Search

Throughout the nervous system, posterior structures are mainly devoted to receptive functions—sensation and perception—while anterior structures are devoted to motor functions. In the cortex, that dichotomy is unclear because perception and action are intertwined in the perception–action cycle, the biocybernetic cycle that adapts the organism to its environment. All neural systems store information (memory), which they enact in behavior and language. There are no “systems of memory” but the memory of systems. The cortex of the frontal lobe is a hierarchical system: motor cortex at the bottom for coordination of simple movements, and prefrontal cortex at the top for complex goal-directed actions. In the coordination of such actions, the frontal hierarchy engages the posterior (perceptual) cortex in the perception–action cycle. Inputs to the cycle come to prefrontal cortex from sensory-evoked perceptual memory and biologic (phyletic) memory. The first comes from neocortex, the second from limbic structures—through orbitomedial cortex. Outputs flow to pyramidal and diencephalic structures. Feedback inputs for monitoring and correction operate at all levels of the cycle. All prefrontal functions—planning, executive attention, working memory, decision-making, and inhibitory controls—are prospective, i.e., have a future perspective for the cycle to reach its goal. Damage to lateral prefrontal cortex impairs all of them. Orbitofrontal damage impairs the exclusionary aspect of attention and often leads to poor impulse control, excessive risk taking, unstable mood, and antisocial behavior. Medial prefrontal damage leads to poor monitoring of behavioral outcome for prevention of errors.

Our perception of the world is represented in widespread, overlapping, and interactive neuronal networks of the cerebral cortex. A majority of physiological studies on the subject have focused on oscillatory synchrony as the binding mechanism for representation and transmission of neural information. Little is known, however, about the stability of that synchrony during prolonged cognitive operations that span more than just a few seconds. The present research, in primates, investigated the dynamic patterns of oscillatory synchrony by two complementary recording methods, surface field potentials (SFPs) and near-infrared spectroscopy (NIRS). The signals were first recorded during the resting state to examine intrinsic functional connectivity. The temporal modulation of coactivation was then examined on both signals during performance of working memory (WM) tasks with long delays (memory retention epochs). In both signals, the peristimulus period exhibited characteristic features in frontal and parietal regions. Examination of SFP signals over delays lasting tens of seconds, however, revealed alternations of synchronization and desynchronization. These alternations occurred within the same frequency bands observed in the peristimulus epoch, without a specific correspondence between any definite cognitive process (e.g., WM) and synchrony within a given frequency band. What emerged instead was a correlation between the degree of SFP signal fragmentation (in time, frequency, and brain space) and the complexity and efficiency of the task being performed. In other words, the incidence and extent of SFP transitions between synchronization and desynchronization—rather than the absolute degree of synchrony—augmented in correct task performance compared with incorrect performance or in a control task without WM demand. An opposite relationship was found in NIRS: increasing task complexity induced more uniform, rather than fragmented, NIRS coactivations. These findings indicate that the particular features of neural oscillations cannot be linearly mapped to cognitive functions. Rather, information and the cognitive operations performed on it are primarily reflected in their modulations over time. The increased complexity and fragmentation of electrical frequencies in WM may reflect the activation of hierarchically diverse cognits (cognitive networks) in that condition. Conversely, the homogeneity in coherence of NIRS responses may reflect the cumulative vascular reactions that accompany that neuroelectrical proliferation of frequencies and the longer time constant of the NIRS signal. These findings are directly relevant to the mechanisms mediating cognitive processes and to physiologically based interpretations of functional brain imaging.

The neural mechanisms of decision-making are understandable only in the structural and dynamic context of the perception–action (PA) cycle. The PA cycle is the biocybernetic processing of information that adapts the organism to its environment. That circular processing involves a variety of neural structures at several hierarchical levels, though with close functional interactions between them. At its lowest level, the PA cycle is largely reflex and automatic, and involves the vegetative and visceral structures of the hypothalamus and the autonomic nervous system. At intermediate levels, the cycle involves limbic structures supporting its emotional and value-assessing mechanisms. At the cortical level, under the commanding role of the prefrontal cortex, the PA cycle incorporates prefrontal cognitive components. The posterior cortex contributes to decision-making mainly information from perceptual memory and knowledge; the frontal cortex contributes mainly executive memory and knowledge. Its prefrontal sector contributes to decision-making predictive and preadaptive control through its top–down executive functions—especially attentional set, working memory, monitoring, and inhibitory control.

In the course of evolution, the prefrontal cortex develops to maximum relative mass in the human brain. That large increase in mass is attributable to the disproportionate development of connective fibers (white matter), rather than cells (gray matter). This points to connectivity as the key to the evolutionary advantage of the human prefrontal cortex. In the light of modern research, it becomes apparent that this cortex, in the human, represents the ultimate embodiment of the capability of the organism to adapt to changes in its environment; that capability rests largely on cortical connectivity. The cognitive code is a relational code, inscribed by connectivity within and between large-scale cortical networks (cognits). In this paper, it is proposed that the prefrontal cortex endows the rest of the cortex with the ability to adapt the organism to its environment in anticipation of predicted changes. This makes the brain a preadaptive organ. Therein is the reason why the executive functions of the prefrontal cortex-mainly top-down attention, working memory, preparatory set, planning, and decision making-all have a critical future dimension. Through its connections with limbic structures and other cortical regions, the prefrontal cortex imparts to the brain its power to preadapt to events in the emotional and cognitive domains.

Converging evidence from humans and nonhuman primates is obliging us to abandon conventional models in favor of a radically different, distributed-network paradigm of cortical memory. Central to the new paradigm is the concept of memory network or cognit—that is, a memory or an item of knowledge defined by a pattern of connections between neuron populations associated by experience. Cognits are hierarchically organized in terms of semantic abstraction and complexity. Complex cognits link neurons in noncontiguous cortical areas of prefrontal and posterior association cortex. Cognits overlap and interconnect profusely, even across hierarchical levels (heterarchically), whereby a neuron can be part of many memory networks and thus many memories or items of knowledge.

This study explores the cortical cell dynamics of unimodal and cross-modal working memory (WM). Neuronal activity was recorded from parietal areas of monkeys performing delayed match-to-sample tasks with tactile or visual samples. Tactile memoranda (haptic samples) consisted of rods with differing surface features (texture or orientation of ridges) perceived by active touch. Visual memoranda (icons) consisted of striped patterns of differing orientation. In a haptic-haptic task, the animal had to retain through a period of delay the surface feature of the sample rod to select a rod that matched it. In a visual-haptic task, the animal had to retain the icon for the haptic choice of a rod with ridges of the same orientation as the icon's stripes. Units in all areas responded with firing change to one or more task events. Also in all areas, cells responded differently to different sample memoranda. Differential sample coherent firing was present in most areas during the memory period (delay). It is concluded that neurons in somatosensory and association areas of parietal cortex participate in broad networks that represent various task events and stimuli (auditory, motor, proprioceptive, tactile, and visual). Neurons in the same networks take part in retaining in WM the memorandum for each trial, whether it is encoded haptically or visually. The VH association by parietal cells in WM is analogous to the auditory-visual association previously observed in prefrontal cortex. Both illustrate the capacity of cortical neurons to associate sensory information across time and across modalities in accord with the rules of a behavioral task.

Persistent elevated neuronal activity has been identified as the neuronal correlate of working memory. It is generally assumed in the literature and in computational and theoretical models of working memory that memory-cell activity is stable and replicable; however, this assumption may be an artifact of the averaging of data collected across trials, and needs experimental verification. In this study, we introduce a classification scheme to characterize the firing frequency trends of cells recorded from the cortex of monkeys during performance of working memory tasks. We examine the frequency statistics and variability of firing during baseline and memory periods. We also study the behavior of cells on individual trials and across trials, and explore the stability of cellular firing during the memory period. We find that cells from different firing-trend classes possess markedly different statistics. We also find that individual cells show substantial variability in their firing behavior across trials, and that firing frequency also varies markedly over the course of a single trial. Finally, the average frequency distribution is wider, the magnitude of the frequency increases from baseline to memory smaller, and the magnitude of frequency decreases larger than is generally assumed. These results may serve as a guide in the evaluation of current theories of the cortical mechanisms of working memory.

Considerable progress has been made in neuroimaging methodology, including improved ways to quantify volumes of gray and white matter, by tractography and diffusion tensor imaging, and functional methods to correlate cortical activity (blood oxygen level-dependent imaging) with cognitive function (increased spatial and temporal resolution). A default network is defined at rest; this spans several cortical areas, including prefrontal cortex, and oscillates at extremely slow frequency. Planning or imagining a series of goal-directed actions activates rostral prefrontal cortex. In attention to sensory or executive information, the prefrontal cortex activates cortical cognitive networks that are expected to process that information. In working memory, the prefrontal cortex is coactivated with posterior cortical networks that engage with that cortex in the cross-temporal integration of information for a successful perception–action cycle. Volumetric deficits in prefrontal gray and/or white matter are found in attention deficit/hyperactivity disorder, schizophrenia, obsessive–compulsive disorder, depression, and dementia.

This chapter aims to present a conceptual model of prefrontal function that, by deductive and synthetic reasoning, accommodates the empirical evidence discussed in previous chapters of the book. The model is essentially based on four general propositions for which there is now overwhelming empirical support: the entirety of the cortex of the frontal lobe is devoted to the representation and production of action at all levels of biological complexity; the neuronal substrate for the production of any action is identical to the substrate for its representation; that substrate is organized hierarchically, with the most elementary actions at low levels of the hierarchy, in orbitofrontal and motor cortex, and the most complex and abstract actions in lateral prefrontal cortex; frontal-lobe functions are also organized hierarchically, with simpler functions nested within, and serving, more global functions. The three principal executive functions of the prefrontal cortex, at the service of the organization and implementation of action, are executive attention, planning, and decision-making. Executive attention is the first major executive function of the prefrontal cortex, and has three aspects or sub-functions: preparatory set, working memory, and control of interference. Planning is the second major executive function of the prefrontal cortex, as it is essential for the formulation and execution of novel plans or structures (gestalts) of goal-directed behavior. Decision-making is the third major executive function of the prefrontal cortex. The orbitomedial prefrontal cortex plays a crucial role in emotional behavior.

This chapter discusses the involvement of certain prefrontal areas in the collection of sensory inputs, the generation of motor outputs, and their visceral and emotional functions, all of which undoubtedly serve the eminently integrative executive functions of the frontal lobe. Electrophysiological data corroborate the connective links of the prefrontal cortex. In accord with anatomical evidence, fiber connections of this cortex with other cortical regions, with the thalamus, and with the basal ganglia have been electrically traced. Significantly complementing and substantiating lesion studies, electrophysiological research has provided insight into the roles of the prefrontal cortex in sensory, motor, visceral/emotional, social, and executive functions. Because of the abundant convergence of sensory inputs on the cortex of the prefrontal convexity of the primate, it is justified to consider most of that cortex to be cortex of sensory association. It mediates behavioral and cognitive associations between stimuli of diverse origin and qualities. The prefrontal cortex also plays a role in sensorial attention. Electrophysiological research provides evidence of the prefrontal control of movement. Neuronal activity in the caudate nucleus, a major collector of output from the prefrontal cortex to motor systems, is modulated by abundant influences from prefrontal cortex. Orbital and medial areas of the prefrontal cortex control a variety of visceral and hormonal functions. Four executive functions have well-substantiated electrophysiological correlates: attention, working memory, anticipatory activity, and monitoring.

This chapter focuses on the anatomy and developmental neurobiology of the prefrontal cortex. It begins with a discussion of issues related to the phylogenetic development and comparative anatomy of the neocortex of the frontal lobe. The chapter also deals with its ontogenetic development and the morphological changes it undergoes as a result of aging. The ontogenetic development of the prefrontal cortex reflects its phylogeny. Orbitomedial areas mature earlier than lateral ones. In early life, neurons in the prefrontal cortex proliferate migrate to their ultimate cortical destination, and experience growth according to the timetable that prevails throughout the neocortex. The chapter then deals with the anatomy and microscopic architecture of the prefrontal cortex in the adult organism. Different regions of the prefrontal cortex have different sets of reciprocal connections. An overview of the afferent and efferent connections of the prefrontal cortex in several species is also provided in the chapter. This overview of connectivity of the prefrontal cortex, arguably the most richly connected of all cortical regions, opens the way to subsequent chapters, where connectivity is found to be the key to all its functions.

We have studied a neurodynamic model of cross-modal and cross-temporal associations. We show that a network of integrate-and-fire neurons can generate spiking activity with realistic dynamics during the delay period of a paired associates task. In particular, the activity of the model resembles reported data from single-cell recordings in the prefrontal cortex.

We describe the use of near-infrared spectroscopy (NIRS) as a suitable means of assessing hemodynamic changes in the cerebral cortex of awake and behaving monkeys. NIRS can be applied to animals performing cognitive tasks in conjunction with electrophysiological methods, thus offering the possibility of investigating cortical neurovascular coupling in cognition. Because it imposes fewer constraints on behavior than fMRI, NIRS appears more practical than fMRI for certain studies of cognitive neuroscience on the primate cortex. In the present study, NIRS and field potential signals were simultaneously recorded from the association cortex (posterior parietal and prefrontal) of monkeys performing two delay tasks, one spatial and the other non-spatial. Working memory was accompanied by an increase in oxygenated hemoglobin mirrored by a decrease in deoxygenated hemoglobin. Both the trends and the amplitudes of these changes differed by task and by area. Field potential records revealed slow negative potentials that preceded the task trials and persisted during their memory period. The negativity during that period was greater in prefrontal than in parietal cortex. Between tasks, the potential differences were less pronounced than the hemodynamic differences. The present feasibility study lays the groundwork for future correlative studies of cognitive function and neurovascular coupling in the primate.

In phylogeny as in ontogeny, the association cortex of the frontal lobe, also known as the prefrontal cortex, is a late-developing region of the neocortex. It is also one of the cortical regions to undergo the greatest expansion in the course of both evolution and individual maturation. In the human adult, the prefrontal cortex constitutes as much as nearly one-third of the totality of the neocortex. The protracted, relatively large, development of the prefrontal cortex is manifest in gross morphology as well as fine structure. In the developing individual, its late maturation is made most apparent by the late myelination of its axonal connections. This and other indices of morphological development of the prefrontal cortex correlate with the development of cognitive functions that neuropsychological studies in animals and humans have ascribed to this cortex. In broad outline, the ventromedial areas of the prefrontal cortex, which with respect to other prefrontal areas develop relatively early, are involved in the expression and control of emotional and instinctual behaviors. On the other hand, the late maturing areas of the lateral prefrontal convexity are principally involved in higher executive functions. The most general executive function of the lateral prefrontal cortex is the temporal organization of goal-directed actions in the domains of behavior, cognition, and language. In all three domains, that global function is supported by a fundamental role of the lateral prefrontal cortex in temporal integration, that is, the integration of temporally discontinuous percepts and neural inputs into coherent structures of action. Temporal integration is in turn served by at least three cognitive functions of somewhat different prefrontal topography: working memory, preparatory set, and inhibitory control. These functions engage the prefrontal cortex in interactive cooperation with other neocortical regions. The development of language epitomizes the development of temporal integrative cognitive functions and their underlying neural substrate, notably the lateral prefrontal cortex and other late-developing cortical regions.

The prefrontal cortex is one of the latest regions of the neocortex to develop, in both phylogeny and ontogeny. In the primate, the prefrontal cortex is anatomically divided into three major sectors: medial, orbital (or inferior), and dorsolateral. The dorsolateral sector is the association cortex of the convexity of the frontal lobe. Phylogenetically and ontogenetically, this part of the prefrontal cortex is the one to develop last and most. It is the neural substrate of the higher cognitive functions that reach their maximum development in the human brain. The most general and distinctive function of the dorsolateral prefrontal cortex is the temporal organization of goal-directed actions. In the human, this role extends to the domains of speech and reasoning. Two temporally symmetrical and mutually complementary cognitive functions—one retrospective and the other prospective—support that general prefrontal function of temporal organization: (1) active short-term memory, also called working memory; (2) prospective or preparatory set. The dorsolateral prefrontal cortex interacts with other cortical and subcortical structures in those two time-bridging functions at the basis of the temporal organization of behavior.

This chapter presents a conceptual model of the representational and executive functions of the cortex of the frontal lobe derived from empirical evidence obtained principally in the monkey. According to this model, the neuronal networks of the frontal lobe that represent motor or executive memories are probably the same networks that cooperate with other cerebral structures in the temporal organization of behavior. The prefrontal cortex, at the top of the perception-action cycle, plays a critical role in the mediation of contingencies of action across time, an essential aspect of the temporal organization of behavior. That role of cross-temporal mediation is based on the interplay of two short-term cognitive functions: one retrospective, of short-term memory or sensory working memory, and the other prospective, of attentive set (or motor working memory). Both appear represented in the neuronal populations of dorsolateral prefrontal cortex. At least one of the mechanisms for the retention of working memory of either kind seems to be the reentry of excitability through recurrent cortical circuits. With those two complementary and temporally symmetrical cognitive functions of active memory for the sensory past and for the motor future, the prefrontal cortex secures the temporal closure at the top of the perception-action cycle.

The cortex of the frontal lobe reaches maximum phylogenetic development in the brain of the human. It is cortex devoted to the organization of action in all neurobiological and cognitive domains - skeletal movement, eye movement, speech and logical reasoning. Thus the frontal cortex may be called 'motor cortex' in the widest sense. The association cortex of the frontal lobe, commonly called prefrontal cortex, is in charge of the temporal organization of behaviour, speech and thinking. Prefrontal lesions frequently lead to disorders of temporal organization, especially in thinking and the spoken language. The prefrontal cortex serves temporal organization by coordinating three cognitive operations that are essential for the formation of 'gestalts' in the time domain: (i) preparatory set; (ii) working memory; and (iii) inhibitory control of interference. Temporal organization is disturbed in the schizophrenic patient, probably because of a functional disorder of the connectivity between the prefrontal cortex and other cortical areas, as well as limbic and striatal structures (a 'disconnection syndrome').

Single-unit activity was recorded from the hand areas of the somatosensory cortex of monkeys trained to perform a haptic delayed matching to sample task with objects of identical dimensions but different surface features. During the memory retention period of the task (delay), many units showed sustained firing frequency change, either excitation or inhibition. In some cases, firing during that period was significantly higher after one sample object than after another. These observations indicate the participation of somatosensory neurons not only in the perception but in the short-term memory of tactile stimuli. Neurons most directly implicated in tactile memory are (i) those with object-selective delay activity, (ii) those with nondifferential delay activity but without activity related to preparation for movement, and (iii) those with delay activity in the haptic-haptic delayed matching task but no such activity in a control visuo-haptic delayed matching task. The results indicate that cells in early stages of cortical somatosensory processing participate in haptic short-term memory.

A delayed match-to-sample (DMS) task of abstract, visual memory was performed during the uptake period of 18F-fluorodeoxyglucose. The increase in glucose uptake of cortical and subcortical regions ("activation") during the DMS task was compared with that during a control, immediate match-to-sample task using positron emission tomography. Both discriminant analysis and paired t tests supported the observation that the dorsolateral prefrontal area underwent the greatest activation, while a factor analysis revealed the functional correlation matrices of the tasks. Activations in the ventral premotor cortex and supramarginal and angular gyri were highly correlated with the change in the dorsolateral prefrontal cortex. The basal forebrain/ventral pole region showed a smaller but independently significant change. The findings support the role of the dorsal prefrontal region in the nonspatial working memory of humans.

Neurons in the cortex exhibit a number of patterns that correlate with working memory. Specifically, averaged across trials of working memory tasks, neurons exhibit different firing rate patterns during the delay of those tasks. These patterns include: 1) persistent fixed-frequency elevated rates above baseline, 2) elevated rates that decay throughout the tasks memory period, 3) rates that accelerate throughout the delay, and 4) patterns of inhibited firing (below baseline) analogous to each of the preceding excitatory patterns. Persistent elevated rate patterns are believed to be the neural correlate of working memory retention and preparation for execution of behavioral/motor responses as required in working memory tasks. Models have proposed that such activity corresponds to stable attractors in cortical neural networks with fixed synaptic weights. However, the variability in patterned behavior and the firing statistics of real neurons across the entire range of those behaviors across and within trials of working memory tasks are typical not reproduced. Here we examine the effect of dynamic synapses and network architectures with multiple cortical areas on the states and dynamics of working memory networks. The analysis indicates that the multiple pattern types exhibited by cells in working memory networks are inherent in networks with dynamic synapses, and that the variability and firing statistics in such networks with distributed architectures agree with that observed in the cortex.

An expanding body of literature describes the existence of concerted brain activations in the absence of any external stimuli. Resting-state networks have been identified and demonstrated to be modulated during the performance of specific cognitive operations. However, despite mounting evidence the possibility still remains that those correlated signal fluctuations reflect non-neural phenomena. In order to isolate functionally relevant spontaneous coactivations, we utilized a multi-level sampling approach to obtain co-registered brain signals across a range of sampling resolution and sensitivity. Surface and local field potentials, hemodynamic signals (near-infrared spectroscopy, NIRS), and cell spiking were recorded from dorsolateral prefrontal and posterior parietal cortices in four monkeys trained to remain motionless in a primate chair. The use of an optical recording technique (NIRS) allows measurement of a signal that is physiologically equivalent to that obtained using BOLD fMRI, though with millisecond temporal resolution and minimal technical or environmental constraints. The different signal types exhibited correlations between the two regions of interest in both the frequency and time domains. This evidence suggests that the resting-state network activations detected by fMRI do in fact reflect functional coactivations of areas across multiple levels of network communication.

The role of prefrontal cortex in working memory (WM) is well established. However, questions remain regarding the topography and “domain-specific differentiation” of different types of information processing in the cortex. While it has been theorized that dorsolateral (DPFC) and ventrolateral (VPFC) prefrontal cortex preferentially process spatial and object WM, respectively, both electrophysiological evidence in the monkey and neuroimaging in the human have largely failed to demonstrate such regional differentiation. In this study we use near-infrared spectroscopy (NIRS) to detect functional changes, across relatively large cortical cell populations, simultaneously from prefrontal and posterior parietal cortices. Imaging data were recorded from a Rhesus macaque performing two types of WM tasks: a spatial task in which the animal had to retain the spatial position of a visual stimulus, and a non-spatial task where he had to retain its color (red or green) during a 20s delay. During performance of the spatial WM task, cerebral activation trends were found in which DPFC exhibited stronger activation than did the VPFC, and posterior parietal cortex maintained higher delay activation than did frontal regions. These differences were less pronounced during performance of the non-spatial task. Additionally, incorrect trials generally elicited lower activations during the delay period than did trials ending with a correct response. Furthermore, NIRS data collected during the performance of a haptic WM task also appear to exhibit inter-regional differences in delay activation. The data thus suggest the presence of preferential cognitive processing between and within posterior and frontal cortical regions.

Publisher Summary This chapter focuses on use of neuroimaging to study parts of brains, including prefrontal cortex. By use of noninvasive methods, it is now possible to assess regional cerebral blood flow (rCBF) or metabolism, and in this manner, indirectly, the levels of neuronal activity in various parts of the brain. Functional neuroimaging provides indirect records of activity simultaneously in various regions of the brain—in other words, functional maps of the brain. All neuroimaging is still subject to unresolved methodological problems that basically stem from the uncertain relationships between neuronal firing and the imaged variables, especially blood flow (neurovascular coupling). Despite these problems, remarkable progress has been made toward unraveling, by essentially noninvasive methods, the functions and dysfunctions of the human prefrontal cortex. Using positron emission tomography (PET), changes and differences in the concentration of radioactive tracers, and thus in neural activity, can be discerned in the millimeter range. For structural imaging of brain, the definition obtained by magnetic resonance imaging (MRI) is unsurpassed. In recent years, functional MRI has been developed and applied to the analysis of temporal changes in oxygenation or blood flow. Functional MRI (fMRI), by the blood oxygen level-dependent (BOLD) method, has thus become the preferred method for imaging the course of oxygenation, and by inference neuronal activity, in nervous tissue. Neuroimaging during sensory stimulation of various modalities substantiates the convergence of cortical sensory pathways upon prefrontal cortex that anatomical and physiological studies indicate.

Publisher Summary This chapter discusses the involvement of certain prefrontal areas in the collection of sensory inputs, the generation of motor outputs, and their visceral and emotional functions, all of which undoubtedly serve the eminently integrative executive functions of the frontal lobe. Electrophysiological data corroborate the connective links of the prefrontal cortex. In accord with anatomical evidence, fiber connections of this cortex with other cortical regions, with the thalamus, and with the basal ganglia have been electrically traced. Significantly complementing and substantiating lesion studies, electrophysiological research has provided insight into the roles of the prefrontal cortex in sensory, motor, visceral/emotional, social, and executive functions. Because of the abundant convergence of sensory inputs on the cortex of the prefrontal convexity of the primate, it is justified to consider most of that cortex to be cortex of sensory association. It mediates behavioral and cognitive associations between stimuli of diverse origin and qualities. The prefrontal cortex also plays a role in sensorial attention. Electrophysiological research provides evidence of the prefrontal control of movement. Neuronal activity in the caudate nucleus, a major collector of output from the prefrontal cortex to motor systems, is modulated by abundant influences from prefrontal cortex. Orbital and medial areas of the prefrontal cortex control a variety of visceral and hormonal functions. Four executive functions have well-substantiated electrophysiological correlates: attention, working memory, anticipatory activity, and monitoring.

Publisher Summary This chapter focuses on studies of the functions of the prefrontal cortex in animals. An experimental lesion in the prefrontal cortex remains a prime tool of neuropsychology. Lesions of the prefrontal cortex elicit characteristic behavioral abnormalities. These fall into three major categories: disorders of motility, disorders of emotion and social behavior, and deficits in performance of cognitive tasks, notably delay tasks. Some of the abnormalities are closely interrelated and denote the alteration of common functions, such as attention. Large ablations of the prefrontal cortex generally result in the impoverishment of emotional life and social isolation of the animal. Certain prefrontal lesions involving medial or basal prefrontal cortex have been seen to induce behavioral changes suggesting disinhibition of aggression and hunger drives, especially in carnivores. Hyperactivity effect of ablation is the most consistently observed in the macaque with an orbital lesion. Dorsolateral lesions may lead to increased aggressiveness, often accompanied by blunted emotional expression and communication. This deficit may be based largely on a cognitive impairment. Among the most consistent cognitive impairments of the animal with a prefrontal lesion are those of attention. The aging of the prefrontal cortex is accompanied by diminishing capacity to learn and perform cognitive tasks that depend on the functional integrity of this cortex, especially working short-term memory tasks.

Publisher Summary This chapter deals with neuropsychological effects of prefrontal damage in humans. The main sources of empirical data on the effects of prefrontal damage in the human are diseases and traumatic lesions of the frontal lobe, and cases of frontal psychosurgery. The neuropsychological effects of prefrontal damage vary greatly depending on the location and the extent of that damage. Apathy and general disinterest are common results of a large prefrontal lesion, especial if it involves lateral or medial cortex. Depression is the most common affective disorder from more circumscribed prefrontal lesions, especially if they involve the left lateral and polar cortex, although some affective disorders can result from orbital damage as well. Orbital lesions are accompanied by hyperreactivity to extraneous or irrelevant stimuli, yet low reactivity to emotional stimuli. They also lead to the weakening of autonomic or visceral signals that are concomitant to normal emotion. All prefrontal lesions, by reason of the emotional and cognitive changes they produce, tend to affect adversely the social life of the patient, usually constricting it. Orbital lesions, however, generally induce the most dramatic changes in social behavior, and these changes are usually opposite to social restraint. In the cognitive sphere, disorders of attention are the most common disorders of executive function caused by prefrontal damage. Those abnormalities of the control of attention may take several forms: loss of general alertness, sensory neglect, excessive distractibility, set-shifting disorder, disorder of ocular control, difficulty in sustaining attention, internal interference, and faulty executive set (executive attention).

Publisher Summary This chapter presents a discussion on chemical neurotransmission and role of chemical neurotransmitters in the prefrontal cortex. It begins with an introduction to neurotransmitters and neurotransmitter receptors. Cells produce certain chemical substances called neurotransmitters and neuromodulators that, through specific receptors embedded in pre- and postsynaptic membranes, modify the electrical activity of other nerve cells. The most important classes of neurotransmitters thus far identified in the cerebral cortex include: amino acids (i.e. glutamate (Glu), aspartate, γ -aminobutyric acid [GABA]); the monoamines, including two catecholamines, dopamine (DA) and norepinephrine (NE), and an indoleamine, 5-hydroxytriptamine (5-HT) or serotonin; Acetylcholine (ACh); and neuropeptides (e.g., enkephalins, substance P, somatostatin, neurotensin). Among the six best-known transmitters in prefrontal transmitters include Glu, GABA, NE, DA, 5-HT, and Ach. GABA is the prime inhibitory neurotransmitter in the central nervous system. Glutamate is the prime excitatory neurotransmitter in the cortex. It serves not only the local prefrontal circuitry but also the excitatory connectivity of the prefrontal cortex with striatal, thalamic, and limbic structures. The three monoaminergic systems, with their cells of origin in the brainstem, innervate the prefrontal cortex by way of ascending fiber paths that bypass the thalamus: the noradrenergic system (its transmitter NE) from the nucleus coeruleus, the dopaminergic system (its transmitter DA) from the ventral tegmentum, and the serotonergic system (its transmitter, serotonin, 5-HT) from the nuclei of the raphe. In addition to the monoamines, the prefrontal cortex, like the rest of the neocortex, receives profuse afferents from the subcortical components of the cholinergic system. Also active in the prefrontal cortex are a number of neuropeptides (somatostatin, substance P, CCK, angiotensin, neurotensin, and others) that act there as neurotransmitters or neuromodulators.

Executive actions are represented and hierarchically organized in the cortex of the frontal lobe. The representation and coordination of an action or series of actions have the same anatomical substrate: an executive neuronal network (cognit) in forntal cortex. That network interacts structurally and dynamically with perceptual networks of posterior cortex at the highest levels of the perception–action cycle.

Cells in the somatosensory cortex of the monkey are known to exhibit sustained elevations of firing frequency during the short-term mnemonic retention of tactile information in a haptic delay task. In this study, we examine the possibility that those firing elevations are accompanied by changes in firing pattern. Patterns are identified by the application of a pattern-searching algorithm to the interspike intervals of spike trains. By sequential use of sets of pattern templates with a range of temporal resolutions, we find patterned activity in the majority of the cells investigated. In general, the degree of patterning significantly increases during active memory. Surrogate analysis suggests that the observed patterns may not be simple linear stochastic functions of instantaneous or average firing frequency. Therefore, during the active retention of a memorandum, the activity of a 'memory cell' may be characterized not only by changes in frequency but also by changes in pattern.

The neural substrate for behavioral, cognitive and linguistic actions is hierarchically organized in the cortex of the frontal lobe. In their methodologically impeccable study, Koechlin et al. reveal the neural dynamics of the frontal hierarchy in behavioral action. Progressively higher areas control the performance of actions requiring the integration of progressively more complex and temporally dispersed information. The study substantiates the crucial role of the prefrontal cortex in the temporal organization of behavior.

Neurons in the monkey’s anterior parietal cortex (Brodmann’s areas 3a, 3b, 1, and 2) have been reported to retain information from a visual cue that has been associated with a tactile stimulus in a haptic memory task. This cross-modal transfer indicates that neurons in somatosensory cortex can respond to non-tactile stimuli if they are associated with tactile information needed for performance of the task. We hypothesized that neurons in somatosensory cortex would be activated by other non-tactile stimuli signaling the haptic movements—of arm and hand—that the task required. We found such cells in anterior parietal areas. They reacted with short-latency activity changes to an auditory signal (a click) that prompted those movements. Further, some of those cells changed their discharge in temporal correlation with the movements themselves, with the touch of the test objects, and with the short-term memory of those objects for subsequent tactile discrimination. These findings suggest that cells in the somatosensory cortex participate in the behavioral integration of auditory stimuli with other sensory stimuli and with motor acts that are associated with those stimuli.

Recent studies show that cells in the somatosensory cortex are involved in the short-term retention of tactile information. In addition, some somatosensory cells appear to retain visual information that has been associated with the touch of an object. The presence of such cells suggests that nontactile stimuli associated with touch have access to cortical neuron networks engaged in the haptic sense. Thus, we inferred that somatosensory cells would respond to behaviorally associated visual and tactile stimuli. To test this assumption, single units were recorded from the anterior parietal cortex (Brodmann's areas 3a, 3b, 1, and 2) of monkeys performing a visuo-haptic delay task, which required the memorization of a visual cue for a tactile choice. Most cells responding to that cue responded also to the corresponding object presented for tactile choice. Significant correlations were observed in some cells between their differential reactions to tactile objects and their differential reactions to the associated visual cues. Some cells were recorded in both the cross-modal task and a haptic unimodal task, where the animal had to retain a tactile cue for a tactile choice. In most of these cells, correlations were observed between stimulus-related firing in corresponding cue periods of the two tasks. These findings suggest that cells in somatosensory cortex are the components of neuronal networks representing tactile information. Associated visual stimuli may activate such networks through visuo-haptic associations established by behavioral training.

The neuronal networks of the frontal lobe that represent motor or executive memories are probably the same networks that cooperate with other cerebral structures in the temporal organization of behavior. The prefrontal cortex, at the top of the perception-action cycle, plays a critical role in the mediation of contingencies of action across time, an essential aspect of temporal organization. That role of cross-temporal mediation is based on the interplay of two short-term cognitive functions: one retrospective, of short-term active perceptual memory, and the other prospective, of attentive set (or active motor memory). Both appear represented in the neuronal populations of dorsolateral prefrontal cortex. At least one of the mechanisms for the retention of active memory of either kind seems to be the reentry of excitability through recurrent cortical circuits. With those two complementary and temporally symmetrical cognitive functions of active memory for the sensory past and for the motor future, the prefrontal cortex seems to secure the temporal closure at the top of the perception-action cycle.

The prefrontal cortex is essential for the temporal integration of sensory information in behavioural and linguistic sequences. Such information is commonly encoded in more than one sense modality, notably sight and sound. Connections from sensory cortices to the prefrontal cortex support its integrative function. Here we present the first evidence that prefrontal cortex cells associate visual and auditory stimuli across time. We gave monkeys the task of remembering a tone of a certain pitch for 10 s and then choosing the colour associated with it. In this task, prefrontal cortex cells responded selectively to tones, and most of them also responded to colours according to the task rule. Thus, their reaction to a tone was correlated with their subsequent reaction to the associated colour. This correlation faltered in trials ending in behavioural error. We conclude that prefrontal cortex neurons are part of integrative networks that represent behaviourally meaningful cross-modal associations. The orderly and timely activation of neurons in such networks is crucial for the temporal transfer of information in the structuring of behaviour, reasoning and language.

Memory networks are formed in the cerebral cortex by associative processes, following Hebbian principles of synaptic modulation. Sensory and motor memory networks are made of elementary representations in cell assemblies of primary sensory and motor cortex (phyletic memory). Higher-order individual memories, e.g. episodic, semantic, conceptual — are represented in hierarchically organized neuronal networks of the cortex of association. Perceptual memories are organized in posterior (post-rolandic) cortex, motor (executive) memories in cortex of the frontal lobe. Memory networks overlap and interact profusely with one another, such that a cellular assembly can be part of many memories or networks. Working memory essentially consists in the temporary activation of a memory network, as needed for the execution of successive acts in a temporal structure of behavior. That activation of the network is maintained by recurrent excitation through reentrant circuits. The recurrent reentry may occur within local circuits as well as between separate cortical areas. In either case. recurrence binds together the associated components of the network and thus of the memory it represents.

In the primate, the cortex of the frontal lobe appears devoted in its entirety to the representation and execution of actions. The frontal cortex as a whole can therefore be considered “motor cortex” in the broadest sense of the word. It coordinates actions in practically all the domains of adaptation of the organism to its environment; skeletal and ocular motility, logical reasoning, communication and the spoken language. Even visceral actions and emotional behavior are regulated by certain orbital and medial areas of the frontal cortex. This chapter outlines the rationale for the role of the dorsolateral prefrontal cortex in the temporal organization of action, as well as some of the mechanisms that support it. It begins with certain basic assumptions about the cortex in general and the frontal cortex in particular. The cognitive functions of the cortex of the frontal lobe, as those of any other part of the neocortex, consist in the activation and processing within and between networks of representation, or memory networks. Those networks are widely distributed and highly specific, defined by their synaptic structure and connectivity. Thus, the memory code is a relational code, and all memory is associative. The cortical networks of memory extend across modules and areas by any anatomical definition. Memory networks overlap and are profusely interconnected with one another. Thus, one neuron or group of neurons anywhere in the cortex can be a part of many networks and thus many memories. This is why it is virtually impossible, by any method, to localize a memory.

The dorsolateral prefrontal cortex (DPFC) and the posterior parietal cortex (PPC) are anatomically and functionally interconnected, and have been implicated in working memory and the preparation for behavioral action. To substantiate those functions at the neuronal level, we designed a visuomotor task that dissociated the perceptual and executive aspects of the perception-action cycle in both space and time. In that task, the trial-initiating cue (a color) indicated with different degrees of certainty the direction of the correct manual response 12 s later. We recorded extracellular activity from 258 prefrontal and 223 parietal units in two monkeys performing the task. In the DPFC, some units (memory cells) were attuned to the color of the cue, independent of the response-direction it connoted. Their discharge tended to diminish in the course of the delay between cue and response. In contrast, few color-related units were found in PPC, and these did not show decreasing patterns of delay activity. Other units in both cortices (set cells) were attuned to response-direction and tended to accelerate their firing in anticipation of the response and in proportion to the predictability of its direction. A third group of units was related to the determinacy of the act; their firing was attuned to the certainty with which the animal could predict the correct response, whatever its direction. Cells of the three types were found closely intermingled histologically. These findings further support and define the role of DPFC in executive functions and in the temporal closure of the perception-action cycle. The findings also agree with the involvement of PPC in spatial aspects of visuomotor behavior, and add a temporal integrative dimension to that involvement. Together, the results provide physiological evidence for the role of a prefrontal-parietal network in the integration of perception with action across time. Language: en

One example of “emergence” is the development, as a result of neural ontogeny and living experience, of cortical networks capable of representing and retaining cognitive information. A large body of evidence from neuropsychology, electrophysiology and neuroimaging indi­cates that so-called working memory and long-term memory share the same neural substrate in the cerebral cortex. That substrate consists in a system of widespread, overlapping and hierarchically organized networks of cortical neurons. In this system, any neuron or group of neurons can be part of many networks, and thus many memories. Working memory is the temporary activation of one such network of long-term memory for the purpose of executing an action in the near future. The activation of the network may be brought about by stimuli that by virtue of prior experience are in some manner associated with the cognitive content of the network, including the response of the organism to those stimuli. The mechanisms by which the network stays activated are presumed to include the recurrent re-entry of impulses through associated neuronal assemblies of the network. Consistent with this notion is the following evidence: (1) working memory depends on the functional integrity of cortico-corti-cal connective loops; and (2) during working memory, remarkable similarities -including “attractor behavior” -have been observed between firing patterns in real cortex and in an artificial recurrent network.

Neuropsychology points to the wide distribution of cortical memory networks. Electrophysiology and neuroimaging indicate that working memory, like long-term memory, is a widely distributed function, largely neocortical. Most of the evidence available from those three methodologies suggests that both working memory and long-term memory share the same substrate: a system of broad, partly overlapping and interconnected neocortical networks. Working memory appears mostly, if not completely, characterized by the sustained activation of one widely distributed network of long-term memory. That activation is at least in part sustained by reentrant excitatory loops through the different neuronal assemblies that constitute the network and that represent the associated features of the memorandum.

Single-unit spike trains recorded from parietal cortex of monkeys performing a tactile short-term memory task show characteristic fluctuations (transitions) in their firing frequency that are related to memory. Spike trains recorded during the memory period, when the animal must retain information for the short term, show a higher rate of such transitions than spike trains recorded during intertrial baseline periods. In the present study, an analysis of multiple temporal resolutions over which these transitions are observed reveals that the memory-related transitions occur most prominently in the 25–50 Hz range. The results of this study suggest that, in the monkey, high frequency fluctuations of neuronal discharge in the parietal cortex are correlated with haptic short-term memory. The presence of such fluctuations are also consistent with theoretical models of short-term memory.

Studies have shown that in the monkey′s associative cerebral cortex, cells undergo sustained activation of discharge while the animal retains information for a subsequent action. Recent work has revealed the presence of such ″memory cells″ in the anterior parietal cortex (Brodmann′s areas 3a, 3b, 1, and 2) – the early stage of the cortical somatosensory system. Here we inferred that, in a cross-modal visuo-haptic short-term memory task, somatosensory cells would react to visual stimuli associated with tactile features. Single-unit discharge was recorded from the anterior parietal cortex – including areas of hand representation – of monkeys performing a visuo-haptic delayed matching-to-sample task. Units changed firing frequency during the presentation of a visual cue that the animal had to remember for making a correct tactile choice between two objects at the end of a delay (retention period). Some units showed sustained activation during the delay. In some of them that activation differed depending on the cue. These findings suggest that units in somatosensory cortex react to visual stimuli behaviorally associated with tactile information. Further, the results suggest that some of these neurons are involved in short-term active memory and may, therefore, be part of cross-modal memory networks.

Bodner, Mark, Yong-Di Zhou, and Joaquı́n M. Fuster. Binary mapping of cortical spike trains in short-term memory. J. Neurophysiol. 77: 2219–2222, 1997. Microelectrode studies in monkeys performing short-term memory tasks show the sustained elevated discharge of cortical neurons during the retention of recalled sensory information. Cortical cells that are part of memory networks are assumed to receive numerous inputs of excitatory as well as inhibitory nature and local as well as remote. Thus it is reasonable to postulate that the temporal and spatial summation of diverse inputs on any cell in an activated network will result in temporally discrete groups of spikes in its firing. The activation of a network in active memory supposedly increases the magnitude and diversity of those inputs and thus increases the discontinuities and frequency fluctuations in the firing of cells in the network. In this study we use a new method of analysis that allows the quantification of firing discontinuities in a spike train. We apply it to parietal cells recorded from monkeys during the performance of a tactile short-term memory task. In our method, time is divided into bins of equal duration and the measure of discontinuities is the total count of the number of transitions between consecutive time bins with and without spikes. The results of the analysis show that in many of the cells studied, discontinuities (transitions between spiking and nonspiking) reflect memory-related activity obscured in the measures of raw spike frequency over a wide range of frequencies. These cells show more firing transitions in active short-term memory than in baseline (intertrial) conditions.

The activity of single neurons was recorded extracellularly from dorsolateral prefrontal cortex (DPC) of monkeys during the performance of a cross-modal audio-visual short-term memory task. Cells in DPC show sustained elevated firing levels (higher than spontaneous discharge) during the retention of the auditory stimulus. In some cells this elevated firing was significantly different depending on the particular auditory memorandum of each trial. These results support the notion that DPC participates in auditory short-term memory and the integration of auditory and visual information for prospective action.

Motor representations are hierarchically organized in dorsolateral frontal cortex. The highest, most global plans and schemes of action appear to be represented in prefrontal cortex, intermediate ones in premotor cortex, and the most elementary motor acts in primary motor cortex. The confluence of external and internal inputs on frontal cortex leads to the activation of frontal neuron networks representing different categories of action. The activation of these networks is the physiological substrate for the initiation and execution of behavioral action.

The main purpose of this study was to explore the role of dorsolateral prefrontal cortex in skilled and sequential haptic performance. Monkeys were trained to perform a delayed matching-to-sample task that required the memorization of three-dimensional objects perceived either by palpation (haptically) or by sight. At the start of a trial the animal was allowed to touch or view an object, the sample; after a period of delay, during which the object remained out of touch and out of sight, the animal was presented with two side-by-side objects--one of them the sample--for either tactile or visual recognition, and the choice of the sample (correct match) was rewarded. Three variants of the task were used: (1) visual sample, haptic match; (2) haptic sample, visual match; and (3) haptic sample, haptic match. The temporary bilateral cooling of dorsolateral prefrontal cortex to 15 degrees C induced a reversible deficit in performance of all three tasks. Cooling to the same degree a portion of posterior parietal cortex of equivalent size did not significantly alter either performance or reaction time. These findings indicate that the functional integrity of the dorsolateral prefrontal cortex is important for performance of sequential behavior dependent on haptic skill. Further, the results suggest that the role of this cortex in active memory, already well documented for spatially and nonspatially defined visual information, extends also to tactile information and associated motor acts.

Studies of subhuman primates and man have shown that the prefrontal cortex is important for spatial working memory. We have used 18fluorodeoxyglucose positron emission tomography (18FDG-PET) to study a non-spatial, abstract visual memory task of in man. Using a regions-of-interest approach with discriminant analysis of the relative regional cerebral metabolic rate of glucose consumption (rCMRGlc), we found that changes in dorsal prefrontal, premotor/motor frontal and posterior cingulate areas differentiated the primary memory task from the control task. Less robust increases in glucose uptake were observed in lateral parietal cortex, while some subcortical and limbic regions showed decreases. This is the first activation study with a non-spatial, visual task. These results complement previous studies in that they substantiate the role of the prefrontal cortex in the mediation of cross-temporal contingencies of behavior, and point to a role of the premotor region in this mediation as well.

Single-neuron discharge was recorded from prefrontal and posterior parietal cortex in monkeys performing a visuo-motor memory task with temporal and spatial separation between cue (color) and directional manual response. During the delay interval between cue and response, neurons in both cortices engaged in two concurrent and reciprocal trends of discharge: (a) sensory-coupled, decelerating firing apparently related to color retention, or (b) motor-coupled, accelerating firing apparently related to the anticipated response direction. In both cortices, the acceleration of the direction-anticipating activity was related to the probability with which the animal could predict, and prepare for, the correct response site. Our findings suggest that neurons from prefrontal and parietal cortex are part of distributed networks, with representational and operational properties, for visuomotor cognitive processing.