From maps to mechanisms through neuroimaging of schizophrenia

Functional and structural brain imaging has identified neural and neurotransmitter systems involved in schizophrenia and their link to cognitive and behavioural disturbances such as psychosis. Mapping such abnormalities in patients, however, cannot fully capture the strong neurodevelopmental component of schizophrenia that pre-dates manifest illness. A recent strategy to address this issue has been to focus on mechanisms of disease risk. Imaging genetics techniques have made it possible to define neural systems that mediate heritable risk linked to candidate and genome-wide-supported common variants, and mechanisms for environmental risk and gene-environment interactions are emerging. Characterizing the neural risk architecture of schizophrenia provides a translational research strategy for future treatments.     

Which neurological abnormalities and neuropsychological impairments share the same substrate in psychosis?

Approximately 60% of subjects with schizophrenia present minor neurological signs (neurological soft signs, NSS), which include abnormalities in sensory and motor performance indicative of a non-specific cerebral dysfunction. These are also present in healthy individuals and relatives of patients with psychosis, at significantly lower rates. The excess of NSS in psychosis may be a potential endophenotype for this disorder, and reflect the same neurodevelopmental brain dysfunction that also underlies the cognitive deficits consistently reported in psychosis. To establish whether neurological and cognitive dysfunction meet the essential criterion required for a refined endophenotype for psychosis, the association with the illness, we explored evidence that certain neurological and cognitive deficits co-occur in affected individuals. This evidence suggests that signs of motor dysfunctions may be specific to patients with psychosis, in whom they are associated with dysfunction in cognitive tasks requiring motor skills. Thus, they may form a promising candidate endophenotype for psychosis.     

Rare chromosomal deletions and duplications increase risk of schizophrenia

Schizophrenia is a severe mental disorder marked by hallucinations, delusions, cognitive deficits and apathy, with a heritability estimated at 73-90% (ref. 1). Inheritance patterns are complex, and the number and type of genetic variants involved are not understood. Copy number variants (CNVs) have been identified in individual patients with schizophrenia and also in neurodevelopmental disorders, but large-scale genome-wide surveys have not been performed. Here we report a genome-wide survey of rare CNVs in 3,391 patients with schizophrenia and 3,181 ancestrally matched controls, using high-density microarrays. For CNVs that were observed in less than 1% of the sample and were more than 100 kilobases in length, the total burden is increased 1.15-fold in patients with schizophrenia in comparison with controls. This effect was more pronounced for rarer, single-occurrence CNVs and for those that involved genes as opposed to those that did not. As expected, deletions were found within the region critical for velo-cardio-facial syndrome, which includes psychotic symptoms in 30% of patients. Associations with schizophrenia were also found for large deletions on chromosome 15q13.3 and 1q21.1. These associations have not previously been reported, and they remained significant after genome-wide correction. Our results provide strong support for a model of schizophrenia pathogenesis that includes the effects of multiple rare structural variants, both genome-wide and at specific loci.     

Recent developments in neuropsychological endophenotypes for schizophrenia: Development of the MATRICS battery,liability syndromes and the near future

Cognitive deficits are now recognized widely as core features of schizophrenia, and as major contributors to the clinical outcome of the disorder. They are also studied widely as ‘endophenotypes’, reflecting a growing consensus that schizophrenia is a broader, more multidimensional illness than the diagnostic criteria required for its formal diagnosis. This evolving view of cognition underlies its utilization in recent initiatives for intervention and assessment in schizophrenia. Two of these initiatives ar...     

Localization of a susceptibility locus for schizophrenia on chromosome 5

Schizophrenia is a common disorder with a life time prevalence of approximately 1 per cent. The illness often develops in young adults, who were previously normal, and is characterized by a constellation of symptoms including hallucinations and delusions (psychotic symptoms) and symptoms such as severely inappropriate emotional responses, a disorder of thinking and concentration, erratic behaviour as well as social and occupational deterioration. A considerable proportion of the variance in the liability to develop schizophrenia may be genetic, but segregation analysis, to establish a mode of transmission, has not produced a consistent result. One of these studies was carried out in Iceland and made use of the large family size and extensive geneaological information present in that country. Here we demonstrate genetic linkage of two DNA polymorphisms on the long arm of human chromosome 5 to schizophrenia in seven British and Icelandic families with multiple affected members. The results indicate the existence of a gene locus with a dominant schizophrenia-susceptibility allele. Inheritance of the allele in the families studied suggests that it may also predispose to psychiatric conditions such as schizophrenia spectrum disorders and a variety of other disorders. This report provides the first strong evidence for the involvement of a single gene in the causation of schizophrenia.     

Is there an anatomical endophenotype for neurodevelopmental disorders？ A review of dual disorder anatomical likelihood estimation （ALE） meta-analyses of grey matter volumes

The term "neurodevelopmental disorder" broadly encompasses conditions thought to arise early in development and includes schizophrenia, bipolar disorder and autism among others. These conditions share a number of genetic and environmental risk factors postulated to lead to common difficulties in socio-emotional processing, communication and cognitive function. The alternative position is that, while the same traits are affected across these conditions, the nature or direction in which they are modified may be distinct. MRI studies provide a rapidly expanding and rich database which we propose can be used to contribute to this debate. Anatomical likelihood estimation (ALE) is a method of meta-analysis applied to voxel-based MRI studies. We have adapted this method to explore the extent to which schizophrenia and bipolar disorder and schizophrenia and autism share a common brain structural phenotype. We will review this work here and discuss whether there is sufficient other evidence to justify a common framework for further research into the inter-relatedness of such conditions.     

Exclusion of linkage to 5q11-13 in families with schizophrenia and other psychiatric disorders

Recently a linkage study on five Icelandic and two English pedigrees has provided evidence for a dominant gene for schizophrenia on 5q11-13 (ref. 1). In that study, families with bipolar illness were not included. Using the same probes, two similar but independent investigations on one Swedish pedigree and on fifteen Scottish families excluded linkage to schizophrenia. To evaluate whether the susceptibility gene on 5q11-13 is a common cause of schizophrenia in other populations, we examined five affected North American pedigrees using probes to the D5S39, D5S76 and dihydrofolate reductase loci. Two families in the present series had cases of bipolar disorder. We found that linkage can be excluded by multipoint analysis. These results, taken together, suggest that the disease gene on 5q11-13 does not account for most cases of familial schizophrenia.     

Which neurological abnormalities and neuropsychological impairments share the same substrate in psychosis?

Approximately 60% of subjects with schizophrenia present minor neurological signs (neurological soft signs, NSS), which include abnormalities in sensory and motor performance indicative of a non-specific cerebral dysfunction. These are also present in healthy individuals and relatives of patients with psychosis, at significantly lower rates. The excess of NSS in psychosis may be a potential endophenotype for this disorder, and reflect the same neurodevelopmental brain dysfunction that also underlies the cog...     

First episode psychosis with extrapyramidal signs prior to antipsychotic drug treatment

Extrapyramidal movement disorders are common in chronic schizophrenia, and may be an intrinsic feature of the illness as well as related to antipsychotic drug treatment. Similar dysfunctions at illness onset may have implications for outcome, and for under- standing the mechanisms of illness. The objectives were to examine the clinical correlates of pre-treatment movement disorders at first episode of psychosis, and determine associations with neuropsychological function and striatal structure. Never medicated subjects were recruited from consecutive admissions to Early Psychosis Programs with defined catchment areas in Hong Kong, China, and Halifax, Canada. Standardized clinical, neuropsychological and brain imaging assessments were carried out at baseline and following acute and long term treatment with typical or atypical antipsychotic drugs. At the Hong Kong site, we studied 84 subjects with first episode psychosis (n = 10 with EPS). At the Halifax site, we studied 40 subjects with first episode psychosis (n = 17 with EPS), and 23 healthy comparison subjects. Subjects with movement disorders prior to treatment (EPS+) had higher total PANSS scores at baseline (mean elevation 19.9% Hong Kong, P = 0.016; 14.7% Halifax, P = 0.049). In subjects treated with atypical antipsychotics (all Halifax), EPS+ status at baseline predicted more movement disorders at long term follow up (P = 0.0005). In both cohorts, EPS+ subjects had poorer acute symptomatic treatment response assessed with the PANSS (Hong Kong P = 0.005; Halifax P = 0.017). Neuropsychological impairment related to executive dysfunction appeared greater in a small sam- ple of EPS+ subjects (Hong Kong, effect size 0.26-0.27, P < 0.05). Caudate volumes were 4.5% larger in EPS+ compared with EPS-subjects (Halifax P = 0.042), and correlations between striatal volumes and age were different in the EPS+ group. In conclu- sion, pre-treatment EPS is present in a substantial minority of subjects with first episode psychosis, appears to persist at long term follow up, and is associated with poorer response of symptoms to treatment. Selective impairment of executive function and stria- tal enlargement provides evidence of abnormalities of brain function and structure associated with this aspect of early psychosis.     

Evidence against linkage of schizophrenia to markers on chromosome 5 in a northern Swedish pedigree

Schizophrenia is a severe mental illness with a typically chronic course affecting nearly 1% of the human population. It is generally accepted that genetic factors have an important pathogenic role in a substantial portion of schizophrenia cases; however, despite decades of family studies, there is no agreed-upon mode of inheritance. The discovery of genetic aetiologic factors and resolution of the inheritance pattern(s) will undoubtably emerge from genetic linkage studies. With these objectives in mind, we undertook a linkage project, starting in 1985, in a previously well-documented kindred from north Sweden. Multipoint linkage analyses were used to screen the proximal long arm of chromosome 5 using restriction fragment length polymorphism (RFLP) markers at five loci and the distal long arm using RFLPs at two loci, one of which was the locus for the glucocorticoid receptor. We found strong evidence against linkage between schizophrenia and the seven loci. These results, together with the positive evidence for linkage of schizophrenia with markers in the proximal long arm of chromosome 5 lead us to conclude that the genetic factors underlying schizophrenia are heterogeneous.     

Neurogenic hypothesis and psychiatric disorders

Psychiatric illness, such as affective disorders, anxiety disorders and schizophrenia, exerts exceptional personal burden on affected individuals. Although not physically noticeable, these disorders cost enormously on ones’ family and society. Currently pharma-ceutical and psychological treatments are generally accepted as effective for psychiatric disorders, while the exact mechanisms underlying the treatment efficacy, etiology and neurobiology of the disorders remain elusive. In the past decade, "neurogenic hy-pothesis" emerged as an attempt to explain the nature of psychiatric illness. The origination of the hypothesis is based on several pre-clinical and clinical observations. First, stress, which is a common risk factor of the disorders, was found to suppress neurogenesis; second, treatment for the illnesses like antidepressants and antipsychotics were shown to improve neurogenesis and behavioral deficits simultaneously; and third, the therapeutic effect of antidepressants was abolished in animal models when neuro-genesis was blocked. Increasing efforts were invested to determine whether neurogenesis is a key to the understanding and treatment of psychiatric disorders, although contrasting results are also found and thus the importance of neurogenesis remains a matter of debate. The present chapter will discuss the recent findings about the involvement of neurogenesis in major depression, anxiety disorders and schizophrenia, and whether neurogenesis would be a potential target for development of the treatment in the future.     

精神分裂症和情感障碍家系中夫妻互患癌的研究

探讨了精神分裂症、情感障碍与癌症之间关系。采用了精神分裂症和情感障碍的家系分析法和对照比较法。结果表明情感障碍组夫妻癌发生率高于精神分裂症组 ;各级亲属患癌率分析表明精神病与癌症之间无明显关联存在。因此 ,癌症的发生与人类的情绪有关 ,不健康的心理状态是癌症发生的不良因素。     

A common mechanism of action for three mood-stabilizing drugs

Lithium, carbamazepine and valproic acid are effective mood-stabilizing treatments for bipolar affective disorder. The molecular mechanisms underlying the actions of these drugs and the illness itself are unknown. Berridge and colleagues suggested that inositol depletion may be the way that lithium works in bipolar affective disorder, but others have suggested that glycogen synthase kinase (GSK3) may be the relevant target. The action of valproic acid has been linked to both inositol depletion and to inhibition of histone deacetylase (HDAC). We show here that all three drugs inhibit the collapse of sensory neuron growth cones and increase growth cone area. These effects do not depend on GSK3 or HDAC inhibition. Inositol, however, reverses the effects of the drugs on growth cones, thus implicating inositol depletion in their action. Moreover, the development of Dictyostelium is sensitive to lithium and to valproic acid, but resistance to both is conferred by deletion of the gene that codes for prolyl oligopeptidase, which also regulates inositol metabolism. Inhibitors of prolyl oligopeptidase reverse the effects of all three drugs on sensory neuron growth cone area and collapse. These results suggest a molecular basis for both bipolar affective disorder and its treatment.     

Tackling heart failure in the twenty-first century

Heart failure, or congestive heart failure, is a condition in which the heart cannot supply the body's tissues with enough blood. The result is a cascade of changes that lead to severe fatigue, breathlessness and, ultimately, death. In the past quarter century, much progress has been made in understanding the molecular and cellular processes that contribute to heart failure, leading to the development of effective therapies. Despite this, chronic heart failure remains a major cause of illness and death. And because the condition becomes more common with increasing age, the number of affected individuals is rising with the rapidly ageing global population. New treatments that target disease mechanisms at the cellular and whole-organ level are needed to halt and reverse the devastating consequences of this disease.     

心理治疗还是药物治疗

心理治疗与药物治疗是精神病领域的两种治疗模式。心理治疗模式认为，个体精神状况正常与否主要受情绪、人格等心理因素影响，精神疾病由后天环境和生活经历所致；药物治疗模式则认为，精神病及各类神经症都有其生理基础，大脑机能的缺陷是导致精神疾病的主要原因，因此主张用药物进行治疗。尽管两者在精神病治疗中都有自己的优势与不足，但是在科学一统天下的今天，生物学模式似乎成了治疗的主流。要想最终解决心理治疗与药物治疗之争，科学预测精神病治疗的未来及新世纪心理治疗的命运，必须首先解决：（1）心理学的学科体系问题；（2）精神疾病的界定问题以及（3）心身关系问题。     

自闭谱系障碍的大脑功能性连接研究进展

自闭谱系障碍是一种以早期社会交往上的广泛性异常、缺乏与人进行沟通的能力、异常局限的兴趣以及刻板重复性行为为特征的复杂的神经发育障碍．自闭谱系障碍的大脑功能性连接研究表明,自闭谱系障碍存在着大脑功能性连接的显著降低,这种神经同步性活动的异常与自闭谱系障碍的社交和沟通障碍的严重程度呈负相关．实验研究采用功能性近红外光谱成像技术,对自闭谱系障碍儿童静息状态下大脑皮层的功能性连接性进行测量,结果发现,自闭谱系障碍儿童的额叶和颞叶左右半球之间的功能性连接是显著降低的,而额叶和颞叶在语言加工和社会认知过程中起着重要作用．功能性近红外光谱成像技术作为一种光学脑成像技术,能够有效且可靠地揭示自闭谱系障碍的大脑异常功能性活动．     

Pathological changes in olfactory neurons in patients with Alzheimer's disease

Alzheimer's disease is a central nervous system disorder characterized by the presence of neurofibrillary tangles, neuritic plaques and dystrophic neurites in susceptible areas of the brain. Investigation of the mechanism and development of the disease has been hampered by the lack of an animal model and the inaccessibility of neural tissue during the illness. Deficits in odour detection and discrimination are among the signs of Alzheimer's and previous anatomical studies suggest that olfactory pathways may be involved early in the illness. Neurons in the olfactory epithelium, which are of central origin, are relatively accessible for biopsy and could be used as a source of living nerve cells for the study of Alzheimer's disease if they can be shown to have characteristics of this disease. As these neurons have the unusual property of arising from stem cells throughout the life of the organism, they are good candidates for the development of cell cultures or cell lines which may express the disorder from living patients. We report here that nasal epithelium tissue taken at autopsy shows unique pathological changes in morphology, distribution and immunoreactivity of neuronal structures in patients with Alzheimer's disease.     

Identification of a serotonin/glutamate receptor complex implicated in psychosis

The psychosis associated with schizophrenia is characterized by alterations in sensory processing and perception. Some antipsychotic drugs were identified by their high affinity for serotonin 5-HT2A receptors (2AR). Drugs that interact with metabotropic glutamate receptors (mGluR) also have potential for the treatment of schizophrenia. The effects of hallucinogenic drugs, such as psilocybin and lysergic acid diethylamide, require the 2AR and resemble some of the core symptoms of schizophrenia. Here we show that the mGluR2 interacts through specific transmembrane helix domains with the 2AR, a member of an unrelated G-protein-coupled receptor family, to form functional complexes in brain cortex. The 2AR-mGluR2 complex triggers unique cellular responses when targeted by hallucinogenic drugs, and activation of mGluR2 abolishes hallucinogen-specific signalling and behavioural responses. In post-mortem human brain from untreated schizophrenic subjects, the 2AR is upregulated and the mGluR2 is downregulated, a pattern that could predispose to psychosis. These regulatory changes indicate that the 2AR-mGluR2 complex may be involved in the altered cortical processes of schizophrenia, and this complex is therefore a promising new target for the treatment of psychosis.