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The prefrontal cortex
Suzanne N. Haber & Trevor Robbins
doi : 10.1038/s41386-021-01184-2
Neuropsychopharmacology volume 47, pages1–2 (2022)
Evolution of prefrontal cortex
Todd M. Preuss & Steven P. Wise
doi : 10.1038/s41386-021-01076-5
Neuropsychopharmacology volume 47, pages3–19 (2022)
Subdivisions of the prefrontal cortex (PFC) evolved at different times. Agranular parts of the PFC emerged in early mammals, and rodents, primates, and other modern mammals share them by inheritance. These are limbic areas and include the agranular orbital cortex and agranular medial frontal cortex (areas 24, 32, and 25). Rodent research provides valuable insights into the structure, functions, and development of these shared areas, but it contributes less to parts of the PFC that are specific to primates, namely, the granular, isocortical PFC that dominates the frontal lobe in humans. The first granular PFC areas evolved either in early primates or in the last common ancestor of primates and tree shrews. Additional granular PFC areas emerged in the primate stem lineage, as represented by modern strepsirrhines. Other granular PFC areas evolved in simians, the group that includes apes, humans, and monkeys. In general, PFC accreted new areas along a roughly posterior to anterior trajectory during primate evolution. A major expansion of the granular PFC occurred in humans in concert with other association areas, with modifications of corticocortical connectivity and gene expression, although current evidence does not support the addition of a large number of new, human-specific PFC areas.
Prefrontal connectomics: from anatomy to human imaging
Suzanne N. Haber, Hesheng Liu, Jakob Seidlitz & Ed Bullmore
doi : 10.1038/s41386-021-01156-6
Neuropsychopharmacology volume 47, pages20–40 (2022)
The fundamental importance of prefrontal cortical connectivity to information processing and, therefore, disorders of cognition, emotion, and behavior has been recognized for decades. Anatomic tracing studies in animals have formed the basis for delineating the direct monosynaptic connectivity, from cells of origin, through axon trajectories, to synaptic terminals. Advances in neuroimaging combined with network science have taken the lead in developing complex wiring diagrams or connectomes of the human brain. A key question is how well these magnetic resonance imaging (MRI)-derived networks and hubs reflect the anatomic “hard wiring” first proposed to underlie the distribution of information for large-scale network interactions. In this review, we address this challenge by focusing on what is known about monosynaptic prefrontal cortical connections in non-human primates and how this compares to MRI-derived measurements of network organization in humans. First, we outline the anatomic cortical connections and pathways for each prefrontal cortex (PFC) region. We then review the available MRI-based techniques for indirectly measuring structural and functional connectivity, and introduce graph theoretical methods for analysis of hubs, modules, and topologically integrative features of the connectome. Finally, we bring these two approaches together, using specific examples, to demonstrate how monosynaptic connections, demonstrated by tract-tracing studies, can directly inform understanding of the composition of PFC nodes and hubs, and the edges or pathways that connect PFC to cortical and subcortical areas.
Development of prefrontal cortex
Sharon M. Kolk & Pasko Rakic
doi : 10.1038/s41386-021-01137-9
Neuropsychopharmacology volume 47, pages41–57 (2022)
During evolution, the cerebral cortex advances by increasing in surface and the introduction of new cytoarchitectonic areas among which the prefrontal cortex (PFC) is considered to be the substrate of highest cognitive functions. Although neurons of the PFC are generated before birth, the differentiation of its neurons and development of synaptic connections in humans extend to the 3rd decade of life. During this period, synapses as well as neurotransmitter systems including their receptors and transporters, are initially overproduced followed by selective elimination. Advanced methods applied to human and animal models, enable investigation of the cellular mechanisms and role of specific genes, non-coding regulatory elements and signaling molecules in control of prefrontal neuronal production and phenotypic fate, as well as neuronal migration to establish layering of the PFC. Likewise, various genetic approaches in combination with functional assays and immunohistochemical and imaging methods reveal roles of neurotransmitter systems during maturation of the PFC. Disruption, or even a slight slowing of the rate of neuronal production, migration and synaptogenesis by genetic or environmental factors, can induce gross as well as subtle changes that eventually can lead to cognitive impairment. An understanding of the development and evolution of the PFC provide insight into the pathogenesis and treatment of congenital neuropsychiatric diseases as well as idiopathic developmental disorders that cause intellectual disabilities.
Computational models of adaptive behavior and prefrontal cortex
Alireza Soltani & Etienne Koechlin
doi : 10.1038/s41386-021-01123-1
Neuropsychopharmacology volume 47, pages58–71 (2022)
The real world is uncertain, and while ever changing, it constantly presents itself in terms of new sets of behavioral options. To attain the flexibility required to tackle these challenges successfully, most mammalian brains are equipped with certain computational abilities that rely on the prefrontal cortex (PFC). By examining learning in terms of internal models associating stimuli, actions, and outcomes, we argue here that adaptive behavior relies on specific interactions between multiple systems including: (1) selective models learning stimulus–action associations through rewards; (2) predictive models learning stimulus- and/or action–outcome associations through statistical inferences anticipating behavioral outcomes; and (3) contextual models learning external cues associated with latent states of the environment. Critically, the PFC combines these internal models by forming task sets to drive behavior and, moreover, constantly evaluates the reliability of actor task sets in predicting external contingencies to switch between task sets or create new ones. We review different models of adaptive behavior to demonstrate how their components map onto this unifying framework and specific PFC regions. Finally, we discuss how our framework may help to better understand the neural computations and the cognitive architecture of PFC regions guiding adaptive behavior.
The role of prefrontal cortex in cognitive control and executive function
Naomi P. Friedman & Trevor W. Robbins
doi : 10.1038/s41386-021-01132-0
Neuropsychopharmacology volume 47, pages72–89 (2022)
Concepts of cognitive control (CC) and executive function (EF) are defined in terms of their relationships with goal-directed behavior versus habits and controlled versus automatic processing, and related to the functions of the prefrontal cortex (PFC) and related regions and networks. A psychometric approach shows unity and diversity in CC constructs, with 3 components in the most commonly studied constructs: general or common CC and components specific to mental set shifting and working memory updating. These constructs are considered against the cellular and systems neurobiology of PFC and what is known of its functional neuroanatomical or network organization based on lesioning, neurochemical, and neuroimaging approaches across species. CC is also considered in the context of motivation, as “cool” and “hot” forms. Its Common CC component is shown to be distinct from general intelligence (g) and closely related to response inhibition. Impairments in CC are considered as possible causes of psychiatric symptoms and consequences of disorders. The relationships of CC with the general factor of psychopathology (p) and dimensional constructs such as impulsivity in large scale developmental and adult populations are considered, as well as implications for genetic studies and RDoC approaches to psychiatric classification.
The role of PFC networks in cognitive control and executive function
Vinod Menon & Mark D’Esposito
doi : 10.1038/s41386-021-01152-w
Neuropsychopharmacology volume 47, pages90–103 (2022)
Systems neuroscience approaches with a focus on large-scale brain organization and network analysis are advancing foundational knowledge of how cognitive control processes are implemented in the brain. Over the past decade, technological and computational innovations in the study of brain connectivity have led to advances in our understanding of how brain networks function, inspiring new conceptualizations of the role of prefrontal cortex (PFC) networks in the coordination of cognitive control. In this review, we describe six key PFC networks involved in cognitive control and elucidate key principles relevant for understanding how these networks implement cognitive control. Implementation of cognitive control in a constantly changing environment depends on the dynamic and flexible organization of PFC networks. In this context, we describe major empirical and theoretical models that have emerged in recent years and describe how their functional architecture and dynamic organization supports flexible cognitive control. We take an overarching view of advances made in the past few decades and consider fundamental issues regarding PFC network function, global brain dynamics, and cognition that still need to be resolved. We conclude by clarifying important future directions for research on cognitive control and their implications for advancing our understanding of PFC networks in brain disorders.
Advances in modeling learning and decision-making in neuroscience
Anne G. E. Collins & Amitai Shenhav
doi : 10.1038/s41386-021-01126-y
Neuropsychopharmacology volume 47, pages104–118 (2022)
An organism’s survival depends on its ability to learn about its environment and to make adaptive decisions in the service of achieving the best possible outcomes in that environment. To study the neural circuits that support these functions, researchers have increasingly relied on models that formalize the computations required to carry them out. Here, we review the recent history of computational modeling of learning and decision-making, and how these models have been used to advance understanding of prefrontal cortex function. We discuss how such models have advanced from their origins in basic algorithms of updating and action selection to increasingly account for complexities in the cognitive processes required for learning and decision-making, and the representations over which they operate. We further discuss how a deeper understanding of the real-world complexities in these computations has shed light on the fundamental constraints on optimal behavior, and on the complex interactions between corticostriatal pathways to determine such behavior. The continuing and rapid development of these models holds great promise for understanding the mechanisms by which animals adapt to their environments, and what leads to maladaptive forms of learning and decision-making within clinical populations.
The prefrontal cortex and (uniquely) human cooperation: a comparative perspective
Yoonseo Zoh, Steve W. C. Chang & Molly J. Crockett
doi : 10.1038/s41386-021-01092-5
Neuropsychopharmacology volume 47, pages119–133 (2022)
Humans have an exceptional ability to cooperate relative to many other species. We review the neural mechanisms supporting human cooperation, focusing on the prefrontal cortex. One key feature of human social life is the prevalence of cooperative norms that guide social behavior and prescribe punishment for noncompliance. Taking a comparative approach, we consider shared and unique aspects of cooperative behaviors in humans relative to nonhuman primates, as well as divergences in brain structure that might support uniquely human aspects of cooperation. We highlight a medial prefrontal network common to nonhuman primates and humans supporting a foundational process in cooperative decision-making: valuing outcomes for oneself and others. This medial prefrontal network interacts with lateral prefrontal areas that are thought to represent cooperative norms and modulate value representations to guide behavior appropriate to the local social context. Finally, we propose that more recently evolved anterior regions of prefrontal cortex play a role in arbitrating between cooperative norms across social contexts, and suggest how future research might fruitfully examine the neural basis of norm arbitration.
Foraging with the frontal cortex: A cross-species evaluation of reward-guided behavior
Peter H. Rudebeck & Alicia Izquierdo
doi : 10.1038/s41386-021-01140-0
Neuropsychopharmacology volume 47, pages134–146 (2022)
Efficient foraging is essential to survival and depends on frontal cortex in mammals. Because of its role in psychiatric disorders, frontal cortex and its contributions to reward procurement have been studied extensively in both rodents and non-human primates. How frontal cortex of these animal models compares is a source of intense debate. Here we argue that translating findings from rodents to non-human primates requires an appreciation of both the niche in which each animal forages as well as the similarities in frontal cortex anatomy and function. Consequently, we highlight similarities and differences in behavior and anatomy, before focusing on points of convergence in how parts of frontal cortex contribute to distinct aspects of foraging in rats and macaques, more specifically. In doing so, our aim is to emphasize where translation of frontal cortex function between species is clearer, where there is divergence, and where future work should focus. We finish by highlighting aspects of foraging for which have received less attention but we believe are critical to uncovering how frontal cortex promotes survival in each species.
Reinforcement-learning in fronto-striatal circuits
Bruno Averbeck & John P. O’Doherty
doi : 10.1038/s41386-021-01108-0
Neuropsychopharmacology volume 47, pages147–162 (2022)
We review the current state of knowledge on the computational and neural mechanisms of reinforcement-learning with a particular focus on fronto-striatal circuits. We divide the literature in this area into five broad research themes: the target of the learning—whether it be learning about the value of stimuli or about the value of actions; the nature and complexity of the algorithm used to drive the learning and inference process; how learned values get converted into choices and associated actions; the nature of state representations, and of other cognitive machinery that support the implementation of various reinforcement-learning operations. An emerging fifth area focuses on how the brain allocates or arbitrates control over different reinforcement-learning sub-systems or “experts”. We will outline what is known about the role of the prefrontal cortex and striatum in implementing each of these functions. We then conclude by arguing that it will be necessary to build bridges from algorithmic level descriptions of computational reinforcement-learning to implementational level models to better understand how reinforcement-learning emerges from multiple distributed neural networks in the brain.
Prefrontal cortex interactions with the amygdala in primates
Elisabeth A. Murray & Lesley K. Fellows
doi : 10.1038/s41386-021-01128-w
Neuropsychopharmacology volume 47, pages163–179 (2022)
This review addresses functional interactions between the primate prefrontal cortex (PFC) and the amygdala, with emphasis on their contributions to behavior and cognition. The interplay between these two telencephalic structures contributes to adaptive behavior and to the evolutionary success of all primate species. In our species, dysfunction in this circuitry creates vulnerabilities to psychopathologies. Here, we describe amygdala–PFC contributions to behaviors that have direct relevance to Darwinian fitness: learned approach and avoidance, foraging, predator defense, and social signaling, which have in common the need for flexibility and sensitivity to specific and rapidly changing contexts. Examples include the prediction of positive outcomes, such as food availability, food desirability, and various social rewards, or of negative outcomes, such as threats of harm from predators or conspecifics. To promote fitness optimally, these stimulus–outcome associations need to be rapidly updated when an associative contingency changes or when the value of a predicted outcome changes. We review evidence from nonhuman primates implicating the PFC, the amygdala, and their functional interactions in these processes, with links to experimental work and clinical findings in humans where possible.
Prefrontal-hippocampal interactions supporting the extinction of emotional memories: the retrieval stopping model
Michael C. Anderson & Stan B. Floresco
doi : 10.1038/s41386-021-01131-1
Neuropsychopharmacology volume 47, pages180–195 (2022)
Neuroimaging has revealed robust interactions between the prefrontal cortex and the hippocampus when people stop memory retrieval. Efforts to stop retrieval can arise when people encounter reminders to unpleasant thoughts they prefer not to think about. Retrieval stopping suppresses hippocampal and amygdala activity, especially when cues elicit aversive memory intrusions, via a broad inhibitory control capacity enabling prepotent response suppression. Repeated retrieval stopping reduces intrusions of unpleasant memories and diminishes their affective tone, outcomes resembling those achieved by the extinction of conditioned emotional responses. Despite this resemblance, the role of inhibitory fronto-hippocampal interactions and retrieval stopping broadly in extinction has received little attention. Here we integrate human and animal research on extinction and retrieval stopping. We argue that reconceptualising extinction to integrate mnemonic inhibitory control with learning would yield a greater understanding of extinction’s relevance to mental health. We hypothesize that fear extinction spontaneously engages retrieval stopping across species, and that controlled suppression of hippocampal and amygdala activity by the prefrontal cortex reduces fearful thoughts. Moreover, we argue that retrieval stopping recruits extinction circuitry to achieve affect regulation, linking extinction to how humans cope with intrusive thoughts. We discuss novel hypotheses derived from this theoretical synthesis.
Interactions between ventrolateral prefrontal and anterior cingulate cortex during learning and behavioural change
Ilya E. Monosov & Matthew F. S. Rushworth
doi : 10.1038/s41386-021-01079-2
Neuropsychopharmacology volume 47, pages196–210 (2022)
Hypotheses and beliefs guide credit assignment – the process of determining which previous events or actions caused an outcome. Adaptive hypothesis formation and testing are crucial in uncertain and changing environments in which associations and meanings are volatile. Despite primates’ abilities to form and test hypotheses, establishing what is causally responsible for the occurrence of particular outcomes remains a fundamental challenge for credit assignment and learning. Hypotheses about what surprises are due to stochasticity inherent in an environment as opposed to real, systematic changes are necessary for identifying the environment’s predictive features, but are often hard to test. We review evidence that two highly interconnected frontal cortical regions, anterior cingulate cortex and ventrolateral prefrontal area 47/12o, provide a biological substrate for linking two crucial components of hypothesis-formation and testing: the control of information seeking and credit assignment. Neuroimaging, targeted disruptions, and neurophysiological studies link an anterior cingulate – 47/12o circuit to generation of exploratory behaviour, non-instrumental information seeking, and interpretation of subsequent feedback in the service of credit assignment. Our observations support the idea that information seeking and credit assignment are linked at the level of neural circuits and explain why this circuit is important for ensuring behaviour is flexible and adaptive.
The prefrontal cortex and OCD
Susanne E. Ahmari & Scott L. Rauch
doi : 10.1038/s41386-021-01130-2
Neuropsychopharmacology volume 47, pages211–224 (2022)
Obsessive Compulsive Disorder (OCD) is a highly prevalent and severe neuropsychiatric disorder, with an incidence of 1.5–3% worldwide. However, despite the clear public health burden of OCD and relatively well-defined symptom criteria, effective treatments are still limited, spotlighting the need for investigation of the neural substrates of the disorder. Human neuroimaging studies have consistently highlighted abnormal activity patterns in prefrontal cortex (PFC) regions and connected circuits in OCD during both symptom provocation and performance of neurocognitive tasks. Because of recent technical advances, these findings can now be leveraged to develop novel targeted interventions. Here we will highlight current theories regarding the role of the prefrontal cortex in the generation of OCD symptoms, discuss ways in which this knowledge can be used to improve treatments for this often disabling illness, and lay out challenges in the field for future study.
Prefrontal cortex and depression
Diego A. Pizzagalli & Angela C. Roberts
doi : 10.1038/s41386-021-01101-7
Neuropsychopharmacology volume 47, pages225–246 (2022)
The prefrontal cortex (PFC) has emerged as one of the regions most consistently impaired in major depressive disorder (MDD). Although functional and structural PFC abnormalities have been reported in both individuals with current MDD as well as those at increased vulnerability to MDD, this information has not translated into better treatment and prevention strategies. Here, we argue that dissecting depressive phenotypes into biologically more tractable dimensions – negative processing biases, anhedonia, despair-like behavior (learned helplessness) – affords unique opportunities for integrating clinical findings with mechanistic evidence emerging from preclinical models relevant to depression, and thereby promises to improve our understanding of MDD. To this end, we review and integrate clinical and preclinical literature pertinent to these core phenotypes, while emphasizing a systems-level approach, treatment effects, and whether specific PFC abnormalities are causes or consequences of MDD. In addition, we discuss several key issues linked to cross-species translation, including functional brain homology across species, the importance of dissecting neural pathways underlying specific functional domains that can be fruitfully probed across species, and the experimental approaches that best ensure translatability. Future directions and clinical implications of this burgeoning literature are discussed.
Prefrontal cortex, amygdala, and threat processing: implications for PTSD
M. Alexandra Kredlow, Robert J. Fenster, Emma S. Laurent, Kerry J. Ressler & Elizabeth A. Phelps
doi : 10.1038/s41386-021-01155-7
Neuropsychopharmacology volume 47, pages247–259 (2022)
Posttraumatic stress disorder can be viewed as a disorder of fear dysregulation. An abundance of research suggests that the prefrontal cortex is central to fear processing—that is, how fears are acquired and strategies to regulate or diminish fear responses. The current review covers foundational research on threat or fear acquisition and extinction in nonhuman animals, healthy humans, and patients with posttraumatic stress disorder, through the lens of the involvement of the prefrontal cortex in these processes. Research harnessing advances in technology to further probe the role of the prefrontal cortex in these processes, such as the use of optogenetics in rodents and brain stimulation in humans, will be highlighted, as well other fear regulation approaches that are relevant to the treatment of posttraumatic stress disorder and involve the prefrontal cortex, namely cognitive regulation and avoidance/active coping. Despite the large body of translational research, many questions remain unanswered and posttraumatic stress disorder remains difficult to treat. We conclude by outlining future research directions related to the role of the prefrontal cortex in fear processing and implications for the treatment of posttraumatic stress disorder.
The prefrontal cortex, pathological anxiety, and anxiety disorders
Margaux M. Kenwood, Ned H. Kalin & Helen Barbas
doi : 10.1038/s41386-021-01109-z
Neuropsychopharmacology volume 47, pages260–275 (2022)
Anxiety is experienced in response to threats that are distal or uncertain, involving changes in one’s subjective state, autonomic responses, and behavior. Defensive and physiologic responses to threats that involve the amygdala and brainstem are conserved across species. While anxiety responses typically serve an adaptive purpose, when excessive, unregulated, and generalized, they can become maladaptive, leading to distress and avoidance of potentially threatening situations. In primates, anxiety can be regulated by the prefrontal cortex (PFC), which has expanded in evolution. This prefrontal expansion is thought to underlie primates’ increased capacity to engage high-level regulatory strategies aimed at coping with and modifying the experience of anxiety. The specialized primate lateral, medial, and orbital PFC sectors are connected with association and limbic cortices, the latter of which are connected with the amygdala and brainstem autonomic structures that underlie emotional and physiological arousal. PFC pathways that interface with distinct inhibitory systems within the cortex, the amygdala, or the thalamus can regulate responses by modulating neuronal output. Within the PFC, pathways connecting cortical regions are poised to reduce noise and enhance signals for cognitive operations that regulate anxiety processing and autonomic drive. Specialized PFC pathways to the inhibitory thalamic reticular nucleus suggest a mechanism to allow passage of relevant signals from thalamus to cortex, and in the amygdala to modulate the output to autonomic structures. Disruption of specific nodes within the PFC that interface with inhibitory systems can affect the negative bias, failure to regulate autonomic arousal, and avoidance that characterize anxiety disorders.
The neurobiology of drug addiction: cross-species insights into the dysfunction and recovery of the prefrontal cortex
Ahmet O. Ceceli, Charles W. Bradberry & Rita Z. Goldstein
doi : 10.1038/s41386-021-01153-9
Neuropsychopharmacology volume 47, pages276–291 (2022)
A growing preclinical and clinical body of work on the effects of chronic drug use and drug addiction has extended the scope of inquiry from the putative reward-related subcortical mechanisms to higher-order executive functions as regulated by the prefrontal cortex. Here we review the neuroimaging evidence in humans and non-human primates to demonstrate the involvement of the prefrontal cortex in emotional, cognitive, and behavioral alterations in drug addiction, with particular attention to the impaired response inhibition and salience attribution (iRISA) framework. In support of iRISA, functional and structural neuroimaging studies document a role for the prefrontal cortex in assigning excessive salience to drug over non-drug-related processes with concomitant lapses in self-control, and deficits in reward-related decision-making and insight into illness. Importantly, converging insights from human and non-human primate studies suggest a causal relationship between drug addiction and prefrontal insult, indicating that chronic drug use causes the prefrontal cortex damage that underlies iRISA while changes with abstinence and recovery with treatment suggest plasticity of these same brain regions and functions. We further dissect the overlapping and distinct characteristics of drug classes, potential biomarkers that inform vulnerability and resilience, and advancements in cutting-edge psychological and neuromodulatory treatment strategies, providing a comprehensive landscape of the human and non-human primate drug addiction literature as it relates to the prefrontal cortex.
Mechanisms underlying dorsolateral prefrontal cortex contributions to cognitive dysfunction in schizophrenia
Jason Smucny, Samuel J. Dienel, David A. Lewis & Cameron S. Carter
doi : 10.1038/s41386-021-01089-0
Neuropsychopharmacology volume 47, pages292–308 (2022)
Kraepelin, in his early descriptions of schizophrenia (SZ), characterized the illness as having “an orchestra without a conductor.” Kraepelin further speculated that this “conductor” was situated in the frontal lobes. Findings from multiple studies over the following decades have clearly implicated pathology of the dorsolateral prefrontal cortex (DLPFC) as playing a central role in the pathophysiology of SZ, particularly with regard to key cognitive features such as deficits in working memory and cognitive control. Following an overview of the cognitive mechanisms associated with DLPFC function and how they are altered in SZ, we review evidence from an array of neuroscientific approaches addressing how these cognitive impairments may reflect the underlying pathophysiology of the illness. Specifically, we present evidence suggesting that alterations of the DLPFC in SZ are evident across a range of spatial and temporal resolutions: from its cellular and molecular architecture, to its gross structural and functional integrity, and from millisecond to longer timescales. We then present an integrative model based upon how microscale changes in neuronal signaling in the DLPFC can influence synchronized patterns of neural activity to produce macrocircuit-level alterations in DLPFC activation that ultimately influence cognition and behavior. We conclude with a discussion of initial efforts aimed at targeting DLPFC function in SZ, the clinical implications of those efforts, and potential avenues for future development.
Neuromodulation of prefrontal cortex cognitive function in primates: the powerful roles of monoamines and acetylcholine
Roshan Cools & Amy F. T. Arnsten
doi : 10.1038/s41386-021-01100-8
Neuropsychopharmacology volume 47, pages309–328 (2022)
The primate prefrontal cortex (PFC) subserves our highest order cognitive operations, and yet is tremendously dependent on a precise neurochemical environment for proper functioning. Depletion of noradrenaline and dopamine, or of acetylcholine from the dorsolateral PFC (dlPFC), is as devastating as removing the cortex itself, and serotonergic influences are also critical to proper functioning of the orbital and medial PFC. Most neuromodulators have a narrow inverted U dose response, which coordinates arousal state with cognitive state, and contributes to cognitive deficits with fatigue or uncontrollable stress. Studies in monkeys have revealed the molecular signaling mechanisms that govern the generation and modulation of mental representations by the dlPFC, allowing dynamic regulation of network strength, a process that requires tight regulation to prevent toxic actions, e.g., as occurs with advanced age. Brain imaging studies in humans have observed drug and genotype influences on a range of cognitive tasks and on PFC circuit functional connectivity, e.g., showing that catecholamines stabilize representations in a baseline-dependent manner. Research in monkeys has already led to new treatments for cognitive disorders in humans, encouraging future research in this important field.
Prefrontal contributions to the stability and variability of thought and conscious experience
Andre Zamani, Robin Carhart-Harris & Kalina Christoff
doi : 10.1038/s41386-021-01147-7
Neuropsychopharmacology volume 47, pages329–348 (2022)
The human prefrontal cortex is a structurally and functionally heterogenous brain region, including multiple subregions that have been linked to different large-scale brain networks. It contributes to a broad range of mental phenomena, from goal-directed thought and executive functions to mind-wandering and psychedelic experience. Here we review what is known about the functions of different prefrontal subregions and their affiliations with large-scale brain networks to examine how they may differentially contribute to the diversity of mental phenomena associated with prefrontal function. An important dimension that distinguishes across different kinds of conscious experience is the stability or variability of mental states across time. This dimension is a central feature of two recently introduced theoretical frameworks—the dynamic framework of thought (DFT) and the relaxed beliefs under psychedelics (REBUS) model—that treat neurocognitive dynamics as central to understanding and distinguishing between different mental phenomena. Here, we bring these two frameworks together to provide a synthesis of how prefrontal subregions may differentially contribute to the stability and variability of thought and conscious experience. We close by considering future directions for this work.
The prefrontal cortex and neurosurgical treatment for intractable OCD
Steven A. Rasmussen & Wayne K. Goodman
doi : 10.1038/s41386-021-01149-5
Neuropsychopharmacology volume 47, pages349–360 (2022)
Over the past two decades, circuit-based neurosurgical procedures have gained increasing acceptance as a safe and efficacious approach to the treatment of the intractable obsessive-compulsive disorder (OCD). Lesions and deep brain stimulation (DBS) of the longitudinal corticofugal white matter tracts connecting the prefrontal cortex with the striatum, thalamus, subthalamic nucleus (STN), and brainstem implicate orbitofrontal, medial prefrontal, frontopolar, and ventrolateral cortical networks in the symptoms underlying OCD. The highly parallel distributed nature of these networks may explain the relative lack of adverse effects observed following surgery. Additional pre-post studies of cognitive tasks in more surgical patients are needed to confirm the role of these networks in OCD and to define therapeutic responses to surgical intervention.
Noninvasive neuromodulation of the prefrontal cortex in mental health disorders
William T. Regenold, Zhi-De Deng & Sarah H. Lisanby
doi : 10.1038/s41386-021-01094-3
Neuropsychopharmacology volume 47, pages361–372 (2022)
More than any other brain region, the prefrontal cortex (PFC) gives rise to the singularity of human experience. It is therefore frequently implicated in the most distinctly human of all disorders, those of mental health. Noninvasive neuromodulation, including electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), and transcranial direct current stimulation (tDCS) among others, can—unlike pharmacotherapy—directly target the PFC and its neural circuits. Direct targeting enables significantly greater on-target therapeutic effects compared with off-target adverse effects. In contrast to invasive neuromodulation approaches, such as deep-brain stimulation (DBS), noninvasive neuromodulation can reversibly modulate neural activity from outside the scalp. This combination of direct targeting and reversibility enables noninvasive neuromodulation to iteratively change activity in the PFC and its neural circuits to reveal causal mechanisms of both disease processes and healthy function. When coupled with neuronavigation and neurophysiological readouts, noninvasive neuromodulation holds promise for personalizing PFC neuromodulation to relieve symptoms of mental health disorders by optimizing the function of the PFC and its neural circuits. ClinicalTrials.gov Identifier: NCT03191058.
Recent findings on the role of sensory and interoceptive-related circuits in relapse to drug seeking
David J. Reiner & Yavin Shaham
doi : 10.1038/s41386-021-01081-8
Neuropsychopharmacology volume 47, pages373–374 (2022)
PFC neuromodulation with theta burst stimulation to impact behavior and neural network activity in schizophrenia and bipolar disorder
Fabio Ferrarelli & Mary L. Phillips
doi : 10.1038/s41386-021-01086-3
Neuropsychopharmacology volume 47, pages375–376 (2022)
Thinner cortices in high-risk offspring: the promises of big data
Myrna M. Weissman & Ardesheer Talati
doi : 10.1038/s41386-021-01085-4
Neuropsychopharmacology volume 47, pages377–378 (2022)
Identifying subtypes of PTSD to promote precision medicine
Carole Siegel & Eugene Laska
doi : 10.1038/s41386-021-01102-6
Neuropsychopharmacology volume 47, pages379–380 (2022)
First in vivo evaluations of synaptic density alterations in the brain
Irina Esterlis & Sophie Holmes
doi : 10.1038/s41386-021-01099-y
Neuropsychopharmacology volume 47, pages381–382 (2022)
New myelin for old memories
Michael C. Kern & Mazen A. Kheirbek
doi : 10.1038/s41386-021-01106-2
Neuropsychopharmacology volume 47, pages383–384 (2022)
The paraventricular nucleus of the thalamus and its potential role in psychopathology
Shelly B. Flagel
doi : 10.1038/s41386-021-01112-4
Neuropsychopharmacology volume 47, pages385–386 (2022)
MicroRNAs as promising peripheral sensors of prefrontal cortex developmental trajectory and psychiatric risk
Alice Morgunova & Cecilia Flores
doi : 10.1038/s41386-021-01113-3
Neuropsychopharmacology volume 47, pages387–388 (2022)
Developing breakthrough psychiatric treatments by modulating G protein-coupled receptors on prefrontal cortex somatostatin interneurons
Nicole A. Crowley & Max E. Joffe
doi : 10.1038/s41386-021-01119-x
Neuropsychopharmacology volume 47, pages389–390 (2022)
Super glue: emerging roles for non-neuronal brain cells in mental health
William A. Carlezon Jr & Galen Missig
doi : 10.1038/s41386-021-01115-1
Neuropsychopharmacology volume 47, pages391–392 (2022)
Brain-enriched CACNA1C isoforms as novel, selective targets for psychiatric indications
Nicola A. L. Hall & Elizabeth M. Tunbridge
doi : 10.1038/s41386-021-01114-2
Neuropsychopharmacology volume 47, pages393–394 (2022)
Densely sampled neuroimaging for maximizing clinical insight in psychiatric and addiction disorders
Sarah W. Yip & Anna B. Konova
doi : 10.1038/s41386-021-01124-0
Neuropsychopharmacology volume 47, pages395–396 (2022)
Orexin modulation of stress reactivity as a novel targeted treatment for anxiety and alcohol use disorder
Stephanie M. Gorka & K. Luan Phan
doi : 10.1038/s41386-021-01120-4
Neuropsychopharmacology volume 47, pages397–398 (2022)
Novel approaches to estimate prefrontal synaptic strength in vivo in humans: of relevance to depression, schizophrenia, and ketamine
Chadi G. Abdallah & Graeme F. Mason
doi : 10.1038/s41386-021-01122-2
Neuropsychopharmacology volume 47, pages399–400 (2022)
“Archealization” of human brain organoids
Alysson R. Muotri
doi : 10.1038/s41386-021-01133-z
Neuropsychopharmacology volume 47, pages401–402 (2022)
Leveraging resting-state neurophenotypes to identify susceptibility to and heterogeneity of posttraumatic stress disorder
Nathaniel G. Harnett & Lauren A. M. Lebois
doi : 10.1038/s41386-021-01134-y
Neuropsychopharmacology volume 47, pages403–404 (2022)
Disease-modifying pharmacological approaches to correcting basal forebrain cholinergic neuronal (BFCN) dysfunction and degeneration
John J. Alam & Ralph A. Nixon
doi : 10.1038/s41386-021-01135-x
Neuropsychopharmacology volume 47, pages405–406 (2022)
Brain sex differences: the androgynous brain is advantageous for mental health and well-being
Qiang Luo & Barbara J. Sahakian
doi : 10.1038/s41386-021-01141-z
Neuropsychopharmacology volume 47, pages407–408 (2022)
Neuropsychopharmacology reviews 2022 hot topics: the prenatal environment and risk for mental illness in young people
Joshua L. Roffman & Erin C. Dunn
doi : 10.1038/s41386-021-01143-x
Neuropsychopharmacology volume 47, pages409–410 (2022)
Mobile DNA and the brain
Amy C. Lossie & Jonathan D. Pollock
doi : 10.1038/s41386-021-01151-x
Neuropsychopharmacology volume 47, pages411–412 (2022)
The evolution of the psychedelic revolution
Lindsay P. Cameron & David E. Olson
doi : 10.1038/s41386-021-01150-y
Neuropsychopharmacology volume 47, pages413–414 (2022)
Mapping causal generators of appetitive motivation-hedonic functions in frontal cortex
Brian A. Baldo & Kent C. Berridge
doi : 10.1038/s41386-021-01154-8
Neuropsychopharmacology volume 47, pages415–416 (2022)
“Neuroanatomical integration of homeostatic and hedonic brain regions to regulate consummatory behavior”
Ashley E. Smith & Jonathan D. Hommel
doi : 10.1038/s41386-021-01165-5
Neuropsychopharmacology volume 47, page417 (2022)
Acute effects of a high-fat diet on estrous cycling and body weight of intact female mice
Melissa E. Lenert & Michael D. Burton
doi : 10.1038/s41386-021-01164-6
Neuropsychopharmacology volume 47, pages418–419 (2022)
Identifying novel mechanisms and treatment targets for irritability and aggression in psychiatric disorders
Manish Kumar Jha & Madhukar H. Trivedi
doi : 10.1038/s41386-021-01166-4
Neuropsychopharmacology volume 47, pages420–421 (2022)
Precision medicine in psychiatry: biomarkers to the forefront
Alexander B. Niculescu & Helen Le-Niculescu
doi : 10.1038/s41386-021-01183-3
Neuropsychopharmacology volume 47, pages422–423 (2022)
