Evolution of prefrontal cortex.

Subdivisions of the prefrontal cortex (PFC) evolved at different times. Agranular parts of the PFC emerged in early mammals, and rodents, primates, and other modern mammals share them by inheritance. These are limbic areas and include the agranular orbital cortex and agranular medial frontal cortex (areas 24, 32, and 25). Rodent research provides valuable insights into the structure, functions, and development of these shared areas, but it contributes less to parts of the PFC that are specific to primates, namely, the granular, isocortical PFC that dominates the frontal lobe in humans. The first granular PFC areas evolved either in early primates or in the last common ancestor of primates and tree shrews. Additional granular PFC areas emerged in the primate stem lineage, as represented by modern strepsirrhines. Other granular PFC areas evolved in simians, the group that includes apes, humans, and monkeys. In general, PFC accreted new areas along a roughly posterior to anterior trajectory during primate evolution. A major expansion of the granular PFC occurred in humans in concert with other association areas, with modifications of corticocortical connectivity and gene expression, although current evidence does not support the addition of a large number of new, human-specific PFC areas.

Evolution, Emotion, and Episodic Engagement.

Although rodent research provides important insights into neural correlates of human psychology, new cortical areas, connections, and cognitive abilities emerged during primate evolution, including human evolution. Comparison of human brains with those of nonhuman primates reveals two aspects of human brain evolution particularly relevant to emotional disorders: expansion of homotypical association areas and expansion of the hippocampus. Two uniquely human cognitive capacities link these phylogenetic developments with emotion: a subjective sense of participating in and reexperiencing remembered events and a limitless capacity to imagine details of future events. These abilities provided evolving humans with selective advantages, but they also created proclivities for emotional problems. The first capacity evokes the "reliving" of past events in the "here-and-now," accompanied by emotional responses that occurred during memory encoding. It contributes to risk for stress-related syndromes, such as posttraumatic stress disorder. The second capacity, an ability to imagine future events without temporal limitations, facilitates flexible, goal-related behavior by drawing on and creating a uniquely rich array of mental representations. It promotes goal achievement and reduces errors, but the mental construction of future events also contributes to developmental aspects of anxiety and mood disorders. With maturation of homotypical association areas, the concrete concerns of childhood expand to encompass the abstract apprehensions of adolescence and adulthood. These cognitive capacities and their dysfunction are amenable to a research agenda that melds experimental therapeutic interventions, cognitive neuropsychology, and developmental psychology in both humans and nonhuman primates.

Separable neuronal contributions to covertly attended locations and movement goals in macaque frontal cortex.

We investigated the spatial representation of covert attention and movement planning in monkeys performing a task that used symbolic cues to decouple the locus of covert attention from the motor target. In the three frontal areas studied, most spatially tuned neurons reflected either where attention was allocated or the planned saccade. Neurons modulated by both covert attention and the motor plan were in the minority. Such dual-purpose neurons were especially rare in premotor and prefrontal cortex but were more common just rostral to the arcuate sulcus. The existence of neurons that indicate where the monkey was attending but not its movement goal runs counter to the idea that the control of spatial attention is entirely reliant on the neuronal circuits underlying motor planning. Rather, the presence of separate neuronal populations for each cognitive process suggests that endogenous attention is under flexible control and can be dissociated from motor intention.

Representational specializations of the hippocampus in phylogenetic perspective.

In a major evolutionary transition that occurred more than 520 million years ago, the earliest vertebrates adapted to a life of mobile, predatory foraging guided by distance receptors concentrated on their heads. Vision and olfaction served as the principal sensory systems for guiding their search for nutrients and safe haven. Among their neural innovations, these animals had a telencephalon that included a homologue of the hippocampus. Experiments on goldfish, turtles, lizards, rodents, macaque monkeys and humans have provided insight into the initial adaptive advantages provided by the hippocampus homologue. These findings indicate that it housed specialized map-like representations of odors and sights encountered at various locations in an animal's home range, including the order and timing in which they should be encountered during a journey. Once these representations emerged in early vertebrates, they also enabled a variety of behaviors beyond navigation. In modern rodents and primates, for example, the specialized representations of the hippocampus enable the learning and performance of tasks involving serial order, timing, recency, relations, sequences of events and behavioral contexts. During primate evolution, certain aspects of these representations gained particular prominence, in part due to the advent of foveal vision in haplorhines. As anthropoid primates-the ancestors of monkeys, apes and humans-changed from small animals that foraged locally into large ones with an extensive home range, they made foraging choices at a distance based on visual scenes. Experimental evidence shows that the hippocampus of monkeys specializes in memories that reflect the representation of such scenes, rather than spatial processing in a general sense. Furthermore, and contrary to the idea that the hippocampus functions in memory to the exclusion of perception, brain imaging studies and lesion effects in humans show that its specialized representations support both the perception and memory of scenes and sequences.

Context-Dependent Duration Signals in the Primate Prefrontal Cortex.

The activity of some prefrontal (PF) cortex neurons distinguishes short from long time intervals. Here, we examined whether this property reflected a general timing mechanism or one dependent on behavioral context. In one task, monkeys discriminated the relative duration of 2 stimuli; in the other, they discriminated the relative distance of 2 stimuli from a fixed reference point. Both tasks had a pre-cue period (interval 1) and a delay period (interval 2) with no discriminant stimulus. Interval 1 elapsed before the presentation of the first discriminant stimulus, and interval 2 began after that stimulus. Both intervals had durations of either 400 or 800 ms. Most PF neurons distinguished short from long durations in one task or interval, but not in the others. When neurons did signal something about duration for both intervals, they did so in an uncorrelated or weakly correlated manner. These results demonstrate a high degree of context dependency in PF time processing. The PF, therefore, does not appear to signal durations abstractedly, as would be expected of a general temporal encoder, but instead does so in a highly context-dependent manner, both within and between tasks.

Automatic comparison of stimulus durations in the primate prefrontal cortex: the neural basis of across-task interference.

Rhesus monkeys performed two tasks, both requiring a choice between a red square and a blue circle. In the duration task, the two stimuli appeared sequentially on each trial, for varying durations, and, later, during the choice phase of the task, the monkeys needed to choose the one that had lasted longer. In the matching-to-sample task, one of the two stimuli appeared twice as a sample, with durations matching those in the duration task, and the monkey needed to choose that stimulus during the choice phase. Although stimulus duration was irrelevant in the matching-to-sample task, the monkeys made twice as many errors when the second stimulus was shorter. This across-task interference supports an order-dependent model of the monkeys' choice and reveals something about their strategy in the duration task. The monkeys tended to choose the second stimulus when its duration exceeded the first and to choose the alternative stimulus otherwise. For the duration task, this strategy obviated the need to store stimulus-duration conjunctions for both stimuli, but it generated errors on the matching-to-sample task. We examined duration coding in prefrontal neurons and confirmed that a population of cells encoded relative duration during the matching-to-sample task, as expected from the order-dependent errors.

Autonomous encoding of irrelevant goals and outcomes by prefrontal cortex neurons.

Two rhesus monkeys performed a distance discrimination task in which they reported whether a red square or a blue circle had appeared farther from a fixed reference point. Because a new pair of distances was chosen randomly on each trial, and because the monkeys had no opportunity to correct errors, no information from the previous trial was relevant to a current one. Nevertheless, many prefrontal cortex neurons encoded the outcome of the previous trial on current trials. A smaller, intermingled population of cells encoded the spatial goal on the previous trial or the features of the chosen stimuli, such as color or shape. The coding of previous outcomes and goals began at various times during a current trial, and it was selective in that prefrontal cells did not encode other information from the previous trial. The monitoring of previous goals and outcomes often contributes to problem solving, and it can support exploratory behavior. The present results show that such monitoring occurs autonomously and selectively, even when irrelevant to the task at hand.

Prefrontal-parietal function: from foraging to foresight.

Comparative neuroanatomy shows that new prefrontal areas emerged during the evolution of anthropoid primates to augment prefrontal, parietal, and temporal areas that had evolved in earlier primates. We recently proposed that the new anthropoid areas reduce foraging errors by generating goals from current contexts and learning to do so rapidly, sometimes based on single events. Among the contexts used to generate these goals, the posterior parietal cortex provides the new prefrontal areas with information about relational metrics such as order, number, duration, length, distance and proportion, which play a crucial role in foraging choices. Here we propose that this specialized network later became adapted to support the human capacity for reasoning and general problem-solving.

Why is there a special issue on perirhinal cortex in a journal called hippocampus? The perirhinal cortex in historical perspective.

Despite its small size, the perirhinal cortex (PRh) plays a central role in understanding the cerebral cortex, vision, and memory; it figures in discussions of cognitive capacities as diverse as object perception, semantic knowledge, feelings of familiarity, and conscious recollection. Two conceptual constructs have encompassed PRh. The current orthodoxy incorporates PRh within the medial temporal lobe (MTL) as a memory area; an alternative considers PRh to be a sensory area with a role in both perception and memory. A historical perspective provides insight into both these ideas. PRh came to be included in the MTL because of two accidents of history. In evolutionary history, the hippocampus migrated from its ancestral situation as medial cortex into the temporal lobe; in the history of neuropsychology, a "memory system" that originally consisted of the amygdala and hippocampus came to include PRh. These two histories explain why a part of the sensory neocortex, PRh, entered into the conceptual construct called the MTL. They also explain why some experimental results seem to exclude a perceptual function for this sensory area, while others embrace perception. The exclusion of perceptual functions results from a history of categorizing tasks as perceptual or mnemonic, often on inadequate grounds. By exploring the role of PRh in encoding, representing, and retrieving stimulus information, it can be understood as a part of the sensory neocortex, one that has the same relationship with the hippocampus as do other parts of the neocortex that evolved at about the same time.

Neuronal activity during a cued strategy task: comparison of dorsolateral, orbital, and polar prefrontal cortex.

We compared neuronal activity in the dorsolateral (PFdl), orbital (PFo), and polar (PFp) prefrontal cortex as monkeys performed three tasks. In two tasks, a cue instructed one of two strategies: stay with the previous response or shift to the alternative. Visual stimuli served as cues in one of these tasks; in the other, fluid rewards did so. In the third task, visuospatial cues instructed each response. A delay period followed each cue. As reported previously, PFdl encoded strategies (stay or shift) and responses (left or right) during the cue and delay periods, while PFo encoded strategies and PFp encoded neither strategies nor responses; during the feedback period, all three areas encoded responses, but not strategies. Four novel findings emerged from the present analysis. (1) The strategy encoded by PFdl and PFo cells during the cue and delay periods was modality specific. (2) The response encoded by PFdl cells was task and modality specific during the cue period, but during the delay and feedback periods it became task and modality general. (3) Although some PFdl and PFo cells responded to or anticipated rewards, we could rule out reward effects for most strategy- and response-related activity. (4) Immediately before feedback, only PFp signaled responses that were correct according to the cued strategy; after feedback, only PFo signaled the response that had been made, whether correct or incorrect. These signals support a role in generating responses by PFdl, assigning outcomes to choices by PFo, and assigning outcomes to cognitive processes by PFp.

Encoding goals but not abstract magnitude in the primate prefrontal cortex.

Functional neuroimaging studies show that perceptual judgments about time and space activate similar prefrontal and parietal areas, and it is known that perceptions in these two cognitive domains interfere with each other. These findings have led to the theory that temporal and spatial perceptions, among other metrics, draw on a common representation of magnitude. Our results indicate that an alternative principle applies to the prefrontal cortex. Analysis at the single-cell level shows that separate, domain-specific populations of neurons encode relative magnitude in time and space. These neurons are intermixed with each other in the prefrontal cortex, along with a separate intermixed population that encodes the goal chosen on the basis of these perceptual decisions. As a result, domain-specific neural processing at the single-cell level seems to underlie domain generality as observed at the regional level, with a common representation of prospective goals rather than a common representation of magnitude.

Frontal pole cortex: encoding ends at the end of the endbrain.

Considerable neuroimaging research in humans indicates that the frontal pole cortex (FPC), also known as Brodmann area 10, contributes to many aspects of cognition. Despite these findings, however, its fundamental function and mechanism remain unclear. Recent neurophysiological results from the FPC of monkeys have implications about both. Neurons in the FPC seem to encode chosen goals at feedback time and nothing else. Goals, the places and objects that serve as targets for action, come in many forms and arise from many cognitive processes. The FPC's signal, although surprisingly simple for neurons at the apex of a prefrontal hierarchy, could promote learning about which kinds of goals and goal-generating processes produce particular costs and benefits, thereby improving future choices.

Prefrontal cortex activity during the discrimination of relative distance.

To compare with our previous findings on relative-duration discrimination, we studied prefrontal cortex activity as monkeys performed a relative-distance discrimination task. We wanted to know whether the same parts of the prefrontal cortex compare durations and distances and, if so, whether they use similar mechanisms. Two stimuli appeared sequentially on a video screen, one above a fixed reference point, the other below it by a different distance. After a delay period, the same two stimuli reappeared (as choice stimuli), and the monkeys' task was to choose the one that had appeared farther from the reference point during its initial presentation. We recorded from neurons in the dorsolateral prefrontal cortex (area 46) and the caudal prefrontal cortex (area 8). Although some prefrontal neurons encoded the absolute distance of a stimulus from the reference point, many more encoded relative distance. Categorical representations ("farther") predominated over parametric ones ("how much farther"). Relative-distance coding was most often abstract, coding the farther or closer stimulus to the same degree, independent of its position on the screen. During the delay period before the choice stimuli appeared, feature-based coding supplanted order-based coding, and position-based coding-always rare-decreased to chance levels. The present results closely resembled those for a duration-discrimination task in the same cortical areas. We conclude, therefore, that these areas contribute to decisions based on both spatial and temporal information.

Comparison of strategy signals in the dorsolateral and orbital prefrontal cortex.

Abstract behavior-guiding rules and strategies allow monkeys to avoid errors in rarely encountered situations. In the present study, we contrasted strategy-related neuronal activity in the dorsolateral prefrontal cortex (PFdl) and the orbital prefrontal cortex (PFo) of rhesus monkeys. On each trial of their behavioral task, the monkeys responded to a foveal visual cue by making a saccade to one of two spatial targets. One response required a leftward saccade, the other required a saccade of equal magnitude to the right. The cues instructed the monkeys to follow one of two response strategies: to stay with their most recent successful response or to shift to the alternative response. Neurons in both areas encoded the stay and shift strategies after the cue appeared, but there were three major differences between the PFo and the PFdl: (1) many strategy-encoding cells in PFdl also encoded the response (left or right), but few, if any, PFo cells did so; (2) strategy selectivity appeared earlier in PFo than in PFdl; and (3) on error trials, PFo neurons encoded the correct strategy-the one that had been cued but not implemented-whereas in PFdl the strategy signals were weak or absent on error trials. These findings indicate that PFo and PFdl both contribute to behaviors guided by abstract response strategies, but do so differently, with PFo encoding a strategy and PFdl encoding a response based on a strategy.

Localization of dysfunction in major depressive disorder: prefrontal cortex and amygdala.

Despite considerable effort, the localization of dysfunction in major depressive disorder (MDD) remains poorly understood. We present a hypothesis about its localization that builds on recent findings from primate neuropsychology. The hypothesis has four key components: a deficit in the valuation of "self" underlies the core disorder in MDD; the medial frontal cortex represents "self"; interactions between the amygdala and cortical representations update their valuation; and inefficiency in using positive feedback by orbital prefrontal cortex contributes to MDD.

Interactions between orbital prefrontal cortex and amygdala: advanced cognition, learned responses and instinctive behaviors.

Recent research indicates that the orbital prefrontal cortex (PFo) represents stimulus valuations and that the amygdala updates these valuations. An exploration of how PFo and the amygdala interact could improve the understanding of both. PFo and the amygdala function cooperatively when monkeys choose objects associated with recently revalued foods. In other tasks, they function in opposition. PFo uses positive feedback to promote learning in object-reward reversal tasks, and PFo also promotes extinction learning. Amygdala function interferes with both kinds of learning. The amygdala underlies fearful responses to a rubber snake from the first exposure on, but PFo is necessary only after the initial exposure. The amygdala mediates an arousal response in anticipation of rewards, whereas PFo sometimes suppresses such arousal. A role for PFo in advanced cognition, for the amygdala in instinctive behavior, and for cortex-subcortex interactions in prioritizing behaviors provides one account for these findings.

What, if anything, can monkeys tell us about human amnesia when they can't say anything at all?

Despite a half century of development, the orthodox monkey model of human amnesia needs improvement, in part because of two problems inherent in animal models of advanced human cognition. First, animal models are perforce comparative, but the principles of comparative and evolutionary biology have not featured prominently in developing the orthodox model. Second, no one understands the relationship between human consciousness and cognition in other animals, but the orthodox model implicitly assumes a close correspondence. If we treat these two difficulties with the deference they deserve, monkeys can tell us a lot about human amnesia and memory. Three future contributions seem most likely: (1) an improved monkey model, one refocused on the hippocampus rather than on the medial temporal lobe as a whole; (2) a better understanding of cortical areas unique to primates, especially the granular prefrontal cortex; and (3), taking the two together, insight into prefrontal-hippocampal interactions. We propose that interactions among the granular prefrontal areas create the kind of cross-domain, analogical and self-referential knowledge that underlies advanced cognition in modern humans. When these products of frontal-lobe function interact with the hippocampus, and its ancestral function in navigation, what emerges is the human ability to embed ourselves in scenarios-real and imagined, self-generated and received-thereby creating a coherent, conscious life experience.

Evaluating self-generated decisions in frontal pole cortex of monkeys.

The frontal pole cortex (FPC) expanded markedly during human evolution, but its function remains uncertain in both monkeys and humans. Accordingly, we examined single-cell activity in this area. On every trial, monkeys decided between two response targets on the basis of a 'stay' or 'shift' cue. Feedback followed at a fixed delay. FPC cells did not encode the monkeys' decisions when they were made, but did so later on, as feedback approached. This finding indicates that the FPC is involved in monitoring or evaluating decisions. Using a control task and delayed feedback, we found that decision coding lasted until feedback only when the monkeys combined working memory with sensory cues to 'self-generate' decisions, as opposed to when they simply followed trial-by-trial instructions. A role in monitoring or evaluating self-generated decisions could account for FPC's expansion during human evolution.

Feature- and order-based timing representations in the frontal cortex.

We examined activity in the frontal cortex as monkeys performed a duration-discrimination task. Two stimuli, one red and the other blue, appeared sequentially on a video screen--in either order. Later, both stimuli reappeared, and to receive a reward the monkeys had to choose the stimulus that had lasted longer during its initial presentation. Some neurons encoded stimulus duration, but a larger number of cells represented their relative duration, which was encoded in three ways: whether the first or second stimulus had lasted longer; whether the red or blue stimulus had lasted longer; or, less commonly, as the difference between the two durations. As the monkeys' choice approached, the signal encoding which stimulus (red or blue) had lasted longer increased as the order-based signal dissipated. By representing stimulus durations and relative durations--both bound to stimulus features and event order--the frontal cortex could contribute to both temporal perception and episodic memory.

Multitasking of attention and memory functions in the primate prefrontal cortex.

In motor and sensory areas of cortex, neuronal activity often depends on the location of a movement target or a sensory stimulus, with each neuron tuned to a single part of space called a preferred direction (when motor) or a receptive field (when sensory). As we previously reported, some neurons in the monkey prefrontal cortex are tuned to two parts of space, which we interpreted as reflecting attention and working memory, respectively. Monkeys performed a behavioral task in which they attended to a visual stimulus at one location while remembering a second place, and these locations were varied from trial to trial to assess spatial tuning. Most spatially tuned neurons specialized in either attentional or mnemonic processing, but about one-third of the cells showed tuning for both. Here, we show that the latter population, called multitasking neurons, improves the encoding of both the attended and remembered locations. These neurons do so for three reasons: (1) the preferred directions for attention and for working memory usually differ (and often diametrically oppose one another), (2) they have stronger tuning than specialized cells, and (3) pairs of multitasking neurons represent these cognitive parameters more efficiently than pairs that include even a single specialized cell. These findings suggest that multitasking neurons provide a computational advantage for behaviors that place simultaneous demands on two or more cognitive processes.