Mapping causal links between prefrontal cortical regions and intra-individual behavioral variability.

Intra-individual behavioral variability is significantly heightened by aging or neuropsychological disorders, however it is unknown which brain regions are causally linked to such variabilities. We examine response time (RT) variability in 21 macaque monkeys performing a rule-guided decision-making task. In monkeys with selective-bilateral lesions in the anterior cingulate cortex (ACC) or in the dorsolateral prefrontal cortex, cognitive flexibility is impaired, but the RT variability is significantly diminished. Bilateral lesions within the frontopolar cortex or within the mid-dorsolateral prefrontal cortex, has no significant effect on cognitive flexibility or RT variability. In monkeys with lesions in the posterior cingulate cortex, the RT variability significantly increases without any deficit in cognitive flexibility. The effect of lesions in the orbitofrontal cortex (OFC) is unique in that it leads to deficits in cognitive flexibility and a significant increase in RT variability. Our findings indicate remarkable dissociations in contribution of frontal cortical regions to behavioral variability. They suggest that the altered variability in OFC-lesioned monkeys is related to deficits in assessing and accumulating evidence to inform a rule-guided decision, whereas in ACC-lesioned monkeys it results from a non-adaptive decrease in decision threshold and consequently immature impulsive responses.

Cycles of goal silencing and reactivation underlie complex problem-solving in primate frontal and parietal cortex.

While classic views proposed that working memory (WM) is mediated by sustained firing, recent evidence suggests a contribution of activity-silent states. Within WM, human neuroimaging studies suggest a switch between attentional foreground and background, with only the foregrounded item represented in active neural firing. To address this process at the cellular level, we recorded prefrontal (PFC) and posterior parietal (PPC) neurons in a complex problem-solving task, with monkeys searching for one or two target locations in a first cycle of trials, and retaining them for memory-guided revisits on subsequent cycles. When target locations were discovered, neither frontal nor parietal neurons showed sustained goal-location codes continuing into subsequent trials and cycles. Instead there were sequences of timely goal silencing and reactivation, and following reactivation, sustained states until behavioral response. With two target locations, goal representations in both regions showed evidence of transitions between foreground and background, but the PFC representation was more complete, extending beyond the current trial to include both past and future selections. In the absence of unbroken sustained codes, different neuronal states interact to support maintenance and retrieval of WM representations across successive trials.

Frontal and temporal coding dynamics in successive steps of complex behavior.

Ventrolateral prefrontal cortex (vlPFC), dorsolateral prefrontal cortex (dlPFC), and temporal cortex (TE) all contribute to visual decision-making. Accumulating evidence suggests that vlPFC may play a central role in multiple cognitive operations, perhaps resembling domain-general regions of the human frontal lobe. We trained monkeys in a task calling for learning, retrieval, and spatial selection of rewarded target objects. Recordings of neural activity covered large areas of vlPFC, dlPFC, and TE. Results suggested a central role for vlPFC in each cognitive operation with strong coding of each task feature, while only location was strongly coded in dlPFC and current object identity in TE. During target selection, target location was communicated first from vlPFC to dlPFC, followed by extensive mutual support. In vlPFC, stimulus identities were independently coded in different task operations. The results suggest a central role for the inferior frontal convexity in controlling successive operations of a complex, multi-step task.

Prefrontal and Medial Temporal Lobe Cortical Contributions to Visual Short-Term Memory.

A number of recent studies have indicated that the medial temporal lobe (MTL) plays a critical role in working memory (WM) and perception, but these results have been highly controversial given the traditional association of MTL with long-term memory. We review the research and highlight important factors that need to be considered in determining the role of MTL in WM including set-size of used stimuli and feature complexity and/or feature conjunctions/bindings embedded in those stimuli. These factors relate to hierarchical and, accordingly, domain-specific theories of functional organization within the temporal lobe. In addition, one must consider process-specific theories too, because two key processes commonly understood to contribute recognition memory, namely, recollection and familiarity, also have robust support from neurophysiological and neuroimaging research as to their functional dissociations within MTL. PFC has long been heavily implicated in WM; however, relatively less is known about how the PFC contributes to recollection and familiarity, although dynamic prefrontal coding models in WM may help to explain their neural mechanisms. The MTL and PFC are heavily interconnected and do not operate independently in underlying WM. We propose that investigation of the interactions between these two regions in WM, particularly their coordinated neural activities, and the modeling of such interactions, will be crucial for the advancing understanding of the neural mechanisms of WM.

Frontopolar cortex shapes brain network structure across prefrontal and posterior cingulate cortex.

Primate frontopolar cortex (FPC), occupied by area 10, sits atop a functional hierarchy of prefrontal cortical regions, yet little is known about its involvement in wider cortical networks. Here we examined resting-state-functional-connectivity (rsfc) in rhesus monkeys with intact or lesioned FPC to identify cortical regions associated with FPC. We present a network of FPC-specific regions of interest (ROIs), whose connectivity was affected by lesion of FPC but not by lesion of neighbouring prefrontal cortex (principal sulcus). This network comprised 'core ROIs' with direct anatomical connections to FPC, located in ventrolateral prefrontal cortex, posterior cingulate cortex, and superior temporal gyrus, and 'peripheral ROIs' well connected to the core network. We further show that the principle effect of a lesion to FPC was to cause a profound disturbance of the functional connectivity of posterior cingulate and ventrolateral prefrontal cortex. We therefore suggest that FPC, posterior cingulate and ventrolateral prefrontal cortex comprise a network of interacting cortical areas whose interactions may be critical for mediating the contribution of FPC to decision making.

Integrated neural dynamics for behavioural decisions and attentional competition in the prefrontal cortex.

In the behaving monkey, complex neural dynamics in the prefrontal cortex contribute to context-dependent decisions and attentional competition. We used demixed principal component analysis to track prefrontal activity dynamics in a cued target detection task. In this task, the animal combined identity of a visual object with a prior instruction cue to determine a target/nontarget decision. From population activity, we extracted principal components for each task feature and examined their time course and sensitivity to stimulus and task variations. For displays containing a single choice object in left or right hemifield, object identity, cue identity and decision were all encoded in population activity, with different dynamics and lateralisation. Object information peaked at 100-200 ms from display onset and was largely confined to the contralateral hemisphere. Cue information was weaker and present even prior to display onset. Integrating information from cue and object, decision information arose more slowly and was bilateral. Individual neurons contributed independently to coding of the three task features. The analysis was then extended to displays with a target in one hemifield and a competing distractor in the other. In this case, the data suggest that each hemisphere initially encoded the identity of the contralateral object. The distractor representation was then rapidly suppressed, with the final target decision again encoded bilaterally. The results show how information is coded along task-related dimensions while competition is resolved and suggest how information flows within and across frontal lobes to implement a learned behavioural decision.

The neural substrate and underlying mechanisms of executive control fluctuations in primates.

Trial-by-trial alterations in response time have been linked to fluctuations of executive control and transient lapses of attention. Here, we report remarkable homologies in performance-dependent fluctuations of response time between humans and monkeys. We examined the effects of selective bilateral lesions in four frontal regions on control fluctuations in the context of a rule-shifting task. Lesions within orbitofrontal cortex (OFC), but not within superior-lateral prefrontal cortex, significantly exaggerated the performance-dependent fluctuations of control and prevented its restoration following feedback. Lesions within dorsolateral prefrontal cortex (DLPFC) or within anterior-cingulate cortex (ACC) led to instability of control and disruption of its link with monkeys' upcoming decisions. Examining the activity of DLPFC and OFC cells shed more lights on the underlying neuronal mechanisms by showing that before the start of each trial, OFC cell activity conveyed detailed information regarding the current state of executive control and the likelihood of success or failure in the future decisions. This further emphasizes the crucial role of OFC in the trial-by-trial allocation (setting) of control to the ongoing task. These findings bring insights to the neural architecture of executive control in primates and suggest that DLPFC and ACC support sustained executive control, but OFC is more involved in setting and restoring the control.

A One-Shot Shift from Explore to Exploit in Monkey Prefrontal Cortex.

Much animal learning is slow, with cumulative changes in behavior driven by reward prediction errors. When the abstract structure of a problem is known, however, both animals and formal learning models can rapidly attach new items to their roles within this structure, sometimes in a single trial. Frontal cortex is likely to play a key role in this process. To examine information seeking and use in a known problem structure, we trained monkeys in an explore/exploit task, requiring the animal first to test objects for their association with reward, then, once rewarded objects were found, to reselect them on further trials for further rewards. Many cells in the frontal cortex showed an explore/exploit preference aligned with one-shot learning in the monkeys' behavior: the population switched from an explore state to an exploit state after a single trial of learning but partially maintained the explore state if an error indicated that learning had failed. Binary switch from explore to exploit was not explained by continuous changes linked to expectancy or prediction error. Explore/exploit preferences were independent for two stages of the trial: object selection and receipt of feedback. Within an established task structure, frontal activity may control the separate processes of explore and exploit, switching in one trial between the two.SIGNIFICANCE STATEMENT Much animal learning is slow, with cumulative changes in behavior driven by reward prediction errors. When the abstract structure a problem is known, however, both animals and formal learning models can rapidly attach new items to their roles within this structure. To address transitions in neural activity during one-shot learning, we trained monkeys in an explore/exploit task using familiar objects and a highly familiar task structure. When learning was rapid, many frontal neurons showed a binary, one-shot switch between explore and exploit. Within an established task structure, frontal activity may control the separate operations of exploring alternative objects to establish their current role, then exploiting this knowledge for further reward.

Low-beta repetitive transcranial magnetic stimulation to human dorsolateral prefrontal cortex during object recognition memory sample presentation, at a task-related frequency observed in local field potentials in homologous macaque cortex, impairs subsequent recollection but not familiarity.

According to dual-process signal-detection (DPSD) theories, short- and long-term recognition memory draws upon both familiarity and recollection. It remains unclear how primate prefrontal cortex (PFC) contributes to these processes, but frequency-specific neuronal activities are considered to play a key role. In Experiment 1, nonhuman primate (NHP) local field potential (LFP) electrophysiological recordings in macaque left dorsolateral PFC (dlPFC) revealed performance-related differences in a low-beta frequency range during the sample presentation phase of a visual object recognition memory task. Experiment 2 employed a similar task in humans and targeted left dlPFC (and vertex as a control) with repetitive transcranial magnetic stimulation (rTMS) at 12.5 Hz during occasional sample presentations. This low-beta frequency rTMS to dlPFC decreased DPSD derived indices of recollection, but not familiarity, in subsequent memory tests of the targeted samples after short delays. The same number of rTMS pulses over the same total duration albeit at a random frequency had no effect on either recollection or familiarity. Neither stimulation protocols had any causal effect upon behaviour when targeted to the control site (vertex). In this study, our hypotheses for our human TMS study were derived from our observations in NHPs; this approach might inspire further translational research through investigation of homologous brain regions and tasks across species using similar neuroscientific methodologies to advance the neural mechanism of recognition memory in primates.

Emergence of abstract rules in the primate brain.

Various aspects of human cognition are shaped and enriched by abstract rules, which help to describe, link and classify discrete events and experiences into meaningful concepts. However, where and how these entities emerge in the primate brain and the neuronal mechanisms underlying them remain the subject of extensive research and debate. Evidence from imaging studies in humans and single-neuron recordings in monkeys suggests a pivotal role for the prefrontal cortex in the representation of abstract rules; however, behavioural studies in lesioned monkeys and data from neuropsychological examinations of patients with prefrontal damage indicate substantial functional dissociations and task dependency in the contribution of prefrontal cortical regions to rule-guided behaviour. This Review describes our current understanding of the dynamic emergence of abstract rules in primate cognition, and of the distributed neural network that supports abstract rule formation, maintenance, revision and task-dependent implementation.

Similar time course of fast familiarity and slow recollection processes for recognition memory in humans and macaques.

According to dual-process theory, recognition memory performance draws upon two processes, familiarity and recollection. The relative contribution to recognition memory are commonly distinguished in humans by analyzing receiver-operating-characteristics (ROC) curves; analogous methods are more complex and very rare in animals but fast familiarity and slow recollective-like processes (FF/SR) have been detected in nonhuman primates (NHPs) based on analyzing recognition error response time profiles. The relative utility of these methods to investigate familiarity and recollection/recollection-like processes across species is uncertain; indeed, even how comparable the FF/SR measures are across humans and NHPs remains unclear. Therefore, in this study a broadly similar recognition memory task was exploited in both humans and a NHP to investigate the time course of the two recognition processes. We first show that the FF/SR dissociation exists in this task in human participants and then we demonstrate a similar profile in the NHP which suggests that FF/SR processes are comparable across species. We then verified, using ROC-derived indices for each time-bin in the FF/SR profile, that the ROC and FF/SR measures are related. Hence, we argue that the FF/SR approach, procedurally easier in nonhuman animals, can be used as a decent proxy to investigate these two recognition processes in future animal studies, important given that scant data exists as to the neural basis underlying recollection yet many of the most informative techniques primarily exist in animal models.

Behavioral flexibility is associated with changes in structure and function distributed across a frontal cortical network in macaques.

One of the most influential accounts of central orbitofrontal cortex-that it mediates behavioral flexibility-has been challenged by the finding that discrimination reversal in macaques, the classic test of behavioral flexibility, is unaffected when lesions are made by excitotoxin injection rather than aspiration. This suggests that the critical brain circuit mediating behavioral flexibility in reversal tasks lies beyond the central orbitofrontal cortex. To determine its identity, a group of nine macaques were taught discrimination reversal learning tasks, and its impact on gray matter was measured. Magnetic resonance imaging scans were taken before and after learning and compared with scans from two control groups, each comprising 10 animals. One control group learned discrimination tasks that were similar but lacked any reversal component, and the other control group engaged in no learning. Gray matter changes were prominent in posterior orbitofrontal cortex/anterior insula but were also found in three other frontal cortical regions: lateral orbitofrontal cortex (orbital part of area 12 [12o]), cingulate cortex, and lateral prefrontal cortex. In a second analysis, neural activity in posterior orbitofrontal cortex/anterior insula was measured at rest, and its pattern of coupling with the other frontal cortical regions was assessed. Activity coupling increased significantly in the reversal learning group in comparison with controls. In a final set of experiments, we used similar structural imaging procedures and analyses to demonstrate that aspiration lesion of central orbitofrontal cortex, of the type known to affect discrimination learning, affected structure and activity in the same frontal cortical circuit. The results identify a distributed frontal cortical circuit associated with behavioral flexibility.

The Role of Primate Prefrontal Cortex in Bias and Shift Between Visual Dimensions.

Imaging and neural activity recording studies have shown activation in the primate prefrontal cortex when shifting attention between visual dimensions is necessary to achieve goals. A fundamental unanswered question is whether representations of these dimensions emerge from top-down attentional processes mediated by prefrontal regions or from bottom-up processes within visual cortical regions. We hypothesized a causative link between prefrontal cortical regions and dimension-based behavior. In large cohorts of humans and macaque monkeys, performing the same attention shifting task, we found that both species successfully shifted between visual dimensions, but both species also showed a significant behavioral advantage/bias to a particular dimension; however, these biases were in opposite directions in humans (bias to color) versus monkeys (bias to shape). Monkeys' bias remained after selective bilateral lesions within the anterior cingulate cortex (ACC), frontopolar cortex, dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex (OFC), or superior, lateral prefrontal cortex. However, lesions within certain regions (ACC, DLPFC, or OFC) impaired monkeys' ability to shift between these dimensions. We conclude that goal-directed processing of a particular dimension for the executive control of behavior depends on the integrity of prefrontal cortex; however, representation of competing dimensions and bias toward them does not depend on top-down prefrontal-mediated processes.

Focused Representation of Successive Task Episodes in Frontal and Parietal Cortex.

Complex cognition is dynamic, with each stage of a task requiring new cognitive processes appropriately linked to stimulus or other content. To investigate control over successive task stages, we recorded neural activity in lateral frontal and parietal cortex as monkeys carried out a complex object selection task, with each trial separated into phases of visual selection and learning from feedback. To study capacity limitation, complexity was manipulated by varying the number of object targets to be learned in each problem. Different task phases were associated with quasi-independent patterns of activity and information coding, with no suggestion of sustained activity linked to a current target. Object and location coding were largely parallel in frontal and inferior parietal cortex, though frontal cortex showed somewhat stronger object representation at feedback, and more sustained location coding at choice. At both feedback and choice, coding precision diminished as task complexity increased, matching a decline in performance. We suggest that, across successive task steps, there is radical but capacity-limited reorganization of frontoparietal activity, selecting different cognitive operations linked to their current targets.

Mnemonic Introspection in Macaques Is Dependent on Superior Dorsolateral Prefrontal Cortex But Not Orbitofrontal Cortex.

The human PFC has been associated more with meta-perceptual as opposed to meta-memory decisions from correlational neuroimaging investigations. Recently, metacognitive abilities have also been shown to be causally dependent upon anterior and dorsal PFC in nonhuman primate lesion studies. Two studies, using postdecision wagering paradigms and reversible inactivation, challenged this meta-perceptual versus meta-memory notion and showed that dorsal and anterior prefrontal areas are associated with metamemory for experienced objects and awareness of ignorance, respectively. Causal investigations are important but scarce; nothing is known, for example, about the causal contributions of prefrontal subregions to spatial metamemory. Here, we investigated the effects of dorsal versus ventral PFC lesions on two-alternative forced-choice spatial discrimination tasks in male macaque monkeys. Importantly, we were rigorous in approach and applied three independent but complementary indices used to quantify individual animals' metacognitive ability ("Type II sensitivity") by two variants of meta-d'/d' and phi coefficient (φ). Our results were consistent across indices: while neither lesions to superior dorsolateral PFC nor orbitofrontal cortex impaired spatial recognition performance, only monkeys with superior dorsolateral PFC lesions were impaired in meta-accuracy. Together with the observation that the same orbitofrontal cortex lesioned monkeys were impaired in updating rule value in a Wisconsin Card Sorting Test analog, we therefore document a functional double-dissociation between these two PFC regions. Our study presents important causal evidence that other dimensions, namely, domain-specific processing (e.g., spatial vs nonspatial metamemory), also need considerations in understanding the functional specialization in the neural underpinnings of introspection.SIGNIFICANCE STATEMENT This study demonstrates macaque monkeys' metacognitive capability of introspecting its own memory success is causally dependent on intact superior dorsolateral prefrontal cortices but not the orbitofrontal cortices. Combining neurosurgical techniques on monkeys and state-of-the-art measures of metacognition, we affirm a critical role of the PFC in supporting spatial meta-recognition memory and delineate functional specificity within PFC for distinct elements of metacognition.

Context-Dependent Adjustments in Executive Control of Goal-Directed Behaviour: Contribution of Frontal Brain Areas to Conflict-Induced Behavioural Adjustments in Primates.

Psychophysical studies in humans indicate that the performance in various tasks is affected by contextual factors such as conflict level and error commission. It is generally believed that contextual factors influence the executive control processes and consequently modulate ongoing behaviour. Imaging studies suggest that dorsolateral prefrontal cortex and anterior cingulate cortex play crucial roles in mediating these context-dependent adjustments in executive control of behaviour. However, the underlying neuronal processes are to a great extent unknown. Recent studies in non-human primates indicate great similarities in conflict-induced behavioural adjustments between humans and macaque monkeys. Animal models have provided the opportunity to conduct various detailed neurobiological techniques to reveal the neural underpinning of conflict-induced behavioural modulations. In this chapter, we review the latest findings in humans and non-human primate models regarding the neural substrate and underlying mechanisms of conflict-dependent executive control adjustments.

Functional reorganisation and recovery following cortical lesions: A preliminary study in macaque monkeys.

Damage following traumatic brain injury or stroke can often extend beyond the boundaries of the initial insult and can lead to maladaptive cortical reorganisation. On the other hand, beneficial cortical reorganisation leading to recovery of function can also occur. We used resting state FMRI to investigate how cortical networks in the macaque brain change across time in response to lesions to the prefrontal cortex, and how this reorganisation correlated with changes in behavioural performance in cognitive tasks. After prelesion testing and scanning, two monkeys received a lesion to regions surrounding the left principal sulcus followed by periodic testing and scanning. Later, the animals received another lesion to the opposite hemisphere and additional testing and scanning. Following the first lesion, we observed both a behavioural impairment and decrease in functional connectivity, predominantly in frontal-frontal networks. Approximately 8 weeks later, performance and connectivity patterns both improved. Following the second lesion, we observed a further behavioural deficit and decrease in connectivity that showed little recovery. We discuss how different mechanisms including alternate behavioural strategies and reorganisation of specific prefrontal networks may have led to improvements in behaviour. Further work will be needed to confirm these mechanisms.

A new approach to solving the feature-binding problem in primate vision.

We discuss a recently proposed approach to solve the classic feature-binding problem in primate vision that uses neural dynamics known to be present within the visual cortex. Broadly, the feature-binding problem in the visual context concerns not only how a hierarchy of features such as edges and objects within a scene are represented, but also the hierarchical relationships between these features at every spatial scale across the visual field. This is necessary for the visual brain to be able to make sense of its visuospatial world. Solving this problem is an important step towards the development of artificial general intelligence. In neural network simulation studies, it has been found that neurons encoding the binding relations between visual features, known as binding neurons, emerge during visual training when key properties of the visual cortex are incorporated into the models. These biological network properties include (i) bottom-up, lateral and top-down synaptic connections, (ii) spiking neuronal dynamics, (iii) spike timing-dependent plasticity, and (iv) a random distribution of axonal transmission delays (of the order of several milliseconds) in the propagation of spikes between neurons. After training the network on a set of visual stimuli, modelling studies have reported observing the gradual emergence of polychronization through successive layers of the network, in which subpopulations of neurons have learned to emit their spikes in regularly repeating spatio-temporal patterns in response to specific visual stimuli. Such a subpopulation of neurons is known as a polychronous neuronal group (PNG). Some neurons embedded within these PNGs receive convergent inputs from neurons representing lower- and higher-level visual features, and thus appear to encode the hierarchical binding relationship between features. Neural activity with this kind of spatio-temporal structure robustly emerges in the higher network layers even when neurons in the input layer represent visual stimuli with spike timings that are randomized according to a Poisson distribution. The resulting hierarchical representation of visual scenes in such models, including the representation of hierarchical binding relations between lower- and higher-level visual features, is consistent with the hierarchical phenomenology or subjective experience of primate vision and is distinct from approaches interested in segmenting a visual scene into a finite set of objects.

Inverted activity patterns in ventromedial prefrontal cortex during value-guided decision-making in a less-is-more task.

Ventromedial prefrontal cortex has been linked to choice evaluation and decision-making in humans but understanding the role it plays is complicated by the fact that little is known about the corresponding area of the macaque brain. We recorded activity in macaques using functional magnetic resonance imaging during two very different value-guided decision-making tasks. In both cases ventromedial prefrontal cortex activity reflected subjective choice values during decision-making just as in humans but the relationship between the blood oxygen level-dependent signal and both decision-making and choice value was inverted and opposite to the relationship seen in humans. In order to test whether the ventromedial prefrontal cortex activity related to choice values is important for decision-making we conducted an additional lesion experiment; lesions that included the same ventromedial prefrontal cortex region disrupted normal subjective evaluation of choices during decision-making.

Managing competing goals - a key role for the frontopolar cortex.

Humans are set apart from other animals by many elements of advanced cognition and behaviour, including language, judgement and reasoning. What is special about the human brain that gives rise to these abilities? Could the foremost part of the prefrontal cortex (the frontopolar cortex), which has become considerably enlarged in humans during evolution compared with other animals, be important in this regard, especially as, in primates, it contains a unique cytoarchitectural field, area 10? The first studies of the function of the frontopolar cortex in monkeys have now provided critical new insights about its precise role in monitoring the significance of current and alternative goals. In human evolution, the frontopolar cortex may have acquired a further role in enabling the monitoring of the significance of multiple goals in parallel, as well as switching between them. Here, we argue that many other forms of uniquely human behaviour may benefit from this cognitive ability mediated by the frontopolar cortex.