Research Domain Criteria: toward future psychiatric nosologies

The Research Domain Criteria (RDoC) project was initiated by the National Institute of Mental Health (NIMH) in early 2009 as the implementation of Goal 1.4 of its just-issued strategic plan. In keeping with the NIMH mission, to “transform the understanding and treatment of mental illnesses through basic and clinical research,” RDoC was explicitly conceived as a research-related initiative. The statement of the relevant goal in the strategic plan reads: “Develop, for research purposes, new ways of classifying mental disorders based on dimensions of observable behavior and neurobiological measures.” Due to the novel approach that RDoC takes to conceptualizing and studying mental disorders, it has received widespread attention, well beyond the borders of the immediate research community. This review discusses the rationale for the experimental framework that RDoC has adopted, and its implications for the nosology of mental disorders in the future.     

Emotor control: computations underlying bodily resource allocation,emotions, and confidence

Emotional processes are central to behavior, yet their deeply subjective nature has been a challenge for neuroscientific study as well as for psychiatric diagnosis. Here we explore the relationships between subjective feelings and their underlying brain circuits from a computational perspective. We apply recent insights from systems neuroscience—approaching subjective behavior as the result of mental computations instantiated in the brain—to the study of emotions. We develop the hypothesis that emotions are the product of neural computations whose motor role is to reallocate bodily resources mostly gated by smooth muscles. This “emotor” control system is analagous to the more familiar motor control computations that coordinate skeletal muscle movements. To illustrate this framework, we review recent research on “confidence.” Although familiar as a feeling, confidence is also an objective statistical quantity: an estimate of the probability that a hypothesis is correct. This model-based approach helped reveal the neural basis of decision confidence in mammals and provides a bridge to the subjective feeling of confidence in humans. These results have important implications for psychiatry, since disorders of confidence computations appear to contribute to a number of psychopathologies. More broadly, this computational approach to emotions resonates with the emerging view that psychiatric nosology may be best parameterized in terms of disorders of the cognitive computations underlying complex behavior.     

Structure and function of complex brain networks

An increasing number of theoretical and empirical studies approach the function of the human brain from a network perspective. The analysis of brain networks is made feasible by the development of new imaging acquisition methods as well as new tools from graph theory and dynamical systems. This review surveys some of these methodological advances and summarizes recent findings on the architecture of structural and functional brain networks. Studies of the structural connectome reveal several modules or network communities that are interlinked by hub regions mediating communication processes between modules. Recent network analyses have shown that network hubs form a densely linked collective called a “rich club,” centrally positioned for attracting and dispersing signal traffic. In parallel, recordings of resting and task-evoked neural activity have revealed distinct resting-state networks that contribute to functions in distinct cognitive domains. Network methods are increasingly applied in a clinical context, and their promise for elucidating neural substrates of brain and mental disorders is discussed.     

Neural systems underlying approach and avoidance in anxiety disorders

Approach-avoidance conflict is an important psychological concept that has been used extensively to better understand cognition and emotion. This review focuses on neural systems involved in approach, avoidance, and conflict decision making, and how these systems overlap with implicated neural substrates of anxiety disorders. In particular, the role of amygdala, insula, ventral striatal, and prefrontal regions are discussed with respect to approach and avoidance behaviors. Three specific hypotheses underlying the dysfunction in anxiety disorders are proposed, including: (i) over-representation of avoidance valuation related to limbic overactivation; (ii) under- or over-representation of approach valuation related to attenuated or exaggerated striatal activation respectively; and (iii) insufficient integration and arbitration of approach and avoidance valuations related to attenuated orbitofrontal cortex activation. These dysfunctions can be examined experimentally using versions of existing decision-making paradigms, but may also require new translational and innovative approaches to probe approach-avoidance conflict and related neural systems in anxiety disorders.     

Sleep disturbances, psychiatric disorders, and psychotropic drugs

Brain neurotransmitter dysfunctions involved in the pathophysiological processes of psychiatric disorders are likely to be reflected by concomitant alterations in sleep continuity and architecture. Since the corrective effects of psychotropic drugs on dysfunctional neurotransmission systems can be evidenced through polysomnographic recordings, one may consider sleep as a kind of "window" on the neurobiology of psychiatric disorders. During the last 10 years, major breakthroughs in our understanding of sleep-wake mechanisms have provided some indications on how psychotropic drugs could influence the sleep-wake cycle. In this review, recent inroads into the understanding of sleep regulatory neural mechanisms are introduced and discussed in terms of the effects of psychotropic drugs. The relationship between the pathophysiological process of a disease, its consequence on sleep, and the corrective effect of a psychotropic drug are exemplified by two psychopathological states: substance withdrawal and major depression. One may conclude that polysomnographic recordings are a unique noninvasive tool to analyze brain functioning, and are particularly well suited to evaluating the objective effects of new psychotropic drugs.     

Alcoholism: the dissection for endophenotypes

Alcohol dependence (alcoholism) is a complex disorder attributed to the interaction of genetic and environmental factors that form a collage of "disease" predisposition, which is not identical for every alcohol-dependent individual. There is considerable evidence to demonstrate that genetic predisposition accounts for roughly half the risk in the development of alcohol dependence. Both family and population studies have identified a number of genomic regions with suggestive links to alcoholism, yet there have been relatively few definitive findings with regard to genetic determinants of alcoholism. This ambiguity can be attributed to a multitude of complications of studying complex mental disorders, such as clinical heterogeneity, polygenic determinants, reduced penetrance, and epistatic effects. Complex mental disorders are clinical manifestations described by combinations of various signs and symptoms. One approach to overcoming the ambiguity in studying the association between genetic risk factors and disease is to dissect the complex, heterogeneous disorder by using intermediate phenotypes--or endophenotypes--to generate more homogeneous diagnostic groupings than an all-encompassing definition, such as the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)-derived term "alcohol dependence" or the commonly used term "alcoholism." The advantage of using endophenotypes is that the number of influential factors that contribute to these characteristics should be fewer and more easily identified than the number of factors affecting the heterogeneous entity of alcohol dependence (alcoholism). A variety of alcohol-related characteristics have been investigated in epidemiological, clinical, and basic research as potential endophenotypes of alcohol dependence. These include phenotypes related to alcohol metabolism, physiological and endocrine measures, neural imaging, electrophysiology, personality, drinking behavior, and responses to alcohol and alcohol-derived cues. This review summarizes the current literature, focused on human data, of promising endophenotypes for dissecting alcoholism.     

Human intelligence and brain networks

Intelligence can be defined as a general mental ability for reasoning, problem solving, and learning. Because of its general nature, intelligence integrates cognitive functions such as perception, attention, memory, language, or planning. On the basis of this definition, intelligence can be reliably measured by standardized tests with obtained scores predicting several broad social outcomes such as educational achievement, job performance, health, and longevity. A detailed understanding of the brain mechanisms underlying this general mental ability could provide significant individual and societal benefits. Structural and functional neuroimaging studies have generally supported a frontoparietal network relevant for intelligence. This same network has also been found to underlie cognitive functions related to perception, short-term memory storage, and language. The distributed nature of this network and its involvement in a wide range of cognitive functions fits well with the integrative nature of intelligence. A new key phase of research is beginning to investigate how functional networks relate to structural networks, with emphasis on how distributed brain areas communicate with each other.     

Gonadal steroids, brain, and behavior: role of context

The nature and extent of the impact of gender and reproductive function on mood has been the subject of speculation and controversy for centuries. Over the past 50 years, however, it has become increasingly clear that not only is the brain a major target of reproductive steroid hormones, but additionally, the steroid hormones, as neuroregulators, create a context thai influences a broad range of brain activities; ie, neural actions and resultant behaviors are markedly different in the presence and absence of gonadal steroids. In turn, the actions of gonadal steroids are themselves context-dependent. Thus, even where it can be demonstrated thai gonadal steroids trigger mood disorders, the triggers are normal levels of gonadal steroids (to be contrasted with the mood disturbances accompanying endocrinopathies), and the mood disorders appear only in a subset of susceptible individuals. The context specificity and differential susceptibility to affective dysregulation seen in women with reproductive endocrine-related mood disorders are undoubtedly important underlying characteristics of a wide range of psychiatric disorders in which the triggers have not yet been identified. Consequently, reproductive endocrine-related mood disorders offer unparalleled promise for the identification of those contextual variables that permit biological stimuli to differentially translate into depression in individuals at risk.     

Cellular plasticity and resilience and the pathophysiology of severe mood disorders

Recent advances in the identification of the neural circuits, neurochemicals, and signal transduction mechanisms involved in the pathophysiology and treatment of mood disorders have led to much progress toward understanding the roles of genetic factors and psychosocial stressors. The monoaminergic neurotransmitter systems have received the most attention, partly because of the observation that effective antidepressant drugs exert their primary biochemical effects by regulating intrasynaptic concentrations of serotonin and norepinephrine. Furthermore, the monoaminergic systems are extensively distributed throughout the network of limbic, striatal, and prefrontal cortical neuronal circuits thought to support the behavioral and visceral manifestations of mood disorders. Increasing numbers of neuroimaging, neuropathological, and biochemical studies indicate impairments in cellular plasticity and resilience in patients who suffer from severe, recurrent mood disorders. In this paper, we describe studies identifying possible structural, functional, and cellular abnormalities associated with depressive disorders, which are potentially the cellular underpinnings of these diseases. We suggest that drugs designed to enhance cellular plasticity and resilience, and attenuate the activity of maladaptive stress-responsive systems, may be useful for the treatment of severe mood disorders.     

Functional neuroimaging studies of the effects of psychotherapy

It has been long established that psychological interventions can markedly alter patients'' thinking patterns, beliefs, attitudes, emotional states, and behaviors. Little was known about the neural mechanisms mediating such alterations before the advent of functional neuroimaging techniques. Since the turn of the new millenium, several functional neuroimaging studies have been conducted to tackle this important issue. Some of these studies have explored the neural impact of various forms of psychotherapy in individuals with major depressive disorder. Other neuroimaging studies have investigated the effects of psychological interventions for anxiety disorders. I review these studies in the present article, and discuss the putative neural mechanisms of change in psychotherapy. The findings of these studies suggest that mental and behavioral changes occurring during psychotherapeutic interventions can lead to a normalization of functional brain activity at a global level.     

Prevention: an achievable goal in personalized medicine

In the past 15 years a considerable number of studies have found evidence that it may be possible to prevent the onset of some mental disorders. Most evidence is available for depressive disorders, but a growing number of studies have focused on anxiety disorders and psychotic disorders. This paper reviews the studies which have examined the effects of preventive interventions on the incidence of mental disorders in people who do not meet criteria for a mental disorder at baseline. More than 20 studies have examined prevention of depressive disorders, and they have found an overall reduction in the incidence of about 25% compared with control groups. The problem of identifying the most optimal target groups for preventive interventions is also illustrated. This is a problem because most risk indicators have a low specificity, and most people with a risk indicator do not develop a mental disorder. Finally, this paper will show how other statistics, such as the exposure rate, the attributable fraction, and the number needed to treat can help in identifying the most optimal target groups for preventive interventions.     

The rise of moral emotions in neuropsychiatry

Clinical psychopathology has largely ignored the developments in the field of social neuroscience. The so-called moral emotions are a group of affective experiences thought to promote cooperation, group cohesion, and reorganization. In this review, we: (i) briefly describe a provisional taxonomy of a limited set of moral emotions and their neural underpinnings; and (ii) discuss how disgust, guilt, anger/indignation, and shame/embarrassment can be conceptualized as key affective experiences in different neuropsychiatric disorders. Based on a concise review of the literature linking moral emotions, psychopathology, and neuropsychiatry, we have devised a simple and preliminary scheme where we conjecture how specific moral emotions can be implicated in some categories of DSM-5 diagnoses, potentially helping to bridge psychopathology and neurobiologically plausible variables, in line with the Research Domain Criteria initiative. We hope this stimulates new empirical work exploring how moral emotional changes and their underlying neurobiology can help elucidating the neural underpinnings of mental disorders.     

Epigenetic alterations in depression and antidepressant treatment

Epigenetic modifications control chromatin structure and function, and thus mediate changes in gene expression, ultimately influencing protein levels. Recent research indicates that environmental events can induce epigenetic changes and, by this, contribute to long-term changes in neural circuits and endocrine systems associated with altered risk for stress-related psychiatric disorders such as major depression. In this review, we describe recent approaches investigating epigenetic modifications associated with altered risk for major depression or response to antidepressant drugs, both on the candidate gene levels as well as the genome-wide level. In this review we focus on DNA methylation, as this is the most investigated epigenetic change in depression research.     

A systematic review of the neural bases of psychotherapy for anxiety and related disorders

Brain imaging studies over two decades have delineated the neural circuitry of anxiety and related disorders, particularly regions involved in fear processing and in obsessive-compulsive symptoms. The neural circuitry of fear processing involves the amygdala, anterior cingulate, and insular cortex, while cortico-striatal-thalamic circuitry plays a key role in obsessive-compulsive disorder. More recently, neuroimaging studies have examined how psychotherapy for anxiety and related disorders impacts on these neural circuits. Here we conduct a systematic review of the findings of such work, which yielded 19 functional magnetic resonance imaging studies examining the neural bases of cognitive-behavioral therapy (CBT) in 509 patients with anxiety and related disorders. We conclude that, although each of these related disorders is mediated by somewhat different neural circuitry, CBT may act in a similar way to increase prefrontal control of subcortical structures. These findings are consistent with an emphasis in cognitive-affective neuroscience on the potential therapeutic value of enhancing emotional regulation in various psychiatric conditions.     

The therapeutic transnosological use of psychotropic drugs

The current clinical use of psychotropic drugs is transnosologically oriented. This is facilitated by the current classification of mental disorders (International Classification of Diseases, 10th Revision [ICD-10]) and is perhaps justified if depression and psychosis (taken here as examples) are considered as being complex syndromes with heterogeneous etiologies, but common pathogenesis, more than specific entities. However, this approach does not identify possible differences between specific psychiatric entities, which could in turn mask differences in therapeutic responses and, therefore, therapeutic outcome. This is compounded by the current disharmony between the nosological classification of diseases, drug development, clinical research, and therapeutic uses of psychotropic drugs. Functional pharmacology targeting abnormal behavioral traits could represent an avenue for future research and treatment.     

Personality disorders at the interface of psychiatry and the law: legal use and clinical classification

Personality disorders have a complex relationship with the law that in many ways reflects their complexity within the clinical and research communities. This paper addresses expert testimony about personality disorders, outlines how personality disorders are assessed in forensic cases, and describes how personality disorders are viewed in different legal contexts. Reasons are identified why personality disorders are not generally accepted as significant mental illness within the legal system, including high incidence of personality dysfunction in criminal populations, frequent comorbidity of personality disorders making it difficult to determine direct causation, and difficulty determining where on a continuum personality traits should be defined as illness (or not). In summary, the legal system, to a significant degree, mirrors the clinical conception of personality disorders as not severe mental diseases or defects, not likely to change, and most often, under volitional control.     

Epidemiology of anxiety disorders in the 21st century

Anxiety disorders, including panic disorder with or without agoraphobia, generalized anxiety disorder, social anxiety disorder, specific phobias, and separation anxiety disorder, are the most prevalent mental disorders and are associated with immense health care costs and a high burden of disease. According to large population-based surveys, up to 33.7% of the population are affected by an anxiety disorder during their lifetime. Substantial underrecognition and undertreatment of these disorders have been demonstrated. There is no evidence that the prevalence rates of anxiety disorders have changed in the past years. In cross-cultural comparisons, prevalence rates are highly variable. It is more likely that this heterogeneity is due to differences in methodology than to cultural influences. Anxiety disorders follow a chronic course; however, there is a natural decrease in prevalence rates with older age. Anxiety disorders are highly comorbid with other anxiety disorders and other mental disorders.     

Optimizing the treatment of mood disorders in the perinatal period

The perinatal period is a time of high risk for women with unipolar and bipolar mood disorders. We discuss treatment considerations for perinatal mood disorders, including unipolar and bipolar depression as well as postpartum psychosis. We further explore the unique issues faced by women and their families across the full trajectory of the perinatal period from preconception planning through pregnancy and following childbirth. Treatment of perinatal mood disorders requires a collaborative care approach between obstetrics practitioners and mental health providers, to ensure that a thoughtful risk : benefit analysis is conducted. It is vital to consider the risks of the underlying illness versus risks of medication exposure during pregnancy or lactation. When considering medication treatment, attention must be paid to prior medication trials that were most efficacious and best tolerated. Lastly, it is important to assess the impact of individual psychosocial stressors and lifestyle factors on treatment response.     

Neuroimaging in anxiety disorders

Over the last few years, neuroimaging techniques have contributed greatly to the identification of the structural and functional neuroanatomy of anxiety disorders. The amygdala seems to be a crucial structure for fear and anxiety, and has consistently been found to be activated in anxiety-provoking situations. Apart from the amygdala, the insula and anterior cinguiate cortex seem to be critical, and ail three have been referred to as the "fear network." In the present article, we review the main findings from three major lines of research. First, we examine human models of anxiety disorders, including fear conditioning studies and investigations of experimentally induced panic attacks. Then we turn to research in patients with anxiety disorders and take a dose look at post-traumatic stress disorder and obsessive-compulsive disorder. Finally, we review neuroimaging studies investigating neural correlates of successful treatment of anxiety, focusing on exposure-based therapy and several pharmacological treatment options, as well as combinations of both.     

Epidemiology of mental disorders in children and adolescents

This article provides a review of the magnitude of mental disorders in children and adolescents from recent community surveys across the world. Although there is substantial variation in the results depending upon the methodological characteristics of the studies, the findings converge in demonstrating that approximately one fourth of youth experience a mental disorder during the past year, and about one third across their lifetimes. Anxiety disorders are the most frequent conditions in children, followed by behavior disorders, mood disorders, and substance use disorders. Fewer than half of youth with current mental disorders receive mental health specialty treatment. However, those with the most severe disorders tend to receive mental health services. Current issues that are now being identified in the field of child psychiatric epidemiology include: refinement of classification and assessment, inclusion of young children in epidemiologic surveys, integration of child and adult psychiatric epidemiology, and evaluation of both mental and physical disorders in children.