Executive Functions in Health and Disease

States

Preface

Elkhonon Goldberg

Neuroscience used to be the monopoly of a few elite universities located in a handful of countries. Neuropsychology used to be a quaint niche discipline relatively unconnected to the larger world of neuroscience and content in its methods with paper-and-pencil tests. Neuroscience itself was relatively unconcerned with higher-order cognition, and the very term cognitive neuroscience was often met with rolled eyes by scientists working in more established areas of brain research (a personal observation made in the 1980s and even 1990s on more than one occasion). And the interest in executive functions was shared by a very small club of neuropsychologists and neuroscientists, a fact often noted in their times by the pioneers of frontal-lobe research Alexander Luria and a generation later Patricia Goldman-Rakic.

None of this is true today. Important neuroscience research is conducted at numerous academic and biomedical centers worldwide. We are witnessing a substantial fusion, or at least blending, of cognitive neuroscience and neuropsychology. The terms executive functions and frontal-lobe functions are no longer used interchangeably, and a more refined understanding of both has emerged. Executive functions in health and disease have become the target of intense investigation by scores of researchers, arguably one of the most heavily populated territories of cognitive and clinical neuroscience (I recall a slide used in her lectures by the late Goldman-Rakic, with the number of stick-men drawn in each lobe reflecting the relative level of research interest in its functions. The slide, with its conspicuous near-absence of stick-men in the frontal lobe, would have to be re-drawn today). The range of research tools deployed for the understanding of executive function and dysfunction has also grown and continues to grow. Today it includes animal models, genetic studies, biochemical approaches, various forms of structural and functional neuroimaging, computational modeling involving neural nets and other methods, lesion and specific disorder studies, as well as a constantly expanding arsenal of sophisticated cognitive probes. In its clinical applications, the research into the nature of executive dysfunction is no longer limited to the traditional neuropsychological territory of focal lesions directly contained within the frontal lobes, and has expanded into a wide range of both focal and non-focal disorders whose impact is not restricted to the prefrontal cortex.

The vast expansion of interest in both healthy and impaired executive functions is reflected in the chapter composition of this book. Among the contributors are recognized authorities who played a pivotal role in shaping the modern understanding of executive functions, as well as young neuroscientists who joined the field relatively recently. The contributors employ a wide range of technologies and tools and conduct their research at universities in North America; Western, Central, and Eastern Europe; Asia; and Australia. Capturing the generational, geographic, and methodological expanse of the interest in executive functions has been the editor’s intent and is a distinguishing feature of the volume.

The book is divided into two sections: Executive Functions in Health and Executive Functions in Disease. In the first section, various aspects of healthy executive functions are examined. The topics include a broad general conceptualization of executive functions by a preeminent pioneer of the field (Joaquin Fuster); cellular mechanisms of executive functions and working memory (Taber Lightbourne and Amy Arnsten); gene expression in the frontal lobes (Zeljka Krznik and Goran Sedmak); large-scale networks and the frontal lobes (Adam Hampshire); computational neural net modeling of executive functions and decision making (Daniel Levine); frontal lobes and consciousness (Seth Lew and Hakwan Lau); neurodevelopmental aspects of executive functions (Layne Kalbfleisch); changes affecting executive functions in aging (Nathan Spreng, Leena Shoemaker, and Gary Turner); and a broad survey of neuropsychological assessment methods used in the neuropsychological research into executive functions (Yana Suchi, Rosemary Ziemnik, and Madison Niermeyer).

In the second sections, multiple forms of executive dysfunction are examined across a wide range of neurological, psychiatric, and medical conditions. Both broad categories of disorders and specific disorders are examined. The broad clinical categories examined include the mechanisms of cognitive, behavioral and emotional inflexibility, and perseveration across a number of neuropsychiatric disorders (Daniel Weisholtz, John Sullivan, Aaron Nelson, Kirk Daffner, and David Silbersweig); large-scale cognitive control network alteration in neuropsychiatric disorders, including autism, schizophrenia, and depression (Melissa-Ann Makie and Jin Fan); executive functions in neurodevelopmental disorders, including ADHD, focal frontal lesions, and epileptic foci (Masao Aihara); executive dysfunction in striatal disorders, including Parkinson’s disease, Huntington’s disease, and chronic stress (Joao Cergueira and Nuno Sousa); executive dysfunction in dementias, including Alzheimer’s disease, vascular dementia, frontotemporal dementia, progressive supranuclear palsy and corticobasal syndrome, motor neuron disease, Parkinson’s disease, Lewy body dementia, and Huntington’s disease (Michal Harciarek, Emilia Sitek, and Anna Barczak); executive dysfunction in medical conditions, including hypertension, diabetes mellitus, chronic kidney disease, HIV encephalopathy, hepatic encephalopathy, thyroid disease, and rheumatoid arthritis (Michal Harciarek and Aleksandra Wojtowicz); addictions to a number of substances, including cannabis, cocaine, methamphetamine, and opioids (Antonio Verdejo-Garcia); examination of the parallels between the effects of lateralized frontal lesions, hemiparkinsonian syndromes, and variants of Tourette’s syndrome (Kjell Hovik, Merete Oie, and Elkhonon Goldberg); as well as a broad survey of neuropsychological assessment methods used for the clinical assessment of executive functions (Yana Suchi). The specific disorders examined include executive dysfunction and efforts to rehabilitate it in traumatic brain injury (Irene Christofori and Jordan Grafman); frontal-lobe seizures (Sara Wildstein and Silvana Riggio); executive deficit in post-traumatic stress disorder (Jennifer Newman and Charles Marmar); and executive dysfunction in Tourette’s syndrome (Kjell Hovik).

From being a niche research enterprise, executive functions research has burgeoned into a vast area of neuroscience with its own niches and sub-niches, often with relatively little interaction between them. While probably unavoidable, such Balkanization of the field is unfortunate and self-defeating. Hopefully, combining in one volume chapters on basic and clinical executive functions research employing a variety of approaches and methodologies will help update the readers’ knowledge of the advances in their own niches as well as help familiarize them with the state of affairs in others; both update the readers about the more recent work by acknowledged leaders in the field, and introduce him to the new generation of neuroscientists advancing our understanding of executive function and dysfunction and representing the future of the field.

December 2016

New York City

Part I

Executive Functions in Health

Outline

Chapter 1 Prefrontal Executive Functions Predict and Preadapt

Chapter 2 The Cellular Mechanisms of Executive Functions and Working Memory: Relevance to Mental Disorders

Chapter 3 Gene Expression in the Frontal Lobe

Chapter 4 A Functional Network Perspective on the Role of the Frontal Lobes in Executive Cognition

Chapter 5 Neural Network Models of Human Executive Function and Decision Making

Chapter 6 Crucial Role of the Prefrontal Cortex in Conscious Perception

Chapter 7 Neurodevelopment of the Executive Functions

Chapter 8 Executive Functions and Neurocognitive Aging

Chapter 9 Assessment of Executive Functions in Research

Chapter 1

Prefrontal Executive Functions Predict and Preadapt

Joaquín M. Fuster,    Semel Institute, School of Medicine, University of California Los Angeles, Los Angeles, CA, United States

Abstract

The prefrontal cortex plays a critical role in the temporal organization of behavior and language within the broad neurobiological framework of the perception–action (PA) cycle, the circular processing of information that regulates the adaptation of the organism to its environment. That temporal organizing role of the prefrontal cortex is supported by three major executive functions that constitute the essential dynamic components of the cognitive control of behavior and language: (1) executive attention, (2) working memory, and (3) decision-making. The three functions are teleonomic in that they have a critical future perspective toward goal or reward. In this chapter, after discussion of the PA cycle and of the physiological role of the prefrontal cortex in it, executive attention, working memory, and decision-making are empirically placed in both cycle and cortex with the available experimental evidence.

Keywords

Prefrontal cortex; perception–action cycle; cognitive control; prospective executive function; attention; working memory; decision-making

Introduction

Based on the theory of evolution and his experience with the effects of brain lesions, Jackson, the father of neurology, was the first to postulate the hierarchical organization of the nervous system, which he considered both a representational and a coordinating system at all levels, from top to bottom (Jackson, 1882). To exemplify the identity of representational and executive neural substrates, he used the motor cortex. Here, the same assemblies of cells that represent a movement are in charge of its execution. By representation in this cortex he meant, of course, the executive memory of skeletal movement, which we may call phyletic memory because it is genetically inherited and common to all members of the species. In the frontal lobe, at the top of the executive motor hierarchy, Jackson placed the highest centers for the representation and execution of complex movement, the highest nerve agencies for the memory and coordination of the actions of the whole organism. He was obviously referring to premotor and prefrontal areas. Thus, extending his hierarchical principle to those cortical regions, he attributed the representation and coordination of purposeful and goal-directed actions. Language was one among them, which he called more specifically as the capacity to propositionise (Jackson, 1915). Luria, later (1966), would not only make that capacity a fundamental fontal function but also extend it to the coordination of all forms of complex action, in other words, to what Lashley (1951) had termed the syntax of action.

To propositionise is to make propositions, which for Jackson meant the commonly accepted ability to construct grammatical sentences with words and ideas. In modern times, however, based on a large body of clinical evidence, it can be confidently asserted that the propositions that higher frontal cortex makes include also proposals, in other words, schemes or plans of action, transcending language, to be executed in the more or less distant future. Luria (1966), probably more clearly than anybody else, attributed to higher frontal cortex the capacity to implement those proposals by organizing complex and purposeful goal-directed behavior in the temporal domain. As a logical consequence, the incapacity to formulate and carry out plans is now universally recognized as a pathognomonic symptom of substantial prefrontal damage (Fuster, 2015). From this, incapacity derives the general notion that as part of its role in the temporal organization of behavior, the normal prefrontal cortex opens the organism to its future, by predicting events, including its own actions, and by preadapting the organism to those events before they happen.

The central topic of this chapter is the future perspective of the three major executive functions of the prefrontal cortex: (1) executive attention, (2) working memory, and (3) decision-making. All three are functionally intertwined and share common biological objectives or teleonomic goals (Monod, 1971), which include the adaptation of the organism to predictable changes in its internal or external environment. Accordingly, in this chapter, I will outline and support the prospective aspects of each of those functions. I will preface the discussion of the three functions with a brief presentation of the general biological principle they obey. That principle is the perception–action (PA) cycle, which is the circular cybernetic processing of information that regulates the relationships between nervous system and environment in goal-directed behavior and language.

The PA Cycle

Biologist Uexküll (1926) remarked that living organisms adapt to their environment by a circular flow of information that runs through the environment and the brain, with a structural sensing interface (mark organ) and an effector interface (action organ). The sea anemone senses the chemistry of the water for nutrients, which reflexively mobilize their action organ toward them for their ingestion. It is a simple feed-forward reflex arc (Fig. 1.1). However, in the brain of higher organisms, Uexküll noted that there is internal feedback that bypasses the environment through the brain and from the action organ that flows back into the mark organ. That internal feedback provides the brain with a measure of additional supraordinate control of the cycle.

Figure 1.1 Uexküll’s diagram of the adaptation of the organism to its environment. He writes (A) The inner world is divided into two parts; one, that receives the impressions, faces the world-as-sensed, and the other, that distributes the effects, faces the world of action. (B) "In the highest animals, however, the creature’s own action-rule penetrates further into the world-as-sensed, and there, assumes direction and control (my italics) … A new circle (red arrow) is introduced within the animal’s own central organ for the support of the external function-circle, and this connects the action organ with the mark-organ." From Uexküll (1926). Theoretical Biology. New York: Harcourt, Brace & Co, 155–157.

In the primate brain, that adaptation cycle, with its internal feedback countercycle, evolves into a hierarchy of concentric cycles of cerebral structures and processes that adjust the animal to its external environment while satisfying immediate and future biological needs. At the highest level of that hierarchy, the cycle involves the cerebral cortex, which harbors networks for processing information from sensory to motor areas through associative cortex. The cycle has received various names from neurologists and neuroscientists; I favor the PA cycle denomination to emphasize the cognitive, memory-related, aspect of sensation in its higher circuits. Essentially, in the integration of complex goal-directed behavior, the PA cycle functions as follows (Fig. 1.2). Inputs from the environment or the internal milieu are processed through cognitive networks or cognits (Fuster, 2009) of posterior cortex (parietal–temporal–occipital, PTO). The output from that processing flows into the prefrontal cortex, where, through executive cognitive networks, it informs consequent action upon the environment; that action is effected through the premotor cortex, the basal ganglia, and the pyramidal system. The action produces changes in the environment, which are processed through the senses and fed back into posterior cortex toward further action. Thus, the entire cycle works as a self-correcting and guiding cybernetic system that regulates behavior and language toward their goals. It is important to note that the cycle can be set in motion by events anywhere within it, in the cortex or in the environment (external or internal milieu), obviating the need for a center of will or central executive.

Figure 1.2 Circuitry of the PA cycle through cortex and environment. A perceptual hierarchy of cognits (cognitive neuronal networks) is depicted on the left and an executive one on the right (The top-left compartment, PTO, includes both unimodal and multimodal association cortex). Major feed-forward connectivity runs through thick arrows. Thin arrows mark intracortical feedback connections that play important roles in cognitive control. PA, perception–action; PTO, parietal–temporal–occipital. Bottom left: Uexkull’s internal feedback in lower animals (red arrow), which in the human cycle at right is represented by the red arrow from prefrontal to PTO cortex. That arrow symbolizes schematically essential components of the three executive functions subsumed by cognitive control (executive attention, working memory, and decision-making).

As in lower organisms, however, there is internal countercyclical feedback from effectors to receptors in the primate brain. That internal feedback, I argue in this chapter, has future-oriented functions that modulate the PA cycle in anticipation of predicted percepts, actions, and rewards. In both the human and nonhuman primate, those are the executive functions of the prefrontal cortex to be discussed below. Their essential infrastructural support is made of corticocortical connections from that cortex upon posterior perceptual cortex and the cognitive networks of this cortex. In the aggregate, those functions constitute what has been termed cognitive control (Miller & Cohen, 2001) argued at the service of the temporal organization of goal-directed behavior (Fuster, 2001).

Based on their work on insects and fish, von Holst and Mittelsteadt (1950) were the first to postulate the predictive properties of the internal feedback from executive to sensing sectors of the brain (red arrow in Figs. 1.1 and 1.2). They called that internal feedback reafference. According to them, it consisted of signals from the motor system, which, immediately before the execution of a reflex motor response to sensory stimulation, flowed back into the sensory system to refine that response and to integrate it with the responses of other parts of the organism. That anticipated feedback, which internally bypassed the environment and overrode the reflex act, had the fundamental property of preparing the organism for better adaptation on the basis of what those authors called the plasticity of both systems, sensory and motor, to memory or experience. The feedback itself contained a neural replicate of the forthcoming movement, named by others the efferent copy or corollary discharge (McCloskey, 1981); the first term reflects its duplicative character and the second its consequential functional implications for the nervous system in the process of integrating impending behavior. Theoretically and partly based on psychophysical and electrophysiological evidence from primates, Teuber (1972) made corollary discharge a fundamental function of the prefrontal cortex. He said that by that function, the organism presets its sensory systems for the anticipated consequences of its own action.

Now we have abundant evidence that Teuber’s prefrontal corollary discharge, mutatis mutandis for complex behavior and language, incorporates the three executive cognitive functions that are the subject of this chapter. All three have a fundamental future dimension to accommodate PA cycles that in the human extend to months and years. The failure of one or more of those functions is at the root of the frontal lobe, patient’s inability to form and execute plans of goal-directed action. However, it should be noted before their discussion that all three are physiologically and psychologically intertwined. Therefore, it is difficult and to a large degree unjustified to allocate any of them to a well-defined anatomical domain of the frontal cortex.

Executive Attention

Attention is the optimal and selective allocation of limited resources to information processing in the central nervous system. It operates in the two major sectors of neurocognitive function: perceptual and executive. In both sectors, attention operates by the tandem use of two simultaneous and reciprocal mechanisms: the excitation of cognitive networks with presently relevant content and the inhibition of those with irrelevant or interfering content. The first mechanism constitutes the inclusive aspect of attention; it serves to focus neural resources on the currently applicable portion of a cognitive sector toward a goal. The second, exclusionary aspect of attention, serves to suppress, block, or inhibit irrelevant or interfering information, whether that comes from the organism itself or from the environment. It protects the organism from distraction. Arguably, this function of inhibitory control is an executive function in its own right (Fuster, 2015), but it does not have the marked prospective properties that characterize the three discussed functions in this chapter.

Executive attention is identical to what we elsewhere have called attentive set (Fuster & Bressler, 2015). In general terms, it consists in the preparation or priming of sensory and motor systems for an expected and predictable adaptive response of the organism to a stimulus or environmental event. In the cortical PA cycle, the carriers of executive attention are connections and signals flowing mainly from prefrontal cortex upon posterior association cortex (perceptual cortex, PTO) and lower stages of the executive hierarchy, such as the premotor cortex and the basal ganglia. In the monkey, those signals seem to originate in the dorsolateral prefrontal cortex. Some of the most direct evidence for the role of that cortex in the attentive set for selective motor action come from studies of monkeys performing delay tasks, where a motor choice is contingent on a stimulus presented a few seconds earlier (Fig. 1.3).

Figure 1.3 Prefrontal neurons attuned to motor response set. (A) Delay task with temporal and spatial separation between color cues and motor responses (below left, contingencies between cue and response). The animal faces three stimulus-response buttons over a pedal on which the operant hand rests at all times except to respond to stimuli. A trial starts with the cue, a brief color illumination on the central button. The cue is followed by a delay of some 10 s, after which the two lateral buttons light up simultaneously, either one red and the other green or both white. If they turn red and green, the animal must choose the color of the cue (red or green). If both turn white, it must choose left for red cue, right for green cue, right for yellow cue, or left for blue cue. Consequently, if the cue has been yellow or blue, during the delay the animal can predict with certainty the response direction (right or left, respectively). If the cue has been red or green, the correct response side can be predicted with only 75% probability (left if red, right if green). Cue color and position of correct choice change at random from trial to trial. c, correct choice. (B) Accelerating activation of motor-coupled neurons during a 12-s delay. These cells are presumably responsible for the priming of the motor system in anticipation of the motor response. The slope of the ramp of their accelerated firing accorded with the predictability of that response: the steepness of the firing ramp was greater when that predictability was 100% than when it was only 75%. C, cue; R, response; R², square of correlation coefficient. From Quintana & Fuster (1999). From perception to action: Temporal integrative functions of prefrontal and parietal neurons. Cerebral Cortex, 9, 213–221; with permission.

In the human, the best electrophysiological evidence of cortical involvement in executive attention consists in the slow potentials that develop on the surface of the scalp between a sensory stimulus and a motor response contingent on it after a period of delay. Those potentials are commonly designated the expectancy wave, the readiness potential, and the contingency negative variation (Brunia, Haagh, & Scheirs, 1985; Deecke, Kornhuber, Lang, Lang, & Schreiber, 1985; Fuster, 2015). Although they have different morphology, polarity, and time course, all of them originate in the dorsal prefrontal cortex and are clearly correlated in amplitude and duration with the attention to, and preparation of, the motor response to the stimulus.

Imaging studies have implicated frontoparietal networks in the executive attentive processes. These networks would be activated and engage in those processes, whereas the default mode network, which is normally active at rest, becomes deactivated (Hellyer et al., 2014; Raichle et al., 2001; Sadaghiani & D’Esposito, 2015). Neuroimaging also provides evidence of specific correlations between prefrontal activation and attentive motor set. Scheidt, Lillis, and Emerson (2010), by using a sensorimotor task, adjusted the direction of manual movements to a predicted motor load, that is, the rectilinearity of the hand path that the subject anticipated would be necessary to execute the motor reaction. In a similar manner as in the monkey experiment described earlier (Fig. 1.3; Quintana & Fuster, 1999), prefrontal activation correlated with a parameter of the expected motor act, in this case the rectilinearity of movement.

Both electrophysiological and neuroimaging signals (Diekhof, Kaps, Falkai, & Gruber, 2012; Kable & Glimcher, 2007; Potts, Martin, Kamp, & Donchin, 2011; Rutledge, Dean, Caplin, & Glimcher, 2010) predict by their magnitude the expected reward and value in the outcome of a prospective action. However, particularly strong signals can be recorded from the anterior cingulate cortex (medial prefrontal cortex) after error or failure of predicted reward (prediction error).

Both the inclusionary and exclusionary aspects of top–down predictive cognitive control are revealed by neuroimaging. In accordance with neuropsychological evidence, imaging methodology suggests a double dissociation of prefrontal cortex regarding the two fundamental mechanisms of attentive set, inclusionary and exclusionary. Whereas the former seems mainly under the control of the dorsolateral cortex (Chadick & Gazzaley, 2011), the exclusionary or inhibitory one seems under the control of the ventrolateral cortex (Bari & Robbins, 2013). These two mechanisms evidently work in tandem, top–down, on the neural substrates of perception and action as part of the cognitive control of so-called biased competition (Desimone & Duncan, 1995) of attentive set. It is obviously essential that in the attentive set, the excitatory component of attention be complemented by the inhibitory component. There are two main reasons for it: (1) attention is selective by definition because it is served by limited neural resources and (2) the inhibition of memory representations of irrelevant or interfering motor acts would detract from the accuracy and contrast of the acts currently in the focus of those resources.

Working Memory

Working memory is by definition a prospective, future-oriented, function. It is the temporary retention of information for performing a task or solving a problem in the near future (Baddeley, 1983). The purpose and intentionality in the definition differentiate working memory from other states and forms of short-term memory.

The first step in the elucidation of the brain mechanisms of working memory was the discovery of memory cells in the prefrontal cortex of monkeys (Funahashi, Bruce, & Goldman-Rakic, 1989; Fuster, 1973; Niki, 1974; Romo, Brody, Hernández, & Lemus, 1999). These are cells that show persistent elevated firing during the retention of a sensory stimulus for a prospective action. The conventional behavioral paradigm to reveal them is the performance of so-called delay tasks, notably delayed response and delayed matching-to-sample.

Although the first memory cells were discovered in the prefrontal cortex, subsequently they were also found in other cortical areas. They were demonstrated in inferotemporal cortex when the working memory memorandum was visual (Fuster & Jervey, 1982; Miller, Li, & Desimone, 1993; Miyashita & Chang, 1988), in anterior parietal cortex when it was tactile or haptic (Koch & Fuster, 1989; Zhou & Fuster, 1996) and in posterior parietal cortex when it was visuospatial (Andersen, Bracewell, Barash, Gnadt, & Fogassi, 1990). Furthermore, cross-modal (auditory–visual or visual–haptic) memory cells have been found in prefrontal cortex (Fuster, Bodner, & Kroger, 2000) and also in inferotemporal cortex (Gibson & Maunsell, 1997) and parietal cortex (Zhou & Fuster, 2000).

In monkeys performing working memory tasks, the cooling of lateral prefrontal cortex—which causes its reversible inactivation—together with the concomitant recording of single units in posterior cortex, or vice versa, indicate that the retention of working memory depends on functional interactions between those cortices (Chafee & Goldman-Rakic, 2000; Fuster, Bauer, & Jervey, 1985; Quintana, Fuster, & Yajeya, 1989); presumably, the interactions take place through anatomically well-demonstrated corticocortical connections (reviewed in Fuster, 2015). Those results are fully consistent with two key conclusions: (1) working memory is maintained by persistent reentrant, recurrent, or reverberating activity in cortical circuits and (2) working memory mediates cross-temporal contingencies in the PA cycle (Fig. 1.4). Both conclusions are supported by empirical computational modeling and by functional neuroimaging.

Figure 1.4 Succession of acts (a1–an) in a plan of action toward its goal. Two-way arrows represent contingencies between acts across time (each contingency is double: if now this then later that, if earlier that then now this). Some contingencies link individual acts to each other, whereas others link individual acts to the plan or goal of the action, and still others the plan to each goal. Top: A chain of well-learned or instinctual acts, where one act is only contingent on the immediately previous and succeeding acts without cross-temporal contingencies. The three executive functions discussed in this chapter, especially working memory, serve the mediation of contingencies in the lower sequence.

On the basis of a large body of neurobiological and behavioral data, it has become an established principle that the fundamental mechanism of working memory consists of reverberating excitation within the cortex or between the latter and subcortical structures such as the thalamus. This has led to numerous computational models that have substantiated the plausibility of that principle (Compte, Brunel, Goldman-Rakic, & Wang, 2000; Durstewitz, 2009; Liang, Wang, & Zhang, 2010; Tang, Li, & Yan, 2010; Verduzco-Flores, Bodner, Ermentrout, Fuster, & Zhou, 2009; Wang et al., 2013; Zipser, Kehoe, Littlewort, & Fuster, 1993). Most of these models have a reentrant functional architecture and are trained or instructed by the modeler to reproduce the persistent activity that characterizes memory cells in working memory. In the real brain, it is almost certain that the reentrant activity that supports working memory makes use of reciprocal corticocortical connections that, anatomically and functionally, link executive frontal cortex with perceptual posterior cortex.

Functional imaging, especially functional magnetic resonance imaging, evinces the reentrant functional connectivity between frontal and posterior cortex in working memory. Whereas some imaging studies focus on temporal correlations of activation between prefrontal and posterior association cortices, other studies, by changing the features of the memory tests administered to the experimental subjects, attempt to define the precise aspect of working memory in which the prefrontal cortex is involved. Explicitly or implicitly, all studies assume a prospective role for that cortex in working memory, and their results are compatible with the reentry principle.

An extensive graphic meta-analysis of numerous imaging studies (Fuster, 2015) reinforces that principle. The analysis showed that in the maintenance of working memory there is a concomitant activation of a prefrontal region together with that of one or several posterior regions, which vary depending on the modality of the memorandum. Those posterior areas are supposed to harbor perceptual memory networks (cognits) updated by the memorandum. In all cases, it appears that a reentrant loop of excitation ties the prefrontal cortex with those posterior areas. That reentrant loop would bridge the memory period—i.e., the cross-temporal contingency—of the working memory task or test. Both prefrontal and posterior cortices would thus engage in reentrant loops leading the PA cycle to its goal or goals. Fig. 1.5, derived from the mentioned meta-analysis, illustrates the activation of the cortical components of that cycle during a working memory test with visual memorandum.

Figure 1.5 Cortical activation at six moments in time (yellow triangles) in the course of a visual memory task (delayed matching-to-sample with a face as the memorandum): 1, sample presentation; 2, beginning of the delay; 3, middle of the delay; 4, end of the delay; 5, matching choice; 6, posttrial. Note the concomitant (reentrant?) activation of inferotemporal and prefrontal cortex during the delay (memory period), also the progression of activation from the former to the latter, presumably the mediation of the cross-temporal contingency between sample and choice in the PA cycle. From a metaanalysis of imaging studies of working memory in Fuster (2015). The prefrontal cortex (5th ed.). London: Academic Press.

The role of corticocortical reentry is further supported by imaging and electrophysiological studies that reveal the coupling between frontal and posterior sensory areas in the course of working memory (Ardestani, Shen, Darvas, Toga, & Fuster, 2016; Baldauf & Desimone, 2014; Lowe, Dzemidzic, Lurito, Mathews, & Phillips, 2000). Reentry is also indicated by a study of effective corticocortical connectivity in verbal working memory (Honey et al., 2002). In conclusion, the imaging and electrical evidence point to a role of the lateral prefrontal cortex, in coordination with posterior associative cortical areas and in the maintenance of working memory. That role follows a time course that reflects the gradual transition of activation of perceptual networks to that of prefrontal executive cognits, all within the PA cycle.

Decision-Making

Making decisions is the third major executive function of the prefrontal cortex. Similar to the other two discussed earlier, this function is prospective and embedded in the workings of the PA cycle. A decision that is a deliberate choice of prospective action among alternatives is determined by numerous factors. Fig. 1.6 offers a broad schematic view of those factors influencing the prefrontal cortex of the human in making a decision, whether the decided action is to take place in the short term or the long term. Those factors can be grouped into two basic categories. One consists of the influences from memory and prior learning, coming to prefrontal cortex from perceptual and executive cognitive networks in posterior and frontal associative cortex, the latter the prefrontal cortex itself. Those networks contain information in long-term memory as well as high-level values and ethical norms of behavior. Their influences on the lateral prefrontal cortex, where complex decisions are converted into action, come to this cortex via corticocortical connections.

Figure 1.6 Schematic representation of neural influences converging on the present for the integration of a decision.

The second category of factors impinging on decision consists of influences from the neural substrates of emotion and biological drives, including the expectation of reward. Those influences come, through inputs to the orbital prefrontal cortex, from the thalamus, the hypothalamus, and limbic structures (Asaad & Eskandar, 2011; Diekhof et al., 2012; Kable & Glimcher, 2007; Kennerley, Behrens, & Wallis, 2011; Rolls & Grabenhorst, 2008; Rushworth & Behrens, 2008; Schultz, 2006; Wunderlich, Dayan, & Dolan, 2012).

Within the broad dynamics of the PA cycle, the two categories of cerebral influences on the decision process, that is, the cortical cognitive and the internal emotional, are susceptible to being triggered or modulated by environmental and internal inputs in the form of sensory or visceral stimuli. In some situations, one such stimulus, after processing through posterior or limbic cortex, may unleash a goal-directed series of actions, the stimulus thus serving as a single determinant of decision (Bunge, 2004; Buschman, Denovellis, Diogo, Bullock, & Miller, 2012; Durstewitz, Vittoz, Floresco, & Seamans, 2010; Eiselt & Nieder, 2013; Montojo & Courtney, 2008; Nee et al., 2013; Reverberi, Gorgen, & Haynes, 2012).

In most situations, however, a decision and the involvement of the prefrontal cortex in it are multifactorial, the result of the confluence of several signals. The signals may be simple and discrete, such as those consisting in a simple sensory stimulus, or complex, such as those dependent on its associated context. Such complex signals may be mixed, encoding what Rigotti et al. (2013), based on primate data, call mixed selectivity.

To sum up in conclusion, decisions processed through the prefrontal cortex may be (1) determined by only one factor, such as a critical internal or external stimulus; (2) vectorial, that is, the result of the interplay of several synergistic factors with different weights (e.g., degree of salience or motivational significance); (3) winner-takes-all, where one factor decisively outweighs the others relevant at that time; or (4) Bayesian, that is, probabilistically grounded on the updating of hypotheses or expectations. Before all decisions, an executive network or cognit is activated in prefrontal cortex by prediction based on experience. It is reasonable to conclude that the prefrontal cortex, informed by posterior cortex, by limbic structures, and by high-level cognits within itself (e.g., rules), leads to decisions and their implementation by the orderly activation of lower stages of the executive hierarchy within the framework of the PA cycle. Functional imaging substantiates that downward trend or cascade of the processing of decided goal-directed actions (Azuar et al., 2014; Badre, Hoffman, Cooney, & D’Esposito, 2009; Charron & Koechlin, 2010; Koechlin & Hyafil, 2007).

It goes without saying that, within the PA cycle, and taking into account the multifactorial character of most decisions, the concept of a single supreme agent, such as the prefrontal cortex itself, loses its meaning. Indeed, the concept of a supraordinate neural entity, such as the prefrontal cortex, leads to an unresolvable infinite regress. To put it simply, postulating that entity unavoidably begs the question of what other entity commands it, and then that one, and so on at infinitum. In the PA cycle, where an action can start anywhere within it and is executed under continuous regulation by the prefrontal cortex through its executive functions, those questions become moot.

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Chapter 2

The Cellular Mechanisms of Executive Functions and Working Memory

Relevance to Mental Disorders

Taber C. Lightbourne and Amy F.T. Arnsten,    Department of Neuroscience, Yale University School of Medicine, New Haven, CT, United States

Abstract

The prefrontal cortex (PFC) is among the most evolved brain regions, serving as the substrate of our highest order cognitive abilities. The PFC guides our behavior, thoughts, and emotions through its unique ability to represent relevant knowledge. This ability facilitates mental processes necessary for navigating our increasingly complex world, such as working memory, inhibition of inappropriate responses, and planning for the future. Although the PFC confers great advantage, it is also vulnerable to dysfunction and has been implicated in many of our most devastating neuropsychiatric disorders, including Schizophrenia, Alzheimer’s disease, and Attention-Deficit Hyperactivity Disorder. PFC function can also go awry in so-called normal individuals under conditions of uncontrollable stress, fatigue, and advanced age. This chapter reviews the topographical organization and molecular mechanisms that modulate activity in the PFC with the goal of elucidating neuropsychiatric pathology and providing new directions for therapeutic intervention.

Keywords

Prefrontal cortex; mental representation; stress; Alzheimer’s disease; schizophrenia; attention-deficit hyperactivity disorder (ADHD); dopamine; norepinephrine

Introduction

The prefrontal cortex (PFC) constitutes one-third of the human cerebral cortex; it plays a central role in high-order cognition and dysfunctions in many neuropsychiatric disorders (Fuster, 2001). The PFC guides our thoughts, emotions, and actions by representing relevant knowledge. The ability to generate mental representations in the absence of sensory stimulation is the foundation of abstract thought and executive functions (Arnsten, 2011). Through these mental representations, the PFC allows us to hold information in mind to inform future action. We are thus able to plan for both the long-term (careers and complex projects) and short-term (connecting the beginning and end of a sentence), so that we can act deliberately and live purposefully (Goldman-Rakic, 1991). The PFC also protects purposeful behavior from distractions and compulsions, underscoring its critical role in self-control and inhibition that is necessary for refined behavior (Aron, Robbins, & Poldrack, 2004). Finally it is key for high-order decision-making (Seo & Lee, 2007) and meta-cognition (i.e., thinking about thinking), which facilitates awareness of self (Jurado et al., 1998), other people’s thoughts (Gilbert et al., 2007), and moral conscience (Anderson et al., 1999). The unique representational abilities of the PFC facilitates its involvement in advanced cognition from working memory and reason to executive functions such as attention regulation and planning for the future (Fuster, 2008; Robbins, 1996; Thompson-Schill et al., 2002). This fundamental property of the PFC is often captured on working memory tasks.

Topography of PFC and Its Relevance to Neuropsychiatric Pathology

The PFC exerts top-down guidance of our thoughts, actions, and emotions in a topographically organized manner (Fig. 2.1). One such organizational schema can be found in the distinction between functions of the lateral versus medial areas of the PFC. The lateral surface represents the external world, whereas the medial and ventral PFC represent our internal, visceral world and emotion (Goldman-Rakic, 1987; Ongur & Price, 2000). For instance, there are circuits in the dorsolateral PFC that represent visual space (Funahashi, Bruce, & Goldman-Rakic, 1989) and circuits in the dorsomedial PFC that represent punishment (Seo & Lee, 2009). This organization arises from the connections of these areas. The lateral surface has reciprocal connections with the visual, auditory, and association cortices (Fig. 2.2; Goldman-Rakic, 1987), the ventral regions receive inputs from olfactory–gustatory circuits, insular cortex, and limbic structures (Fig. 2.3; Ongur & Price, 2000), whereas the medial surface serves as a visceromotor center and projects to limbic structures (e.g., hypothalamus) and brainstem (Fig. 2.3; Ongur & Price, 2000). The same topography extends to the basal ganglia where the dorsolateral PFC projects to the dorsal striatum (caudate) and the ventromedial PFC projects to the ventral striatum.

Figure 2.1 Topographic organization of PFC in primates.

(A) The PFC provides top-down guidance of attention and thought (blue), action (purple), and emotion (red) through extensive neural projections. PFC is topographically organized and major patterns discussed in the text are highlighted here. First is caudal–rostral, denoted by maroon arrow, where the PFC manages increasingly abstract information the further rostral you go. Second is lateral–medial, where lateral PFC processes information from our external world, while ventral and medial regions represent our internal world, e.g., emotions and visceral sensation. This organization is reflected in PFC projection to basal ganglia via dorsal and ventral striatum. (B) Last topographical pattern is hemispheric lateralization where the left hemisphere is associated with generative processes, while the right is involved in inhibition and impulse control. PFC, prefrontal cortex; ADHD, attention-deficit hyperactivity disorder; ODR, oculomotor delayed response.

Figure 2.2 Visual and auditory processing streams in PFC (spatial and feature nuclei).

Parallel visual pathways for the processing of visual space and features begin in the primary visual cortex (V1). Pathways remain in parallel as they project into the PFC. Similar distinctions can be found in the auditory processing stream, where parallel pathways exist for auditory space versus feature information. Visuospatial circuit is shown in shades of purple; auditory spatial is shown in orange; visual feature is shown in blue; auditory feature is shown in green. PFC, prefrontal cortex. Adapted from a Goldman-Rakic neuroscience lecture at Yale and Amy Arnsten’s review paper on the history and neurobiology of thought.

Figure 2.3 Summary of cortical connections within the ventral and medial prefrontal cortex.

(A) The orbital network receives sensory inputs and integrates information from three major modalities: olfaction (green), visceral (red), and gustatory (blue). (B) In contrast the medial network, serves as a visceromotor output system for the interconnected processing streams in the orbitomedial prefrontal cortex with projections to nuclei in the hypothalamus and periaqueductal gray. Adapted from summary of orbital and medial networks presented in review paper on orbital and medial PFC networks, Ongur, D., & Price, J. L. (2000). The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Cerebral Cortex, 10(3), 206–219.

The PFC can also be thought of as having a rostral-caudal organization (Fig. 2.1), where the more rostral areas are involved in processing abstract information (Badre & D’Esposito, 2007). For instance, the most rostral areas are involved in metacognition, the act of thinking about thinking (Fleming, Huijgen, & Dolan, 2012). Rostral and dorsomedial areas of the PFC are involved in social cognition, including Theory of Mind, the ability to consider what another person might be thinking (Amodio & Frith, 2006). Finally, the PFC in humans exhibits hemispheric lateralization, where the left hemisphere is specialized in generative processes (Robinson et al., 1985), while the right hemisphere drives the inhibition of inappropriate thoughts, actions, and emotions (Aron, 2011).

This topographical organization is reflected in the pattern of PFC dysfunction in clinical disorders (Fig. 2.1). It thus follows that cognitive disorders such as Alzheimer’s disease (AD) and schizophrenia involve dysfunction of the dorsolateral prefrontal cortex (dlPFC). Postmortem studies of patients with schizophrenia have demonstrated reduced density of neuropil, dendrites, and spines from pyramidal cells in deep layer III and possibly layer V (Black et al., 2004; Glantz & Lewis, 2000; Selemon & Goldman-Rakic, 1999). While previous findings from rodent studies using N-methyl-D-aspartate receptor (NMDAR) antagonism as a model for schizophrenia have suggested that pathology might be due to excessive glutamate signaling, recent studies in postmortem tissue of patients with schizophrenia have implied the opposite (Napolitano et al., 2014). Recent transcriptome analyses on pyramidal cells of layer III and V in patients with schizophrenia have suggested an underactive state as evinced by mitochondrial markers (Arion et al., 2015). In addition, neuropathology studies in patients with schizophrenia have demonstrated compensatory GABA interneuron underactivity (Curley et al., 2013; Lewis, 2014).

In contrast to schizophrenia where extensive neuronal connections are lost while cell bodies survive, in AD, layers III and V dlPFC pyramidal cells are engulfed by neurofibrillary tangles and degenerate (Bussiere et al., 2003). Tau pathology afflicts the pyramidal cells in the association cortices with the most cortical–cortical connections (Bussiere et al., 2003). Interestingly, primary sensory cortices are spared in this AD pathology, highlighting a key difference in the vulnerability of these tissues (Lewis et al., 1987; Pearson et al., 1985).

Pathology of the ventromedial cortex, responsible for representation of our internal world, has been implicated in mood disorders, such as depression (Fig. 2.1; Drevets et al., 1997; Mayberg et al., 2005). Imaging studies have revealed the subgenual cingulate (also known as BA 25) to be active when healthy subjects think of sad events and overactive in patients with depression (Mayberg et al., 1999; Mayberg, 2009). However, effective treatment of depression has been shown to reduce activity in BA 25 (Mayberg et al., 2005). Based on this evidence, deep brain stimulation (DBS) has been used to reduce activity in BA 25 and associated white matter tracts in patients with treatment resistant depression. Some patients have reported rapid and profound relief (Mayberg, 2009). Additionally, regions of the ventromedial cortex have also been implicated in obsessive compulsive disorder (OCD) (Insel, 1992). Neuroimaging studies have revealed increased activity in several brain regions of patients with OCD relative to healthy controls: orbital PFC, anterior cingulate, and head of the caudate. This hyperactivity has been shown to be decreased with successful treatment of OCD (Maia, Cooney, & Peterson, 2008).

Finally, the laterality distinctions mentioned earlier are also reflected in certain disease states. For instance, the right PFC has been implicated in disorders marked by impaired impulse control such as attention-deficit hyperactivity disorder (ADHD) and the manic phase of bipolar disorder (Aron, Robbins, & Poldrack, 2014; Blumberg et al., 1999; Shaw et al., 2009). A longitudinal neuroimaging study by Shaw et al. (2009) revealed abnormal development of the right inferior PFC in children with ADHD with respect to healthy controls. The same area was also shown to be underactive in bipolar patients during mania in a positron emission tomographic study (Blumberg et al., 1999). Blumberg and colleagues replicated these findings in an fMRI study in which subjects performed a Stroop task requiring suppression of certain responses. They found that bipolar patients in a manic state showed blunted right PFC activation during the task when compared to healthy controls or patients in a depressed state (Blumberg et al.,