搜索结果：Frontiers in human neuroscience

Frontiers of Neurology and Neuroscience Series Editor: J. Bogousslavsky, Editors: K. M. Woodbury-Harris , Vol. 25: Clinical Trials in the Neurosciences , Published by Karger , Basel, Switzerland , 2009 , Hard cover 2009-04-02 USD 228.00, ISSN 1660-4431 This is the recent volume in the series Frontiers of Neurology and Neuroscience. Like previous volumes, this is a brief (approximately 200 pages) multi-author review aimed mainly, as indicated by the flyer, at clinical neurologists. As there are over 30 chapters, each chapter is relatively short. The present volume addresses the question of clinical trials. Although its focus is disorders of the central nervous system, the discussion of trial methodology is generally applicable to all clinical areas. The book systemically covers all stages of drug development up to the point of obtaining a marketing licence, and does not deal with postmarketing surveillance and pharmacovigilance. After two brief introductory chapters, which have the role of ‘setting the scene’, there are four chapters devoted to preclinical trials. These interesting chapters consider animal studies from the point of view of the design of subsequent clinical trials and the translation of information obtained from animal models into the clinical situation. The remainder of the book is devoted to the assessment of the efficacy and safety of drugs in human populations. Phase I and II trials are considered together, describing the principles of design and data analysis. There is a helpful chapter on biomarkers in neurology, discussing the features and roles of biomarkers in general, followed by examples in neurodegenerative diseases and stroke. The next two sections take up the bulk of the book: discussion of issues relating to Phase III trials. The first two chapters in this section deal with regulatory requirements in the USA and Europe. This is followed by a general discussion of design, analysis, clinical end-points and data management. A large section of the book is specifically devoted to multicentre trials, discussing principles of design and analysis, recruitment, obtaining informed consent, the role of local ethics committees (‘institutional review boards’ in the USA), budgeting, medical monitoring, and general management. An interesting section is devoted to special populations, such as patients suffering from progressive neurological diseases, children, neurological emergencies when the patients are unable to give consent, and trials with a genetic focus. Finally, there are chapters discussing the potential role of brain imaging in clinical trials and a chapter on training issues. Overall, this is a broadly-based book whose major virtue is placing the placebo-controlled randomized trial, ‘the gold standard’ for the assessment of the efficacy and safety of new therapeutic agents, into the general context of the process of drug development. However, although the large field covered has the advantage of giving a general perspective, inevitably this is achieved at the expense of factual detail and in-depth analysis. Furthermore, the reference to neurosciences is rather arbitrary: although some chapters are clearly related to some neurological disorders (mainly neurodegenerative diseases and stroke), many do not have such a focus and relate to trial principles and practice in general. Thus, issues of clinical neurology serve as illustrations rather than providing the main focus of the book. Indeed, many neurological disorders (e.g. multiple sclerosis, epilepsy) with huge on-going clinical trial activity, hardly receive a mention. In conclusion, this is a useful overview of clinical trial methodology and some issues associated with it in general, but it provides only limited information about clinical trial activity related to disorders of the central nervous system. A minor quibble: this is an almost entirely American book (out of 45 authors there is only one from Europe), and even the chapter on European regulatory requirements is written by an American. I think that the general appeal of the book, at least on this side of the Atlantic, would have been enhanced by a more international authorship.

Since the concept of working memory was introduced over 50 years ago, different schools of thought have offered different definitions for working memory based on the various cognitive domains that it encompasses. The general consensus regarding working memory supports the idea that working memory is extensively involved in goal-directed behaviors in which information must be retained and manipulated to ensure successful task execution. Before the emergence of other competing models, the concept of working memory was described by the multicomponent working memory model proposed by Baddeley and Hitch. In the present article, the authors provide an overview of several working memory-relevant studies in order to harmonize the findings of working memory from the neurosciences and psychological standpoints, especially after citing evidence from past studies of healthy, aging, diseased, and/or lesioned brains. In particular, the theoretical framework behind working memory, in which the related domains that are considered to play a part in different frameworks (such as memory's capacity limit and temporary storage) are presented and discussed. From the neuroscience perspective, it has been established that working memory activates the fronto-parietal brain regions, including the prefrontal, cingulate, and parietal cortices. Recent studies have subsequently implicated the roles of subcortical regions (such as the midbrain and cerebellum) in working memory. Aging also appears to have modulatory effects on working memory; age interactions with emotion, caffeine and hormones appear to affect working memory performances at the neurobiological level. Moreover, working memory deficits are apparent in older individuals, who are susceptible to cognitive deterioration. Another younger population with working memory impairment consists of those with mental, developmental, and/or neurological disorders such as major depressive disorder and others. A less coherent and organized neural pattern has been consistently reported in these disadvantaged groups. Working memory of patients with traumatic brain injury was similarly affected and shown to have unusual neural activity (hyper- or hypoactivation) as a general observation. Decoding the underlying neural mechanisms of working memory helps support the current theoretical understandings concerning working memory, and at the same time provides insights into rehabilitation programs that target working memory impairments from neurophysiological or psychological aspects.

Since its first description four decades ago, attachment theory (AT) has become one of the principal developmental psychological frameworks for describing the role of individual differences in the establishment and maintenance of social bonds between people. Yet, still little is known about the neurobiological underpinnings of attachment orientations and their well-established impact on a range of social and affective behaviors. In the present review, we summarize data from recent studies using cognitive and imaging approaches to characterize attachment styles and their effect on emotion and social cognition. We propose a functional neuroanatomical framework to integrate the key brain mechanisms involved in the perception and regulation of social emotional information, and their modulation by individual differences in terms of secure versus insecure (more specifically avoidant, anxious, or resolved versus unresolved) attachment traits. This framework describes how each individual's attachment style (built through interactions between personal relationship history and predispositions) may influence the encoding of approach versus aversion tendencies (safety versus threat) in social encounters, implicating the activation of a network of subcortical (amygdala, hippocampus, striatum) and cortical (insula, cingulate) limbic areas. These basic and automatic affective evaluation mechanisms are in turn modulated by more elaborate and voluntary cognitive control processes, subserving mental state attribution and emotion regulation capacities, implicating a distinct network in medial prefrontal cortex (mPFC), superior temporal sulcus (STS), and temporo-parietal junction (TPJ), among others. Recent neuroimaging data suggest that affective evaluation is decreased in avoidantly but increased in anxiously attached individuals. In turn, although data on cognitive control is still scarce, it points toward a possible enhancement of mental state representations associated with attachment insecurity and particularly anxiety. Emotion regulation strategies such as reappraisal or suppression of social emotions are also differentially modulated by attachment style. This research does not only help better understand the neural underpinnings of human social behavior, but also provides important insights on psychopathological conditions where attachment dysregulation is likely to play an important (causal) role.

The existence of so-called ‘basic emotions’ and their defining attributes represents a long lasting and yet unsettled issue in psychology. Recently, neuroimaging evidence, especially related to the advent of neuroimaging meta-analytic methods, has revitalized this debate in the endeavour of systems and human neuroscience. The core theme focuses on the existence of unique neural bases that are specific and characteristic for each instance of basic emotion. Here we review this evidence, outlining contradictory findings, strengths and limits of different approaches. Constructionism dismisses the existence of dedicated neural structures for basic emotions, considering that the assumption of a one-to-one relationship between neural structures and their functions is central to basic emotion theories. While these critiques are useful to pinpoint current limitations of basic emotions theories, we argue that they do not always appear equally generative in fostering new testable accounts on how the brain relates to affective functions. We then consider evidence beyond PET and fMRI, including results concerning the relation between basic emotions and awareness and data from neuropsychology on patients with focal brain damage. Evidence from lesion studies are indeed particularly informative, as they are able to bring correlational evidence typical of neuroimaging studies to causation, thereby characterizing which brain structures are necessary for, rather than simply related to, basic emotion processing. These other studies shed light on attributes often ascribed to basic emotions, such as automaticity of perception, quick onset, and brief duration. Overall, we consider that evidence in favour of the neurobiological underpinnings of basic emotions outweighs dismissive approaches. In fact, the concept of basic emotions can still be fruitful, if updated to current neurobiological knowledge that overcomes traditional one-to-one localization of functions in the brain. In particular, we propose that the structure-function relationship between brain and emotions is better described in terms of pluripotentiality, which refers to the fact that one neural structure can fulfil multiple functions, depending on the functional network and pattern of co-activations displayed at any given moment.

BACKGROUND: Brain research has documented that the cortical mechanisms for language and action are tightly interwoven and, concurrently, new approaches to language therapy in neurological patients are being developed that implement language training in the context of relevant linguistic and non-linguistic actions, therefore taking advantage of the mutual connections of language and action systems in the brain. A further well-known neuroscience principle is that learning at the neuronal level is driven by correlation; consequently, new approaches to language therapy emphasise massed practice in a short time, thus maximising therapy quantity and frequency and, therefore, correlation at the behavioural and neuronal levels. Learned non-use of unsuccessful actions plays a major role in the chronification of neurological deficits, and behavioural approaches to therapy have therefore employed shaping and other learning techniques to counteract such non-use. AIMS: Advances in theoretical and experimental neuroscience have important implications for clinical practice. We exemplify this in the domain of aphasia rehabilitation. MAIN CONTRIBUTION: Whereas classical wisdom had been that aphasia cannot be significantly improved at a chronic stage, we here review evidence that one type of intensive language-action therapy (ILAT)-constraint-induced aphasia therapy-led to significant improvement of language performance in patients with chronic aphasia. We discuss perspectives for further improving speech-language therapy, including drug treatment that may be particularly fruitful when applied in conjunction with behavioural treatment. In a final section we highlight intensive and rapid therapy studies in chronic aphasia as a unique tool for exploring the cortical reorganisation of language. CONCLUSIONS: We conclude that intensive language action therapy is an efficient tool for improving language functions even at chronic stages of aphasia. Therapy studies using this technique can open new perspectives for research into the plasticity of human language circuits.

The global population of individuals over the age of 65 is growing at an unprecedented rate and is expected to reach 1.6 billion by 2050. Most older individuals are affected by multiple chronic diseases, leading to complex drug treatments and increased risk of physical and cognitive disability. Improving or preserving the health and quality of life of these individuals is challenging due to a lack of well-established clinical guidelines. Physicians are often forced to engage in cycles of "trial and error" that are centered on palliative treatment of symptoms rather than the root cause, often resulting in dubious outcomes. Recently, geroscience challenged this view, proposing that the underlying biological mechanisms of aging are central to the global increase in susceptibility to disease and disability that occurs with aging. In fact, strong correlations have recently been revealed between health dimensions and phenotypes that are typical of aging, especially with autophagy, mitochondrial function, cellular senescence, and DNA methylation. Current research focuses on measuring the pace of aging to identify individuals who are "aging faster" to test and develop interventions that could prevent or delay the progression of multimorbidity and disability with aging. Understanding how the underlying biological mechanisms of aging connect to and impact longitudinal changes in health trajectories offers a unique opportunity to identify resilience mechanisms, their dynamic changes, and their impact on stress responses. Harnessing how to evoke and control resilience mechanisms in individuals with successful aging could lead to writing a new chapter in human medicine.

The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies. Results for the final phase of the 1000 Genomes Project are presented including whole-genome sequencing, targeted exome sequencing, and genotyping on high-density SNP arrays for 2,504 individuals across 26 populations, providing a global reference data set to support biomedical genetics. The 1000 Genomes Project has sought to comprehensively catalogue human genetic variation across populations, providing a valuable public genomic resource. The data obtained so far have found applications ranging from association studies and fine mapping studies to the filtering of likely neutral variants in rare-disease cohorts. The authors now report on the final phase of the project, phase 3, which covers previously uncharacterized areas of human genetic diversity in terms of the populations sampled and categories of characterized variation. The sample now includes more than 2,500 individuals from 26 global populations, with low coverage whole-genome and deep exome sequencing, as well as dense microarray genotyping. They find that while most common variants are shared across populations, rarer variants are often restricted to closely related populations. The authors also demonstrate the use of the phase 3 dataset as a reference panel for imputation to improve the resolution in genetic association studies.

Part I: Biological System. Caporael, Evolutionary Theory for Social and Cultural Psychology. Blascovich, Seery, Visceral and Somatic Indexes of Social Psychological Constructs: History, Principles, Propositions, and Case Studies. Ochsner, Social Cognitive Neuroscience: Historical Development, Core Principles, and Future Promise. Part II: Cognitive System. Dunning, Prediction: The Inside View. Roese, Sherman, Expectancy. Kruglanski, Sleeth-Keppler, The Principles of Social Judgment. Andersen, Moscowitz, Blair, Nosek, Automatic Thought. Fiedler, Information Ecology and the Explanation of Social Cognition and Behavior. Forster, Liberman, Knowledge Activation. Hilton, Causal Explanation: From Social Perception to Knowledge-Based Causal Attribution. Petty, Brinol, Tormala, Wegener, The Role of Metacognition in Social Judgment. Wyer, Jr. Principles of Mental Representation. Biernat, Eidelman, Standards. Shafir, Decisions Constructed Locally: Some Fundamental Principles of the Psychology of Decision Making. Liberman, Trope, Stephan, Psychological Distance. Part III: Personal Motivational System. Schwarz, Clore, Feelings and Phenomenal Experiences. Strack, Deutsch, The Role of Impulse in Social Behavior. Oyserman, Social Identity and Self-Regulation. Higgins, Value. Pittman, Zeigler, Basic Human Needs. Fishbach, Ferguson, The Goal Construct in Social Psychology. Baumeister, Schmeichel, Vohs, Self-Regulation and the Executive Function: The Self as Controlling Agent. Van Lange, De Cremer, Van Dijk, Van Vugt, Self-Interest and Beyond: Basic Principles of Social Interaction. Part IV: Interpersonal System. Maio, Haddock, Attitude Change. Simpson, Foundations of Interpersonal Trust. DeDreu, Beersma, Steinel, Van Kleef, The Psychology of Negotiation: Principles and Basic Processes. Semin, Grounding Communication: Synchrony. Shaver, Mikulincer, Attachment Theory and Research: Core Concepts, Basic Principles, Conceptual Bridges. Fiske, Berdahl, Social Power. Part V: Group and Cultural System. Brewer, The Social Psychology of Intergroup Relations: Social Categorization, Ingroup Bias, and Outgroup Prejudice. Hogg, Social Psychology of Leadership. Vallacher, Nowak, Dynamical Social Psychology: Finding Order in the Flow of Human Experience. Levine, Kerr, Inclusion and Exclusion: Implications for Group Processes. Chiu, Hong, Cultural Processes: Basic Principles. Part VI: Applications of Social Psychology. Tyler, Jost, Psychology and the Law: Reconciling Normative and Descriptive Accounts of Social Justice and System Legitimacy. Rothman, Salovey, The Reciprocal Relation between Principles and Practice: Social Psychology and Health Behavior. Strauman, Costanzo, Jones, McLean, Merrill, Contributions of Social Psychology to Clinical Psychology: Three Views of a Research Frontier. Johnson, Pham, Johar, Consumer Behavior and Marketing. Tetlock, Psychology and Politics: The Challenges of Integrating Levels of Analysis in Social Science. Thompson, Pozner, Organizational Behavior. Snyder, Omoto, Social Action.

Noninvasive brain stimulation (NIBS) techniques, such as transcranial magnetic stimulation or transcranial direct and alternating current stimulation, are advocated as measures to enable causal inference in cognitive neuroscience experiments. Transcending the limitations of purely correlative neuroimaging measures and experimental sensory stimulation, they allow to experimentally manipulate brain activity and study its consequences for perception, cognition, and eventually, behavior. Although this is true in principle, particular caution is advised when interpreting brain stimulation experiments in a causal manner. Research hypotheses are often oversimplified, disregarding the underlying (implicitly assumed) complex chain of causation, namely, that the stimulation technique has to generate an electric field in the brain tissue, which then evokes or modulates neuronal activity both locally in the target region and in connected remote sites of the network, which in consequence affects the cognitive function of interest and eventually results in a change of the behavioral measure. Importantly, every link in this causal chain of effects can be confounded by several factors that have to be experimentally eliminated or controlled to attribute the observed results to their assumed cause. This is complicated by the fact that many of the mediating and confounding variables are not directly observable and dose-response relationships are often nonlinear. We will walk the reader through the chain of causation for a generic cognitive neuroscience NIBS study, discuss possible confounds, and advise appropriate control conditions. If crucial assumptions are explicitly tested (where possible) and confounds are experimentally well controlled, NIBS can indeed reveal cause-effect relationships in cognitive neuroscience studies.

Why bodies? It is rather puzzling that given the massive interest in affective neuroscience in the last decade, it still seems to make sense to raise the question 'Why bodies' and to try to provide an answer to it, as is the goal of this article. There are now hundreds of articles on human emotion perception ranging from behavioural studies to brain imaging experiments. These experimental studies complement decades of reports on affective disorders in neurological patients and clinical studies of psychiatric populations. The most cursory glance at the literature on emotion in humans, now referred to by the umbrella term of social and affective neuroscience, shows that over 95 per cent of them have used faces as stimuli. Of the remaining 5 per cent, a few have used scenes or auditory information including human voices, music or environmental sounds. But by far the smallest number has looked into whole-body expressions. As a rough estimate, a search on PubMed today, 1 May 2009, yields 3521 hits for emotion x faces, 1003 hits for emotion x music and 339 hits for emotion x bodies. When looking in more detail, the body x emotion category in fact yields a majority of papers on well-being, nursing, sexual violence or organ donation. But the number of cognitive and affective neuroscience studies of emotional body perception as of today is lower than 20. Why then have whole bodies and bodily expressions not attracted the attention of researchers so far? The goal of this article is to contribute some elements for an answer to this question. I believe that there is something to learn from the historical neglect of bodies and bodily expressions. I will next address some historical misconceptions about whole-body perception, and in the process I intend not only to provide an impetus for this kind of work but also to contribute to a better understanding of the significance of the affective dimension of behaviour, mind and brain as seen from the vantage point of bodily communication. Subsequent sections discuss available evidence for the neurofunctional basis of facial and bodily expressions as well as neuropsychological and clinical studies of bodily expressions.

Intrinsic motivation refers to people's spontaneous tendencies to be curious and interested, to seek out challenges and to exercise and develop their skills and knowledge, even in the absence of operationally separable rewards. Over the past four decades, experimental and field research guided by self-determination theory (SDT; Ryan and Deci, 2017) has found intrinsic motivation to predict enhanced learning, performance, creativity, optimal development and psychological wellness. Only recently, however, have studies begun to examine the neurobiological substrates of intrinsic motivation. In the present article, we trace the history of intrinsic motivation research, compare and contrast intrinsic motivation to closely related topics (flow, curiosity, trait plasticity), link intrinsic motivation to key findings in the comparative affective neurosciences, and review burgeoning neuroscience research on intrinsic motivation. We review converging evidence suggesting that intrinsically motivated exploratory and mastery behaviors are phylogenetically ancient tendencies that are subserved by dopaminergic systems. Studies also suggest that intrinsic motivation is associated with patterns of activity across large-scale neural networks, namely, those that support salience detection, attentional control and self-referential cognition. We suggest novel research directions and offer recommendations for the application of neuroscience methods in the study of intrinsic motivation.

Tremendous progress has been made in basic neuroscience in recent decades. One area that has been especially successful is research on how the brain detects and responds to threats. Such studies have demonstrated comparable patterns of brain-behavior relationships underlying threat processing across a range of mammalian species, including humans. This would seem to be an ideal body of information for advancing our understanding of disorders in which altered threat processing is a key factor, namely, fear and anxiety disorders. But research on threat processing has not led to significant improvements in clinical practice. The authors propose that in order to take advantage of this progress for clinical gain, a conceptual reframing is needed. Key to this conceptual change is recognition of a distinction between circuits underlying two classes of responses elicited by threats: 1) behavioral responses and accompanying physiological changes in the brain and body and 2) conscious feeling states reflected in self-reports of fear and anxiety. This distinction leads to a "two systems" view of fear and anxiety. The authors argue that failure to recognize and consistently emphasize this distinction has impeded progress in understanding fear and anxiety disorders and hindered attempts to develop more effective pharmaceutical and psychological treatments. The two-system view suggests a new way forward.

An essential tension can be found between researchers interested in ecological validity and those concerned with maintaining experimental control. Research in the human neurosciences often involves the use of simple and static stimuli lacking many of the potentially important aspects of real world activities and interactions. While this research is valuable, there is a growing interest in the human neurosciences to use cues about target states in the real world via multimodal scenarios that involve visual, semantic, and prosodic information. These scenarios should include dynamic stimuli presented concurrently or serially in a manner that allows researchers to assess the integrative processes carried out by perceivers over time. Furthermore, there is growing interest in contextually embedded stimuli that can constrain participant interpretations of cues about a target's internal states. Virtual reality environments proffer assessment paradigms that combine the experimental control of laboratory measures with emotionally engaging background narratives to enhance affective experience and social interactions. The present review highlights the potential of virtual reality environments for enhanced ecological validity in the clinical, affective, and social neurosciences.

Real-world environments are typically dynamic, complex, and multisensory in nature and require the support of top-down attention and memory mechanisms for us to be able to drive a car, make a shopping list, or pour a cup of coffee. Fundamental principles of perception and functional brain organization have been established by research utilizing well-controlled but simplified paradigms with basic stimuli. The last 30 years ushered a revolution in computational power, brain mapping, and signal processing techniques. Drawing on those theoretical and methodological advances, over the years, research has departed more and more from traditional, rigorous, and well-understood paradigms to directly investigate cognitive functions and their underlying brain mechanisms in real-world environments. These investigations typically address the role of one or, more recently, multiple attributes of real-world environments. Fundamental assumptions about perception, attention, or brain functional organization have been challenged-by studies adapting the traditional paradigms to emulate, for example, the multisensory nature or varying relevance of stimulation or dynamically changing task demands. Here, we present the state of the field within the emerging heterogeneous domain of real-world neuroscience. To be precise, the aim of this Special Focus is to bring together a variety of the emerging "real-world neuroscientific" approaches. These approaches differ in their principal aims, assumptions, or even definitions of "real-world neuroscience" research. Here, we showcase the commonalities and distinctive features of the different "real-world neuroscience" approaches. To do so, four early-career researchers and the speakers of the Cognitive Neuroscience Society 2017 Meeting symposium under the same title answer questions pertaining to the added value of such approaches in bringing us closer to accurate models of functional brain organization and cognitive functions.

The human stress response has evolved to maintain homeostasis under conditions of real or perceived stress. This objective is achieved through autoregulatory neural and hormonal systems in close association with central and peripheral clocks. The hypothalamic-pituitary-adrenal axis is a key regulatory pathway in the maintenance of these homeostatic processes. The end product of this pathway - cortisol - is secreted in a pulsatile pattern, with changes in pulse amplitude creating a circadian pattern. During acute stress, cortisol levels rise and pulsatility is maintained. Although the initial rise in cortisol follows a large surge in adrenocorticotropic hormone levels, if long-term inflammatory stress occurs, adrenocorticotropic hormone levels return to near basal levels while cortisol levels remain raised as a result of increased adrenal sensitivity. In chronic stress, hypothalamic activation of the pituitary changes from corticotropin-releasing hormone-dominant to arginine vasopressin-dominant, and cortisol levels remain raised due at least in part to decreased cortisol metabolism. Acute elevations in cortisol levels are beneficial to promoting survival of the fittest as part of the fight-or-flight response. However, chronic exposure to stress results in reversal of the beneficial effects, with long-term cortisol exposure becoming maladaptive, which can lead to a broad range of problems including the metabolic syndrome, obesity, cancer, mental health disorders, cardiovascular disease and increased susceptibility to infections. Neuroimmunoendocrine modulation in disease states and glucocorticoid-based therapeutics are also discussed.

Counterfactual reasoning is a hallmark of human thought, enabling the capacity to shift from perceiving the immediate environment to an alternative, imagined perspective. Mental representations of counterfactual possibilities (e.g., imagined past events or future outcomes not yet at hand) provide the basis for learning from past experience, enable planning and prediction, support creativity and insight, and give rise to emotions and social attributions (e.g., regret and blame). Yet remarkably little is known about the psychological and neural foundations of counterfactual reasoning. In this review, we survey recent findings from psychology and neuroscience indicating that counterfactual thought depends on an integrative network of systems for affective processing, mental simulation, and cognitive control. We review evidence to elucidate how these mechanisms are systematically altered through psychiatric illness and neurological disease. We propose that counterfactual thinking depends on the coordination of multiple information processing systems that together enable adaptive behavior and goal-directed decision making and make recommendations for the study of counterfactual inference in health, aging, and disease.