Showing papers in "Dialogues in Clinical Neuroscience in 2010"
TL;DR: The main cognitive ability areas affected in schizophrenia are described, and the degree of impairment in each ability area as found in studies of schizophrenia patients is summarized, based on meta-analytic findings.
Abstract: Overwhelming evidence suggests that compromised neuropsychological function is frequently observed in schizophrenia. The neuropsychological profile is typically characterized by prominent specific deficits in memory and learning, working memory, executive functions, attention, and processing speed, which are evident on a background of a generalized cognitive deficit. This paper provides a review of studies of neuropsychological functioning in schizophrenia. The main cognitive ability areas affected in schizophrenia are described, and the degree of impairment in each ability area as found in studies of schizophrenia patients is summarized, based on meta-analytic findings. Recent studies that have compared neuropsychological functioning across psychotic disorders are presented, and finally, neuropsychological assessment batteries specifically developed for schizophrenia are introduced.
224 citations
TL;DR: The clinical concept of schizophrenia is supported by empirical evidence that its multiple facets form a broad syndrome with non-negligible internal cohesion and a characteristic evolution over time.
Abstract: More than a century since the delineation of dementia praecox by Kraepelin, the etiology, neuropathology, and pathophysiology of schizophrenia remain elusive. Despite the availability of criteria allowing reliable diagnostic identification, schizophrenia essentially remains a broad clinical syndrome defined by reported subjective experiences (symptoms), loss of function (behavioral impairments), and variable patterns of course. Research has identified a number of putative biological markers associated with the disorder, including neurocognitive dysfunction, brain dysmorphology, and neurochemical abnormalities. Yet none of these variables has to date been definitively proven to possess the sensitivity and specificity expected of a diagnostic test. Genetic linkage and association studies have targeted multiple candidate loci and genes, but failed to demonstrate that any specific gene variant, or a combination of genes, is either necessary or sufficient to cause schizophrenia. Thus, the existence of a specific brain disease underlying schizophrenia remains a hypothesis. Against a background of an ever-increasing volume of research data, the inconclusiveness of the search for causes of the disorder fuels doubts about the validity of the schizophrenia construct as presently defined. Given the protean nature of the symptoms of schizophrenia and the poor coherence of the clinical and biological findings, such doubts are not without reason. However, simply dismantling the concept is unlikely to result in an alternative model that would account for the host of clinical phenomena and research data consistent with a disease hypothesis of schizophrenia. For the time being, the clinical concept of schizophrenia is supported by empirical evidence that its multiple facets form a broad syndrome with non-negligible internal cohesion and a characteristic evolution over time. The dissection of the syndrome with the aid of endophenotypes is beginning to be perceived as a promising approach in schizophrenia genetics.
210 citations
TL;DR: 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.
Abstract: 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.
200 citations
TL;DR: Advances in the understanding of the nature of primary-process emotional affects can promote the development of better preclinical models of psychiatric disorders and thereby also allow clinicians new and useful ways to understand the foundational aspects of their clients' problems.
Abstract: Cross-species affective neuroscience studies confirm that primary-process emotional feelings are organized within primitive subcortical regions of the brain that are anatomically, neurochemically, and functionally homologous in all mammals that have been studied. Emotional feelings (affects) are intrinsic values that inform animals how they are faring in the quest to survive. The various positive affects indicate that animals are returning to "comfort zones" that support survival, and negative affects reflect "discomfort zones" that indicate that animals are in situations that may impair survival. They are ancestral tools for living--evolutionary memories of such importance that they were coded into the genome in rough form (as primary brain processes), which are refined by basic learning mechanisms (secondary processes) as well as by higher-order cognitions/thoughts (tertiary processes). To understand why depression feels horrible, we must fathom the affective infrastructure of the mammalian brain. Advances in our understanding of the nature of primary-process emotional affects can promote the development of better preclinical models of psychiatric disorders and thereby also allow clinicians new and useful ways to understand the foundational aspects of their clients' problems. These networks are of clear importance for understanding psychiatric disorders and advancing psychiatric practice.
187 citations
TL;DR: Future research will require the collaboration of multidisciplinary teams of investigators to achieve sufficiently large samples of individuals with OCD; apply the state-of-the-art laboratory techniques; and perform the bioinformatic analyses essential to the identification of risk loci.
Abstract: Obsessive-compulsive disorder (OCD) is a serious psychiatric disorder that affects approximately 2% of the populations of children and adults. Family aggregation studies have demonstrated that OCD is familial, and results from twin studies demonstrate that the familiality is due in part to genetic factors. Only three genome-wide linkage studies have been completed to date, with suggestive but not definitive results. In addition, over 80 candidate gene studies have been published. Most of these studies have focused on genes in the serotonergic and dopaminergic pathways. Unfortunately, none have achieved genome-wide significance, and, with the exception of the glutamate transporter gene, none have been replicated. Future research will require the collaboration of multidisciplinary teams of investigators to (i) achieve sufficiently large samples of individuals with OCD; (ii) apply the state-of-the-art laboratory techniques; and ( iii) perform the bioinformatic analyses essential to the identification of risk loci.
181 citations
TL;DR: 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, and the role of amygdala, insula, ventral striatal, and prefrontal regions is discussed.
Abstract: 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
166 citations
Journal Article•
TL;DR: Studies on the validity, frequency, and predictors of symptomatic remission in schizophrenia and studies on patients' perspectives suggest that the RSWG remission criteria are valid and useful and should be consistently applied in clinical trials.
Abstract: In March 2005, the Remission in Schizophrenia Working Group (RSWG) proposed a consensus definition of symptomatic remission in schizophrenia and developed specific operational criteria for its assessment. They pointed out, however, that the validity and the relationship to other outcome dimensions required further examination. This article reviews studies on the validity, frequency, and predictors of symptomatic remission in schizophrenia and studies on patients' perspectives. These studies have demonstrated that the RSWG remission criteria appear achievable and sustainable for a significant proportion of patients, and are related to a better overall symptomatic status and functional outcome and, to a less clear extent, to a better quality of life and cognitive performance. However, achieving symptomatic remission is not automatically concurrent with an adequate status in other outcome dimensions. The results of the present review suggest that the RSWG remission criteria are valid and useful. As such, they should be consistently applied in clinical trials. However the lack of consensus definitions of functional remission and adequate quality of life hampers research on their predictive validity on these outcome dimensions. Future research should therefore search for criteria of these dimensions and test whether the RSWG remission criteria consistently predict a "good" outcome with respect to functioning and quality of life.
149 citations
TL;DR: The neuroanatomy and neurochemistry of brain serotonergic circuitries are described and it is argued that the specificity of the local chemocommunication between5-HT and other neuronal elements mainly depends on mechanisms regulating the extracellular concentration of 5-HT, the diversity of high-affinity membrane receptors, and their specific transduction modalities.
Abstract: Brain serotonergic circuitries interact with other neurotransmitter systems on a multitude of different molecular levels. In humans, as in other mammalian species, serotonin (5-HT) plays a modulatory role in almost every physiological function. Furthermore, serotonergic dysfunction is thought to be implicated in several psychiatric and neurodegenerative disorders. We describe the neuroanatomy and neurochemistry of brain serotonergic circuitries. The contribution of emergent in vivo imaging methods to the regional localization of binding site receptors and certain aspects of their functional connectivity in correlation to behavior is also discussed. 5-HT cell bodies, mainly localized in the raphe nuclei, send axons to almost every brain region. It is argued that the specificity of the local chemocommunication between 5-HT and other neuronal elements mainly depends on mechanisms regulating the extracellular concentration of 5-HT the diversity of high-affinity membrane receptors, and their specific transduction modalities.
139 citations
TL;DR: Current cognitive behavioral therapy (CBT) with an emphasis on variants of exposure and ritual or response prevention (EX/RP) treatments, the therapy that has shown the most empirical evidence of its efficacy.
Abstract: Until the mid-1960s, obsessive-compulsive disorder (OCD) was considered to be treatment-resistant, as both psychodynamic psychotherapy and medication had been unsuccessful in significantly reducing OCD symptoms. The first real breakthrough came in 1966 with the introduction of exposure and ritual prevention. This paper will discuss the cognitive behavioral conceptualizations that influenced the development of cognitive behavioral treatments for OCD. There will be a brief discussion of the use of psychodynamic psychotherapy and early behavioral therapy, neither of which produced successful outcomes with OCD. The main part of the paper will be devoted to current cognitive behavioral therapy (CBT) with an emphasis on variants of exposure and ritual or response prevention (EX/RP) treatments, the therapy that has shown the most empirical evidence of its efficacy.
126 citations
TL;DR: This review will highlight the interactive and integrative potential that exists in the brain to bring together the cognitive and emotional domains and discuss a dual competition framework, which describes cognitive-emotional interactions in terms of perceptual and cognitive competition mechanisms.
Abstract: Emotion and cognition have been viewed as largely separate entities in the brain. Within this framework, significant progress has been made in understanding specific aspects of behavior. Research in the past two decades, however, has started to paint a different picture of brain organization, one in which network interactions are key to understanding complex behaviors. From both basic and clinical perspectives, the characterization of cognitive-emotional interactions constitutes a fundamental issue in the investigation of the mind and brain. This review will highlight the interactive and integrative potential that exists in the brain to bring together the cognitive and emotional domains. First, anatomical evidence will be provided, focusing on structures such as hypothalamus, basal forebrain, amygdala, cingulate cortex, orbitofrontal cortex, and insula. Data on functional interactions will then be discussed, followed by a discussion of a dual competition framework, which describes cognitive-emotional interactions in terms of perceptual and cognitive competition mechanisms.
113 citations
Journal Article•
TL;DR: Evidence for structural neuroimaging abnormalities is reviewed, beginning with evidence for focal brain abnormalities, primarily in gray matter, and proceeding to the quest to identify abnormalities in brain systems and circuits by focusing on damage to white matter connections in the brain.
Abstract: Historically, Kraepelin speculated that dementia praecox resulted from damage to the cerebral cortex, most notably the frontal and temporal cortices. It is only recently, however, that tools have been available to test this hypothesis. Now, more than a century later, we know that schizophrenia is a brain disorder. This knowledge comes from critical advances in imaging technology--including computerized axial tomography, magnetic resonance imaging, and diffusion imaging--all of which provide an unprecedented view of neuroanatomical structures, in vivo. Here, we review evidence for structural neuroimaging abnormalities, beginning with evidence for focal brain abnormalities, primarily in gray matter, and proceeding to the quest to identify abnormalities in brain systems and circuits by focusing on damage to white matter connections in the brain. We then review future prospects that need to be explored and pursued in order to translate our current knowledge into an understanding of the neurobiology of schizophrenia, which can then be translated into novel treatments.
TL;DR: Current research is focussing on the significance of minor psychotic symptoms in the general population, gene-environmental interaction, and how risk factors impact on pathogenesis; perhaps all risk factors ultimately impact on striatal dopamine as the final common pathway.
Abstract: Major advances have been made in our understanding of the epidemiology of schizophrenia. We now know that the disorder is more common and severe in young men, and that the incidence varies geographically and temporally. Risk factors have been elucidated; biological risks include a family history of the disorder, advanced paternal age, obstetric complications, and abuse of drugs such as stimulants and cannabis. In addition, recent research has also identified social risk factors such as being born and brought up in a city, migration, and certain types of childhood adversity such as physical abuse and bullying, as well as social isolation and adverse events in adult life. Current research is focussing on the significance of minor psychotic symptoms in the general population, gene-environmental interaction, and how risk factors impact on pathogenesis; perhaps all risk factors ultimately impact on striatal dopamine as the final common pathway.
TL;DR: An epigenetic explanation for many characteristics of psychiatric disease is presented, the current literature on the epigenetic mechanisms involved in major psychosis, Alzheimer's disease, and autism spectrum disorders are reviewed, and some future directions in the field of psychiatric epigenomics are described.
Abstract: Psychiatric diseases place a tremendous burden on affected individuals, their caregivers, and the health care system. Although evidence exists for a strong inherited component to many of these conditions, dedicated efforts to identify DNA sequence-based causes have not been exceptionally productive, and very few pharmacologic treatment options are clinically available. Many features of psychiatric diseases are consistent with an epigenetic dysregulation, such as discordance of monozygotic twins, late age of onset, parent-of-origin and sex effects, and fluctuating disease course. In recent years, experimental technologies have significantly advanced, permitting in-depth studies of the epigenome and its role in maintenance of normal genomic functions, as well as disease etiopathogenesis. Here, we present an epigenetic explanation for many characteristics of psychiatric disease, review the current literature on the epigenetic mechanisms involved in major psychosis, Alzheimer's disease, and autism spectrum disorders, and describe some future directions in the field of psychiatric epigenomics.
Journal Article•
TL;DR: The investigation provides the first evidence for the effectiveness of the myMCT for OCD, a self-help manual aimed at raising patients' awareness about cognitive biases that seem to subserve OCD.
Abstract: Despite advances in the understanding and treatment of obsessive-compulsive disorder (OCD), many patients undergoing interventions display incomplete symptom reduction, Our research group has developed a self-help manual entitled "My Metacognitive Training for OCD" (myMCT) aimed at raising patients' awareness about cognitive biases that seem to subserve OCD. The training is particularly intended for patients currently unable or unwilling to attend standard therapy, or in cases where such a treatment option is not available. For the present study, 86 individuals suffering from OCD were recruited over the Internet. Following the initial assessment, participants were either immediately emailed the myMCT manual or allocated to a waitlist group. After 4 weeks, a second assessment was performed, The myMCT group showed significantly greater improvement for OCD symptoms according to the Y-BOCS total score compared with the waitlist group (d = .63), particularly for obsessions (d= .69). Medium to strong differences emerged for the OCI-R (d = .70) and the BDI-SF (d = .50). The investigation provides the first evidence for the effectiveness of the myMCT for OCD.
TL;DR: Novel research approaches, such as preliminary treatment studies with glutamatergic substances, and trials with further drugs, as well as needed aspects of future research, are reviewed.
Abstract: Knowledge of pharmacotherapeutic treatment options in obsessive-compulsive disorder (OCD) has grown considerably over the past 40 years Serotonergic antidepressants, such as selective serotonin reuptake inhibitors (SSRls) and clomipramine, are the established pharmacologic first-line treatment of OCD Medium to large dosages and acute treatment for at least 3 months are recommended until efficacy is assessed In case of significant improvement, maintenance treatment is necessary, Unfortunately, about half of the patients do not respond sufficiently to oral serotonergic antidepressants; augmentation with atypical antipsychotics is an established second-line drug treatment strategy Alternatives include intravenous serotonergic antidepressants and combination with or switch to cognitive behavioral psychotherapy Remarkably, a considerable proportion of OCD patients still do not receive rational drug treatment Novel research approaches, such as preliminary treatment studies with glutamatergic substances, and trials with further drugs, as well as needed aspects of future research, are reviewed
TL;DR: Features of fMRI methodology are summarized and its application in neurobehavioral studies in schizophrenia is highlighted to help bridge integration with neuropharmacologic and genomic investigations.
Abstract: The integration of functional magnetic resonance imaging (fMRI) with cognitive and affective neuroscience paradigms enables examination of the brain systems underlying the behavioral deficits manifested in schizophrenia; there have been a remarkable increase in the number of studies that apply fMRI in neurobiological studies of this disease. This article summarizes features of fMRI methodology and highlights its application in neurobehavioral studies in schizophrenia. Such work has helped elucidate potential neural substrates of deficits in cognition and affect by providing measures of activation to neurobehavioral probes and connectivity among brain regions. Studies have demonstrated abnormalities at early stages of sensory processing that may influence downstream abnormalities in more complex evaluative processing. The methodology can help bridge integration with neuropharmacologic and genomic investigations.
TL;DR: New treatment options are needed that affect nondopaminergic targets with relevance for symptom reduction, relapse prevention, enhanced efficacy for nonresponders, and reduced key adverse effects.
Abstract: Despite pharmacologic advances, the treatment of schizophrenia remains a challenge, and suboptimal outcomes are still all too frequent. Although treatment goals of response, remission, and recovery have been defined more uniformly, a good “effectiveness” measure mapping onto functional outcomes is still lacking. Moreover, the field has to advance in transferring measurement-based approaches from research to clinical practice. There is an ongoing debate whether, and which, first- or second-generation antipsychotics should be used. However, an individualized treatment approach needs to consider current symptoms, comorbid conditions, past therapeutic response, and adverse effects, as well as patient choice and expectations. Moreover, acute and long-term goals and effects of medication treatment need to be balanced. While the acute response to appropriately dosed first-generation antipsychotics may not differ much from second-generation antipsychotics, advantages of lower rates of extrapyramidal side effects, tardive dyskinesia, and, possibly, relapse may favor second-generation antipsychotics. However, when considering individual adverse effect prof iles, the differentiation into first- and second-generation antipsychotics as unified classes can not be upheld, and a more differentiated view and treatment selection is required. To date, clozapine is the only evidence-based treatment for refractory patients, and the role of antipsychotic polypharmacy and other augmentation strategies remains unclear, at best. To improve the treatment outcomes in schizophrenia, research efforts are needed that elucidate biomarkers of the illness and of treatment response (both therapeutic and adverse effects). Moreover, new treatment options are needed that affect nondopaminergic targets with relevance for symptom reduction, relapse prevention, enhanced efficacy for nonresponders, and reduced key adverse effects.
TL;DR: The Personal Genome Project's effort to develop a GET database as a public genomics resource broadly accessible to both researchers and research participants is examined, while pursuing the highest standards in research ethics.
Abstract: The cost of a diploid human genome sequence has dropped from about $70M to $2000 since 2007- even as the standards for redundancy have increased from 7x to 40x in order to improve call rates. Coupled with the low return on investment for common single-nucleotide polymorphisms, this has caused a significant rise in interest in correlating genome sequences with comprehensive environmental and trait data (GET). The cost of electronic health records, imaging, and microbial, immunological, and behavioral data are also dropping quickly. Sharing such integrated GET datasets and their interpretations with a diversity of researchers and research subjects highlights the need for informed-consent models capable of addressing novel privacy and other issues, as well as for flexible data-sharing resources that make materials and data available with minimum restrictions on use. This article examines the Personal Genome Project's effort to develop a GET database as a public genomics resource broadly accessible to both researchers and research participants, while pursuing the highest standards in research ethics.
TL;DR: Considering the status of current research, the concept of OCD and OCD-related spectrum conditions seems fluid in 2010, and in need of ongoing reappraisal.
Abstract: Obsessive-compulsive disorder (OCD) is a clinical syndrome whose hallmarks are excessive, anxiety-evoking thoughts and compulsive behaviors that are generally recognized as unreasonable, but which cause significant distress and impairment. When these are the exclusive symptoms, they constitute uncomplicated OCD. OCD may also occur in the context of other neuropsychiatric disorders, most commonly other anxiety and mood disorders. The question remains as to whether these combinations of disorders should be regarded as independent, cooccurring disorders or as different manifestations of an incompletely understood constellation of OCD spectrum disorders with a common etiology. Additional considerations are given here to two potential etiology-based subgroups: (i) an environmentally based group in which OCD occurs following apparent causal events such as streptococcal infections, brain injury, or atypical neuroleptic treatment; and (ii) a genomically based group in which OCD is related to chromosomal anomalies or specific genes. Considering the status of current research, the concept of OCD and OCD-related spectrum conditions seems fluid in 2010, and in need of ongoing reappraisal.
TL;DR: The most parsimonious explanation of these findings is that neurodevelopment is a process that is ongoing throughout life, and that schizophrenia occurs as a consequence of aberrations in neurodevelopmental processes that could occur at various stages of life.
Abstract: Defining the lifetime trajectory of schizophrenia and the mechanisms that drive it is one of the major challenges of schizophrenia research. Kraepelin assumed that the mechanisms were neurodegenerative ("dementia praecox"), and the early imaging work using computerized tomography seemed to support this model. Prominent ventricular enlargement and increased cerebrospinal fluid on the brain surface suggested that the brain had atrophied. In the 1980s, however, both neuropathological findings and evidence from magnetic resonance imaging (MRI) provided evidence suggesting that neurodevelopmental mechanisms might be a better explanation. This model is supported by both clinical and MRI evidence, particularly the fact that brain abnormalities are already present in first-episode patients. However, longitudinal studies of these patients have found evidence that brain tissue is also lost during the years after onset. The most parsimonious explanation of these findings is that neurodevelopment is a process that is ongoing throughout life, and that schizophrenia occurs as a consequence of aberrations in neurodevelopmental processes that could occur at various stages of life.
TL;DR: Findings from postmortem, imaging, and drug-challenge studies are integrated to elucidate a corticolimbic “pathologic circuit” in schizophrenia that may be particularly relevant to the negative symptoms and cognitive impairments of schizophrenia.
Abstract: All current drugs approved to treat schizophrenia appear to exert their antipsychotic effects through blocking the dopamine D2 receptor Recent meta-analyses and comparative efficacy studies indicate marginal differences in efficacy of newer atypical antipsychotics and the older drugs, and little effects on negative and cognitive symptoms This review integrates findings from postmortem, imaging, and drug-challenge studies to elucidate a corticolimbic "pathologic circuit" in schizophrenia that may be particularly relevant to the negative symptoms and cognitive impairments of schizophrenia Potential sites for pharmacologic intervention targeting glutatatergic, GABAergic, and cholinergic neurotransmission to treat these symptoms of schizophrenia are discussed
TL;DR: This review summarizes recent developments in genetic research into schizophrenia and bipolar disorder, and discusses possible future directions in this field.
Abstract: Schizophrenia and bipolar disorder have a largely unknown pathophysiology and etiology, but they are highly heritable Although linkage and association studies have identified a series of chromosomal regions likely to contain susceptibility genes, progress in identifying causative genes has been largely disappointing However, rapid technological advances are beginning to lead to new insights Systematic genome-wide association and follow-up studies have reported genome-wide significant association findings of common variants for schizophrenia and bipolar disorder The risk conferred by individual variants is small, and some variants confer a risk for both disorders In addition, recent studies have identified rare, large structural variants (copy number variants) that confer a greater risk for schizophrenia This review summarizes recent developments in genetic research into schizophrenia and bipolar disorder, and discusses possible future directions in this field
TL;DR: Genotyping the highly variable cytochrome P 4 5 0 2D 6 gene now provides clinicians with the opportunity to identify both poor metabolizers and ultrarapid metabolizers of 2D6 substrate medications.
Abstract: The clinical adoption of psychiatric pharmacogenomic testing has taken place rapidly over the past 7 years. Initially, drug-metabolizing enzyme genes, such as the cytochrome P 4 5 0 2D6 gene (CYP2D6), were identified. Genotyping the highly variable cytochrome P 4 5 0 2D6 gene now provides clinicians with the opportunity to identify both poor metabolizers and ultrarapid metabolizers of 2D6 substrate medications. Subsequently, genes influencing the pharmacodynamic response of medications have been made available for clinical practice. Among the earliest “target genes” was the serotonin transporter gene (SLC6A4) which has variants that have been shown to influence the clinical response of patients of European ancestry when they are treated with selective serotonin reuptake inhibitors. Genotyping of some of the serotonin receptor genes is also available to guide clinical practice. The quantification of the clinical utility of pharmacogenomic testing is evolving, and ethical considerations for testing have been established. Given the increasingly clear cost-effectiveness of genotyping, it has recently been predicted that pharmacogenomic testing will routinely be ordered to guide the selection and dosing of psychotropic medications.
TL;DR: A preliminary randomized controlled trial of cognitive training exercises based onMeta-analytic data from over a decade of cognitive remediation demonstrated significant improvements in working memory, verbal learning and memory, and global cognition in patients with schizophrenia.
Abstract: Meta-analytic data from over a decade of research in cognitive remediation, when combined with recent findings from basic and clinical neuroscience, have resulted in a new understanding of the critical elements that can contribute to successful cognitive training approaches for schizophrenia. Some of these elements include: the use of computerized repetitive practice methods, high dosing schedules, a focus on sensory processing, and carefully constrained and individually adapted learning trials. In a preliminary randomized controlled trial of cognitive training exercises based on these principles, we demonstrated significant improvements in working memory, verbal learning and memory, and global cognition in patients with schizophrenia. These cognitive improvements were accompanied by neurobiological findings suggestive of learning-induced cortical plasticity. Future directions for research and essential remaining questions are discussed.
TL;DR: This work reviews selected aspects of the imaging genetics literature, starting with a widely studied candidate gene - the catechol-0-methyltransferase gene (COMT)- discussing other candidate genes in the dopaminergic system, and then discussing variants with genome-wide support.
Abstract: Recent years have seen an explosive growth of interest in the application of imaging genetics to understand neurogenetic mechanisms of schizophrenia. Imaging genetics applies structural and functional neuroimaging to study subjects carrying genetic risk variants that relate to a psychiatric disorder. We review selected aspects of this literature, starting with a widely studied candidate gene - the catechol-0-methyltransferase gene (COMT)- discussing other candidate genes in the dopaminergic system, and then discussing variants with genome-wide support. In future perspectives, approaches to characterize epistatic effects, the identification of new risk genes through forward-genetic approaches using imaging phenotypes, and the study of rare structural variants are considered.
TL;DR: The role of alcoholism-related white matter fiber degradation as a substrate of clinical impairment in emotional dysregulation in alcoholism is supported by studies documenting brain-behavior relationships.
Abstract: Chronic alcoholism is characterized by impaired control over emotionally motivated actions towards alcohol use. Neuropathologically, it is associated with widespread brain structural compromise marked by gray matter shrinkage, ventricular enlargement, and white matter degradation. The extent to which cortical damage itself or cortical disconnection by white matter fiber pathway disruption contribute to deficits in emotion, cognition, and behavior can be investigated with in vivo structural neuroimaging and diffusion tensor imaging (DTI)-based quantitative fiber tracking. Tractography in alcoholism has revealed abnormalities in selective white matter fiber bundles involving limbic fiber tracts (fornix and cingulum) that connect cortico-limbic-striatal nodes of emotion and reward circuits. Studies documenting brain-behavior relationships support the role of alcoholism-related white matter fiber degradation as a substrate of clinical impairment. An understanding of the role of cortico-limbic fiber degradation in emotional dysregulation in alcoholism is now emerging.
TL;DR: A consistent observation among the GWAS studies is the association with schizophrenia of genetic markers in the major histocompatibility complex (6p22.1)-containing genes including NOTCH4 and histone protein loci.
Abstract: Understanding the genetic basis of schizophrenia continues to be major challenge. The research done during the last two decades has provided several candidate genes which unfortunately have not been consistently replicated across or within a population. The recent genome-wide association studies (GWAS) and copy number variation (CNV) studies have provided important evidence suggesting a role of both common and rare large CNVs in schizophrenia genesis. The burden of rare copy number variations appears to be increased in schizophrenia patients. A consistent observation among the GWAS studies is the association with schizophrenia of genetic markers in the major histocompatibility complex (6p22.1)-containing genes including NOTCH4 and histone protein loci. Molecular genetic studies are also demonstrating that there is more overlap between the susceptibility genes for schizophrenia and bipolar disorder than previously suspected. In this review we summarize the major findings of the past decade and suggest areas of future research.
TL;DR: The fields of genetic epidemiology and molecular genetics are reviewed, providing examples from the literature to illustrate the key concepts emerging from this work.
Abstract: Both genetic and nongenetic risk factors, as well as interactions and correlations between them, are thought to contribute to the etiology of psychiatric and behavioral phenotypes. Genetic epidemiology consistently supports the involvement of genes in liability. Molecular genetic studies have been less successful in identifying liability genes, but recent progress suggests that a number of specific genes contributing to risk have been identified. Collectively, the results are complex and inconsistent, with a single common DNA variant in any gene influencing risk across human populations. Few specific genetic variants influencing risk have been unambiguously identified. Contemporary approaches, however, hold great promise to further elucidate liability genes and variants, as well as their potential inter-relationships with each other and with the environment. We will review the fields of genetic epidemiology and molecular genetics, providing examples from the literature to illustrate the key concepts emerging from this work.
TL;DR: The authors conclude that CB and PG are probably not related to OCD, and there is insufficient evidence to place them within an OC spectrum in DSM-V, and a new diagnosis of CB should be created and be classified as an ICD.
Abstract: Both compulsive buying (CB) and pathological gambling (PG) have been proposed as members of a spectrum of disorders related to obsessive-compulsive disorder (OCD). The spectrum hypothesis originated in the early 1990s and has gained considerable support, despite the lack of empirical evidence. Interest in this hypothesis has become critical because some investigators have recommended the creation of a new category that includes these disorders in DSM-5, now under development. In this article, the authors describe the origin of the obsessive-compulsive (OC) spectrum and its theoretical underpinnings, review both CB and PG, and discuss the data both in support of and against an OC spectrum. Both disorders are described in terms of their history, definition, classification, phenomenology family history, pathophysiology, and clinical management. The authors conclude that: (i) CB and PG are probably not related to OCD, and there is insufficient evidence to place them within an OC spectrum in DSM-V; (ii) PG should stay with the impulse-control disorders (ICDs); and (iii) a new diagnosis of CB should be created and be classified as an ICD.
TL;DR: Different modes of attention can account for a very wide range of repeated observations relating to hemisphere specialization, and suggest that hemisphere differences lie not in discrete functional domains as such, but distinct modes of functioning within any one domain.
Abstract: The cerebral hemispheres are anatomically and neurophysiologically asymmetrical. The evolutionary basis for these differences remains uncertain. There are, however, highly consistent differences between the hemispheres, evident in reptiles, birds, and mammals, as well as in humans, in the nature of the attention each applies to the environment. This permits the simultaneous application of precisely focused, but narrow, attention, needed for grasping food or prey, with broad, open, and uncommitted attention, needed to watch out for predators and to interpret the intentions of conspecifics. These different modes of attention can account for a very wide range of repeated observations relating to hemisphere specialization, and suggest that hemisphere differences lie not in discrete functional domains as such, but distinct modes of functioning within any one domain. These modes of attention are mutually incompatible, and their application depends on inhibitory transmission in the corpus callosum. There is also an asymmetry of interaction between the hemispheres at the phenomenological level.