Generalized encoding of the relative subjective value of cognitive effort in dorsal ACC.

Making choices about whether and when to engage cognitive effort are a common feature of everyday experience, with important consequences for academic, career, and health outcomes. Yet, despite their hypothesized importance, very little is understood about the underlying mechanisms that support this form of human cost-benefit decision-making. To investigate these mechanisms, we used the Cognitive Effort Discounting Paradigm (Cog-ED) during fMRI scanning to precisely quantify the neural encoding of varying cognitive effort demands relative to reward outcomes, within two distinct cognitive domains (working memory, speech comprehension). The findings provide strong evidence that the dorsal anterior cingulate cortex (dACC) plays a central and selective role in this decision-making process. Trial-by-trial modulations in dACC activation tracked the relative subjective value of the low-effort, low-reward option, with the strongest activity occurring when this was of greater value than the high-effort, high-reward option. In contrast, dACC activity was not modulated by decision difficulty, though such effects were found in other frontoparietal regions. Critically, dACC activity was also strongly correlated across the two decision-making task domains, and further predicted subsequent choice behavior in both. Together, the results suggest that dACC activity modulation reflects a domain-general valuation comparison mechanism, which acts to bias participants away from decisions to engage in cognitive effort, when the perceived subjective costs of such engagement outweigh the reward-related benefits. These findings complement work in other cost domains and species by pointing to a clear role of dACC in representing subjective value differences between choice options during cost-benefit decision-making.Significance Statement Despite the growing popularity of decision-making paradigms to study the neural mechanisms underlying choices to engage in cognitive effort, there is still little consensus about how such decisions are implemented in the human brain. This study used two distinct versions of a cognitive effort decision-making paradigm during fMRI scanning to identify generalized brain mechanisms engaged while participants decided whether to engage in cognitive effort. Importantly, the results provide additional evidence that the dorsal anterior cingulate cortex is a key locus of cognitive effort-based decision-making. Specifically, this brain region signals the difference in relative value across choice options, making it an attractive target for future studies aimed at investigating the altered decision-making observed in populations for which apathy is commonly observed.

Dorsal Anterior Cingulate Cortex Encodes the Integrated Incentive Motivational Value of Cognitive Task Performance.

Humans can seamlessly combine value signals from diverse motivational incentives, yet it is not well understood how these signals are "bundled" in the brain to modulate cognitive control. The dorsal ACC (dACC) is theorized to integrate motivational value dimensions in the service of goal-directed action, although this hypothesis has yet to receive rigorous confirmation. In the present study, we examined the role of human dACC in motivational incentive integration. Healthy young adult men and women were scanned with fMRI while engaged in an experimental paradigm that quantifies the combined effects of liquid (e.g., juice, neutral, saltwater) and monetary incentives on cognitive task performance. Monetary incentives modulated trial-by-trial dACC activation, whereas block-related effects of liquid incentives on dACC activity were observed. When bundled together, incentive-related dACC modulation predicted fluctuations in both cognitive performance and self-report motivation ratings. Statistical mediation analyses suggest that dACC encoded the incentives in terms of their integrated subjective motivational value, and that this value signal was most proximally associated with task performance. Finally, we confirmed that these incentive integration effects were selectively present in dACC. Together, the results support an account in which dACC integrates motivational signals to compute the expected value of goal-directed cognitive control.SIGNIFICANCE STATEMENT How are primary and secondary incentives integrated in the brain to influence goal-directed behavior? Using an innovative experimental fMRI paradigm that combines motivational incentives that have historically been studied independently between species (e.g., monetary rewards for humans, food rewards for animals), we examine the relationship between incentive motivational value and cognitive control allocation. We find evidence that the integrated incentive motivational value of combined incentives is encoded in human dorsal ACC. Further, self-reported motivational shifts mediated the effects of incentive-modulated dorsal ACC activity on task performance, revealing convergence in how self-reported and experimentally induced motivation are encoded in the human brain. Our findings may inform future translational studies examining affective/motivational and cognitive impairments in psychopathology (e.g., anxiety, depression, addiction).

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.

Cognitive Effort-Based Decision-Making Across Experimental and Daily Life Indices in Younger and Older Adults.

OBJECTIVES: The study investigated whether cognitive effort decision-making measured via a neuroeconomic paradigm that manipulated framing (gain vs. loss outcomes), could predict daily life engagement in mentally demanding activities in both younger and older adults. METHOD: Younger and older adult participants (N = 310) completed the Cognitive Effort Discounting paradigm (Cog-ED), under both gain and loss conditions, to provide an experimental index of cognitive effort costs for each participant in each framing condition. A subset of participants (N = 230) also completed a 7-day Ecological Momentary Assessment (EMA) protocol measuring engagement in mentally demanding daily life activities. RESULTS: In a large, online sample, we replicated a robust increase in cognitive effort costs among older, relative to younger, adults. Additionally, costs were found to be reduced in the loss relative to gain frame, although these effects were only reliable at high levels of task difficulty and were not moderated by age. Critically, participants who had lower effort costs in the gain frame tended to report engaging in more mentally demanding daily life activities, but the opposite pattern was observed in the loss frame. Further analyses demonstrated the specificity of reward-related cognitive motivation in predicting daily life mentally demanding activities. DISCUSSION: Together, these results suggest that cognitive effort costs, as measured through behavioral choice patterns in a neuroeconomic decision-making task, can be used to predict and explain engagement in mentally demanding activities during daily life among both older and younger adults.

Multivariate associations between dopamine receptor availability and risky investment decision-making across adulthood.

Enhancing dopamine increases financial risk taking across adulthood but it is unclear whether baseline individual differences in dopamine function are related to risky financial decisions. Here, thirty-five healthy adults completed an incentive-compatible risky investment decision task and a PET scan at rest using [11C]FLB457 to assess dopamine D2-like receptor availability. Participants made choices between a safe asset (bond) and a risky asset (stock) with either an expected value less than the bond ("bad stock") or expected value greater than the bond ("good stock"). Five measures of behavior (choice inflexibility, risk seeking, suboptimal investment) and beliefs (absolute error, optimism) were computed and D2-like binding potential was extracted from four brain regions of interest (midbrain, amygdala, anterior cingulate, insula). We used canonical correlation analysis to evaluate multivariate associations between decision-making and dopamine function controlling for age. Decomposition of the first dimension (r = 0.76) revealed that the strongest associations were between measures of choice inflexibility, incorrect choice, optimism, amygdala binding potential, and age. Follow-up univariate analyses revealed that amygdala binding potential and age were both independently associated with choice inflexibility. The findings suggest that individual differences in dopamine function may be associated with financial risk taking in healthy adults.

Increased cognitive effort costs in healthy aging and preclinical Alzheimer's disease.

Life-long engagement in cognitively demanding activities may mitigate against declines in cognitive ability observed in healthy or pathological aging. However, the "mental costs" associated with completing cognitive tasks also increase with age and may be partly attributed to increases in preclinical levels of Alzheimer's disease (AD) pathology, specifically amyloid. We test whether cognitive effort costs increase in a domain-general manner among older adults, and further, whether such age-related increases in cognitive effort costs are associated with working memory (WM) capacity or amyloid burden, a signature pathology of AD. In two experiments, we administered a behavioral measure of cognitive effort costs (cognitive effort discounting) to a sample of older adults recruited from online sources (Experiment 1) or from ongoing longitudinal studies of aging and dementia (Experiment 2). Experiment 1 compared age-related differences in cognitive effort costs across two domains, WM and speech comprehension. Experiment 2 compared cognitive effort costs between a group of participants who were rated positive for amyloid relative to those with no evidence of amyloid. Results showed age-related increases in cognitive effort costs were evident in both domains. Cost estimates were highly correlated between the WM and speech comprehension tasks but did not correlate with WM capacity. In addition, older adults who were amyloid positive had higher cognitive effort costs than those who were amyloid negative. Cognitive effort costs may index a domain-general trait that consistently increases in aging. Differences in cognitive effort costs associated with amyloid burden suggest a potential neurobiological mechanism for age-related differences. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

An fMRI protocol for administering liquid incentives to human participants.

This protocol describes the materials and approaches for administering liquid incentives to human participants during fMRI scanning. We first describe preparation of the liquid solutions (e.g., neutral solution and saltwater) and liquid delivery setups. We then detail steps to connect the setups to the computer-controlled syringe pump in the MRI control room, followed by procedures for testing the syringe pump dispensing a liquid bolus during the task. Description of custom software and required adapters for implementing the liquid setup are included. For complete details on the use and execution of this protocol, please refer to Yee et al. (2021).

Incorporating ecological momentary assessment into multimethod investigations of cognitive aging: Promise and practical considerations.

Ecological momentary assessment (EMA) represents a promising approach to study cognitive aging. In contrast to laboratory-based studies, EMA involves the repeated sampling of experiences in daily life contexts, enabling investigators to gain access to dynamic processes (e.g., situational contexts, intraindividual variability) that are likely to strongly contribute to aging and age-related change across the adult life-span. As such, EMA approaches complement the prevailing research methods in the field of cognitive aging (e.g., laboratory-based paradigms, neuroimaging), while also providing the opportunity to replicate and extend findings from the laboratory in more naturalistic contexts. Following an overview of the methodological and conceptual strengths of EMA approaches in cognitive aging research, we discuss best practices for researchers interested in implementing EMA studies. A key goal is to highlight the tremendous potential for combining EMA methods with other laboratory-based approaches, in order to increase the robustness, replicability, and real-world implications of research findings in the field of cognitive aging. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Domain-general cognitive motivation: Evidence from economic decision-making - Final Registered Report.

Stable individual differences in cognitive motivation (i.e., the tendency to engage in and enjoy effortful cognitive activities) have been documented with self-report measures, yet convergent support for a trait-level construct is still lacking. In the present study, we used an innovative decision-making paradigm (COG-ED) to quantify the costs of cognitive effort, a metric of cognitive motivation, across two distinct cognitive domains: working memory (an N-back task) and speech comprehension (understanding spoken sentences in background noise). We hypothesized that cognitive motivation operates similarly within individuals, regardless of domain. Specifically, in 104 adults aged 18-40 years, we tested whether individual differences in effort costs are stable across domains, even after controlling for other potential sources of shared individual variation. Conversely, we evaluated whether the costs of cognitive effort across domains may be better explained in terms of other relevant cognitive and personality-related constructs, such as working memory capacity or reward sensitivity. We confirmed a reliable association among effort costs in both domains, even when these other sources of individual variation, as well as task load, are statistically controlled. Taken together, these results add support for trait-level variation in cognitive motivation impacting effort-based decision making across multiple domains.

Domain-general cognitive motivation: evidence from economic decision-making.

Stable individual differences in cognitive motivation (i.e., the tendency to engage in and enjoy effortful cognitive activities) have been documented with self-report measures, yet convergent support for a trait-level construct is still lacking. In the present study, we use an innovative decision-making paradigm (COG-ED) to quantify the costs of cognitive effort, a metric of cognitive motivation, across two distinct cognitive domains (working memory and speech comprehension). We hypothesize that cognitive motivation operates similarly within individuals, regardless of domain. Specifically, we test whether individual differences in effort costs are stable across domains, even after controlling for other potential sources of shared individual variation. Conversely, we evaluate whether the costs of cognitive effort across domains may be better explained in terms of other relevant cognitive and personality-related constructs, such as working memory capacity or reward sensitivity.

Dissociable Effects of Monetary, Liquid, and Social Incentives on Motivation and Cognitive Control.

Humans are social creatures and, as such, can be motivated by aspects of social life (e.g., approval from others) to guide decision-making in everyday contexts. Indeed, a common view is that people may have stronger orientation toward social goals or incentives relative to other incentive modalities, such as food or money. However, current studies have only rarely addressed how social incentives compare to other types of rewards in motivating goal-directed behavior. The current study tested this claim; across two separate experiments, the effects of liquid and social incentives were compared in terms of their subsequent impact on task performance and self-reported affect and motivation. Critically, valenced social incentives offered both ecological validity (short video clips-Experiment 1) and continuity with prior stimuli used in the social reward and motivation literature (static images-Experiment 2) when examining their effect on behavior. Across both studies, the results replicate and extend prior work, demonstrating robust effects of liquid incentives on task performance and self-reported affect and motivation, while also supporting an interpretation of weaker motivational and affective effects for social incentives. These patterns of results highlight the complex and wide-ranging effects of social incentives and call into question the effectiveness of social incentives, relative to other incentive modalities, in motivating behavior.

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.

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).

Bone marrow CFU-GM and human tumor xenograft efficacy of three tubulin binding agents.

PURPOSE: The dynamic instability of microtubules in cells is one of the key targets of anticancer therapeutics. Microtubule-disrupting agents such as vinca alkaloids and microtubule-stabilizing agents such as taxanes are important antitumor agents. The bone marrow toxicity and human tumor xenograft activity of three tubulin-binding compounds, vincristine, paclitaxel, and tasidotin were compared. METHODS: Mouse and human bone marrow were subjected to colony-forming (CFU-GM) assays over a 5-log concentration range in culture. In vivo, a range of tasidotin doses was compared with vincristine, paclitaxel, and docetaxel for efficacy in several human tumor xenografts. RESULTS: The IC(90) concentrations for vincristine and paclitaxel for mouse CFU-GM were 30 and 27 nM, and for human CFU-GM were 3 and 9 nM, giving mouse to human differentials of ten- and threefold. Tasidotin produced IC(90)s of >300 nM in mouse and 65 nM in human CFU-GM, thus a >4.6-fold differential between species. In vivo, tasidotin resulted in a dose-dependent increase in tumor growth delay in the RL lymphoma, the RPMI 8226 multiple myeloma, and MX-1 breast carcinoma models. Vincristine and tasidotin were also very effective against these tumors. The PC-3 prostate carcinoma was very responsive to full-dose paclitaxel and docetaxel while tasidotin generated a dose dependent effect. CONCLUSIONS: Bringing together bone marrow toxicity data, pharmacokinetic parameters, and human tumor xenograft efficacy provides valuable information for the translation of preclinical findings to the clinic.

Resuscitation in the hospital: circadian variation of cardiopulmonary arrest.

PURPOSE: Over 25 reports have found outpatient frequency of sudden cardiac death peaks between 6 am and noon; few studies, with inconsistent results, have examined circadian variation of death in hospitalized patients. This study assesses circadian variation in cardiopulmonary arrest of in-hospital patients across patient, hospital, and event variables and its effect on survival to discharge. METHODS: A retrospective, single institution registry included all admissions to the Medical Center of Central Georgia in which resuscitation was attempted between January 1987 and December 2000. The registry included 4692 admissions; only the first attempt was reported. Analyses of 1-, 2-, 4-, and 8-hour intervals were performed; 1- and 4-hour intervals are presented. RESULTS: Significant circadian variation was found at 1 hour (P=.01), but not at 4-hour intervals. Significant circadian variation was found for initial rhythms that were perfusing (P=.03) and asystole (P=.01). A significantly higher percentage of unwitnessed events were found as asystole during the overnight hours (P=.002). Using simple logistic regression, time in 4-hour intervals and rhythm were each significantly related to patient survival until hospital discharge (P=.003 and P <.0001). In multivariate analysis, only rhythm remained significant. CONCLUSIONS: Circadian variation of cardiopulmonary arrest in this hospital has several temporal versions and is related to survival. Late night variation in witnessed events and rhythm suggests a delay between onset of clinical death and discovery, which contributes to poorer outcomes.