Choice coding in frontal cortex during stimulus-guided or action-guided decision-making.

To optimally obtain desirable outcomes, organisms must track outcomes predicted by stimuli in the environment (stimulus-outcome or SO associations) and outcomes predicted by their own actions (action-outcome or AO associations). Anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC) are implicated in tracking outcomes, but anatomical and functional studies suggest a dissociation, with ACC and OFC responsible for encoding AO and SO associations, respectively. To examine whether this dissociation held at the single neuron level, we trained two subjects to perform choice tasks that required using AO or SO associations. OFC and ACC neurons encoded the action that the subject used to indicate its choice, but this encoding was stronger in OFC during the SO task and stronger in ACC during the AO task. These results are consistent with a division of labor between the two areas in terms of using rewards associated with either stimuli or actions to guide decision-making.

Single-neuron mechanisms underlying cost-benefit analysis in frontal cortex.

Effective decision-making requires consideration of costs and benefits. Previous studies have implicated orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (DLPFC), and anterior cingulate cortex (ACC) in cost-benefit decision-making. Yet controversy remains about whether different decision costs are encoded by different brain areas, and whether single neurons integrate costs and benefits to derive a subjective value estimate for each choice alternative. To address these issues, we trained four subjects to perform delay- and effort-based cost-benefit decisions and recorded neuronal activity in OFC, ACC, DLPFC, and the cingulate motor area (CMA). Although some neurons, mainly in ACC, did exhibit integrated value signals as if performing cost-benefit computations, they were relatively few in number. Instead, the majority of neurons in all areas encoded the decision type; that is whether the subject was required to perform a delay- or effort-based decision. OFC and DLPFC neurons tended to show the largest changes in firing rate for delay- but not effort-based decisions; whereas, the reverse was true for CMA neurons. Only ACC contained neurons modulated by both effort- and delay-based decisions. These findings challenge the idea that OFC calculates an abstract value signal to guide decision-making. Instead, our results suggest that an important function of single PFC neurons is to categorize sensory stimuli based on the consequences predicted by those stimuli.

Medial-lateral organization of the orbitofrontal cortex.

Emerging evidence suggests that specific cognitive functions localize to different subregions of OFC, but the nature of these functional distinctions remains unclear. One prominent theory, derived from human neuroimaging, proposes that different stimulus valences are processed in separate orbital regions, with medial and lateral OFC processing positive and negative stimuli, respectively. Thus far, neurophysiology data have not supported this theory. We attempted to reconcile these accounts by recording neural activity from the full medial-lateral extent of the orbital surface in monkeys receiving rewards and punishments via gain or loss of secondary reinforcement. We found no convincing evidence for valence selectivity in any orbital region. Instead, we report differences between neurons in central OFC and those on the inferior-lateral orbital convexity, in that they encoded different sources of value information provided by the behavioral task. Neurons in inferior convexity encoded the value of external stimuli, whereas those in OFC encoded value information derived from the structure of the behavioral task. We interpret these results in light of recent theories of OFC function and propose that these distinctions, not valence selectivity, may shed light on a fundamental organizing principle for value processing in orbital cortex.

Oscillatory phase coupling coordinates anatomically dispersed functional cell assemblies.

Hebb proposed that neuronal cell assemblies are critical for effective perception, cognition, and action. However, evidence for brain mechanisms that coordinate multiple coactive assemblies remains lacking. Neuronal oscillations have been suggested as one possible mechanism for cell assembly coordination. Prior studies have shown that spike timing depends upon local field potential (LFP) phase proximal to the cell body, but few studies have examined the dependence of spiking on distal LFP phases in other brain areas far from the neuron or the influence of LFP-LFP phase coupling between distal areas on spiking. We investigated these interactions by recording LFPs and single-unit activity using multiple microelectrode arrays in several brain areas and then used a unique probabilistic multivariate phase distribution to model the dependence of spike timing on the full pattern of proximal LFP phases, distal LFP phases, and LFP-LFP phase coupling between electrodes. Here we show that spiking activity in single neurons and neuronal ensembles depends on dynamic patterns of oscillatory phase coupling between multiple brain areas, in addition to the effects of proximal LFP phase. Neurons that prefer similar patterns of phase coupling exhibit similar changes in spike rates, whereas neurons with different preferences show divergent responses, providing a basic mechanism to bind different neurons together into coordinated cell assemblies. Surprisingly, phase-coupling-based rate correlations are independent of interneuron distance. Phase-coupling preferences correlate with behavior and neural function and remain stable over multiple days. These findings suggest that neuronal oscillations enable selective and dynamic control of distributed functional cell assemblies.

Capacity and precision in an animal model of visual short-term memory.

Temporary storage of information in visual short-term memory (VSTM) is a key component of many complex cognitive abilities. However, it is highly limited in capacity. Understanding the neurophysiological nature of this capacity limit will require a valid animal model of VSTM. We used a multiple-item color change detection task to measure macaque monkeys' VSTM capacity. Subjects' performance deteriorated and reaction times increased as a function of the number of items in memory. Additionally, we measured the precision of the memory representations by varying the distance between sample and test colors. In trials with similar sample and test colors, subjects made more errors compared to trials with highly discriminable colors. We modeled the error distribution as a Gaussian function and used this to estimate the precision of VSTM representations. We found that as the number of items in memory increases the precision of the representations decreases dramatically. Additionally, we found that focusing attention on one of the objects increases the precision with which that object is stored and degrades the precision of the remaining. These results are in line with recent findings in human psychophysics and provide a solid foundation for understanding the neurophysiological nature of the capacity limit of VSTM.

Reward-dependent modulation of working memory in lateral prefrontal cortex.

Although research implicates lateral prefrontal cortex (PFC) in executive control and goal-directed behavior, it remains unclear how goals influence executive processes. One possibility is that goal-relevant information, such as expected rewards, could modulate the representation of information relating to executive control, thereby ensuring the efficient allocation of cognitive resources. To investigate this, we examined how reward modulated spatial working memory. Past studies investigating spatial working memory have focused on dorsolateral PFC, but this area only weakly connects with areas processing reward. Ventrolateral PFC has better connections in this regard. Thus, we contrasted the functional properties of single neurons in ventrolateral and dorsolateral PFC as two subjects performed a task that required them to hold spatial information in working memory under different expectancies of reward for correct performance. We balanced the order of presentation of spatial and reward information so we could assess the neuronal encoding of the two pieces of information independently and conjointly. Neurons in ventrolateral PFC encoded both spatial and reward information earlier, stronger and in a more sustained manner than neurons in dorsolateral PFC. Within ventrolateral PFC, spatial selectivity was more prevalent on the inferior convexity than within the principal sulcus. Finally, when reward increased spatial selectivity, behavioral performance improved, whereas when reward decreased spatial selectivity, behavioral performance deteriorated. These results suggest that ventrolateral PFC may be a locus whereby information about expected rewards can modulate information in working memory. The pattern of results is consistent with a role for ventrolateral PFC in attentional control.

Dynamic encoding of responses and outcomes by neurons in medial prefrontal cortex.

Medial prefrontal cortex (MPFC) and lateral prefrontal cortex (LPFC) both contribute to goal-directed behavior, but their precise role remains unclear. Several lines of evidence suggest that MPFC is more important than LPFC for outcome-guided response selection. To examine this, we trained two subjects to perform a task that required them to monitor the specific outcome associated with a specific response on a trial-by-trial basis. While the subjects performed this task, we recorded the electrical activity of single neurons simultaneously from MPFC and LPFC. There were marked differences in the neuronal properties of these two areas. Neurons encoding the response were present in both areas, but in MPFC, there were also neurons that encoded the outcome. In particular, neurons encoded the subject's intended response and how preferable the received outcome was. Thus, only in MPFC was all the information necessary to solve the task encoded. In addition, largely separate populations of MPFC neurons encoded the response and the outcome. Neurons encoding the outcome were in the anterior parts of MPFC: posterior to the corpus callosum, there was a marked drop in their incidence. Our results suggest differences in the contribution of MPFC and LPFC to action control. MPFC neurons encode the desirability of the outcome produced by a specific response on a trial-by-trial basis. This capability may contribute to several of the functions of MPFC, such as action valuation, error detection, and decision making.

Encoding of gustatory working memory by orbitofrontal neurons.

The content model regarding the functional organization of working memory in prefrontal cortex (PFC) states that different PFC areas encode different types of information in working memory depending on their afferent connections with other brain areas. Previous studies that tested this model focused on visual, auditory and somatosensory information. However, posterior areas processing this information project to widespread and overlapping regions of lateral PFC, making it difficult to establish the veracity of the model. In contrast, gustatory information enters PFC via orbitofrontal cortex (OFC), and so the content model would argue that OFC should be responsible for maintaining gustatory information in working memory. To test this, we recorded the activity of single neurons throughout PFC and gustatory cortex (GUS) from two subjects while they performed a gustatory delayed-match-to-sample task with intervening gustatory distraction. Neurons that encoded the identity of the gustatory stimulus across the delay, consistent with a role in gustatory working memory, were most prevalent in OFC and GUS compared with dorsolateral PFC and ventrolateral PFC. Gustatory information in OFC was more resilient to intervening distraction, paralleling previous findings regarding visual working memory processes in PFC and posterior sensory cortex. Our findings provide support for the content model of working memory organization. Maintaining gustatory information may be one aspect of a wider function for OFC in reward working memory that could contribute to its role in decision-making.

Cortical representation of ipsilateral arm movements in monkey and man.

A fundamental organizational principle of the primate motor system is cortical control of contralateral limb movements. Motor areas also appear to play a role in the control of ipsilateral limb movements. Several studies in monkeys have shown that individual neurons in primary motor cortex (M1) may represent, on average, the direction of movements of the ipsilateral arm. Given the increasing body of evidence demonstrating that neural ensembles can reliably represent information with a high temporal resolution, here we characterize the distributed neural representation of ipsilateral upper limb kinematics in both monkey and man. In two macaque monkeys trained to perform center-out reaching movements, we found that the ensemble spiking activity in M1 could continuously represent ipsilateral limb position. Interestingly, this representation was more correlated with joint angles than hand position. Using bilateral electromyography recordings, we excluded the possibility that postural or mirror movements could exclusively account for these findings. In addition, linear methods could decode limb position from cortical field potentials in both monkeys. We also found that M1 spiking activity could control a biomimetic brain-machine interface reflecting ipsilateral kinematics. Finally, we recorded cortical field potentials from three human subjects and also consistently found evidence of a neural representation for ipsilateral movement parameters. Together, our results demonstrate the presence of a high-fidelity neural representation for ipsilateral movement and illustrates that it can be successfully incorporated into a brain-machine interface.

Encoding of reward and space during a working memory task in the orbitofrontal cortex and anterior cingulate sulcus.

Several lines of research indicate that emotional and motivational information may be useful in guiding the allocation of attentional resources. Two areas of the frontal lobe that are particularly implicated in the encoding of motivational information are the orbital prefrontal cortex (PFo) and the dorsomedial region of prefrontal cortex, specifically the anterior cingulate sulcus (PFcs). However, it remains unclear whether these areas use this information to influence spatial attention. We used single-unit neurophysiology to examine whether, at the level of individual neurons, there was evidence for integration between reward information and spatial attention. We trained two subjects to perform a task that required them to attend to a spatial location across a delay under different expectancies of reward for correct performance. We balanced the order of presentation of spatial and reward information so we could assess the neuronal encoding of the two pieces of information independently and conjointly. We found little evidence for encoding of the spatial location in either PFo or PFcs. In contrast, both areas encoded the expected reward. Furthermore, PFo consistently encoded reward more quickly than PFcs, although reward encoding was subsequently more prevalent and stronger in PFcs. These results suggest a differential contribution of PFo and PFcs to reward encoding, with PFo potentially more important for initially determining the value of rewards predicted by sensory stimuli. They also suggest that neither PFo nor PFcs play a direct role in the control of spatial attention.

Evaluating choices by single neurons in the frontal lobe: outcome value encoded across multiple decision variables.

Damage to the frontal lobe can cause severe decision-making impairments. A mechanism that may underlie this is that neurons in the frontal cortex encode many variables that contribute to the valuation of a choice, such as its costs, benefits and probability of success. However, optimal decision-making requires that one considers these variables, not only when faced with the choice, but also when evaluating the outcome of the choice, in order to adapt future behaviour appropriately. To examine the role of the frontal cortex in encoding the value of different choice outcomes, we simultaneously recorded the activity of multiple single neurons in the anterior cingulate cortex (ACC), orbitofrontal cortex (OFC) and lateral prefrontal cortex (LPFC) while subjects evaluated the outcome of choices involving manipulations of probability, payoff and cost. Frontal neurons encoded many of the parameters that enabled the calculation of the value of these variables, including the onset and offset of reward and the amount of work performed, and often encoded the value of outcomes across multiple decision variables. In addition, many neurons encoded both the predicted outcome during the choice phase of the task as well as the experienced outcome in the outcome phase of the task. These patterns of selectivity were more prevalent in ACC relative to OFC and LPFC. These results support a role for the frontal cortex, principally ACC, in selecting between choice alternatives and evaluating the outcome of that selection thereby ensuring that choices are optimal and adaptive.

Neuronal mechanisms in prefrontal cortex underlying adaptive choice behavior.

This chapter aims to address two questions relating to the role of the prefrontal cortex (PFC) in reward-guided choice behavior. First, do PFC neurons encode rewards per se, or are they encoding behavioral sequelae of reward? To address this, we recorded simultaneously from multiple PFC subregions, with the rationale that neuronal selectivity that directly encoded the reward outcome should occur before selectivity that reflected reward-related sequelae. Our results indicate that neurons in the orbitofrontal cortex (OFC) encode reward information before neurons in the dorsolateral PFC (DLPFC). Furthermore, whereas DLPFC neurons encoded both the upcoming response as well as the expected reward, OFC neurons encoded the reward alone. Our interpretation of these results is that the OFC encodes the reward and passes this information to the DLPFC, which uses it to determine the behavioral response. The second question is whether the encoding is specific to the reward outcome or reflective of a more abstract value signal that could facilitate decision making. We examined this by determining whether the PFC encodes other types of information relevant to decision making, such as probability of success and effort. We found that many PFC neurons encoded at least one of these variables, but neurons in the OFC and the medial PFC (MPFC) encoded combinations of the variables indicative of encoding an abstract value signal. This signal could provide decision making with flexibility and a capacity to deal with novelty, which are two of the hallmark features of prefrontal function. Future research will focus on delineating the differential contributions of the OFC and the MPFC to decision making.

Neural correlates of categories and concepts.

The ability to readily adapt to novel situations requires something beyond storing specific stimulus-response associations. Instead, many animals can detect basic characteristics of events and store them as generalized classes. Because these representations are abstracted beyond specific details of sensory inputs and motor outputs, they can be easily generalized and adapted to new circumstances. Explorations of neural mechanisms of sensory processing and motor output have progressed to the point where studies can begin to address the neural basis of abstract, categorical representations. Recent studies have revealed their neural correlates in various cortical areas of the non-human primate brain.

Decoding subjective decisions from orbitofrontal cortex.

When making a subjective choice, the brain must compute a value for each option and compare those values to make a decision. The orbitofrontal cortex (OFC) is critically involved in this process, but the neural mechanisms remain obscure, in part due to limitations in our ability to measure and control the internal deliberations that can alter the dynamics of the decision process. Here we tracked these dynamics by recovering temporally precise neural states from multidimensional data in OFC. During individual choices, OFC alternated between states associated with the value of two available options, with dynamics that predicted whether a subject would decide quickly or vacillate between the two alternatives. Ensembles of value-encoding neurons contributed to these states, with individual neurons shifting activity patterns as the network evaluated each option. Thus, the mechanism of subjective decision-making involves the dynamic activation of OFC states associated with each choice alternative.

The Role of Prefrontal Cortex in Working Memory: A Mini Review.

A prominent account of prefrontal cortex (PFC) function is that single neurons within the PFC maintain representations of task-relevant stimuli in working memory. Evidence for this view comes from studies in which subjects hold a stimulus across a delay lasting up to several seconds. Persistent elevated activity in the PFC has been observed in animal models as well as in humans performing these tasks. This persistent activity has been interpreted as evidence for the encoding of the stimulus itself in working memory. However, recent findings have posed a challenge to this notion. A number of recent studies have examined neural data from the PFC and posterior sensory areas, both at the single neuron level in primates, and at a larger scale in humans, and have failed to find encoding of stimulus information in the PFC during tasks with a substantial working memory component. Strong stimulus related information, however, was seen in posterior sensory areas. These results suggest that delay period activity in the PFC might be better understood not as a signature of memory storage per se, but as a top down signal that influences posterior sensory areas where the actual working memory representations are maintained.

Capturing the temporal evolution of choice across prefrontal cortex.

Activity in prefrontal cortex (PFC) has been richly described using economic models of choice. Yet such descriptions fail to capture the dynamics of decision formation. Describing dynamic neural processes has proven challenging due to the problem of indexing the internal state of PFC and its trial-by-trial variation. Using primate neurophysiology and human magnetoencephalography, we here recover a single-trial index of PFC internal states from multiple simultaneously recorded PFC subregions. This index can explain the origins of neural representations of economic variables in PFC. It describes the relationship between neural dynamics and behaviour in both human and monkey PFC, directly bridging between human neuroimaging data and underlying neuronal activity. Moreover, it reveals a functionally dissociable interaction between orbitofrontal cortex, anterior cingulate cortex and dorsolateral PFC in guiding cost-benefit decisions. We cast our observations in terms of a recurrent neural network model of choice, providing formal links to mechanistic dynamical accounts of decision-making.

Executive control processes underlying multi-item working memory.

A dominant view of prefrontal cortex (PFC) function is that it stores task-relevant information in working memory. To examine this and determine how it applies when multiple pieces of information must be stored, we trained two subjects to perform a multi-item color change detection task and recorded activity of neurons in PFC. Few neurons encoded the color of the items. Instead, the predominant encoding was spatial: a static signal reflecting the item's position and a dynamic signal reflecting the subject's covert attention. These findings challenge the notion that PFC stores task-relevant information. Instead, we suggest that the contribution of PFC is in controlling the allocation of resources to support working memory. In support of this, we found that increased power in the alpha and theta bands of PFC local field potentials, which are thought to reflect long-range communication with other brain areas, was correlated with more precise color representations.

A hierarchy of intrinsic timescales across primate cortex.

Specialization and hierarchy are organizing principles for primate cortex, yet there is little direct evidence for how cortical areas are specialized in the temporal domain. We measured timescales of intrinsic fluctuations in spiking activity across areas and found a hierarchical ordering, with sensory and prefrontal areas exhibiting shorter and longer timescales, respectively. On the basis of our findings, we suggest that intrinsic timescales reflect areal specialization for task-relevant computations over multiple temporal ranges.

Inferring the value of the world.

A prominent view of the function of orbitofrontal cortex (OFC) is that it is responsible for calculating the value of things in the environment. A recent study shows that this role is restricted to cases in which the value must be inferred from our knowledge of the world.