could have widespread financial and public health implications, and should be investigated in a definitive trial., Clinical Trial: International Standard Randomized Controlled Trial Number (ISRCTN), 12614821, http://www.isrctn.com/ISRCTN12614821., (© Sleep Research Society 2023. Published by Oxford University Press on behalf of the Sleep Research Society.)

Background: Depressive symptoms are highly prevalent and have broad-ranging negative implications. Digital interventions are increasingly available in the workplace context, but supporting evidence is limited., Objective: This study aimed to evaluate the feasibility, acceptability, and preliminary efficacy of 3 digital interventions for depressive symptoms in a sample of UK-based working adults experiencing mild to moderate symptoms., Methods: This was a parallel, multiarm, pilot randomized controlled trial. Participants were allocated to 1 of 3 digital interventions or a waitlist control group and had 3 weeks to complete 6 to 8 short self-guided sessions. The 3 interventions are available on the Unmind mental health app for working adults and draw on behavioral activation, cognitive behavioral therapy, and acceptance and commitment therapy. Web-based assessments were conducted at baseline, postintervention (week 3), and at 1-month follow-up (week 7). Participants were recruited via Prolific, a web-based recruitment platform, and the study was conducted entirely on the web. Feasibility and acceptability were assessed using objective engagement data and self-reported feedback. Efficacy outcomes were assessed using validated self-report measures of mental health and functioning and linear mixed models with intention-to-treat principles., Results: In total, 2003 individuals were screened for participation, of which 20.22% (405/2003) were randomized. A total of 92% (373/405) of the participants were retained in the study, 97.4% (295/303) initiated their allocated intervention, and 66.3% (201/303) completed all sessions. Moreover, 80.6% (229/284) of the participants rated the quality of their allocated intervention as excellent or good, and 79.6% (226/284) of the participants were satisfied or very satisfied with their intervention. All active groups showed improvements in well-being, functioning, and depressive and anxiety symptoms compared with the control group, which were maintained at 4 weeks. Hedges g effect sizes for depressive symptoms ranged from -0.53 (95% CI -0.25 to -0.81) to -0.74 (95% CI -0.45 to -1.03)., Conclusions: All interventions were feasible and acceptable, and the preliminary efficacy findings indicated that their use may improve depressive symptoms, well-being, and functioning. The predefined criteria for a definitive trial were met., Trial Registration: International Standard Randomised Controlled Trial Number (ISRCTN) ISRCTN13067492; https://www.isrctn.com/ISRCTN13067492., (©Rachael Wallis Taylor, Rhian Male, Marcos Economides, Heather Bolton, Kate Cavanagh. Originally published in JMIR Formative Research (https://formative.jmir.org), 16.06.2023.)

Testing for antibody against hepatitis C virus (anti-HCV) is a low-cost diagnostic method worldwide; however, an optimal screening test for HCV in patients with cancer has not been established. We sought to identify an appropriate screening test for HCV infection in patients with hematologic malignancies and/or hematopoietic cell transplants (HCT). Patients in our center were simultaneously screened using serological (anti-HCV) and molecular (HCV RNA) assays (February 2019-November 2019). In total, 214 patients were enrolled in this study. Three patients (1.4%) were positive for anti-HCV, and 2 (0.9%) were positive for HCV RNA. The overall percentage agreement was 99.5% (95% CI: 97.4-99.9). There were no cases of seronegative HCV virus infection. The positive percentage agreement was 66.7% (95% CI: 20.8-93.9), and the negative percentage agreement was 100.0% (95% CI: 98.2-100.0). Cohen kappa coefficient was 0.80 (95% CI: 0.41-1.00, P < .0001). The diagnostic yield of screening for chronic HCV infection in patients with cancer is similar for serologic and molecular testing., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: There is growing interest in digital platforms as a means of implementing scalable, accessible, and cost-effective mental health interventions in the workplace. However, little is known about the efficacy of such interventions when delivered to employee groups., Objective: This study aims to evaluate the feasibility and preliminary efficacy of a digital mental health platform for the workplace, which incorporates evidence-based practices such as cognitive behavioral therapy and acceptance and commitment therapy. A total of 3 brief, unguided interventions designed to address stress, anxiety, and resilience, respectively, are evaluated. The primary aim is to determine the feasibility of the study methods and interventions in preparation for a definitive randomized controlled trial., Methods: The study used a fully remote, parallel, multi-arm, external pilot randomized controlled trial, with 3 intervention arms and a no-intervention control group. Participants were working adults representative of the general UK population with respect to age, sex, and ethnicity who were recruited from a web-based participant platform. Primary outcomes included objective and self-report measures of feasibility, acceptability, engagement, transferability, relevance, and negative effects. Secondary outcomes included 4 self-report measures of mental health and well-being, completed at baseline (time point 0 [t0]), postintervention (time point 1 [t1]), and the 1-month follow-up (time point 2 [t2]). Secondary outcomes were analyzed via linear mixed-effects models using intention-to-treat principles. Preregistered criteria for progression to a definitive trial were evaluated., Results: Data were collected between January and March of 2021. A total of 383 working adult participants meeting trial eligibility were randomized, of whom 356 (93%) were retained at t2. Objective engagement data showed that 67.8% (196/289) of participants randomized to an intervention arm completed their intervention. Overall, 87.1% (203/233) of participants reported being satisfied or very satisfied with their intervention and rated the quality of their intervention as good or excellent. All intervention groups reported significantly greater improvements than the control group on at least one secondary outcome at t1, with between-group Hedges g effect sizes for the pooled interventions ranging from 0.25 (95% CI 0.05-0.46) to 0.43 (95% CI 0.23-0.64). All the improvements were maintained at t2., Conclusions: The study methods were feasible, and all preregistered criteria for progression to a definitive trial were met. Several minor protocol amendments were noted. Preliminary efficacy findings suggest that the study interventions may result in improved mental health outcomes when offered to working adults., Trial Registration: ISRCTN Registry 80309011; http://www.isrctn.com/ISRCTN80309011., (©Marcos Economides, Heather Bolton, Rhian Male, Kate Cavanagh. Originally published in JMIR Formative Research (https://formative.jmir.org), 03.03.2022.)

Background: Unmind is a workplace, digital, mental health platform with tools to help users track, maintain, and improve their mental health and well-being (MHWB). Psychological measurement plays a key role on this platform, providing users with insights on their current MHWB, the ability to track it over time, and personalized recommendations, while providing employers with aggregate information about the MHWB of their workforce., Objective: Due to the limitations of existing measures for this purpose, we aimed to develop and validate a novel well-being index for digital use, to capture symptoms of common mental health problems and key aspects of positive well-being., Methods: In Study 1A, questionnaire items were generated by clinicians and screened for face validity. In Study 1B, these items were presented to a large sample (n=1104) of UK adults, and exploratory factor analysis was used to reduce the item pool and identify coherent subscales. In Study 2, the final measure was presented to a new nationally representative UK sample (n=976), along with a battery of existing measures, with 238 participants retaking the Umind Index after 1 week. The factor structure and measurement invariance of the Unmind Index was evaluated using confirmatory factor analysis, convergent and discriminant validity by estimating correlations with existing measures, and reliability by examining internal consistency and test-retest intraclass correlations., Results: Studies 1A and 1B yielded a 26-item measure with 7 subscales: Calmness, Connection, Coping, Happiness, Health, Fulfilment, and Sleep. Study 2 showed that the Unmind Index is fitted well by a second-order factor structure, where the 7 subscales all load onto an overall MHWB factor, and established measurement invariance by age and gender. Subscale and total scores correlate well with existing mental health measures and generally diverge from personality measures. Reliability was good or excellent across all subscales., Conclusions: The Unmind Index is a robust measure of MHWB that can help to identify target areas for intervention in nonclinical users of a mental health app. We argue that there is value in measuring mental ill health and mental well-being together, rather than treating them as separate constructs., (©Anika Sierk, Eoin Travers, Marcos Economides, Bao Sheng Loe, Luning Sun, Heather Bolton. Originally published in JMIR Mental Health (https://mental.jmir.org), 17.01.2022.)

Introduction: Two separate antiangiogenic tyrosine kinase inhibitors (TKIs) and immunotherapy (IO) combinations are FDA-approved as front-line treatment for metastatic renal cell carcinoma (mRCC). Little is known about off-protocol and post-front-line experience with combination TKI-IO approaches., Methods: We conducted a retrospective analysis of mRCC patients who received combination TKI-IO post-first-line therapy between November 2015 and January 2019 at MD Anderson Cancer Center and Duke Cancer Institute. Chart review detailed patient characteristics, treatments, toxicity, and survival. Independent radiologists, blinded to clinical data, assessed best radiographic response using RECIST v1.1., Results: We identified 48 mRCC patients for inclusion: median age 65 years, 75.0% clear cell histology, 68.8% IMDC intermediate risk, and median two prior systemic therapies. TKI-IO combinations included nivolumab-cabozantinib (N +C; 24 patients), nivolumab-pazopanib (N+P; 13), nivolumab-axitinib (6), nivolumab-lenvatinib (2), and nivolumab-ipilimumab-cabozantinib (3). The median progression-free survival was 11.6 months and the median overall survival was not reached. Response data were available in 45 patients: complete response (CR; n = 3, 6.7%), partial response (PR; 20, 44.4%), stable disease (SD; 19, 42.2%), and progressive disease (3, 6.7%). Overall response rate was 51% and disease control rate (CR+PR+SD) was 93%. Only one patient had a grade ≥3 adverse event., Conclusion: To our knowledge, this is the first case series reporting off-label use of combination TKI-IO for mRCC. TKI-IO combinations, particularly N+P and N+C, are well tolerated and efficacious. Although further prospective research is essential, slow disease progression on IO or TKI monotherapy may be safely controlled with addition of either TKI or IO., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

A rise in the prevalence of depression underscores the need for accessible and effective interventions. The objectives of this study were to determine if the addition of a treatment component showing promise in treating depression, heart rate variability-biofeedback (HRV-B), to our original smartphone-based, 8-week digital intervention was feasible and whether patients in the HRV-B ("enhanced") intervention were more likely to experience clinically significant improvements in depressive symptoms than patients in our original ("standard") intervention. We used a quasi-experimental, non-equivalent (matched) groups design to compare changes in symptoms of depression in the enhanced group (n = 48) to historical outcome data from the standard group (n = 48). Patients in the enhanced group completed a total average of 3.86 h of HRV-B practice across 25.8 sessions, and were more likely to report a clinically significant improvement in depressive symptom score post-intervention than participants in the standard group, even after adjusting for differences in demographics and engagement between groups (adjusted OR 3.44, 95% CI [1.28-9.26], P = .015). Our findings suggest that adding HRV-B to an app-based, smartphone-delivered, remote intervention for depression is feasible and may enhance treatment outcomes.

Human decisions can be habitual or goal-directed, also known as model-free (MF) or model-based (MB) control. Previous work suggests that the balance between the two decision systems is impaired in psychiatric disorders such as compulsion and addiction, via overreliance on MF control. However, little is known whether the balance can be altered through task training. Here, 20 healthy participants performed a well-established two-step task that differentiates MB from MF control, across five training sessions. We used computational modelling and functional near-infrared spectroscopy to assess changes in decision-making and brain hemodynamic over time. Mixed-effects modelling revealed overall no substantial changes in MF and MB behavior across training. Although our behavioral and brain findings show task-induced changes in learning rates, these parameters have no direct relation to either MF or MB control or the balance between the two systems, and thus do not support the assumption of training effects on MF or MB strategies. Our findings indicate that training on the two-step paradigm in its current form does not support a shift in the balance between MF and MB control. We discuss these results with respect to implications for restoring the balance between MF and MB control in psychiatric conditions., Competing Interests: The authors have declared that no competing interests exist.

Background: Depression is one of the most common mental health disorders and severely impacts one's physical, psychological, and social functioning. To address access barriers to care, we developed Ascend-a smartphone-delivered, therapist-supported, 8-week intervention based on several evidence-based psychological treatments for depression and anxiety. A previous feasibility study with 102 adults with elevated depression reported that Ascend is associated with a postintervention reduction in depression symptoms., Objective: We aimed to examine whether Ascend is associated with a reduction in symptoms of anxiety, and importantly, whether reductions in symptoms of depression and anxiety are maintained up to 12-months postintervention., Methods: We assessed whether the previously reported, end-of-treatment improvements seen in the 102 adults with elevated symptoms of depression extended up to 12 months posttreatment for depression symptoms (measured by the Patient Health Questionnaire-9 [PHQ-9]) and up to 6 months posttreatment for anxiety symptoms (added to the intervention later and measured using the Generalized Anxiety Disorder-7 [GAD-7] scale). We used linear mixed effects models with Tukey contrasts to compare time points and reported intention-to-treat statistics with a sensitivity analysis., Results: The intervention was associated with reductions in symptoms of depression that were maintained 12 months after the program (6.67-point reduction in PHQ-9 score, 95% CI 5.59-7.75; P<.001; Hedges g=1.14, 95% CI 0.78-1.49). A total of 60% of the participants with PHQ-9 scores above the cutoff for major depression at baseline (PHQ≥10) reported clinically significant improvement at the 12-month follow-up (at least 50% reduction in PHQ-9 score and postprogram score <10). Participants also reported reductions in symptoms of anxiety that were maintained for at least 6 months after the program (4.26-point reduction in GAD-7 score, 95% CI 3.14-5.38; P<.001; Hedges g=0.91, 95% CI 0.54-1.28)., Conclusions: There is limited evidence on whether outcomes associated with smartphone-based interventions for common mental health problems are maintained posttreatment. Participants who enrolled in Ascend experienced clinically significant reductions in symptoms of depression and anxiety that were maintained for up to 1 year and 6 months after the intervention, respectively. Future randomized trials are warranted to test Ascend as a scalable solution to the treatment of depression and anxiety., (©Marcos Economides, Kristian Ranta, Albert Nazander, Outi Hilgert, Philippe R Goldin, Anu Raevuori, Valerie Forman-Hoffman. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 26.08.2019.)

Background: Previous evidence suggests that mindfulness training may improve aspects of psychosocial well-being. Whilst mindfulness is traditionally taught in person, consumers are increasingly turning to mindfulness-based smartphone apps as an alternative delivery medium for training. Despite this growing trend, few studies have explored whether mindfulness delivered via a smartphone app can enhance psychosocial well-being within the general public., Methods: The present pilot randomised controlled trial compared the impact of engaging with the self-guided mindfulness meditation (MM) app 'Headspace' (n = 38) for a period of 10 or 30 days, to a wait-list (WL) control (n = 36), using a cohort of adults from the general population. The Satisfaction with Life Scale, Perceived Stress Scale, and Wagnild Resilience Scale were administered online at baseline and after 10 and 30 days of the intervention., Results: Twelve participants (MM n = 9, WL n = 3) were lost to follow-up for unknown reasons. Relative to the WL control, the MM app positively impacted self-reported satisfaction with life, stress, and resilience at day 10, with further improvements emerging at day 30 (Cohen's d = 0.57, 1.42, 0.63 respectively). The rate of improvement was largest at the 10-day assessment point, dropping moderately by day 30. Participants that rated the MM app as easy to engage with experienced the largest self-reported benefits. Moreover, the MM app was able to protect against an unexpected increase in perceived stress that emerged in the control group., Conclusions: This pilot randomised controlled trial shows that self-reported improvements in psychosocial outcomes can be achieved at low cost through short-term engagement with a mindfulness-based smartphone app, and should be followed up with more substantive studies., Trial Registration: ISRCTN ISRCTN34618894., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: Author ME was employed by Headspace Inc. for the duration of this study. Authors LC & CC have no competing interests to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

There is a paucity of data regarding mixed mold pulmonary infections (MMPIs) in patients with haematological malignancies with or without haematopoietic stem cell transplantation (HSCT). We retrospectively studied 27 such patients (2005-2015) and compared them to patients with invasive pulmonary aspergillosis (IPA) caused by Aspergillus fumigatus. Factors associated with the diagnosis of MMPIs were significant corticosteroid use [20 (74%) vs 6 (22%), P < 0.001], sputum as the source specimen [13 (48%) vs 3 (11%), P = 0.003], younger age (median age: 58 vs 66 years, P = 0.006), and male sex [22 (81%) vs 13 (48%), P = 0.01]. Haematological cancers other than acute myeloid leukaemia (AML)/myelodysplastic syndromes (MDS) were less common in MMPIs than in IPA patients [AML/MDS: 6 (22%) vs 14 (52%), P = 0.04]. Only significant corticosteroid use [95% CI (2.7-42.7), P < 0.001], and sputum as the source specimen [95% (1.6-41.6), P = 0.012] were statistically significant as independently associated with increased risk of MMPIs diagnosis in multivariate analysis. Total mortality rate at day 42 postdiagnosis was comparable in both groups., (© 2018 Blackwell Verlag GmbH.)

Mindfulness training, which involves observing thoughts and feelings without judgment or reaction, has been shown to improve aspects of psychosocial well-being when delivered via in-person training programs such as mindfulness-based stress reduction (MBSR) and mindfulness-based cognitive therapy (MBCT). Less is known about the efficacy of digital training mediums, such as smartphone apps, which are rapidly rising in popularity. In this study, novice meditators were randomly allocated to an introductory mindfulness meditation program or to a psychoeducational audiobook control featuring an introduction to the concepts of mindfulness and meditation. The interventions were delivered via the same mindfulness app, were matched across a range of criteria, and were presented to participants as well-being programs. Affect, irritability, and two distinct components of stress were measured immediately before and after each intervention in a cohort of healthy adults. While both interventions were effective at reducing stress associated with personal vulnerability, only the mindfulness intervention had a significant positive impact on irritability, affect, and stress resulting from external pressure (between group Cohen's d  = 0.44, 0.47, 0.45, respectively). These results suggest that brief mindfulness training has a beneficial impact on several aspects of psychosocial well-being, and that smartphone apps are an effective delivery medium for mindfulness training., Competing Interests: Compliance with Ethical StandardsAll procedures performed in studies involving human participants were in accordance with the ethical standards of the University College London (UCL) Ethics Committee (project ID 2789/001) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study. ME, JM, MJB, and BS were employed by Headspace Inc. at the time of conducting this study.

Background: Antiviral therapy improves hepatic outcomes in hepatitis C virus (HCV)-infected cancer patients. However, such patients are not treated simultaneously with antivirals and chemotherapy, owing to overlapping toxicities with previous standard of care treatment of pegylated interferon and ribavirin., Aim: To examine the safety and clinically-significant drug-drug interactions observed in patients who received simultaneous treatment with direct-acting antivirals (DAAs) and chemotherapy., Methods: Safety was determined by the presence of adverse events which were graded according to the division of AIDS Table (version 2.0). Adverse events were monitored throughout antiviral treatment and up to 3 months after its completion. Drug-drug interactions were assessed using current online databases. Sustained virological response (SVR) was defined as absence of serum HCV RNA 12 weeks after end of DAA treatment. Cirrhosis was diagnosed via imaging, biopsy or with the use of non-invasive fibrosis markers., Results: Twenty-one patients received concomitant treatment with DAAs and chemotherapy between January 2013 and September 2016. Concomitant treatment was started either for virological (14; 67%) or oncologic (7; 33%) reasons. DAAs used were sofosbuvir, ledipasvir, simeprevir, daclatasvir ± ribavirin. The adverse events observed were mainly constitutional (12; 57%), hematological and gastrointestinal (7; 33% each). Physicians changed the DAA regimens in two patients (10%) in anticipation of drug-drug interactions with daclatasvir and dexamethasone. The overall SVR rate was 95% (20/21)., Conclusions: Hepatitis C virus-targeted antiviral therapy can be used concomitantly with selected anti-neoplastic agents under close monitoring for drug-drug interactions. This therapeutic intervention may prevent delay in the administration of chemotherapy in HCV-infected cancer patients., Competing Interests: Statement of interests Disclosures: Dr. Torres is or has been the principal investigator for research grants from Gilead Sciences, Merck & Co., Inc., and Vertex Pharmaceuticals, with all funds paid to MD Anderson. He also is or has been a paid scientific advisor for Gilead Sciences, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Vertex Pharmaceuticals, Genentech, Novartis, Astellas Pharma, Pfizer Inc., and Theravance Biopharma, Inc.; the terms of these arrangements are being managed by MD Anderson in accordance with its conflict of interest policies. The other authors have no conflicts to disclose., (© 2016 John Wiley & Sons Ltd.)

Fast internally generated sequences of neural representations are suggested to support learning and online planning. However, these sequences have only been studied in the context of spatial tasks and never in humans. Here, we recorded magnetoencephalography (MEG) while human subjects performed a novel non-spatial reasoning task. The task required selecting paths through a set of six visual objects. We trained pattern classifiers on the MEG activity elicited by direct presentation of the visual objects alone and tested these classifiers on activity recorded during periods when no object was presented. During these object-free periods, the brain spontaneously visited representations of approximately four objects in fast sequences lasting on the order of 120 ms. These sequences followed backward trajectories along the permissible paths in the task. Thus, spontaneous fast sequential representation of states can be measured non-invasively in humans, and these sequences may be a fundamental feature of neural computation across tasks., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Correlative evidence provides support for the idea that brain oscillations underpin neural computations. Recent work using rhythmic stimulation techniques in humans provide causal evidence but the interactions of these external signals with intrinsic rhythmicity remain unclear. Here, we show that sensorimotor cortex follows externally applied rhythmic TMS (rTMS) stimulation in the beta-band but that the elicited responses are strongest at the intrinsic individual beta peak frequency. While these entrainment effects are of short duration, even subthreshold rTMS pulses propagate through the network and elicit significant cortico-spinal coupling, particularly when stimulated at the individual beta-frequency. Our results show that externally enforced rhythmicity interacts with intrinsic brain rhythms such that the individual peak frequency determines the effect of rTMS. The observed downstream spinal effect at the resonance frequency provides evidence for the causal role of brain rhythms for signal propagation., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Model-based and model-free reinforcement learning (RL) have been suggested as algorithmic realizations of goal-directed and habitual action strategies. Model-based RL is more flexible than model-free but requires sophisticated calculations using a learnt model of the world. This has led model-based RL to be identified with slow, deliberative processing, and model-free RL with fast, automatic processing. In support of this distinction, it has recently been shown that model-based reasoning is impaired by placing subjects under cognitive load--a hallmark of non-automaticity. Here, using the same task, we show that cognitive load does not impair model-based reasoning if subjects receive prior training on the task. This finding is replicated across two studies and a variety of analysis methods. Thus, task familiarity permits use of model-based reasoning in parallel with other cognitive demands. The ability to deploy model-based reasoning in an automatic, parallelizable fashion has widespread theoretical implications, particularly for the learning and execution of complex behaviors. It also suggests a range of important failure modes in psychiatric disorders.

The impulse to act for immediate reward often conflicts with more deliberate evaluations that support long-term benefit. The neural architecture that negotiates this conflict remains unclear. One account proposes a single neural circuit that evaluates both immediate and delayed outcomes, while another outlines separate impulsive and patient systems that compete for behavioral control. Here we designed a task in which a complex payout structure divorces the immediate value of acting from the overall long-term value, within the same outcome modality. Using model-based fMRI in humans, we demonstrate separate neural representations of immediate and long-term values, with the former tracked in the anterior caudate (AC) and the latter in the ventromedial prefrontal cortex (vmPFC). Crucially, when subjects' choices were compatible with long-run consequences, value signals in AC were down-weighted and those in vmPFC were enhanced, while the opposite occurred when choice was impulsive. Thus, our data implicate a trade-off in value representation between AC and vmPFC as underlying controlled versus impulsive choice., (Copyright © 2015. Published by Elsevier Inc.)

Rationale: Decision-making involves two fundamental axes of control namely valence, spanning reward and punishment, and action, spanning invigoration and inhibition. We recently exploited a go/no-go task whose contingencies explicitly decouple valence and action to show that these axes are inextricably coupled during learning. This results in a disadvantage in learning to go to avoid punishment and in learning to no-go to obtain a reward. The neuromodulators dopamine and serotonin are likely to play a role in these asymmetries: Dopamine signals anticipation of future rewards and is also involved in an invigoration of motor responses leading to reward, but it also arbitrates between different forms of control. Conversely, serotonin is implicated in motor inhibition and punishment processing., Objective: To investigate the role of dopamine and serotonin in the interaction between action and valence during learning.Methods We combined computational modeling with pharmacological manipulation in 90 healthy human volunteers, using levodopa and citalopram to affect dopamine and serotonin, respectively., Results: We found that, after administration of levodopa,action learning was less affected by outcome valence when compared with the placebo and citalopram groups. This highlights in this context a predominant effect of levodopa in controlling the balance between different forms of control.Citalopram had distinct effects, increasing participants'tendency to perform active responses independent of outcome valence, consistent with a role in decreasing motor inhibition., Conclusions: Our findings highlight the rich complexities of the roles played by dopamine and serotonin during instrumental learning.

Actions can lead to an immediate reward or punishment and a complex set of delayed outcomes. Adaptive choice necessitates the brain track and integrate both of these potential consequences. Here, we designed a sequential task whereby the decision to exploit or forego an available offer was contingent on comparing immediate value and a state-dependent future cost of expending a limited resource. Crucially, the dynamics of the task demanded frequent switches in policy based on an online computation of changing delayed consequences. We found that human subjects choose on the basis of a near-optimal integration of immediate reward and delayed consequences, with the latter computed in a prefrontal network. Within this network, anterior cingulate cortex (ACC) was dynamically coupled to ventromedial prefrontal cortex (vmPFC) when adaptive switches in choice were required. Our results suggest a choice architecture whereby interactions between ACC and vmPFC underpin an integration of immediate and delayed components of value to support flexible policy switching that accommodates the potential delayed consequences of an action.

Subjects routinely control the vigor with which they emit motoric responses. However, the bulk of formal treatments of decision-making ignores this dimension of choice. A recent theoretical study suggested that action vigor should be influenced by experienced average reward rate and that this rate is encoded by tonic dopamine in the brain. We previously examined how average reward rate modulates vigor as exemplified by response times and found a measure of agreement with the first suggestion. In the current study, we examined the second suggestion, namely the potential influence of dopamine signaling on vigor. Ninety healthy subjects participated in a double-blind experiment in which they received one of the following: placebo, L-DOPA (which increases dopamine levels in the brain), or citalopram (which has a selective, if complex, effect on serotonin levels). Subjects performed multiple trials of a rewarded odd-ball discrimination task in which we varied the potential reward over time in order to exercise the putative link between vigor and average reward rate. Replicating our previous findings, we found that a significant fraction of the variance in subjects' responses could be explained by our experimentally manipulated changes in average reward rate. Crucially, this relationship was significantly stronger under L-Dopa than under Placebo, suggesting that the impact of average reward levels on action vigor is indeed subject to a dopaminergic influence.