Translational cognitive neuroscience of dementia with touchscreen operant chambers

Translational cognitive neuroscience of dementia involves mainly two areas: the validation of newly developed dementia animal models and the preclinical assessment of novel drug candidates in such model animals. To validate new animal models, a multidomain panel (battery) approach is essential in that dementia is, by definition, not merely a memory disorder but rather a multidomain cognitive/behavior disorder: animal modeling with a certain type of dementia would develop cognitive impairments in multiple (two at minimum) domains in a specific order according to unique spreading patterns of its neuropathology. In new drug development, the availability of highly sensitive tools assessing animal cognition is crucial to the detection of cognitive decline at the earliest stage of the disease, which may be an optimal time point to test a drug candidate. Using interspecies translatable (analogous) cognitive tasks would also be necessary to successfully predict the efficacy of drug candidates in subsequent clinical trials. Currently, this translational prediction is seriously limited given discrepancies in behavioral assessment methods between animals and humans in the preclinical and clinical trials, respectively. Since neurodegenerative diseases are often accompanied by not only cognitive but also affective and movement disorders, simultaneous assessment of task-relevant locomotor behavior and motivation is also important to rule out the effects of potential confounders. The touchscreen operant platform may satisfy these needs by offering several advantages over conventional methodology. In this review, we discuss the touchscreen operant chamber system and highlight some of its qualities as a promising and desirable tool for translational research of dementia.     

A Genetic Deconstruction of Neurocognitive Traits in Schizophrenia and Bipolar Disorder

Background

Impairments in cognitive functions are common in patients suffering from psychiatric disorders, such as schizophrenia and bipolar disorder. Cognitive traits have been proposed as useful for understanding the biological and genetic mechanisms implicated in cognitive function in healthy individuals and in the dysfunction observed in psychiatric disorders.

Methods

Sets of genes associated with a range of cognitive functions often impaired in schizophrenia and bipolar disorder were generated from a genome-wide association study (GWAS) on a sample comprising 670 healthy Norwegian adults who were phenotyped for a broad battery of cognitive tests. These gene sets were then tested for enrichment of association in GWASs of schizophrenia and bipolar disorder. The GWAS data was derived from three independent single-centre schizophrenia samples, three independent single-centre bipolar disorder samples, and the multi-centre schizophrenia and bipolar disorder samples from the Psychiatric Genomics Consortium.

Results

The strongest enrichments were observed for visuospatial attention and verbal abilities sets in bipolar disorder. Delayed verbal memory was also enriched in one sample of bipolar disorder. For schizophrenia, the strongest evidence of enrichment was observed for the sets of genes associated with performance in a colour-word interference test and for sets associated with memory learning slope.

Conclusions

Our results are consistent with the increasing evidence that cognitive functions share genetic factors with schizophrenia and bipolar disorder. Our data provides evidence that genetic studies using polygenic and pleiotropic models can be used to link specific cognitive functions with psychiatric disorders.     

精神障碍的神经电生理循证医学证据

寻找客观标记物是精神医学研究最重要的课题之一,近期融合了循证医学的神经电生理研究为此提供了重要的途径,并取得了较为可观的研究成果,然而现有的研究结果仍然存在较多争议,难以取得一致共识.本文全面总结和归纳了结合以元分析(meta-analysis)为代表的循证医学方法和以脑电图(electroencephalography)为代表的神经电生理技术的精神障碍相关脑电研究成果,将事件相关电位划分为早期和晚期成分,并结合定量EEG分析,从感知加工、认知控制、情绪反应和社会认知等不同认知过程出发,系统分析和评述了精神障碍患者及高危人群的神经认知功能异常情况.我们发现:精神分裂症患者存在从早期到晚期的各种感知、情感和社会认知方面的缺陷,注意缺陷/多动障碍(ADHD)患者存在从早期到晚期的认知控制缺陷,焦虑和强迫障碍患者则存在早期的认知控制缺陷,而孤独症谱系障碍(ASD)患者则存在早期的感知加工和社会认知缺陷.此外,反映注意资源分配和认知加工速度的P300异常特征跨越了多个诊断类型,这表明该脑电成分可能反映了精神障碍的一般性认知缺陷.未来研究可利用多中心大样本数据库探寻精神疾病的神经电生理客观标记物...     

Ca2+‐Dependent Hyperpolarization Pathways in Sleep Homeostasis and Mental Disorders

Although we are beginning to understand the neuronal and biochemical nature of sleep regulation, questions remain about how sleep is homeostatically regulated. Beyond its importance in basic physiology, understanding sleep may also shed light on psychiatric and neurodevelopmental disorders. Recent genetic studies in mammals revealed several non‐secretory proteins that determine sleep duration. Interestingly, genes identified in these studies are closely related to psychiatric and neurodevelopmental disorders, suggesting that the sleep‐wake cycle shares some common mechanisms with these disorders. Here we review recent sleep studies, including reverse and forward genetic studies, from the perspectives of sleep duration and homeostasis. We then introduce a recent hypothesis for mammalian sleep in which the fast and slow Ca²⁺‐dependent hyperpolarization pathways are pivotal in generating the SWS firing pattern and regulating sleep homeostasis, respectively. Finally, we propose that these intracellular pathways are potential therapeutic targets for achieving depolarization/hyperpolarization (D/H) balance in psychiatric and neurodevelopmental disorders.     

Cross‐species genetics converge to TLL2 for mouse avoidance behavior and human bipolar disorder

Interspecies genetic analysis of neurobehavioral traits is critical for identifying neurobiological mechanisms underlying psychiatric disorders, and for developing models for translational research. Recently, after screening a chromosome substitution strain panel in an automated home cage environment, chromosomes 15 and 19 were identified in female mice for carrying genetic loci that contribute to increased avoidance behavior (sheltering preference). Furthermore, we showed that the quantitative trait locus (QTL) for baseline avoidance behavior on chromosome 15 is homologous with a human linkage region for bipolar disorder (8q24). Similarly, we now performed comparative analysis on the QTL for avoidance behavior found on chromosome 19 and correspondingly revealed an overlap of the mouse interval and human homologous region 10q23‐24, which has been previously linked to bipolar disorders. By means of a comparative genetic strategy within the human homologous region, we describe an association for TLL2 with bipolar disorder using the genome‐wide association study (GWAS) data set generated by the Wellcome Trust Case Control Consortium (WTCCC). On the basis of genetic homology and mood stabilizer sensitivity, our data indicate the intriguing possibility that mouse home cage avoidance behavior may translate to a common biochemical mechanisms underlying bipolar disorder susceptibility. These findings pave new roads for the identification of the molecular mechanisms and novel treatment possibilities for this psychiatric disorder, as well as for the validity of translational research of associated psychiatric endophenotypes .     

An Operant Intra-/Extra-dimensional Set-shift Task for Mice

Alterations in executive control and cognitive flexibility, such as attentional set-shifting abilities, are core features of several neuropsychiatric diseases. The most widely used neuropsychological tests for the evaluation of attentional set-shifting in human subjects are the Wisconsin Card Sorting Test (WCST) and the CANTAB Intra-/Extra-dimensional set shift task (ID/ED). These tasks have proven clinical relevance and have been modified and successfully adapted for research in animal models. However, currently available tasks for rodents present several limitations, mainly due to their manual-based testing procedures, which are hampering translational advances in psychiatric medicine. To overcome these limitations and to better mimic the original version in primates, we present the development of a novel operant-based two-chamber ID/ED "Operon" task for rodents. We demonstrated the effectiveness of this novel task to measure different facets of cognitive flexibility in mice including attentional set formation and shifting, and reversal learning. Moreover, we show the high flexibility of this task in which three different perceptual dimensions can be manipulated with a high number of stimuli cues for each dimension. This novel ID/ED Operon task can be an effective preclinical tool for drug testing and/or large genetic screening relevant to the study of executive dysfunction and cognitive symptoms found in psychiatric disorders.     

Neuroimaging of psychiatric and pedopsychiatric disorders

Over the last two decades, imaging techniques have allowed to establish the cerebral neurophysiologic correlates of psychiatric disorders and have highlighted the impact of psychopathologic events, therapeutic drugs, addictions, on the growth and plasticity of brain. In this review, we intend to illustrate how neuroimaging has improved our knowledge of such alterations in brain maturation (schizophrenia, autistic disorders), fronto-limbic (depressive syndromes) or fronto-striatal (compulsive disorders) regions in psychiatric illnesses, but also in psychopharmacology, or pedopsychiatry. Statistically significant alterations in the structure and/or function of brain are detected in all psychiatric disorders and these are often detectable already during childhood or teenage. Furthermore, neuroimaging has allowed to underline the importance of cerebral networks specific to each disorder, but also to uncover those which are common to different diseases provided that they share common clinical or cognitive features. Besides their value in basic research, neuroimaging findings have been key in changing the perception that society has of these diseases which contributed to their therapeutic approach.     

The Attentional Set Shifting Task: A Measure of Cognitive Flexibility in Mice

Cognitive impairment, particularly involving dysfunction of circuitry within the prefrontal cortex (PFC), represents a core feature of many neuropsychiatric and neurodevelopmental disorders, including depression, post-traumatic stress disorder, schizophrenia and autism spectrum disorder. Deficits in cognitive function also represent the most difficult symptom domain to successfully treat, as serotonin reuptake inhibitors and tricyclic antidepressants have only modest effects. Functional neuroimaging studies and postmortem analysis of human brain tissue implicate the PFC as being a primary region of dysregulation in patients with these disorders. However, preclinical behavioral assays used to assess these deficits in mouse models which can be readily manipulated genetically and could provide the basis for studies of new treatment avenues have been underutilized. Here we describe the adaptation of a behavioral assay, the attentional set shifting task (AST), to be performed in mice to assess prefrontal cortex mediated cognitive deficits. The neural circuits underlying behavior during the AST are highly conserved across humans, nonhuman primates and rodents, providing excellent face, construct and predictive validity.     

From temporal processing to developmental language disorders: mind the gap

The ‘rapid temporal processing’ and the ‘temporal sampling framework’ hypotheses have been proposed to account for the deficits in language and literacy development seen in specific language impairment and dyslexia. This paper reviews these hypotheses and concludes that the proposed causal chains between the presumed auditory processing deficits and the observed behavioural manifestation of the disorders are vague and not well established empirically. Several problems and limitations are identified. Most data concern correlations between distantly related tasks, and there is considerable heterogeneity and variability in performance as well as concerns about reliability and validity. Little attention is paid to the distinction between ostensibly perceptual and metalinguistic tasks or between implicit and explicit modes of performance, yet measures are assumed to be pure indicators of underlying processes or representations. The possibility that diagnostic categories do not refer to causally and behaviourally homogeneous groups needs to be taken seriously, taking into account genetic and neurodevelopmental studies to construct multiple-risk models. To make progress in the field, cognitive models of each task must be specified, including performance domains that are predicted to be deficient versus intact, testing multiple indicators of latent constructs and demonstrating construct reliability and validity.     

Genetic models of schizophrenia and related psychotic disorders: progress and pitfalls across the methodological “minefield”

The challenge of modelling a complex and multifaceted disorder such as schizophrenia is epitomised by the considerable degree of phenotypic variability described in patients and by the absence of specific and consistent neuropathological biomarkers. The pattern and severity of a range of clinical features, including florid psychotic symptoms such as hallucinations and delusions, negative symptoms and cognitive dysfunction, together with age at onset, course of illness and other indices, can vary greatly between individual patients. The undefined nature of the relationship between diagnosis and underlying aetiology has complicated research in the field of clinical and preclinical neuroscience, thereby making it difficult to generate or evaluate appropriate disease models of schizophrenia. In the present review, we explore those conceptual and practical issues that relate specifically to the genetic modelling of schizophrenia and related disorders in rodents. Practical issues that impact on the robustness of endophenotypic findings and their translational relevance are discussed with reference to evidence from selective genetic models of candidate risk genes and copy number variants implicated in schizophrenia.     

Fatty acid metabolism in neurodevelopmental disorder: a new perspective on associations between attention-deficit/hyperactivity disorder, dyslexia, dyspraxia and the autistic spectrum

There is increasing evidence that abnormalities of fatty acid and membrane phospholipid metabolism play a part in a wide range of neurodevelopmental and psychiatric disorders. This proposal is discussed here in relation to attention-deficit/hyperactivity disorder (ADHD), dyslexia, developmental coordination disorder (dyspraxia) and the autistic spectrum. These are among the most common neurodevelopmental disorders of childhood, with significant implications for society as well as for those directly affected. However, controversy still surrounds both the identification and management of these conditions, and while their aetiology is recognized as being complex and multifactorial, little progress has yet been made in elucidating predisposing factors at the biological level.An overview is provided here of the contents of this Special Issue, which contains a selection of reports from a unique multidisciplinary workshop involving both researchers and clinicians. Its purpose was to explore the possibility that ADHD, dyslexia, dyspraxia and autism fall within a phospholipid spectrum of disorders. This proposal could explain the high degree of co-morbidity between these conditions, their aggregation within families and relation to other psychiatric disorders, and a range of associated features that are already well known at a clinical level. The existing evidence for fatty acid abnormalities in these disorders is summarized, and new approaches are outlined that have the potential to improve both the identification and the management of these and related neurodevelopmental and psychiatric conditions.     

Schizophrenia and the neurodevelopmental continuum:evidence from genomics

The idea that disturbances occurring early in brain development contribute to the pathogenesis of schizophrenia, often referred to as the neurodevelopmental hypothesis, has become widely accepted. Despite this, the disorder is viewed as being distinct nosologically, and by implication pathophysiologically and clinically, from syndromes such as autism spectrum disorders, attention‐deficit/hyperactivity disorder (ADHD) and intellectual disability, which typically present in childhood and are grouped together as “neurodevelopmental disorders”. An alternative view is that neurodevelopmental disorders, including schizophrenia, rather than being etiologically discrete entities, are better conceptualized as lying on an etiological and neurodevelopmental continuum, with the major clinical syndromes reflecting the severity, timing and predominant pattern of abnormal brain development and resulting functional abnormalities. It has also been suggested that, within the neurodevelopmental continuum, severe mental illnesses occupy a gradient of decreasing neurodevelopmental impairment as follows: intellectual disability, autism spectrum disorders, ADHD, schizophrenia and bipolar disorder. Recent genomic studies have identified large numbers of specific risk DNA changes and offer a direct and robust test of the predictions of the neurodevelopmental continuum model and gradient hypothesis. These findings are reviewed in detail. They not only support the view that schizophrenia is a disorder whose origins lie in disturbances of brain development, but also that it shares genetic risk and pathogenic mechanisms with the early onset neurodevelopmental disorders (intellectual disability, autism spectrum disorders and ADHD). They also support the idea that these disorders lie on a gradient of severity, implying that they differ to some extent quantitatively as well as qualitatively. These findings have important implications for nosology, clinical practice and research.     

Modeling psychiatric disorders through reprogramming

Psychiatric disorders, including autism spectrum disorders and schizophrenia, are extremely heritable complex genetic neurodevelopmental disorders. It is now possible to directly reprogram fibroblasts from psychiatric patients into human induced pluripotent stem cells (hiPSCs) and subsequently differentiate these disorder-specific hiPSCs into neurons. This means that researchers can generate nearly limitless quantities of live human neurons with genetic backgrounds that are known to result in psychiatric disorders, without knowing which genes are interacting to produce the disease state in each patient. With these new human-cell-based models, scientists can investigate the precise cell types that are affected in these disorders and elucidate the cellular and molecular defects that contribute to disease initiation and progression. Here, we present a short review of experiments using hiPSCs and other sophisticated in vitro approaches to study the pathways underlying psychiatric disorders.     

The interface between genetics and psychology: lessons from developmental dyslexia

Developmental dyslexia runs in families, and twin studies have confirmed that there is a substantial genetic contribution to poor reading. The way in which discoveries in molecular genetics are reported can be misleading, encouraging us to think that there are specific genes that might be used to screen for disorder. However, dyslexia is not a classic Mendelian disorder that is caused by a mutation in a single gene. Rather, like many other common disorders, it appears to involve combined effects of many genes and environmental factors, each of which has a small influence, possibly supplemented by rare variants that have larger effects but apply to only a minority of cases. Furthermore, to see clearer relationships between genotype and phenotype, we may need to move beyond the clinical category of dyslexia to look at underlying cognitive deficits that may be implicated in other neurodevelopmental disorders.     

Testing structural models of psychopathology at the genomic level

Genome‐wide association studies (GWAS) have revealed hundreds of genetic loci associated with the vulnerability to major psychiatric disorders, and post‐GWAS analyses have shown substantial genetic correlations among these disorders. This evidence supports the existence of a higher‐order structure of psychopathology at both the genetic and phenotypic levels. Despite recent efforts by collaborative consortia such as the Hierarchical Taxonomy of Psychopathology (HiTOP), this structure remains unclear. In this study, we tested multiple alternative structural models of psychopathology at the genomic level, using the genetic correlations among fourteen psychiatric disorders and related psychological traits estimated from GWAS summary statistics. The best‐fitting model included four correlated higher‐order factors – externalizing, internalizing, thought problems, and neurodevelopmental disorders – which showed distinct patterns of genetic correlations with external validity variables and accounted for substantial genetic variance in their constituent disorders. A bifactor model including a general factor of psychopathology as well as the four specific factors fit worse than the above model. Several model modifications were tested to explore the placement of some disorders – such as bipolar disorder, obsessive‐compulsive disorder, and eating disorders – within the broader psychopathology structure. The best‐fitting model indicated that eating disorders and obsessive‐compulsive disorder, on the one hand, and bipolar disorder and schizophrenia, on the other, load together on the same thought problems factor. These findings provide support for several of the HiTOP higher‐order dimensions and suggest a similar structure of psychopathology at the genomic and phenotypic levels.     

Validity and utility of Hierarchical Taxonomy of Psychopathology (HiTOP): III. Emotional dysfunction superspectrum

The Hierarchical Taxonomy of Psychopathology (HiTOP) is a quantitative nosological system that addresses shortcomings of traditional mental disorder diagnoses, including arbitrary boundaries between psychopathology and normality, frequent disorder co‐occurrence, substantial heterogeneity within disorders, and diagnostic unreliability over time and across clinicians. This paper reviews evidence on the validity and utility of the internalizing and somatoform spectra of HiTOP, which together provide support for an emotional dysfunction superspectrum. These spectra are composed of homogeneous symptom and maladaptive trait dimensions currently subsumed within multiple diagnostic classes, including depressive, anxiety, trauma‐related, eating, bipolar, and somatic symptom disorders, as well as sexual dysfunction and aspects of personality disorders. Dimensions falling within the emotional dysfunction superspectrum are broadly linked to individual differences in negative affect/neuroticism. Extensive evidence establishes that dimensions falling within the superspectrum share genetic diatheses, environmental risk factors, cognitive and affective difficulties, neural substrates and biomarkers, childhood temperamental antecedents, and treatment response. The structure of these validators mirrors the quantitative structure of the superspectrum, with some correlates more specific to internalizing or somatoform conditions, and others common to both, thereby underlining the hierarchical structure of the domain. Compared to traditional diagnoses, the internalizing and somatoform spectra demonstrated substantially improved utility: greater reliability, larger explanatory and predictive power, and greater clinical applicability. Validated measures are currently available to implement the HiTOP system in practice, which can make diagnostic classification more useful, both in research and in the clinic.     

The use of transgenic and knock-in mice to study Huntington's disease

The trinucleotide repeat disorders comprise an ever expanding list of diseases, all of which are caused by an unstable expanded trinucleotide repeat tract. Huntington's disease (HD) is a member of this family of diseases and more specifically, is a Type II trinucleotide repeat disorder. This means that the mutation in HD is an unstable expanded polyglutamine repeat tract, which is expressed at protein level. There is no cure or beneficial treatment for this fatal neurodegenerative disorder, and patients suffer from progressive motor, cognitive and psychiatric dysfunction. Recent years has seen the development of many genetic models of HD, which allow study of the early phases of disease process, at several different levels of cell function. In addition, these models are being used to investigate the potential of a variety of therapeutic agents for clinical use. Here we review these findings, and their implication for HD pathogenesis.     

Mutation of Semaphorin-6A disrupts limbic and cortical connectivity and models neurodevelopmental psychopathology

Psychiatric disorders such as schizophrenia and autism are characterised by cellular disorganisation and dysconnectivity across the brain and can be caused by mutations in genes that control neurodevelopmental processes. To examine how neurodevelopmental defects can affect brain function and behaviour, we have comprehensively investigated the consequences of mutation of one such gene, Semaphorin-6A, on cellular organisation, axonal projection patterns, behaviour and physiology in mice. These analyses reveal a spectrum of widespread but subtle anatomical defects in Sema6A mutants, notably in limbic and cortical cellular organisation, lamination and connectivity. These mutants display concomitant alterations in the electroencephalogram and hyper-exploratory behaviour, which are characteristic of models of psychosis and reversible by the antipsychotic clozapine. They also show altered social interaction and deficits in object recognition and working memory. Mice with mutations in Sema6A or the interacting genes may thus represent a highly informative model for how neurodevelopmental defects can lead to anatomical dysconnectivity, resulting, either directly or through reactive mechanisms, in dysfunction at the level of neuronal networks with associated behavioural phenotypes of relevance to psychiatric disorders. The biological data presented here also make these genes plausible candidates to explain human linkage findings for schizophrenia and autism.     

Towards a second-person neuropsychiatry

Psychiatric disorders can affect our ability to successfully and enjoyably interact with others. Conversely, having difficulties in social relations is known to increase the risk of developing a psychiatric disorder. In this article, the assumption that psychiatric disorders can be construed as disorders of social interaction is reviewed from a clinical point of view. Furthermore, it is argued that a psychiatrically motivated focus on the dynamics of social interaction may help to provide new perspectives for the field of social neuroscience. Such progress may be crucial to realize social neuroscience''s translational potential and to advance the transdiagnostic investigation of the neurobiology of psychiatric disorders.