Multimodal frontostriatal connectivity underlies individual differences in self-esteem

A heightened sense of self-esteem is associated with a reduced risk for several types of affective and psychiatric disorders, including depression, anxiety and eating disorders. However, little is known about how brain systems integrate self-referential processing and positive evaluation to give rise to these feelings. To address this, we combined diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) to test how frontostriatal connectivity reflects long-term trait and short-term state aspects of self-esteem. Using DTI, we found individual variability in white matter structural integrity between the medial prefrontal cortex and the ventral striatum was related to trait measures of self-esteem, reflecting long-term stability of self-esteem maintenance. Using fMRI, we found that functional connectivity of these regions during positive self-evaluation was related to current feelings of self-esteem, reflecting short-term state self-esteem. These results provide convergent anatomical and functional evidence that self-esteem is related to the connectivity of frontostriatal circuits and suggest that feelings of self-worth may emerge from neural systems integrating information about the self with positive affect and reward. This information could potentially inform the etiology of diminished self-esteem underlying multiple psychiatric conditions and inform future studies of evaluative self-referential processing.     

Rodent models of genetic and chromosomal variations in psychiatric disorders

Elucidating the molecular basis of complex human psychiatric disorders is challenging due to the multitude of factors that underpin these disorders. Genetic and chromosomal changes are two factors that have been suggested to be involved in psychiatric disorders. Indeed, numerous risk loci have been identified in autism spectrum disorders, schizophrenia, and related psychiatric disorders. Here, we introduce genetic animal models that disturb excitatory‐inhibitory balance in the brain and animal models mirroring human chromosomal abnormalities, both of which may be implicated in autism spectrum disorder pathophysiology. In addition, we discuss recent unique translational research using rodent models, such as Cntnap2 knockout mouse, Mecp2 mutant mouse, Pick1 knockout mouse, and neonatal ventral hippocampal lesion rat. By using these models, several types of drugs are administered during the developmental period to see the effect on psychotic symptoms and neural activities in adults. The accumulating evidence from recent animal studies provides an informative intervention strategy as a translational research.     

Triple-pulse TMS to study interactions between neural circuits in human cortex

Transcranial magnetic stimulation (TMS) is a widely used brain stimulation technique that allows noninvasive examination of different excitatory and inhibitory circuits at the systems level in the intact human brain. In recent years, considerable knowledge has been accumulated about the physiology of?several of these facilitatory and inhibitory processes individually. However, activity in the corresponding neural circuits is not independent of each other. This paper reviews the experiments using triple-pulse TMS that are specifically designed to study interactions between intracortical circuits. These studies have provided evidence for a complex network of interconnected neural circuits within and across cerebral hemispheres. The current knowledge about the functional organization of this network, its pharmacology and functional implications for human motor control are discussed in detail. These findings have clinical relevance because specific interactions between neural circuits may be impaired in neurologic and psychiatric disorders. We conclude that triple-pulse TMS studies will help to integrate and better understand the physiologic processes involved in human motor behavior.     

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.     

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.     

Hedonic hot spots in the brain.

Hedonic "liking" for sensory pleasures is an important aspect of reward, and excessive 'liking' of particular rewards might contribute to excessive consumption and to disorders such as obesity. The present review aims to summarize recent advances in the identification of brain substrates for food 'liking' with a focus on opioid hot spots in the nucleus accumbens and ventral pallidum. Drug microinjection studies have shown that opioids in both areas amplify the 'liking' of sweet taste rewards. Modern neuroscience tools such as Fos plume mapping have further identified hedonic hot spots within the accumbens and pallidum, where opioids are especially tuned to magnify 'liking' of food rewards. Hedonic hot spots in different brain structures may interact with each other within the larger functional circuitry that interconnects them. Better understanding of how brain hedonic hot spots increase the positive affective impact of natural sensory pleasures will help characterize the neural mechanisms potentially involved in 'liking' for many rewards.     

Applications of TMS to therapy in psychiatry.

Transcranial magnetic stimulation (TMS) has been applied to a growing number of psychiatric disorders as a noninvasive probe to study the underlying neurobiologic processes involved in psychiatric disorders and as a putative treatment. Transcranial magnetic stimulation is unparalleled in its ability to test the hypotheses generated by functional neuroimaging studies by modulating activity in selected neural circuits. As a focal intervention that may in some cases exert lasting effects, TMS offers the hope of targeting and ameliorating the circuitry underlying psychiatric disorders. The ultimate success of such an approach depends on our knowledge of the neural circuitry underlying these disorders, of how TMS exerts its effects, and of how to control the application of TMS to exert the desired effects. Although most clinical trials have focused on the treatment of major depression, increasing attention has been paid to schizophrenia and anxiety disorders. Many of these trials have supported a significant effect of TMS, but in some studies the effect is small and short lived. Current challenges in the field include determining how to enhance the efficacy of TMS in these disorders and how to identify patients for whom TMS may be efficacious.     

White matter injury,neural connectivity and the pathophysiology of psychiatric disorders

Psychiatric disorders are characterized by diverse clinical manifestations that include deficits in cognition, perception, mood and arousal. These complex processes are not mediated by any specific brain region but require the coordinated activity of several areas that are anatomically connected. Impairments in these neural circuits may therefore be expected to result in an attenuation of the functions regulated by them. The white matter provides the structural and physiological substrate of neural circuits in the central nervous system. We propose that injury to the white matter, from diverse biological sources, may compromise neural connectivity by associated axonal injury or impaired conductivity. Either mechanism could result in clusters of signs and symptoms that are currently recognized as psychiatric disorders. The role of white matter impairment in the pathophysiology of psychiatric illness is under-appreciated in the neurosciences. Focused translational research aimed at identifying the links between white matter compromise and specific behaviors are necessary for a more thorough understanding of the etiology of mental illness to emerge.     

Nucleus incertus--an emerging modulatory role in arousal, stress and memory

A major challenge in systems neuroscience is to determine the underlying neural circuitry and associated neurotransmitters and receptors involved in psychiatric disorders, such as anxiety and depression. A focus of many of these studies has been specific brainstem nuclei that modulate levels of arousal via their ascending monoaminergic projections (e.g. the serotonergic dorsal raphé, noradrenergic locus ceruleus and cholinergic laterodorsal tegmental nucleus). After years of relative neglect, the subject of recent studies in this context has been the GABAergic nucleus incertus,¹ which is located in the midline periventricular central gray in the ‘prepontine’ hindbrain, with broad projections throughout the forebrain. Nucleus incertus neurons express receptors for the stress hormone, corticotropin-releasing factor (CRF), are activated by psychological stressors, and project to key nuclei involved in stress responses and behavioral activation. The nucleus incertus is also a node in neural circuits capable of modulating hippocampal theta rhythm, which is related to control of spatial navigation and memory. A significant population of nucleus incertus neurons express the recently discovered, highly conserved neuropeptide, relaxin-3; and the recent availability of structurally-related, chimeric peptides that selectively activate or inhibit the relaxin-3 receptor, RXFP3, is facilitating studies of relaxin-3/RXFP3 networks and associated GABA and CRF systems. It is predicted that such targeted research will help elucidate the functions of ascending nucleus incertus pathways, including their possible involvement in arousal (sleep/wakefulness), stress reponses, and learning and memory; and in the pathology of related psychiatric diseases such as insomnia, anxiety and depression, and cognitive deficits.     

Neural processing of reward in adolescent rodents

Immaturities in adolescent reward processing are thought to contribute to poor decision making and increased susceptibility to develop addictive and psychiatric disorders. Very little is known; however, about how the adolescent brain processes reward. The current mechanistic theories of reward processing are derived from adult models. Here we review recent research focused on understanding of how the adolescent brain responds to rewards and reward-associated events. A critical aspect of this work is that age-related differences are evident in neuronal processing of reward-related events across multiple brain regions even when adolescent rats demonstrate behavior similar to adults. These include differences in reward processing between adolescent and adult rats in orbitofrontal cortex and dorsal striatum. Surprisingly, minimal age related differences are observed in ventral striatum, which has been a focal point of developmental studies. We go on to discuss the implications of these differences for behavioral traits affected in adolescence, such as impulsivity, risk-taking, and behavioral flexibility. Collectively, this work suggests that reward-evoked neural activity differs as a function of age and that regions such as the dorsal striatum that are not traditionally associated with affective processing in adults may be critical for reward processing and psychiatric vulnerability in adolescents.     

The alcoholic brain: neural bases of impaired reward-based decision-making in alcohol use disorders

Neuroeconomics is providing insights into the neural bases of decision-making in normal and pathological conditions. In the neuropsychiatric domain, this discipline investigates how abnormal functioning of neural systems associated with reward processing and cognitive control promotes different disorders, and whether such evidence may inform treatments. This endeavor is crucial when studying different types of addiction, which share a core promoting mechanism in the imbalance between impulsive subcortical neural signals associated with immediate pleasurable outcomes and inhibitory signals mediated by a prefrontal reflective system. The resulting impairment in behavioral control represents a hallmark of alcohol use disorders (AUDs), a chronic relapsing disorder characterized by excessive alcohol consumption despite devastating consequences. This review aims to summarize available magnetic resonance imaging (MRI) evidence on reward-related decision-making alterations in AUDs, and to envision possible future research directions. We review functional MRI (fMRI) studies using tasks involving monetary rewards, as well as MRI studies relating decision-making parameters to neurostructural gray- or white-matter metrics. The available data suggest that excessive alcohol exposure affects neural signaling within brain networks underlying adaptive behavioral learning via the implementation of prediction errors. Namely, weaker ventromedial prefrontal cortex activity and altered connectivity between ventral striatum and dorsolateral prefrontal cortex likely underpin a shift from goal-directed to habitual actions which, in turn, might underpin compulsive alcohol consumption and relapsing episodes despite adverse consequences. Overall, these data highlight abnormal fronto-striatal connectivity as a candidate neurobiological marker of impaired choice in AUDs. Further studies are needed, however, to unveil its implications in the multiple facets of decision-making.     

Serotonin-related pathways and developmental plasticity: relevance for psychiatric disorders

Risk for adult psychiatric disorders is partially determined by early-life alterations occurring during neural circuit formation and maturation. In this perspective, recent data show that the serotonin system regulates key cellular processes involved in the construction of cortical circuits. Translational data for rodents indicate that early-life serotonin dysregulation leads to a wide range of behavioral alterations, ranging from stress-related phenotypes to social deficits. Studies in humans have revealed that serotonin-related genetic variants interact with early-life stress to regulate stress-induced cortisol responsiveness and activate the neural circuits involved in mood and anxiety disorders. Emerging data demonstrate that early-life adversity induces epigenetic modifications in serotonin-related genes. Finally, recent findings reveal that selective serotonin reuptake inhibitors can reinstate juvenile-like forms of neural plasticity, thus allowing the erasure of long-lasting fear memories. These approaches are providing new insights on the biological mechanisms and clinical application of antidepressants.     

Adult vulnerability for psychiatric disorders: interactive effects of negative childhood experiences and recent stress

The effects of negative childhood experiences on adult psychiatric status remain unclear because of inconsistent findings in previous studies. In this study, we examine the extent to which parental separation/divorce before the age of 10, parental death before the age of 10, and self-reports of parental mental illness during early childhood interact with recent stressful life events to increase the probability of multiple psychiatric disorders and psychiatric symptoms during adulthood. Data are from a stratified random sample of 3801 adults residing in a five-county catchment area in North Carolina. The Diagnostic Interview Schedule was used to measure psychiatric disorders and symptoms during the 6 months prior to the interview. Regression analyses were used to determine whether negative childhood experiences interact with recent stressful life events to increase the probability of psychiatric disorders or symptoms, with other risk factors statistically controlled. Results suggest that: a) parental mental illness increases the likelihood that stressful life events will result in depression, although it is unclear whether this increased vulnerability is due to genetic or environmental factors; b) parental separation/divorce interacts with stressful life events to increase vulnerability to alcohol problems and psychiatric disorders more generally; and c) parental death does not interact with recent events to affect the likelihood of psychiatric problems.     

Functional neuroimaging of reward processing and decision-making: a review of aberrant motivational and affective processing in addiction and mood disorders

The adequate integration of reward- and decision-related information provided by the environment is critical for behavioral success and subjective well being in everyday life. Functional neuroimaging research has already presented a comprehensive picture on affective and motivational processing in the healthy human brain and has recently also turned its interest to the assessment of impaired brain function in psychiatric patients. This article presents an overview on neuroimaging studies dealing with reward processing and decision-making by combining most recent findings from fundamental and clinical research. It provides an outline on the neural mechanisms guiding context-adequate reward processing and decision-making processes in the healthy brain, and also addresses pathophysiological alterations in the brain's reward system that have been observed in substance abuse and mood disorders, two highly prevalent classes of psychiatric disorders. The overall goal is to critically evaluate the specificity of neurophysiological alterations identified in these psychiatric disorders and associated symptoms, and to make suggestions concerning future research.     

A virtual reality-based FMRI study of reward-based spatial learning

Although temporo-parietal cortices mediate spatial navigation in animals and humans, the neural correlates of reward-based spatial learning are less well known. Twenty-five healthy adults performed a virtual reality fMRI task that required learning to use extra-maze cues to navigate an 8-arm radial maze and find hidden rewards. Searching the maze in the spatial learning condition compared to the control conditions was associated with activation of temporo-parietal regions, albeit not including the hippocampus. The receipt of rewards was associated with activation of the hippocampus in a control condition when using the extra-maze cues for navigation was rendered impossible by randomizing the spatial location of cues. Our novel experimental design allowed us to assess the differential contributions of the hippocampus and other temporo-parietal areas to searching and reward processing during reward-based spatial learning. This translational research will permit parallel studies in animals and humans to establish the functional similarity of learning systems across species; cellular and molecular studies in animals may then inform the effects of manipulations on these systems in humans, and fMRI studies in humans may inform the interpretation and relevance of findings in animals.     

Risk and resilience: Genetic and environmental influences on development of the stress response

Exposure to stressful events during development has consistently been shown to produce long‐lasting alterations in the hypothalamic‐pituitary‐adrenal (HPA) axis, which may increase vulnerability to disease, including posttraumatic stress disorder and other mood and anxiety disorders. Recently reported genetic association studies indicate that these effects may be mediated, in part, by gene×environment interactions involving polymorphisms within two key genes, CRHR1 and FKBP5. Data suggest that these genes regulate HPA axis function in conjunction with exposure to child maltreatment or abuse. In addition, a large and growing body of preclinical research suggests that increased activity of the amygdala‐HPA axis induced by experimental manipulation of the amygdala mimics several of the physiological and behavioral symptoms of stress‐related psychiatric illness in humans. Notably, interactions between the developing amygdala and HPA axis underlie critical periods for emotional learning, which are modulated by developmental support and maternal care. These translational findings lead to an integrated hypothesis: high levels of early life trauma lead to disease through the developmental interaction of genetic variants with neural circuits that regulate emotion, together mediating risk and resilience in adults. Depression and Anxiety Depression and Anxiety 26:984–992, 2009. Published 2009 Wiley‐Liss, Inc.     

Integrating functional brain neuroimaging and developmental cognitive neuroscience in child psychiatry research

ObjectiveTo provide an overview of clinical research aiming to develop a mechanistic understanding of brain dysfunction in child psychiatric disorders.MethodTechnological, conceptual, and translational approaches relevant to the investigation of brain function in pediatric psychiatric illnesses are explored. Research in the area of pediatric bipolar disorder is used as a prototypic model illustrating the use of complementary techniques of functional magnetic neuroimaging and neurocognitive studies to identify abnormalities in neural circuitry function.ResultsStudies of bipolar youths indicate impairment in cognitive and affective neural systems and in the interface of these two circuits. This evolving field paves a future pathway for identifying diagnostic biomarkers for the disorder, providing tools for monitoring response to pharmacotherapy, examining illness-associated alterations in developmental trajectory, and facilitating the use of animal research for guiding the development of novel treatment strategies.ConclusionsStudies of brain function in child psychiatry are establishing a platform of knowledge and methods that offer promise for revolutionizing both models of illness pathophysiology and future diagnostic and therapeutic practice.     

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.     

Iowa gambling task in Parkinson's disease

Cognitive impairments are common in patients with Parkinson's disease (PD) from the early stages. Recent studies reported that medicated PD patients have poor performances, with respect to age-matched healthy controls, in a decision-making task like the Iowa Gambling Task (IGT), which detects the ability to alter choice behavior in response to fluctuations in reward contingencies. The IGT principally activates functions related to the orbitofrontal cortex, which plays a crucial role in the generation of outcome expectancies and processing of rewards. The analysis of IGT performances of PD patients is of particular interest because PD represents a good clinical model to study reward processing when its neural bases are affected by a neuropathology or are overdosed by dopaminergic therapies. As a matter of fact, either PD-related neuropathology in advanced stages of the disease or the dopamine replacement therapy from earlier stages of PD may affect the functioning of the orbitofrontal cortex. Three causal hypotheses on a dysfunctional decision making in PD patients, as assessed by IGT, are discussed. Finally, the possible relation between the phenomenon of decision-making impairment and impulse control disorders, a psychiatric complication observed with increasing frequency in PD patients, is discussed.