The neurodevelopmental hypothesis of schizophrenia: a review of recent developments

The neurodevelopmental hypothesis (NDH) of schizophrenia suggests that a disruption of brain development during early life underlies the later emergence of psychosis during adulthood. The aim of this review is to chart the challenges and subsequent refinements to this hypothesis, with particular reference to the static versus progressive nature of the putative neurobiological processes underlying the NDH. A non-systematic literature review was undertaken, with an emphasis on major review papers relevant to the NDH. Weaknesses in the explanatory power of the NDH have led to a new generation of more refined hypotheses in recent years. In particular, recent versions of the hypothesis have incorporated evidence from structural neuroimaging which suggests changes in brain volumes after the onset of schizophrenia. More detailed models that incorporate progressive neurobiological processes have replaced early versions of the NDH, which were based on a 'static encephalopathy'. In addition, recent models have suggested that two or more 'hits' are required over the lifespan rather than only one early-life event. Animal models are providing important insights into the sequelae of disturbed early brain development. The NDH has provided great impetus to the schizophrenia research community. Recent versions of the hypothesis have encouraged more focused and testable hypotheses.     

神经干细胞在精神分裂症患者治疗中的研究进展

精神分裂症作为一种慢性、致残率高的精神疾病，存在多巴胺假说、失连接假说、神经发育障碍假说、氧化应激假说等多种假说解释其发病机制。神经干细胞具有分裂分化的潜能和修复中枢损伤的作用，在中枢神经系统多个脑区广泛分布。相关研究表明，精神分裂症与胚胎神经干细胞异常和神经发生有关。目前药物治理是精神疾病的主要临床治疗手段，但不可避免地存在多种弊端。根据多巴胺假说，腹侧海马在精神分裂症的治疗中处在关键地位，是各个假说的“共同通路”。借助诱导性多能干细胞建立精神分裂症疾病模型，对疾病发病机制的研究陆续取得进展。神经干细胞在胚胎发育和神经系统发生损伤时的修复过程中发挥着重要作用，将其用于精神分裂症的治疗具有显著优势，这为精神分裂症的治疗提供了新的思路。     

Risk genes for schizophrenia: Translational opportunities for drug discovery

Despite intensive research over many years, the treatment of schizophrenia remains a major health issue. Current and emerging treatments for schizophrenia are based upon the classical dopamine and glutamate hypotheses of disease. Existing first and second generation antipsychotic drugs based upon the dopamine hypothesis are limited by their inability to treat all symptom domains and their undesirable side effect profiles. Third generation drugs based upon the glutamate hypothesis of disease are currently under evaluation but are more likely to be used as add on treatments. Hence there is a large unmet clinical need. A major challenge in neuropsychiatric disease research is the relatively limited knowledge of disease mechanisms. However, as our understanding of the genetic causes of the disease evolves, novel strategies for the development of improved therapeutic agents will become apparent. In this review we consider the current status of knowledge of the genetic basis of schizophrenia, including methods for identifying genetic variants associated with the disorder and how they impact on gene function. Although the genetic architecture of schizophrenia is complex, some targets amenable to pharmacological intervention can be discerned. We conclude that many challenges lie ahead but the stratification of patients according to biobehavioural constructs that cross existing disease classifications but with common genetic and neurobiological bases, offer opportunities for new approaches to effective drug discovery.     

Current progress,challenges and future prospects of diagnostic and therapeutic interventions in Alzheimer's disease

Alzheimer''s disease (AD) is the most prevalent, progressive and multifaceted neurodegenerative disorder associated with cognition, memory and behavioural impairments. There is no approved diagnosis or cure for AD, and it affects both developed and developing countries and causes a significant social and economic burden. Extracellular senile plaques of amyloid beta (Aβ) and intracellular neurofibrillary tangles of phosphorylated Tau (pTau) in the brain are considered to be the pathophysiological hallmarks of AD. In an attempt to explain the complexity and multifactorial nature of AD, various hypotheses (Aβ aggregation, Tau aggregation, metal dyshomeostasis, oxidative stress, cholinergic dysfunction, inflammation and downregulation of autophagy) based on pathophysiological changes that occur during the onset and progression of AD have been proposed. However, none of the hypotheses is capable of independently explaining the pathological conditions observed in AD. The complex and multifaceted pathophysiological nature of AD has hampered the identification and validation of effective biomarkers for early diagnosis and the development of disease-modifying therapies. Nevertheless, the amyloid hypothesis is the most widely accepted and is closely correlated with disease symptoms of AD that encompass all the disease hypotheses. Therefore, amyloid plaques are ideal biomarkers for the development of an early diagnosis of AD. Similarly, the formation of amyloid plaques can also serve as a target for the design of therapeutic tools via an inclusive approach that considers multiple disease pathways involved in AD. Our review article briefly introduces pathophysiological factors involved in AD using interdependent but diverse hypotheses. Recent advances in the development of effective molecular tools and techniques for diagnostic and therapeutic interventions in AD, especially those in the advanced stages (clinical trials) of development, are given special consideration. In addition, contributions from our laboratory to the development of selective molecular tools for diagnostic and therapeutic interventions that target multifaceted toxicity in AD are also covered. In summary, we discuss diverse aspects of molecular mechanisms that underlie the pathogenesis of multifactorial AD, current progress and possible bottlenecks that have hampered the development of early diagnostic tools and effective drugs. Challenges and future prospects include the integration of various disease pathways for the successful development of an early diagnosis and effective drugs for the treatment of AD.

The diverse pathological mechanisms and their implications for the development of effective diagnostic and therapeutic interventions in Alzheimer''s disease are presented with current progress, challenges and future prospects.     

Social cognition and frontal lobe pathology in schizophrenia: a voxel-based morphometric study

Impaired social cognition in schizophrenia is considered as the core contributor in the poor psychosocial functioning of schizophrenic patients. In this study, in order to better understand the neurobiological processes underlying social dysfunction in schizophrenia, we investigated regional structural brain abnormalities and emotion-attribution abilities in these patients. Twenty schizophrenic patients and 20 group-matched healthy comparison participants underwent magnetic resonance imaging (MRI) and were examined for emotion-attribution abilities by using the Perception of Affect Task (PAT). Voxel-based morphometry (VBM) was applied to investigate regional brain structural alterations. Relative to the healthy participants, the schizophrenic patients exhibited reduced gray matter concentrations in the left superior temporal gyrus, the medial prefrontal cortex (MPFC), right anterior cingulate gyrus, bilateral ventrolateral prefrontal cortex, and right insula. The schizophrenic patients performed poorly on emotion-attribution tasks. Importantly, poor performance on emotion attribution to protagonists in social situations was found to be associated with reductions in gray matter in the MPFC of the patient group. This preliminary result suggests that in schizophrenia, difficulties in understanding the emotional experiences of others are possible manifestations of structural abnormalities in the MPFC. This study provides the neurobiological correlates of social dysfunction in schizophrenia and links structural abnormalities with impaired social cognitive abilities.     

The family and schizophrenia

There has been controversy about the role of family in the etiology and course of schizophrenia for almost 70 years. Psychoanalysts and family therapists have proposed theories about the development of schizophrenia that overtly blamed parents, and recently, expressed emotion (EE) research has been criticized as implicating families once again. However, the study of schizophrenia as a brain disorder has resulted in new understandings of the influence of the family. This article reviews recent research revealing a unique vulnerability to stress in persons with schizophrenia and suggesting that communication difficulties may be due to a shared genetic heritage. Advanced practice mental health nurses who have a solid foundation in neurobiology are ideally suited to help the person with schizophrenia and his or her family. Knowledge about the neurobiological basis of schizophrenia has become very sophisticated and complex, but that knowledge is nevertheless essential to understand the otherwise puzzling patterns of behavior shown by persons with schizophrenia.     

THE FAMILY AND SCHIZOPHRENIA

There has been controversy about the role of family in the etiology and course of schizophrenia for almost 70 years. Psychoanalysts and family therapists have proposed theories about the development of schizophrenia that overtly blamed parents, and recently, expressed emotion (EE) research has been criticized as implicating families once again. However, the study of schizophrenia as a brain disorder has resulted in new understandings of the influence of the family. This article reviews recent research revealing a unique vulnerability to stress in persons with schizophrenia and suggesting that communication difficulties may be due to a shared genetic heritage. Advanced practice mental health nurses who have a solid foundation in neurobiology are ideally suited to help the person with schizophrenia and his or her family. Knowledge about the neurobiological basis of schizophrenia has become very sophisticated and complex, but that knowledge is nevertheless essential to understand the otherwise puzzling patterns of behavior shown by persons with schizophrenia.     

Schizophrenia and genetics: a review and critique for the psychiatric nurse

Nursing authors such as McCrone and Gournay persist in the orthodox view that the genetic heritability of schizophrenia is an established scientific fact. In this article I take issue with the view they propound by way of an examination of the literature pertaining to schizophrenia and genetics. My reading of the literature suggests that the certainty they seek is not to be found in any of the scientific evidence so far put forward in support of the genetic hypothesis. Much of the early work in this field is fatally flawed and can no longer be used to support the genetic argument. More recent work tends to give increasing support to a greater role for environmental factors than is compatible with a hereditarian argument. Fifty years of research in this field has consistently failed to provide reliable scientific evidence in support of any of the genetic hypotheses relating to schizophrenia. Nurses, it is argued, should not be dispensing advice to patients on the basis of a genetic model that is at best mere hypothesis.     

Neurobiology of depression: an integrated view of key findings

AIMS: The objectives of the present review were to summarise the key findings from the clinical literature regarding the neurobiology of major depressive disorder (MDD) and their implications for maximising treatment outcomes. Several neuroanatomical structures in the prefrontal and limbic areas of the brain are involved in affective regulation. In patients with MDD, alterations in the dynamic patterns of activity among these structures have profound implications for the pathogenesis of this illness. DISCUSSION: The present work reviews the evidence for the progressive nature of MDD along with associated changes in neuroanatomical structure and function, especially for the hippocampus. The role of glucocorticoids, inflammatory cytokines and brain-derived growth factors are discussed as mediators of these pathological alterations. From this integrated model, the role of antidepressant therapy in restoring normative processes is examined along with additional treatment guidelines. CONCLUSION: Major depressive disorder is an illness with significant neurobiological consequences involving structural, functional and molecular alterations in several areas of the brain. Antidepressant pharmacotherapy is associated with restoration of the underlying physiology. Clinicians are advised to intervene with MDD using an early, comprehensive treatment approach that has remission as the goal.     

Distinct neural mechanisms of risk and ambiguity: a meta-analysis of decision-making

Converging evidence from human and animal studies suggests that decision-making relies upon a distributed neural network based in the frontal lobes. In particular, models of decision-making emphasize the involvement of orbitofrontal cortices (OFC) and the medial wall. While decision-making has been studied broadly as a class of executive function, recent models have suggested the differentiation between risky and ambiguous decision-making. Given recent emphasis on the role of OFC in affectively laden "hot" executive function and dorsolateral prefrontal cortex (DLPFC) in more purely cognitive "cool" executive function, we hypothesize that the neural substrates of decision-making may differ depending on the nature of the decision required. To test this hypothesis, we used recently developed meta-analytic techniques to examine the existent functional neuroimaging literature. An initial meta-analysis of decision-making, both risky and ambiguous, found significantly elevated probabilities of activation in frontal and parietal regions, thalamus, and caudate. Ambiguous decision-making was associated with activity in DLPFC, regions of dorsal and subcallosal anterior cingulate cortex (ACC), and parietal cortex. Risky decision-making was associated with activity in OFC, rostral portions of the ACC, and parietal cortex. Direct statistical comparisons revealed significant differences between risky and ambiguous decision-making in frontal regions, including OFC, DLPFC, and ACC, that were consistent with study hypotheses. These findings provide evidence for the dissociation of neural circuits underlying risky and ambiguous decision-making, reflecting differential involvement of affective "hot" and cognitive "cool" processes.     

Resting state functional connectivity in addiction: Lessons learned and a road ahead

Despite intensive scientific investigation and public health imperatives, drug addiction treatment outcomes have not significantly improved in more than 50 years. Non-invasive brain imaging has, over the past several decades, contributed important new insights into the neuroplastic adaptations that result from chronic drug intake, but additional experimental approaches and neurobiological hypotheses are needed to better capture the totality of the motivational, affective, cognitive, genetic and pharmacological complexities of the disease. Recent advances in assessing network dynamics through resting-state functional connectivity (rsFC) may allow for such systems-level assessments. In this review, we first summarize the nascent addiction-related rsFC literature and suggest that in using this tool, circuit connectivity may inform specific neurobiological substrates underlying psychological dysfunctions associated with reward, affective and cognitive processing often observed in drug addicts. Using nicotine addiction as an exemplar, we subsequently provide a heuristic framework to guide future research by linking recent findings from intrinsic network connectivity studies with those interrogating nicotine's neuropharmacological actions. Emerging evidence supports a critical role for the insula in nicotine addiction. Likewise, the anterior insula, potentially together with the anterior cingulate cortex, appears to pivotally influence the dynamics between large-scale brain networks subserving internal (default-mode network) and external (executive control network) information processing. We suggest that a better understanding of how the insula modulates the interaction between these networks is critical for elucidating both the cognitive impairments often associated with withdrawal and the performance-enhancing effects of nicotine administration. Such an understanding may be usefully applied in the design and development of novel smoking cessation treatments.     

Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment

The glutamate system is involved in many aspects of neuronal synaptic strength and function during development and throughout life. Synapse formation in early brain development, synapse maintenance, and synaptic plasticity are all influenced by the glutamate system. The number of neurons and the number of their connections are determined by the activity of the glutamate system and its receptors. Malfunctions of the glutamate system affect neuroplasticity and can cause neuronal toxicity. In schizophrenia, many glutamate-regulated processes seem to be perturbed. Abnormal neuronal development, abnormal synaptic plasticity, and neurodegeneration have been proposed to be causal or contributing factors in schizophrenia. Interestingly, it seems that the glutamate system is dysregulated and that N-methyl-D-aspartate receptors operate at reduced activity. Here we discuss how the molecular aspects of glutamate malfunction can explain some of the neuropathology observed in schizophrenia, and how the available treatment intervenes through the glutamate system.     

A possible role for the endocannabinoid system in the neurobiology of depression

The present review synthetically describes the currently advanced hypotheses for a neurobiological basis of depression, ranging from the classical monoaminergic to the more recent neurotrophic hypothesis. Moreover, the Authors review the available preclinical and clinical evidence suggesting a possible role for the endocannabinoid system in the physiopathology of depression. Indeed, in spite of the reporting of conflicting results, the pharmacological enhancement of endocannabinoid activity at the CB1 cannabinoid receptor level appears to exert an antidepressant-like effect in some animal models of depression. On the contrary, a reduced activity of the endogenous cannabinoid system seems to be associated with the animal model of depression, namely the chronic mild stress model. Moreover, a few studies have reported an interaction of antidepressants with the endocannabinoid system. With regard to clinical studies, several authors have reported an alteration of endocannabinoid serum levels in depression, while post mortem studies have demonstrated increased levels of endocannabinoids associated to a concomitant hyperactivity of CB1 receptor in the prefrontal cortex of suicide victims. No clinical trials carried out using cannabinoids in the treatment of affective disorders have been published to date, although anecdotal reports have described both antidepressant and antimanic properties of cannabis as well as the ability of cannabis to induce mania that has also been documented. These findings are discussed, leading us to conclude that, although data available are sufficient to suggest a possible involvement of the endogenous cannabinoid system in the neurobiology of depression, additional studies should be performed in order to better elucidate the role of this system in the physiopathology of depression.     

弥散张量成像在胎儿脑发育中的研究进展

胎脑从妊娠第3周末一个简单的神经管结构发育成出生后功能结构复杂的脑组织,期间经历了脑原始诱导发育、神经细胞增殖、神经元移行、两侧大脑半球皮质层状结构形成、脑室、沟、裂、脑回发育,以及白质纤维出现到成熟的髓鞘化过程。这些发育过程极其精确复杂,但是遵从严格的顺序。产前超声仅能筛查早期胎脑较明显的先天异常,无法评估这些细微的脑结构发育情况。近年来发展的磁共振成像技术为胎脑发育的研究提供了有用工具,尤其是弥散张量成像技术通过检测脑组织的水分子弥散运动,提供了从微观结构层面观察胎脑信息的视角,同胎脑组织学研究形成互补。本文将简要介绍弥散张量成像(diffusion tensor imaging,DTI)技术应用于胎脑方面的优势及其主要应用手段,DTI对皮质层状结构的显示,以及显示白质纤维束出现的时间、顺序、胎脑纤维束连接的变化、白质髓鞘化前成熟过程等,还总结了目前DTI技术用于胎儿脑成像的主要技术难题与解决办法,为进一步应用弥散张量成像研究正常胎儿脑发育奠定理论基础。     

Altered structural connectivity in neonates at genetic risk for schizophrenia: a combined study using morphological and white matter networks

Recently, an increasing body of evidence suggests that developmental abnormalities related to schizophrenia may occur as early as the neonatal stage. Impairments of brain gray matter and wiring problems of axonal fibers are commonly suspected to be responsible for the disconnection hypothesis in schizophrenia adults, but significantly less is known in neonates. In this study, we investigated 26 neonates who were at genetic risk for schizophrenia and 26 demographically matched healthy neonates using both morphological and white matter networks to examine possible brain connectivity abnormalities. The results showed that both populations exhibited small-world network topology. Morphological network analysis indicated that the brain structural associations of the high-risk neonates tended to have globally lower efficiency, longer connection distance, and less number of hub nodes and edges with relatively higher betweenness. Subgroup analysis showed that male neonates were significantly disease-affected, while the female neonates were not. White matter network analysis, however, showed that the fiber networks were globally unaffected, although several subcortical-cortical connections had significantly less number of fibers in high-risk neonates. This study provides new lines of evidence in support of the disconnection hypothesis, reinforcing the notion that the genetic risk of schizophrenia induces alterations in both gray matter structural associations and white matter connectivity.     

精神分裂症动物模型

精神分裂症是涉及思维、情感、认知广泛受损的重症精神疾病之一,但迄今病因未明。动物模型是研究精神分裂症神经生物学基础的一个重要临床前工具,在监测疾病进展方面,它提供了一个更加快速的平台。本文综述了目前研究精神分裂症的常用动物模型,旨在为精神分裂症实验室研究动物模型的建立提供理论指导。     

Amino acid metabolism in endogenous psychoses: significance of amino acids as neurotransmitter, precursor of monoamines and allosteric regulator of neuro-receptors]

Amino acid metabolism in endogenous psychoses has been discussed in relation to monoamine synthesis. There are no consistent findings which prove altered monoamine syntheses to be the primary change. Our finding, which suggests decreased amino acid transport across the blood-brain barrier in schizophrenia, does not necessarily mean an insufficient amino acid supply to the brain. Several lines of investigation have shown the possibility of the involvement of glutamatergic dysfunction in the pathogenesis of schizophrenia. Our recent finding of decreased CSF asparagine concentration in schizophrenia and its positive correlation with the response to neuroleptics may support this hypothesis. Recently, free D-serine, an allosteric agonist on NMDA-receptor, has been reported to exist in the rat brain, suggesting that D-serine is an intrinsic ligand. The pathogeneses of endogenous psychoses might be studied in terms of disturbed metabolism of amino acid, as allosteric regulater of neuro-receptor, as well as neurotransmitter and precursor of monoamines.     

抑郁易感性的fMRI研究进展

抑郁易感性是一种在特定条件下可以诱发抑郁症产生的内在素质,它是疾病发生的内在基础,已越来越被研究者重视,其与生物、人格、认知、环境等因素有关,已出现了不少的理论研究成果。近年来随着功能性磁共振成像(functional magnetic resonance imaging,f MRI)技术在神经精神领域的发展,研究者开始将f MRI技术用于探索抑郁易感性的神经生物学基础,期望使用f MRI技术检测抑郁认知易感者脑灰质体积和静息态下脑功能特征,探讨抑郁易感者特异性的神经生物学标记,为其生物学机制提供新线索和依据。本文拟从抑郁易感性的定义及分类、抑郁易感者的脑结构与脑功能改变等方面对抑郁易感性的f MRI研究进展作一综述。     

Neural foundations of risk–return trade-off in investment decisions

Many decisions people make can be described as decisions under risk. Understanding the mechanisms that drive these decisions is an important goal in decision neuroscience. Two competing classes of risky decision making models have been proposed to describe human behavior, namely utility-based models and risk–return models. Here we used a novel investment decision task that uses streams of (past) returns as stimuli to investigate how consistent the two classes of models are with the neurobiological processes underlying investment decisions (where outcomes usually follow continuous distributions). By showing (a) that risk–return models can explain choices behaviorally and (b) that the components of risk–return models (value, risk, and risk attitude) are represented in the brain during choices, we provide evidence that risk–return models describe the neural processes underlying investment decisions well. Most importantly, the observed correlation between risk and brain activity in the anterior insula during choices supports risk–return models more than utility-based models because risk is an explicit component of risk–return models but not of the utility-based models.     

Hippocampal volume deficits and shape deformities in young biological relatives of schizophrenia probands

Hippocampal volume decrement may be one of the changes that most closely pre-date schizophrenia onset. Studying hippocampal developmental morphology in adolescent or young adult biological relatives of schizophrenia probands has the potential to further our understanding of the neurodevelopmental etiology of schizophrenia and to discover biomarkers that may aid its early identification. We utilized an artificial neural network segmentation algorithm to automatically define and reliably measure MRI hippocampus volumes. We compared 46 young, nonpsychotic biological relatives of probands against 46 healthy controls without family history of schizophrenia and 46 schizophrenia probands (age range = 13 to 28 years). We further contrasted hippocampal shape differences using spherical harmonic functions and assessed how obstetric complications (a trigger for aberrant in utero neurodevelopment) may contribute to hippocampal abnormalities. Similar to schizophrenia probands, unaffected biological relatives of probands had significantly smaller hippocampus volumes than controls; which correspond to inward displacements in shape deformities principally in the anterior hippocampal subregions. Examination of hippocampus volume–age relationships indicate that hippocampus volume normally decreases with age during late adolescence through early adulthood. In contrast, relatives of probands did not show these age-expected changes. Deviant hippocampus volume–age relationships suggest aberrant hippocampal neurodevelopment among biological relatives. Relatives with a history of obstetric complications had significantly smaller left and right hippocampi than relatives without obstetrics complications, including a dose relationship such that greater number of birth complications correlated with smaller hippocampus. Similar hippocampal volume deficits–obstetric complications relationships were observed among schizophrenia probands. Hippocampal abnormalities in schizophrenia are likely to be mediated by different neurobiological mechanisms, including factors associated with obstetric complications which occur during early neurodevelopment. Other brain maturational anomalies affecting the hippocampus in schizophrenia may manifest closer to illness onset in adolescence/early adulthood.