Ernst Strüngmann Forum

Bruno B. Averbeck, David Badre, Bernard Balleine, Marie T. Banich, Christian Beste, Timothy J. Buschman, Christos Constantinidis, Roshan Cools, Clayton E. Curtis, Dibyadeep Datta, Mark D’Esposito, John Duncan, Lesley K. Fellows, Christian J. Fiebach, Naomi P. Friedman, Caterina Gratton, Suzanne N. Haber, Michael M. Halassa, Alexandru D. Iordan, Alicia Izquierdo, Susanne M. Jaeggi, Etienne Koechlin, Zach Ladwig, Conor Liston, Beatriz Luna, Anna S. Mitchell, Elisabeth A. Murray, John D. Murray, John O’Doherty, Nicola Palomero-Gallagher, Diana C. Perez, Steven A. Rasmussen, Erin L. Rich, Trevor W. Robbins, Angela C. Roberts, James B. Rowe, Peter H. Rudebeck, Juha Salmi, Nicolas Schuck, Amitai Shenhav, Rajita Sinha, Jeroen B. Smaers, Robert P. Vertes, Xiao-Jing Wang, Kevin Weiner

Science is a highly specialized enterprise—one that enables areas of enquiry to be minutely pursued, establishes working paradigms and normative standards, and supports rigor in experimental research. All too often, however, “problems” encountered in research fall outside the scope of any one area of study and to progress, new perspectives are needed to expand conceptualization, increase understanding, and define pathways for research to pursue.

The Ernst Strüngmann Forum was established in 2006 to address these types of topics. Founded on the tenets of scientific independence and the inquisitive nature of the human mind, we provide a platform for experts to scrutinize topics that require input from multiple areas of expertise. Our gatherings, or Forums, take the form of intellectual retreats: existing perspectives are questioned, gaps in knowledge exposed, and strategies are collectively sought to fill these gaps. To ensure access to the emerging insights, the results of the entire process are disseminated through the Strüngmann Forum Report series.

This volume reports on the organization and function of frontal lobe networks. Proposed by Marie Banich, Suzanne Haber, and Trevor W. Robbins, they were eager to create a cross-disciplinary discourse aimed at integrating information across limbic, cognitive, social, and motor control subregions of the prefrontal cortex. After the proposal’s acceptance by our Scientific Advisory Board, Amy Arnsten, Mark D’Esposito, and John O’Doherty joined us on the Program Advisory Committee to transform the proposal into a framework that would support an extended, multidisciplinary discussion. The committee worked together to delineate discussion topics, identify potential participants, and finetune the overarching goal: To examine the circuitry, neuronal mechanisms, and computations by which different regions and associated networks in the prefrontal cortex mediate key component mental operations (e.g., limbic-affective, cognitive, social, and motoric) that enable higher-level thought and behavior in health and neuropsychiatric disorders. Further, the committee defined focal themes and guiding questions for the working groups:

• Group 1: Evolutionary perspectives: Homologies and analogies
• Group 2: Functional fractionation and integration: Physiology, networks,
  and behaviors
• Group 3: Integrative psychological, computational, and mechanistic
  approaches to frontal lobe function
• Group 4: How can understanding of the PFC be translated to the bedside
  and society at large?

Given the wide-ranging expertise involved in the Forum (e.g., behavioral neuroscience, cognitive neuroscience, computational neuroscience, evolutionary biology, neuroanatomy, neurobiology, neurophysiology, psychopharmacology, systems neuroscience), invited “background papers” presented information in a most lively discussion. This volume synthesizes the ideas and perspectives that emerged from the entire process.

An endeavor of this kind, especially one developed amidst COVID lockdowns, creates unique group dynamics and puts demands on everyone. I wish to thank each person who participated in this Forum for their time, efforts, and positive attitudes. A special word of gratitude goes to the Program AdvisoryCommittee (Amy Arnsten, Marie Banich, Mark D’Esposito, Suzanne Haber, John O’Doherty, and Trevor W. Robbins) as well as to the authors and reviewers of the background papers. In addition, the moderators of the discussion groups (Trevor W. Robbins, Mark D’Esposito, John O’Doherty, and Suzanne Haber) and rapporteurs (Kevin Weiner, Elizabeth A. Murray, Amitai Shenhav,and James B. Rowe) deserve special recognition, for to enable lively debate and transform this into a coherent, multiauthor report is never a simple matter. Finally, I extend my appreciation to Marie Banich, Suzanne Haber, and Trevor Robbins, whose expertise and leadership were essential to the entire project.

Through the generous backing of the Ernst Strüngmann Foundation, established y Dr. Andreas and Dr. Thomas Strüngmann in honor of their father, the Ernst Strüngmann Forum is able to conduct its work in the service of science and society. The efforts of our Scientific Advisory Board are also gratefully acknowledged, as is the partnership with the Ernst Strüngmann Institute, which shared its vibrant intellectual setting with us during the Forum.

It is never easy to extend the boundaries to knowledge, and long-held views are often difficult to put aside. Yet once such limitations are recognized, the act of formulating strategies to move past this point becomes a most invigorating activity. On behalf of everyone involved in this 35th Ernst Strüngmann Forum,we hope this volume will inform future analysis of this critically important brain region and spur further investigation, notably into the translation of findingsfrom animal to human models, the role of connectivity in frontal function, and the unique aspects of human cognition supported by the frontal lobes.

It is generally acknowledged that understanding the human brain would represent a pinnacle of scientific achievement. A major part of that goal is to identify the causal relationships between neural mechanisms and behavior and cognition, the ultimate functions of the brain. Key to this crucial issue in mammalian cognition are the functions of the frontal lobes. These lobes, which are most expanded in humans as compared to other species, include the prefrontal cortex (PFC) and associated structures, such as anterior cingulate cortex (ACC), and are known to play a key role in higher-order thinking, executive function, and cognitive control, processes by which an organism can effortfully guide adaptive behavior.

Like most of the cerebral cortex, there is evidence of quite extensive specialization within frontal brain regions. The PFC is typically divided into subregions that mediate these functions (Friedman and Robbins 2022; Haber and Behrens 2014; Monosov and Rushworth 2022; Rudebeck and Izquierdo 2022). The orbitofrontal cortex (OFC) is involved in value encoding (revaluation and devaluation) of reward-related sensory input and outcomes. The caudal OFC and ventrolateral (vl) PFC have been implicated in a number of functions, including credit assignment (determining the previous events that resulted in a specific outcome) and behavioral flexibility. The dorsolateral (dl) PFC is in a central position to mediate cognitive control, working memory and higher-order thinking. Finally, frontopolar regions are linked to dlPFC and vlPFC regions and allow for meta-cognitive abilities. As such, there is a matrix of subregions and their interactions that characterize PFC organization.

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Abstract

The steepest rise in publications on prefrontal cortex (PFC) function over the past decade has been in mouse studies. If we adhere to cell layer organization criteria for what constitutes PFC, rodent researchers may be studying a different PFC to primate PFC. Indeed, this chapter reviews several unique aspects of primate brain: primate cortical evolution favored a clustering of cell types more than rodent; primate PFC is more specialized in the expression of interneurons compared to rodent; and where comparative transcriptomic studies of different cell types in PFC have been conducted, they reveal unique similarities only within primate species. In contrast to these differences between species, strong similarities are also reviewed: connectivity patterns across rodent and primate PFC, specifically agranular orbitofrontal cortex and anterior cingulate cortex, as well as common features of foraging with some innovations that may have contributed to PFC specializations in primate. The study of cell types should be better integrated in the study of PFC across species, and this integration should, in principle, be closely related to a characterization of the cells along a spatial and behavioral gradient that reflects phylogenetic refinement. Currently, few studies combine neural activity with molecularly defined cell types within a species, and even fewer take a comparative approach. Combining transcriptomically defined cell-type information with other characteristics, such as task-related signaling in PFC and their connectivity patterns across rodent and primate species, represents a major challenge to the field, but would be an impactful way forward.

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Abstract

The prefrontal cortex (PFC) plays a critical role in human cognition, but the precise mechanisms by which its circuitry accomplishes its proposed functions are unclear. Nonhuman animals are indispensable in revealing such mechanisms, as the ability to monitor and manipulate their circuitry provides necessary insights. A major impediment to linking the growing progress in animal research to insights for human cognition and applications to human health is the lack of consensus on how the PFC is homologous across species. In this perspective, we follow the classification of human PFC into medial and lateral streams, with the medial being primarily evaluative and the lateral being executive. Based on anatomy, physiology and function, we advance the proposal that the rodent medial prefrontal cortex contains elements of both streams, with functional parallels between primate ventromedial and dorsolateral PFC with rodent infralimbic and prelimbic areas, respectively. To support this argument, we highlight the granular nature of the prelimbic cortex in Tupaia belangeri, a basal primate whose PFC macrostructure is rodent-like. Our perspective may help provide additional input to the debate on PFC homology and lead to new testable hypotheses.

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Determining homologies and analogies of brain structure and function across species is of major interest in systems neuroscience, comparative biology, and brain mapping. Prefrontal cortex (PFC) is a continued target of such analyses because it has expanded considerably throughout evolution. It is heavily differentiated and expanded in primates compared to mouse, rat, tree shrew, and marmoset brains, and it performs computational functions that are more complex than other association cortex.

This chapter reviews the major regions and circuits observed across species within PFC. It looks at the evolution of PFC and how this could produce higher-order cognition, including social behavior, as well as language elements in humans. It provides a synopsis of some main organizational principles of PFC as well as potential mechanisms by which major circuits in PFC exert control. It then reviews how unique contributions of optogenetics, chemogenetics, large-scale electrophysiology, and calcium imaging contribute to understanding PFC function. It also addresses the utility of animal models for understanding the structure and function of PFC.

The discussions that contributed to this chapter provide a modern foundation for the ongoing goal of generating a consensus statement regarding the ambition of determining the homologies and analogies of PFC, as well as the cognitive, developmental, and translational insights gleaned from the promise of such an eventual consensus statement.

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Abstract

A long history of research in neuropsychology has supported the idea that there is functional specialization within the prefrontal cortex (PFC). To better understand how a region subserves a specific function, neuron activity is often recorded from multiple areas as subjects engage in prefrontal-dependent cognitive tasks. Contrary to expectations, these studies have generally found that neurons across PFC encode all manner of task-relevant information, with relatively little difference among regions. These data are important because they demonstrate the vast representational capacity and flexibility of PFC, yet they have been less useful when trying to glean a mechanistic understanding of how regions differ and interact with each other. In this chapter, these data are first reviewed, then considerations are proposed that might better direct future studies. Discussion includes the anatomy and evolutionary origins of the primate PFC, which suggest a gradient organization, with a main division between dorsal and ventral trends, rather than a series of smaller discrete regions. These gradients are observable in neural recordings within and across regions and may provide insights into the functional organization of PFC. It is important to note that gradients are consistent with functional differentiation across PFC, but they suggest continuous rather than discrete changes in function. Second, recent advances in neural analysis are reviewed, which focus on representations and temporal dynamics in neural populations, as opposed to individual neurons. These population codes may reveal unique insights into local function and cross-regional interactions and help us understand the unique properties of the main divisions of PFC.

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Abstract

The prefrontal cortex (PFC) exerts control on the flow of sensory information in cortical circuits, integrates current stimulus streams with stored memories, and plans motor action. Prefrontal neurons exhibit quantitatively distinct firing properties relative to its afferent inputs. These can be traced to unique anatomical morphology, neurotransmitter receptor composition, and relative distribution of different interneuron types. This evidence suggests a position of PFC on the top of the cortical hierarchy that processes sensory information and controls behavior. A functional specialization is also present within the PFC, as it comprises multiple areas that are hierarchically organized. Other brain structures exert influence on PFC activity critical for the control of behavior, including the thalamus and neuromodulator systems. In that sense, PFC is a critical node of the broader circuit that instantiates intelligent behavior.

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Abstract

An influential view of lateral prefrontal cortex (lPFC) is that it is organized hierarchically to support cognitive control function. Specifically, regions more rostrally are hypothesized to engage in more abstract control processing than those caudally. Further, rostral regions are proposed to asymmetrically influence those caudal to them. This chapter provides an updated background on this view of lPFC organization and reviews evidence for two theoretical commitments of lPFC hierarchy: (a) functional differentiation along the rostro-caudal dimension of the lPFC and (b) super-to-subordinate hierarchical interactions within the lPFC. It will be seen that the standard view has undergone important revisions. In particular, what makes control more or less abstract along the rostro-caudal axis has been defined and redefined. The original assumption of a rostro-caudal gradient has been revised in favor of a hierarchy of interacting networks, which include association cortex outside of lPFC and subcortical structures. In addition, the apex of the hierarchy has shifted from rostro-lateral prefrontal cortex at the most anterior extent of the PFC to the mid-dorsolateral prefrontal cortex (mid-dlPFC) that lies just caudal to it. This discussion speaks directly to the topic of the functional organization of the PFC.

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Abstract

From the early 1900s onward, anatomists have parcellated the cerebral cortex, including the frontal cortex. Initial approaches were based on both the features of stained cell bodies and the pattern of myelinated fibers, together called architectonics. The labels provided by these architectonic investigations are still widely used today. This chapter considers the extant evidence for functional fractionation of the frontal lobes, and whether the organization of the frontal lobes should be conceptualized in terms of functional and anatomical gradients, instead of discrete areas with well-delineated boundaries. Discussion includes how the frontal lobes interact with other parts of the brain to influence behavior as well as the identification of critical gaps in knowledge. The authors conclude that a greater understanding of frontal lobe function would emerge from advances in theory that connects different levels of explanation, that take into account evolutionary perspectives, and that lead to the development of a common cognitive-behavioral ontological framework.

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Abstract

Different executive functions, such as response inhibition, working memory updating, and mental set shifting, are correlated but separable. The focus of this chapter is the neural substrates of this “unity and diversity,” with particular reference to the “multiple demand” (MD) system, a set of well-localized frontal, parietal, and posterior temporal brain regions that are active in tasks with diverse cognitive demands. After evidence for unity and diversity in behavioral studies is reviewed, the anatomy and function of the MD system is described and its potential mapping to unity and diversity discussed. Unity is evident in strong patterns of activation in core MD regions across tasks with different demands. Diversity is evident in differential activation of adjacent, more domain-specific regions, with strongest activation sometimes at the boundary between the MD core and these adjacent regions, suggesting communication between the two. It is suggested that the MD core serves to combine information from many brain regions and networks, integrating the diverse contents of an attended cognitive operation. Overlaps of the MD system and executive function unity with general cognitive ability are discussed, as are difficulties in integrating studies focusing on group-mean contrasts with individual-differences results. Understanding how behavior arises from the brain will involve understanding how information is represented, communicated, and transformed within and between brain networks, with the MD system likely contributing a core, integrative role.

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Abstract

The frontal lobe cortex is among the brain regions that evolve the most across mammals. In rodents, the prefrontal cortex (PFC) comprises the orbitofrontal cortex, the anterior cingulate complex (ACC), as well as the prelimbic and infralimbic areas in the medial wall. In primates, the PFC has evolved with the addition of the lateral PFC. In humans, the PFC features the further development of its most anterior part, especially in the lateral sector, and is often named the frontopolar cortex. Human patients with PFC lesions exhibit little impairments in basic sensorimotor, memory, learning, and language functions. Thus, the PFC function fulfills additional, more abstract functional demands. Its characterization has long remained elusive through the use of poorly defined notions such as executive/cognitive control, working memory, or cognitive flexibility. Here, computational models are shown to overcome these theoretical shortcomings by providing more precise accounts, predictions, and simulations of PFC function at the neuronal and behavioral levels. Two approaches have been developed in neurobiology and cognitive neuroscience, respectively. Time is ripe to integrate the two for a cross-level understanding of PFC function.

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Regions in the human frontal lobe form distributed large-scale brain networks, with connections to one another and other locations in the cortex, striatum, thalamus, and cerebellum. Here, evidence is reviewed that multiple networks lie side by side in the frontal lobe, and these networks are largely (but not entirely) parallel, or separate, from one another. These network findings improve our understanding of frontal lobe organization and help constrain theories of executive function and the impact of brain disorders. Ongoing challenges in the study of frontal lobe networks are discussed related to tracking functional associations of brain networks, individual differences, and changes in networks over time.

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Abstract

Since the earliest accounts of the prefrontal cortex (PFC), its core functions have remained elusive and hotly debated. Here, an attempt is made to bring order to these varied accounts and to account for the heterogeneous observations that have been made across methodologies and species. After cataloging the myriad functions that have been attributed to PFC and the approaches that have been taken to taxonomize these functions, a new framework is proposed for conceptualizing PFC function. This framework is based on a set of four canonical computations that is argued to collectively provide a more formal, coherent, and comprehensive account of existing findings regarding PFC function. These canonical computations include goal-directed integration, active maintenance, selection of task-relevant information, and monitoring. Discussion includes how previous PFC findings can be understood through one or more of these functions, and ways in which these computations may collectively form a motif that repeats throughout regions of PFC over different forms of inputs and outputs. Finally, critical directions for future research to validate or falsify this account of PFC functions are highlighted, including the leveraging of new and emerging directions for experimentation and analysis.

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Abstract

There is an ever-expanding range of pharmacological treatments for psychiatric disorders but our understanding of their efficacy at the level of disorders, symptoms, and especially at the level of individuals is extremely limited. Neuroimaging studies reveal dysregulation in the higher-order cognitive and emotional control networks of the prefrontal and anterior cingulate cortices in patients suffering from affective disorders such as depression and anxiety. Moreover, successful treatment by antidepressants or anxiolytics is often associated with an amelioration of the dysregulation in these control networks. Treatment resistance is a common occurrence across patients, and without a detailed understanding of the neurobiological actions of efficacious pharmacotherapies, we are still far from being able to tailor the specific classes of pharmacotherapies to any one individual. Important insights into how the different prefrontal control networks may be differentially affected by different classes of antidepressants can be revealed by considering the marked heterogeneity in the neurochemical modulation of prefrontal and anterior cingulate cortices. For example, the distribution of receptors, transporters, and neuronal subtypes that are the targets of current antidepressants, including the monoamine, glutamate, GABA and opiate systems, differentially target those prefrontal and anterior cingulate regions involved in reward, affective, salience, executive, and default mode networks. However, while large-scale patient neuroimaging studies have implicated changes in activity within specific regions of prefrontal and anterior cingulate cortex (and associated networks) as mediators, predictors, and/or moderators of antidepressant efficacy, insight into the differential actions of the different classes of antidepressants has not been forthcoming. Experimental studies in animals, on the other hand, are beginning to provide important insights into cellular and molecular plasticity mechanisms within prefrontal cortex that may underlie antidepressant efficacy. Still, a major unanswered question is why there is such marked variation in efficacy between individual patients. Future work needs to directly compare the neuroimaging profiles of different classes of antidepressants in patients and take into account efficacy at the level of specific symptoms as well as treatment history. In addition, a greater focus on the comparison of the actions of different classes of antidepressants is needed in animals alongside a comparison of their actions within distinct regions of prefrontal and anterior cingulate cortex. Only then can we begin to identify the factors that may determine the treatment strategy for any given individual.

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Abstract

Executive functions (EFs) are essential for everyday functioning. Implicated in many neurodevelopmental and psychiatric disorders, they are also highly susceptible to the effects of aging. There is a critical need to develop effective interventions to improve EFs. This chapter focuses on a particular type of intervention that directly targets EFs by repeatedly practicing on EF tasks using adaptive procedures. There is emerging evidence that such interventions are beneficial: not only do they improve skills related to the trained domain, but they also benefit other domains and symptoms as well as lead to changes in brain structure and function, especially in circuitry related to the prefrontal cortex. At the same time, little is known about the exact underlying mechanisms that drive behavioral and neural changes. Thus, a better understanding of individual differences and training-related factors that mediate and moderate training outcomes is needed to develop more effective interventions that take into account individuals’ strengths and needs.

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Recent advances in functional and diffusion imaging, as well as neuromodulatory devices that can both stimulate and record, have opened up new avenues for advancing hypothesis-driven circuit-based treatments of neuropsychiatric disorders. Neuromodulatory treatments will also expand our understanding of prefrontal cortical function in humans. Across neuropsychiatric illnesses, obsessive-compulsive disorder (OCD) stands out as being a condition where we have an initial understanding of the neural circuitry associated with the illness. Converging evidence has implicated ventrolateral orbital, rostral anterior cingulate, and medio-orbitofrontal and medial frontopolar cortex in OCD psychopathology. Expanded interest of basic scientists in the clinical phenomena of OCD and interdisciplinary collaboration will be essential to further delineate the neurobiologic basis of the illness as well as the mechanism of action of circuit-based treatments.

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Abstract

The prefrontal cortex (PFC) is implicated in a wide range of neuropsychiatric disorders. Many of these become manifest in adolescence (e.g., anxiety, obsessive-compulsive disorders, addiction, attention-deficit hyperactivity disorders) while others arise from selective neurodegeneration of the frontal lobe in later life. A major challenge to research into the disorders associated with the PFC has been the lack of one-to-one mappings between clinical syndromes, their underlying pathophysiology, and root neuro­biological causes. Here, we propose a multilevel framework in which syndromes can be linked to symptom profiles, symptoms to cognitive processes, and cognitive processes to pharmacological and computational processes embedded in PFC and its associated networks. This approach explains the frequency of multi-morbidity of neuropsychiatric disorders. The multilevel framework has enabled animal models of underlying biology and psychological processes to inform the understanding and treatment of clinical disorders without necessitating full recapitulation of the complexity of human neurological and psychiatric disorders. Discussion include the causes and treatment potential of the prefrontal cortical circuit disorders, based on convergent evidence across animal and human studies of the mechanisms of action of lesion, stimulation, pharmacological and cognitive behavioral therapies. Challenges are emphasized in the development, validation, and precision-medicine application of such treatments and consideration given to the prefrontal systems and prefrontal disorders in the context of global opportunities for education, health and social policy.

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Abstract

In this concluding chapter we examine some of the cross-cutting themes that emerged from the Forum. Here, we consider issues that transcend the individual working groups, which we believe are ripe for further discussion and investigation, notably translation from animal to human models, the role of connectivity in frontal function, and unique aspects of human cognition that are supported by the frontal lobes.

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