Rule-dependent prefrontal cortex activity across episodic and perceptual decisions: an fMRI investigation of the criterial classification account

Although lateral prefrontal cortex (LPFC) is clearly involved in decision-making, competing functional characterizations exist. One characterization posits that activation reflects the need to select among competing representations. In contrast, recent fMRI research suggests that activation is driven by the criterial classification of representations, even with minimal competition. To adjudicate between these hypotheses, we used event-related fMRI and contrasted tasks that required different numbers of criterial classifications prior to response in both perceptual and memory domains. Additionally, we manipulated the level of interstimulus competition by increasing the number of probes. Experiment 1 demonstrated that LPFC activation tracked the number of intermediate classifications during trials yet was insensitive to the number of competing probes and the behavioral decline accompanying competition. Furthermore, Experiment 2 demonstrated equivalent increases in LPFC activation for a task requiring two overt criterial classifications (independent classification) and one requiring two covert criterial classifications prior to the single overt response (same-different judgment). As found in Experiment 1, both tasks showed greater activation than a judgment requiring only one classification act (forced choice). These data indicate that LPFC responses reflect the number of executed criterial classifications or judgments, independent of the number of competing stimuli and the overt response demands of the decision task.     

Increases in brain activity during social competition predict decreases in working memory performance and later recall

In our fMRI experiment, participants completed a learning task in both a noncompetitive and a socially competitive learning environment. Despite reporting a preference for completing the task while competing, participants remembered significantly more during the task and later recalled more from the noncompetitive learning environment. Furthermore, during working memory maintenance, there was performance‐related deactivation in the medial prefrontal cortex (mPFC) and the precuneus/PCC. During feedback presentation, there was greater activation in the mPFC and the precuneus/PCC while competing. Differential activation in the precuneus/PCC predicted worse later recall for information learned competitively. Since previous research suggests that the mPFC is involved in social‐referencing, while the precuneus/PCC is implicated in off‐task thoughts, our results suggest that receiving feedback regarding competition produces more activation in brain regions implicated in social interaction, as well as task distraction. While competition may make a task more enjoyable, the goal of winning may distract from maximizing performance. Hum Brain Mapp 38:457–471, 2017. © 2016 Wiley Periodicals, Inc.     

Valuation of uncertain and delayed rewards in primate prefrontal cortex

Humans and animals often must choose between rewards that differ in their qualities, magnitudes, immediacy, and likelihood, and must estimate these multiple reward parameters from their experience. However, the neural basis for such complex decision making is not well understood. To understand the role of the primate prefrontal cortex in determining the subjective value of delayed or uncertain reward, we examined the activity of individual prefrontal neurons during an inter-temporal choice task and a computer-simulated competitive game. Consistent with the findings from previous studies in humans and other animals, the monkey’s behaviors during inter-temporal choice were well accounted for by a hyperbolic discount function. In addition, the activity of many neurons in the lateral prefrontal cortex reflected the signals related to the magnitude and delay of the reward expected from a particular action, and often encoded the difference in temporally discounted values that predicted the animal’s choice. During a computerized matching pennies game, the animals approximated the optimal strategy, known as Nash equilibrium, using a reinforcement learning algorithm. We also found that many neurons in the lateral prefrontal cortex conveyed the signals related to the animal’s previous choices and their outcomes, suggesting that this cortical area might play an important role in forming associations between actions and their outcomes. These results show that the primate lateral prefrontal cortex plays a central role in estimating the values of alternative actions based on multiple sources of information.     

Someone has to give in: theta oscillations correlate with adaptive behavior in social bargaining

During social bargain, one has to both figure out the others’ intentions and behave strategically in such a way that the others’ behaviors will be consistent with one’s expectations. To understand the neurobiological mechanisms underlying these behaviors, we used electroencephalography while subjects played as proposers in a repeated ultimatum game. We found that subjects adapted their offers to obtain more acceptances in the last round and that this adaptation correlated negatively with prefrontal theta oscillations. People with higher prefrontal theta activity related to a rejection did not adapt their offers along the game to maximize their earning. Moreover, between-subject variation in posterior theta oscillations correlated positively with how individual theta activity influenced the change of offer after a rejection, reflecting a process of behavioral adaptation to the others’ demands. Interestingly, people adapted better their offers when they knew that they where playing against a computer, although the behavioral adaptation did not correlate with prefrontal theta oscillation. Behavioral changes between human and computer games correlated with prefrontal theta activity, suggesting that low adaptation in human games could be a strategy. Taken together, these results provide evidence for specific roles of prefrontal and posterior theta oscillations in social bargaining.     

Encoding of social state information by neuronal activities in the macaque caudate nucleus

Social animals adjust their behavior according to social relationships and momentary circumstances. Dominant-submissive relationships modulate, but do not completely determine, their competitive behaviors. For example, a submissive monkey's decision to retrieve food depends not only on the presence of dominant partners but also on their observed behavior. Thus, behavioral expression requires a dynamic evaluation of reward outcome and momentary social states. The neural mechanisms underlying this evaluation remain elusive. The caudate nucleus (CN) plays a pivotal role in representing reward expectation and translating it into action selection. To investigate whether their activities encode social state information, we recorded from CN neurons in monkeys while they performed a competitive food-grab task against a dominant competitor. We found two groups of CN neurons: one primarily responded to reward outcome, while the other primarily tracked the monkey's social state. These social state-dependent neurons showed greater activity when the monkeys freely retrieved food without active challenges from the competitor and reduced activity when the monkeys were in a submissive state due to the competitor's active behavior. These results indicate that different neuronal activities in the CN encode social state information and reward-related information, which may contribute to adjusting competitive behavior in dynamic social contexts.     

Encoding of social state information by neuronal activities in the macaque caudate nucleus

Social animals adjust their behavior according to social relationships and momentary circumstances. Dominant–submissive relationships modulate, but do not completely determine, their competitive behaviors. For example, a submissive monkey's decision to retrieve food depends not only on the presence of dominant partners but also on their observed behavior. Thus, behavioral expression requires a dynamic evaluation of reward outcome and momentary social states. The neural mechanisms underlying this evaluation remain elusive. The caudate nucleus (CN) plays a pivotal role in representing reward expectation and translating it into action selection. To investigate whether their activities encode social state information, we recorded from CN neurons in monkeys while they performed a competitive food-grab task against a dominant competitor. We found two groups of CN neurons: one primarily responded to reward outcome, while the other primarily tracked the monkey's social state. These social state-dependent neurons showed greater activity when the monkeys freely retrieved food without active challenges from the competitor and reduced activity when the monkeys were in a submissive state due to the competitor's active behavior. These results indicate that different neuronal activities in the CN encode social state information and reward-related information, which may contribute to adjusting competitive behavior in dynamic social contexts.     

Reinforcement learning and decision making in monkeys during a competitive game

Animals living in a dynamic environment must adjust their decision-making strategies through experience. To gain insights into the neural basis of such adaptive decision-making processes, we trained monkeys to play a competitive game against a computer in an oculomotor free-choice task. The animal selected one of two visual targets in each trial and was rewarded only when it selected the same target as the computer opponent. To determine how the animal's decision-making strategy can be affected by the opponent's strategy, the computer opponent was programmed with three different algorithms that exploited different aspects of the animal's choice and reward history. When the computer selected its targets randomly with equal probabilities, animals selected one of the targets more often, violating the prediction of probability matching, and their choices were systematically influenced by the choice history of the two players. When the computer exploited only the animal's choice history but not its reward history, animal's choice became more independent of its own choice history but was still related to the choice history of the opponent. This bias was substantially reduced, but not completely eliminated, when the computer used the choice history of both players in making its predictions. These biases were consistent with the predictions of reinforcement learning, suggesting that the animals sought optimal decision-making strategies using reinforcement learning algorithms.     

Microstimulation of the dorsolateral prefrontal cortex biases saccade target selection

A long-standing issue concerning the executive function of the primate dorsolateral prefrontal cortex is how the activity of prefrontal neurons is linked to behavioral response selection. To establish a functional relationship between prefrontal memory fields and saccade target selection, we trained three macaque monkeys to make saccades to the remembered location of a visual cue in a delayed spatial match-to-sample saccade task. We electrically stimulated sites in the prefrontal cortex with subthreshold currents during the delay epoch while monkeys performed this task. Our results show that the artificially injected signal interacts with the neural activity responsible for target selection, biasing saccade choices either towards the receptive/movement field (RF/MF) or away from the RF/MF, depending on the stimulation site. These findings might reflect a functional link between prefrontal signals responsible for the selection bias by modulating the balance between excitation and inhibition in the competitive interactions underlying behavioral selection.     

Cooperation and biased competition model can explain attentional filtering in the prefrontal cortex

Recent neurophysiological experimental results suggest that the prefrontal cortex plays an important role in filtering out unattended visual inputs. Here we propose a neurodynamical computational model of a part of the prefrontal cortex to account for the neural mechanisms defining this attentional filtering effect. Similar models have been employed to explain experimental results obtained during the performance of attention and working memory tasks. In this previous work the principle of biased competition was shown to successfully account for the experimental data. To model the attentional filtering effect, the biased competition model was extended to enable cooperation between stimulus selective neurons. We show that, in a biological relevant minimal model, competition and cooperation between the neurons are sufficient conditions for reproducing the attentional effect. Furthermore, a characterization of the parameter regime where the cooperation effect is observed is presented. Finally, we also reveal parameter regimes where the network has different modes of operation: selective working memory, attentional filtering, pure competition and noncompetitive amplification.     

Investigation of anatomical thalamo-cortical connectivity and FMRI activation in schizophrenia

The purpose of this study was to examine measures of anatomical connectivity between the thalamus and lateral prefrontal cortex (LPFC) in schizophrenia and to assess their functional implications. We measured thalamocortical connectivity with diffusion tensor imaging (DTI) and probabilistic tractography in 15 patients with schizophrenia and 22 age- and sex-matched controls. The relationship between thalamocortical connectivity and prefrontal cortical blood-oxygenation-level-dependent (BOLD) functional activity as well as behavioral performance during working memory was examined in a subsample of 9 patients and 18 controls. Compared with controls, schizophrenia patients showed reduced total connectivity of the thalamus to only one of six cortical regions, the LPFC. The size of the thalamic region with at least 25% of model fibers reaching the LPFC was also reduced in patients compared with controls. The total thalamocortical connectivity to the LPFC predicted working memory task performance and also correlated with LPFC BOLD activation. Notably, the correlation with BOLD activation was accentuated in patients as compared with controls in the ventral LPFC. These results suggest that thalamocortical connectivity to the LPFC is altered in schizophrenia with functional consequences on working memory processing in LPFC.     

Neuronal activity in primate dorsolateral and orbital prefrontal cortex during performance of a reward preference task

An important function of the prefrontal cortex (PFC) is the control of goal-directed behaviour. This requires information as to whether actions were successful in obtaining desired outcomes such as rewards. While lesion studies implicate a particular PFC region, the orbitofrontal cortex (OFC), in reward processing, neurons encoding reward have been reported in both the OFC and the dorsolateral prefrontal cortex (DLPFC). To compare and contrast their roles, we recorded simultaneously from both areas while two rhesus monkeys (Macaca mulatta) performed a reward preference task. The monkeys had to choose between pictures associated with different amounts of a juice reward. Neuronal activity in both areas reflected the reward amount. However, neurons in the DLPFC encoded both the reward amount and the monkeys' forthcoming response, while neurons in the OFC more often encoded the reward amount alone. Further, reward selectivity arose more rapidly in the OFC than the DLPFC. These results are consistent with reward information entering the PFC via the OFC, where it is passed to the DLPFC and used to control behaviour.     

Postnatal development of the cholecystokinin innervation of monkey prefrontal cortex

Although the structure and function of primate prefrontal cortex undergo substantial modifications during postnatal development, relatively little is known about the maturation of neurotransmitter systems in these cortical regions. In the primate brain, cholecystokinin is present in the greatest concentrations in prefrontal regions. Thus, in this study, we used immunohistochemical techniques to investigate the postnatal development of the cholecystokinin innervation of monkey prefrontal cortex. In animals aged 4 days through adult, cholecystokinin immunoreactivity was present in nonpyramidal neurons that appeared to represent at least two distinct cell types. The most common type was a vertically oval bitufted neuron, located in layers II-superficial III, which typically had a radially descending axon that gave rise to short collaterals in layer IV. Another frequently observed cell type was a larger multipolar neuron located in the superficial half of layer III. The axon of these neurons branched locally in the vicinity of the cell body. The greatest density of cholecystokinin-containing neurons and processes was present in monkeys less than 1 month of age. The density of immunoreactive structures in every prefrontal region then progressively declined with increasing age, with the most marked changes occurring during the first postnatal year. As a result, the density of labeled neurons in adult monkeys was less than one-third of that in neonatal monkeys. However, labeled structures were significantly more dense in some ventromedial and orbital regions than in dorsal regions of the prefrontal cortex in neonatal, but not in older animals. In all animals, cholecystokinin-containing neurons were present in highest density in layers II-superficial III, and labeled terminal fields were observed in layers II, IV, and VI. In animals less than 1 month of age, fascicles of radial fibers traversed through layers III and V, whereas in animals 1 to 3 months of age, individual radial fibers rather than fiber bundles were present in layers III and V. In addition, immunoreactive pericellular arrays, which appeared to surround unlabeled nonpyramidal cells, were present in layers V and VI and the subcortical white matter in the youngest monkeys. Although many aspects of the cholecystokinin innervation of monkey prefrontal cortex remain constant during postnatal life, the distinct developmental changes in the cholecystokinin innervation of these regions suggest that it may play an important role in the maturation of the cortical circuitry that mediates the acquisition of certain cognitive abilities. © 1993 Wiley-Liss, Inc.     

Domain-related differentiation of working memory in the Japanese macaque (Macaca fuscata) frontal cortex: a positron emission tomography study

The lateral prefrontal cortex (LPFC) is important for working memory (WM) task performance. Neuropsychological and neurophysiological studies in monkeys suggest that the lateral prefrontal cortex is functionally segregated based on the working memory domain (spatial vs. non-spatial). However, this is not supported by most human neuroimaging studies, and the discrepancy might be due to differences in methods and/or species (monkey neuropsychology/physiology vs. human neuroimaging). We used positron emission topography to examine the functional segregation of the lateral prefrontal cortex of Japanese macaques (Macaca fuscata) that showed near 100% accuracy on spatial and non-spatial working memory tasks. Compared with activity during the non-working memory control tasks, the dorsolateral prefrontal cortex (DLPFC) was more active during the non-spatial, but not during the spatial, working memory task, although a muscimol microinjection into the dorsolateral prefrontal cortex significantly impaired the performance of both working memory tasks. A direct comparison of the brain activity between the two working memory tasks revealed no differences within the lateral prefrontal cortex, whereas the premotor area was more active during the spatial working memory task. Comparing the delay-specific activity, which did not include task-associated stimulus/response-related activity, revealed more spatial working memory-related activity in the posterior parietal and premotor areas, and more non-spatial working memory-related activity in the dorsolateral prefrontal cortex and hippocampus. These results suggest that working memory in the monkey brain is segregated based on domain, not within the lateral prefrontal cortex but rather between the posterior parietal-premotor areas and the dorsolateral prefrontal-hippocampus areas.     

Taking risks for personal gain: An investigation of self-construal and testosterone responses to competition

Recent research on testosterone and risk-taking behavior is beginning to focus on the role of context-dependent changes in testosterone. Extending this research, our study investigated the association between testosterone reactivity to competitive outcomes and risk-taking in the context of a video game based competition. The study also examined whether self-construal moderated this relationship. Results indicated that a rise in testosterone during competition did not predict subsequent risk-taking behavior. However, a rise in testosterone during competition predicted subsequent risk-taking behaviors within winners with independent self-construals. Nevertheless, results did not reveal an association between basal testosterone and risk-taking, nor did competitive outcomes modulate a differential testosterone response. Overall, we treat these findings as preliminary, as there were multiple analyses conducted and effect sizes were relatively small. We discuss these results in the context of recent animal findings that testosterone facilitates success at future competitions after winning a competition, as well as recent research suggesting self-construal moderates associations between testosterone and aggression.     

Neural activity in monkey prefrontal cortex is modulated by task context and behavioral instruction during delayed-match-to-sample and conditional prosaccade-antisaccade tasks

Complex behavior often requires the formation of associations between environmental stimuli and motor responses appropriate to those stimuli. Moreover, the appropriate response to a given stimulus may vary depending on environmental context. Stimulus-response associations that are adaptive in one situation may not be in another. The prefrontal cortex (PFC) has been shown to be critical for stimulus-response mapping and the implementation of task context. To investigate the neural representation of sensory-motor associations and task context in the PFC, we recorded the activity of prefrontal neurons in two monkeys while they performed two tasks. The first task was a delayed-match-to-sample task in which monkeys were presented with a sample picture and rewarded for making a saccade to the test picture that matched the sample picture following a delay period. The second task was a conditional visuomotor task in which identical sample pictures were presented. In this task, animals were rewarded for performing either prosaccades or antisaccades following the delay period depending on sample picture identity. PFC neurons showed task selectivity, object selectivity, and combinations of task and object selectivity. These modulations of activity took the form of a reduction in stimulus and delay-related activity, and a pro/anti instruction-based grouping of delay activity in the conditional visuomotor task. These data show that activity in PFC neurons is modulated by experimental context, and that this activity represents the formal demands of the task currently being performed.     

Prefrontal regional correlates of self-control in male psychiatric patients: Impulsivity facets and aggression

Investigating the organization of trait aggression and impulsivity in the prefrontal cortex (PFC) advances our understanding of the neuropsychobiology of self-control. While the orbital aspect of the PFC (OFC) has received attention, there is reason to believe the lateral aspect is also relevant. In the current study using magnetic resonance imaging, gray matter volumes in lateral PFC (LPFC) were derived in a heterogeneous male psychiatric sample (N = 36) in which OFC volumes had previously been reported. In an analysis using self-report measures of trait impulsivity and aggression, the left LPFC accounted for significant variance in attentional aspects of impulsivity (13%) and aggression (10%) but not motor aspects of impulsivity, as hypothesized. The OFC was associated with motor impulsivity (left-20%; right-14%) and was also more robustly associated with aggression (left-36%; right-16%). A social/emotional information processing model was explored, based upon whether the LPFC or the OFC depended upon one another for their association to trait aggression and impulsivity. It was demonstrated that association of the LPFC to both aggression and attentional impulsivity depended upon the OFC, while the converse was not supported. The LPFC appears relevant to the higher-order aspects of a cortical self-control network, and that relevance is dependent upon the robust contribution of the OFC.     

Gender differences in the mesocorticolimbic system during computer game-play

Little is known about the underlying neural processes of playing computer/video games, despite the high prevalence of its gaming behavior, especially in males. In a functional magnetic resonance imaging study contrasting a space-infringement game with a control task, males showed greater activation and functional connectivity compared to females in the mesocorticolimbic system. These findings may be attributable to higher motivational states in males, as well as gender differences in reward prediction, learning reward values and cognitive state during computer video games. These gender differences may help explain why males are more attracted to, and more likely to become "hooked" on video games than females.     

Evaluation of a manual wheelchair interface to computer games

The sedentary lifestyle of many people with spinal cord injury (SCI) has lead to cardiovascular diseases being a major health concern. A suitable exercise program may help improve the SCI individual's cardiovascular fitness level. GAMEWheels is an interface between a custom wheelchair roller system and a computer that enables an individual to control computer video games by driving his or her wheelchair. The purpose of Phase 1 was to evaluate the design of the GAMEWheels system and to determine the type of computer video game that is likely to motivate wheelchair users to exercise. Phase 2 included physiologic testing of wheelchair users and the GAMEWheels system to investigate whether the system elicits an exercise training response. Thirty-five subjects were recruited to evaluate the GAMEWheels by playing three commercial computer games (Phase 1) and to identify the computer game that they would prefer to use when exercising. The feedback from Phase 1 was used with test subjects to verify that the GAMEWheels system elicits an exercise training effect (Phase 2). Phase 2 included 10 subjects using the GAMEWheels system to play Need for Speed II. During game play, physiologic data were collected and the subjects' oxygen consumption and heart rate were analyzed. Analysis showed that the GAMEWheels system induced nine subjects to reach their training zone, defined as 50% and 60% of their maximum oxygen consumption and heart rate, respectively. This study demonstrates that the GAMEWheels system elicits an exercise training response.     

Visual recognition impairment follows ventromedial but not dorsolateral prefrontal lesions in monkeys

Visual recognition in monkeys appears to involve the participation of two limbothalamic pathways, one including the amygdala and the magnocellular portion of the medial dorsal nucleus (MDmc) and the other, the hippocampus and the anterior nuclei of the thalamus (Ant N). Both MDmc and Ant N project, in turn, to the prefrontal cortex, mainly to its ventral and medial portions. To test whether the prefrontal projection targets of the two limbothalamic pathways also participate in memory functions, performance on a variety of learning and memory tasks was assessed in monkeys with lesions of the ventromedial prefrontal cortex (Group VM). Normal monkeys and monkeys with lesions of dorsolateral prefrontal cortex (Group DL) served as controls. Group VM was severely impaired on a test of object recognition, whereas Group DL did not differ appreciably from normal animals. Conversely, the animals in Group VM were able to learn a spatial delayed response task, whereas 2 of the 3 animals in Group DL could not. Neither group was impaired in the acquisition of visual discrimination habits, even though the successive trials on a given discrimination were separated by 24-h intervals. The patterns of deficit suggest that ventromedial prefrontal cortex constitutes another station in the limbothalamic system underlying cognitive memory processes, whereas the dorsolateral prefrontal cortex lies outside this system. The results support the view that the classical delayed-response deficit observed after dorsolateral prefrontal lesions represents a perceptuo-mnemonic impairment in spatial functions selectively rather than a memory loss of a more general nature.     

Social isolation rearing affects prefrontal cortical response to ventral tegmental area stimulation.

BACKGROUND: Animals reared in social isolation exhibit attentional deficits that parallel those found in schizophrenia patients. Such disturbances are frequently attributed to a dysfunction of the mesocortical system. Here we investigated whether electrophysiologic characteristics of prefrontal cortical pyramidal neurons or mesocortical responses were changed in isolated animals. METHODS: In vivo intracellular recordings were obtained from prefrontal cortical pyramidal neurons in animals raised in social isolation or in socialized control animals before and after ventral tegmental area stimulation mimicking dopamine cell burst firing. RESULTS: Prefrontal cortical pyramidal neurons recorded from isolated animals showed bimodal characteristics resembling those of their socialized littermates. Stimulation of the ventral tegmental area evoked plateau depolarizations in both groups, but this was accompanied by abnormal firing or a short hyperpolarization in most of the isolated animals. CONCLUSION: These findings suggest that social isolation rearing may affect mesocortical information processing.