Robust mixture modeling reveals category-free selectivity in reward region neuronal ensembles.

Classification of neurons into clusters based on their response properties is an important tool for gaining insight into neural computations. However, it remains unclear to what extent neurons fall naturally into discrete functional categories. We developed a Bayesian method that models the tuning properties of neural populations as a mixture of multiple types of task-relevant response patterns. We applied this method to data from several cortical and striatal regions in economic choice tasks. In all cases, neurons fell into only two clusters: one multiple-selectivity cluster containing all cells driven by task variables of interest and another of no selectivity for those variables. The single cluster of task-sensitive cells argues against robust categorical tuning in these areas. The no-selectivity cluster was unanticipated and raises important questions about what distinguishes these neurons and what role they play. Moreover, the ability to formally identify these nonselective cells allows for more accurate measurement of ensemble effects by excluding or appropriately down-weighting them in analysis. Our findings provide a valuable tool for analysis of neural data, challenge simple categorization schemes previously proposed for these regions, and place useful constraints on neurocomputational models of economic choice and control. NEW & NOTEWORTHY We present a Bayesian method for formally detecting whether a population of neurons can be naturally classified into clusters based on their response tuning properties. We then examine several data sets of reward system neurons for variables and find in all cases that neurons can be classified into only two categories: a functional class and a non-task-driven class. These results provide important constraints for neural models of the reward system.

Pure correlates of exploration and exploitation in the human brain.

Balancing exploration and exploitation is a fundamental problem in reinforcement learning. Previous neuroimaging studies of the exploration-exploitation dilemma could not completely disentangle these two processes, making it difficult to unambiguously identify their neural signatures. We overcome this problem using a task in which subjects can either observe (pure exploration) or bet (pure exploitation). Insula and dorsal anterior cingulate cortex showed significantly greater activity on observe trials compared to bet trials, suggesting that these regions play a role in driving exploration. A model-based analysis of task performance suggested that subjects chose to observe until a critical evidence threshold was reached. We observed a neural signature of this evidence accumulation process in the ventromedial prefrontal cortex. These findings support theories positing an important role for anterior cingulate cortex in exploration, while also providing a new perspective on the roles of insula and ventromedial prefrontal cortex.

Neuronal selectivity for spatial positions of offers and choices in five reward regions.

When we evaluate an option, how is the neural representation of its value linked to information that identifies it, such as its position in space? We hypothesized that value information and identity cues are not bound together at a particular point but are represented together at the single unit level throughout the entirety of the choice process. We examined neuronal responses in two-option gambling tasks with lateralized and asynchronous presentation of offers in five reward regions: orbitofrontal cortex (OFC, area 13), ventromedial prefrontal cortex (vmPFC, area 14), ventral striatum (VS), dorsal anterior cingulate cortex (dACC), and subgenual anterior cingulate cortex (sgACC, area 25). Neuronal responses in all areas are sensitive to the positions of both offers and of choices. This selectivity is strongest in reward-sensitive neurons, indicating that it is not a property of a specialized subpopulation of cells. We did not find consistent contralateral or any other organization to these responses, indicating that they may be difficult to detect with aggregate measures like neuroimaging or studies of lesion effects. These results suggest that value coding is wed to factors that identify the object throughout the reward system and suggest a possible solution to the binding problem raised by abstract value encoding schemes.

Postreward delays and systematic biases in measures of animal temporal discounting.

Intertemporal choice tasks, which pit smaller/sooner rewards against larger/later ones, are frequently used to study time preferences and, by extension, impulsivity and self-control. When used in animals, many trials are strung together in sequence and an adjusting buffer is added after the smaller/sooner option to hold the total duration of each trial constant. Choices of the smaller/sooner option are not reward maximizing and so are taken to indicate that the animal is discounting future rewards. However, if animals fail to correctly factor in the duration of the postreward buffers, putative discounting behavior may instead reflect constrained reward maximization. Here, we report three results consistent with this discounting-free hypothesis. We find that (i) monkeys are insensitive to the association between the duration of postreward delays and their choices; (ii) they are sensitive to the length of postreward delays, although they greatly underestimate them; and (iii) increasing the salience of the postreward delay biases monkeys toward the larger/later option, reducing measured discounting rates. These results are incompatible with standard discounting-based accounts but are compatible with an alternative heuristic model. Our data suggest that measured intertemporal preferences in animals may not reflect impulsivity, or even mental discounting of future options, and that standard human and animal intertemporal choice tasks measure unrelated mental processes.

Neurons in dorsal anterior cingulate cortex signal postdecisional variables in a foraging task.

The dorsal anterior cingulate cortex (dACC) is a key hub of the brain's executive control system. Although a great deal is known about its role in outcome monitoring and behavioral adjustment, whether and how it contributes to the decision process remain unclear. Some theories suggest that dACC neurons track decision variables (e.g., option values) that feed into choice processes and is thus "predecisional." Other theories suggest that dACC activity patterns differ qualitatively depending on the choice that is made and is thus "postdecisional." To compare these hypotheses, we examined responses of 124 dACC neurons in a simple foraging task in which monkeys accepted or rejected offers of delayed rewards. In this task, options that vary in benefit (reward size) and cost (delay) appear for 1 s; accepting the option provides the cued reward after the cued delay. To get at dACC neurons' contributions to decisions, we focused on responses around the time of choice, several seconds before the reward and the end of the trial. We found that dACC neurons signal the foregone value of the rejected option, a postdecisional variable. Neurons also signal the profitability (that is, the relative value) of the offer, but even these signals are qualitatively different on accept and reject decisions, meaning that they are also postdecisional. These results suggest that dACC can be placed late in the decision process and also support models that give it a regulatory role in decision, rather than serving as a site of comparison.

Ramping ensemble activity in dorsal anterior cingulate neurons during persistent commitment to a decision.

We frequently need to commit to a choice to achieve our goals; however, the neural processes that keep us motivated in pursuit of delayed goals remain obscure. We examined ensemble responses of neurons in macaque dorsal anterior cingulate cortex (dACC), an area previously implicated in self-control and persistence, in a task that requires commitment to a choice to obtain a reward. After reward receipt, dACC neurons signaled reward amount with characteristic ensemble firing rate patterns; during the delay in anticipation of the reward, ensemble activity smoothly and gradually came to resemble the postreward pattern. On the subset of risky trials, in which a reward was anticipated with 50% certainty, ramping ensemble activity evolved to the pattern associated with the anticipated reward (and not with the anticipated loss) and then, on loss trials, took on an inverted form anticorrelated with the form associated with a win. These findings enrich our knowledge of reward processing in dACC and may have broader implications for our understanding of persistence and self-control.

Clinical parameters before and after the transition to dialysis.

INTRODUCTION: The transition from pre-dialysis chronic kidney disease (CKD) to post-dialysis start is a critical period associated with high patient mortality and increased hospital admissions. Little is known about the trends of key clinical and laboratory parameters through this time of transition to start dialysis. METHODS: De-identified data including demographics, vital signs, lab results, and eGFR from the Fresenius Medical Care-CKD Registry were analyzed to determine trends in clinical and laboratory parameters through the time of transition from 12 months pre-dialysis start to 12 months post-dialysis start. Trends in key clinical and laboratory parameters associated with cardiovascular, nutritional, mineral metabolism and inflammatory domains were examined in association with the transition to dialysis start and first year dialysis survival. FINDINGS: All parameters show divergence for patients who survive vs. do not survive the first year of dialysis. Of note, during pre-dialysis CKD the absolute systolic blood pressure (SBP) level is lower and the slope for SBP decline is significantly steeper for patients who do not survive the first year on dialysis. DISCUSSION: This study uniquely demonstrates the trajectories of key parameters though the transition from pre-dialysis to post-dialysis start. Significant differences are noted in the pre-dialysis period for patients who survive vs. those who do not survive the first year of dialysis. Early recognition of adverse trends in the pre-dialysis period may create opportunity to intervene to improve early dialysis outcomes.

Monkeys are more patient in a foraging task than in a standard intertemporal choice task.

Studies of animal impulsivity generally find steep subjective devaluation, or discounting, of delayed rewards - often on the order of a 50% reduction in value in a few seconds. Because such steep discounting is highly disfavored in evolutionary models of time preference, we hypothesize that discounting tasks provide a poor measure of animals' true time preferences. One prediction of this hypothesis is that estimates of time preferences based on these tasks will lack external validity, i.e. fail to predict time preferences in other contexts. We examined choices made by four rhesus monkeys in a computerized patch-leaving foraging task interleaved with a standard intertemporal choice task. Monkeys were significantly more patient in the foraging task than in the intertemporal choice task. Patch-leaving behavior was well fit by parameter-free optimal foraging equations but poorly fit by the hyperbolic discount parameter obtained from the intertemporal choice task. Day-to-day variation in time preferences across the two tasks was uncorrelated with each other. These data are consistent with the conjecture that seemingly impulsive behavior in animals is an artifact of their difficulty understanding the structure of intertemporal choice tasks, and support the idea that animals are more efficient rate maximizers in the multi-second range than intertemporal choice tasks would suggest.

Orbitofrontal cortex uses distinct codes for different choice attributes in decisions motivated by curiosity.

Decision makers are curious and consequently value advance information about future events. We made use of this fact to test competing theories of value representation in area 13 of orbitofrontal cortex (OFC). In a new task, we found that monkeys reliably sacrificed primary reward (water) to view advance information about gamble outcomes. While monkeys integrated information value with primary reward value to make their decisions, OFC neurons had no systematic tendency to integrate these variables, instead encoding them in orthogonal manners. These results suggest that the predominant role of the OFC is to encode variables relevant for learning, attention, and decision making, rather than integrating them into a single scale of value. They also suggest that OFC may be placed at a relatively early stage in the hierarchy of information-seeking decisions, before evaluation is complete. Thus, our results delineate a circuit for information-seeking decisions and suggest a neural basis for curiosity.

Hot-hand bias in rhesus monkeys.

Human decision-makers often exhibit the hot-hand phenomenon, a tendency to perceive positive serial autocorrelations in independent sequential events. The term is named after the observation that basketball fans and players tend to perceive streaks of high accuracy shooting when they are demonstrably absent. That is, both observing fans and participating players tend to hold the belief that a player's chance of hitting a shot are greater following a hit than following a miss. We hypothesize that this bias reflects a strong and stable tendency among primates (including humans) to perceive positive autocorrelations in temporal sequences, that this bias is an adaptation to clumpy foraging environments, and that it may even be ecologically rational. Several studies support this idea in humans, but a stronger test would be to determine whether nonhuman primates also exhibit a hot-hand bias. Here we report behavior of 3 monkeys performing a novel gambling task in which correlation between sequential gambles (i.e., temporal clumpiness) is systematically manipulated. We find that monkeys have better performance (meaning, more optimal behavior) for clumped (positively correlated) than for dispersed (negatively correlated) distributions. These results identify and quantify a new bias in monkeys' risky decisions, support accounts that specifically incorporate cognitive biases into risky choice, and support the suggestion that the hot-hand phenomenon is an evolutionary ancient bias.

Reward value comparison via mutual inhibition in ventromedial prefrontal cortex.

Recent theories suggest that reward-based choice reflects competition between value signals in the ventromedial prefrontal cortex (vmPFC). We tested this idea by recording vmPFC neurons while macaques performed a gambling task with asynchronous offer presentation. We found that neuronal activity shows four patterns consistent with selection via mutual inhibition: (1) correlated tuning for probability and reward size, suggesting that vmPFC carries an integrated value signal; (2) anti-correlated tuning curves for the two options, suggesting mutual inhibition; (3) neurons rapidly come to signal the value of the chosen offer, suggesting the circuit serves to produce a choice; and (4) after regressing out the effects of option values, firing rates still could predict choice-a choice probability signal. In addition, neurons signaled gamble outcomes, suggesting that vmPFC contributes to both monitoring and choice processes. These data suggest a possible mechanism for reward-based choice and endorse the centrality of vmPFC in that process.

Biases in preferences for sequences of outcomes in monkeys.

Movies, vacations, and meals are all examples of events composed of a sequence of smaller events. How do we go from our evaluations of each scene in a movie to an evaluation of the sequence as a whole? In theory, we should simply average the values of the individual events. In practice, however, we are biased towards sequences where each element tends to be better than the previous, where the last value is large, and we overweight the best (or worst) part of the sequence. To study how general these biases are we examined monkeys' preferences for sequences of rewards in a novel reward repeat task. Monkeys were first given a sequence of rewards and then chose between repeating the sequence or receiving a standard comparator sequence. We found that, like humans, monkeys overweight events that happen later in a sequence, so much so that adding a small reward to the end of a sequence can paradoxically reduce its value. Monkeys were also biased towards sequences with large peak values (the highest value in the sequence), but only following a working memory challenge, suggesting that this preference may be driven by memory limitations. These results demonstrate the cross-species nature of biases in preferences for sequences of outcomes. In addition, monkeys' consistent preference for sequences in which large values occur later challenges the generality of discounting models of intertemporal choice in animals.