Schizophrenia as a disconnection syndrome. Studies with functional magnetic resonance imaging and structural equation modeling

Aside from characteristic psychopathological symptoms, cognitive deficits are a core feature of schizophrenia. These deficits can only be addressed within the context of widespread functional interactions among different brain areas. To examine these interactions, structural equation modeling (SEM) was used for the analysis of fMRI datasets. In a series of studies, both in antipsychotic-treated and drug-free schizophrenic patients, a pattern of enhanced thalamocortical functional connectivity could be observed as an indicator for possible disruptions of frontostriatal thalamocortical circuitry. Moreover, drug-free patients and those receiving typical antipsychotic drugs were characterized by reduced interhemispheric corticocortical connectivity. This difference relative to normal controls was less in patients under atypical antipsychotic drugs. The results could be interpreted as a beneficial effect of atypical antipsychotic drugs on information processing in schizophrenic patients. The present findings are consistent with the model of schizophrenia as a disconnection syndrome and earlier concepts of "cognitive dysmetria" in schizophrenia.     

A truly simultaneous combination of functional transcranial Doppler sonography and H(2)(15)O PET adds fundamental new information on differences in cognitive activation between schizophrenics and healthy control subjects.

Working memory deficits are a cardinal feature of the pathophysiology of schizophrenia. Lesion studies and functional blood flow-dependent imaging methods with coarse temporal resolution, such as PET and functional MRI (fMRI), tend to paint a fairly static picture of the cortical regions involved. In contrast, functional transcranial Doppler sonography (fTCD) provides a high temporal resolution. Truly simultaneous fTCD-fMRI is not yet possible for technical reasons, but H(2)(15)O PET and fTCD can be used really simultaneously. However, this combination has not yet been used for cognitive activations in schizophrenia. We therefore investigated the extent to which there are both spatial (PET) and temporal changes (fTCD) in the activation patterns of schizophrenic patients. METHODS: Eleven clinically stable chronic schizophrenic, right-handed patients and 10 healthy, right-handed control subjects, matched for age, sex, education, and intelligence quotient, participated in the study. We selected stable chronic schizophrenic patients who could perform a working memory task (N-back task) as well as healthy volunteers to exclude the possibility of imaged artifacts due to poor performance. All subjects were examined with a truly simultaneous fTCD-H(2)(15)O PET combination under cognitive activation. RESULTS: Schizophrenic patients activate a significantly larger cortical volume for adequate task performance (P < 0.05), but with a significantly lower blood flow increase in this volume (P < 0.01), than do control subjects. Furthermore, they cannot significantly increase blood flow velocity during the time course of cognitive activation as control subjects do. There were only significant correlations between neuropsychologic performance and imaging parameters (fTCD changes, PET blood flow changes) in control subjects (all r >or= /0.65/; P < 0.05), but no significant correlations in schizophrenics (all r < /0.3/; P > 0.4). CONCLUSION: We demonstrated that schizophrenic patients exhibit qualitative differences in the spatial and temporal resolution of cognitive processing. All facts could be interpreted as a sign of alternative, less efficient problem-solving strategies in schizophrenia that lead to the working memory deficits observed during the further course of this disease. Truly simultaneous fTCD-PET can be used in neuroscience to add fundamental new information on spatial and temporal cognitive activation behavior to understand the true physiologic nature of the disease-specific differences of mental illnesses that are seen as disorders of the mind arising in the brain.     

首发精神分裂症药物治疗前后的fMRI研究

目的:探讨首发精神分裂症患者治疗前后倒背数字作业测验(BDST)fMRI脑内激活区的特点.方法:符合ICD-10精神分裂症诊断标准的首发患者及正常志愿者各18例,以BDST作为刺激任务,进行fMRI检查,氯丙嗪治疗后的患者中9例再次接受fMRI检查.结果:在BDST的fMRI检查中,对照组的左侧额上回、双侧额中回、左侧额下回、左侧中央前回、左侧顶上小叶、左侧缘上回、左侧颞下回及左侧枕颞外侧回等脑区均有明显激活;而首发精神分裂症患者的左侧额上回、左侧额下回及双侧顶叶后下部等脑区激活低下.9例用氯丙嗪治疗后的患者左侧额上回及左侧额下回的激活低下明显改善(P＜0.05).结论:fMRI不仅可以为首发精神分裂症患者的临床诊断提供可靠的诊断依据,而且还能为精神分裂症临床药物疗效的评价提供了一个新的客观指标.     

Funktionelle Magnetresonanztomographie und Antipsychotika

Recently, there has been growing interest in using functional magnetic resonance imaging (fMRI) for the evaluation of psychopharmacological drugs. fMRI studies in healthy human volunteers and psychiatric patients focus on cerebral activity following acute drug administration (single challenge) and on adaptive effects on neural networks due to long-term medication. In our own fMRI studies, the effects of olanzapine or amisulpride in never treated or medication-free schizophrenic patients using robust motor, visual, and acoustic tasks was longitudinally examined. In agreement with previous reports in the literature it could be shown that, in contrast to traditional neuroleptics, atypical drugs do not decrease the activation of the sensorimotor cortex but rather normalize the reduced frontoparietal activation as well as the neuropsychological test results. This encourages the assumption that atypical antipsychotics seem to support the recovery or normalization of frontoparietal brain dysfunction in schizophrenia. However, with these new opportunities additional methodological considerations and limitations emerge.     

Neuronale Korrelate gestörter Arbeitsgedächtnisfunktionen bei schizophrenen Patienten

This article briefly reviews some methodological limitations of functional neuroimaging studies in psychiatric patients. We argue that the investigation of the neural substrates of cognitive deficits in psychiatric disorders requires a combination of functional neuroimaging studies in healthy subjects with corresponding behavioral experiments in patients. In order to exemplify this methodological approach we review recent findings regarding the functional neuroanatomy of distinct components of human working memory and provide evidence for selective dysfunctions of cortical networks that underlie specific working memory deficits in schizophrenia. This identification of subgroups of schizophrenic patients according to neurocognitive parameters may facilitate the establishment of behavioral and neurophysiological endophenotypes and the development of a neurobiological classification of psychiatric disorders.     

Gene expression on liver toxicity induced by administration of haloperidol in rats with severe fatty liver

Sudden deaths are often encountered in schizophrenic patients prescribed with antipsychotic drugs, and fatty liver may be more prevalent among patients with schizophrenia. The aim of this study is to investigate the adverse effects of antipsychotic drugs on fatty liver. We administered haloperidol intraperitoneally to fatty liver rats and examined the mRNA expression in the liver. Basic expressions of cytochrome P450 (CYP)1A2, CYP2C11 and CYP3A2 decreased, and response of these CYPs to haloperidol was reduced in the fatty liver. Metabolism of haloperidol was also suppressed in the fatty liver rats. Moreover, hepatic injury by administration of haloperidol was shown pathohistologically and molecular-biologically in severe fatty liver. These results suggest that fatty liver increases susceptibility to adverse effects of haloperidol, possibly leading to life-threatening events. It should be noted by clinicians that excessive dose of antipsychotic drugs may be more harmful in patients with fatty liver.     

Probing targets for antipsychotic drug action with PET and SPET receptor imaging.

The use of in vivo receptor imaging by positron emission tomography (PET) and single photon emission tomography (SPET) has permitted exploration of targets for antipsychotic drug action in living patients. Early PET and SPET studies focused on striatal D2 dopamine receptors. There is broad agreement that unwanted extrapyramidal (parkinsonian) side effects of antipsychotic drugs result from high striatal dopamine D2/D3 receptor blockade by these drugs. The dopamine hypothesis of antipsychotic drug action suggests that clinical response is directly related to the level of striatal D2/D3 receptor occupancy of antipsychotic drugs. This may be true for classical antipsychotic drugs, but recent evidence suggests that novel, atypical antipsychotic drugs produce efficacy in association with modest and transient striatal D2/D3 receptor occupancy levels. Furthermore, atypical antipsychotic drugs appear to show preferential occupancy of limbic cortical dopamine D2 receptors. Cortical dopamine D2/D2-like receptors may be a common site of action for all antipsychotic drugs. Data from receptor challenge paradigms has highlighted the need to explore the neurotransmitter systems involved in regulating or stabilising dopamine transmission, either via dopamine autoreceptors or non-dopaminergic pathways. These may be promising targets for drug development. In vivo PET and SPET imaging has produced unique data contributing to the design of better, less toxic drugs for schizophrenia.     

军人精神分裂症患者全病程医疗服务管理模式疗效观察

目的 探讨全病程医疗服务管理模式对精神分裂症患者疗效、服药依从性及社会功能的影响.方法 选择2007年3月-2008年3月84例军人首发精神分裂症住院患者,均为男性,随机均分为试验组和对照组(n=42).试验组采用全病程医疗服务管理模式治疗,对照组单纯服用抗精神病药物治疗.两组分别在入组时(基线)、出院时及出院后第3、...     

Clozapine treatment of schizophrenia: implications for forensic psychiatry

Clozapine, a new antipsychotic medication, is now the first-line treatment for neuroleptic refractory schizophrenia. Preliminary observations on its efficacy in treating schizophrenic patients with co-morbid substance abuse and, particularly, schizophrenic patients with persistent aggressive behaviour suggests that clozapine may provide a useful treatment option in forensic patient populations. Potential applications of clozapine and management considerations that are relevant to the forensic setting are discussed.     

精神分裂症患者脑结构及功能的多模态影像Meta分析

目的 研究在未用药物干扰前提下精神分裂症患者的脑结构及功能变化及两者之间的关系.方法 系统地从PubMed、Embase、Web of Science和The Cochrane Library数据库上检索相应文献.多模态分析方法采用软件"Seed-based d Mapping".结果 纳入14篇结构研究,包括446例患者和461例正常对照.纳入的15篇功能MRI及PET研究中,共有360例患者和396例正常对照.多模态结果分析表明结构和功能大部分重叠的脑区在额颞叶,双侧扣带回/扣带旁回,双侧岛叶,基底节及左侧小脑.结论 排除药物干扰后发现精神分裂症患者结构和功能重叠的脑区大部分在默认网络(DMN)和听觉网络(AN).在这2种网络中,结构和功能变化的方向不一致,可能反映了精神分裂症患者大脑不同的病理生理改变.     

Fatality due to amisulpride toxicity: a case report

Amisulpride is an atypical antipsychotic agent effective in the treatment of schizophrenia. There are few cases in the literature relating to the toxicity of this agent and reported fatalities are rare. Drug induced prolongation of the QT interval of the electrocardiograph (ECG) is increasingly recognised with various classes of drugs and in particular with antipsychotics. Cardiotoxicity can manifest as ventricular tachyarrhythmia, including torsades de pointes (TdP), complicating QT prolongation. We report a case of fatal amisulpride toxicity where the post-mortem blood concentration was 48 mg/L. Hitherto under-recognised toxic effects of novel chemotherapeutic agents can pose challenges for the forensic pathologist charged with performing medico-legal autopsies in cases of sudden unexpected death in young adults and particularly in those with schizophrenia. A knowledge of the ability of antipsychotic agents to induce fatal cardiac arrhythmias should inform the approach to the autopsy (including determination of the cause and mechanism of death) in such cases, as should an appreciation of the dangers inherent in the interpretation of post-mortem toxicology.     

抗精神分裂症药物的研究进展

精神分裂症是一种严重影响患者及家属生活质量的致残性精神障碍。目前对精神分裂症的治疗仍以药物疗法和电惊厥疗法为主,尽管心理疗法和康复疗法也是不容忽视的治疗手段,但在临床上抗精神分裂症药物的应用仍然占据核心地位。典型抗精神病药能减少精神分裂症的阳性症状,却伴发锥体外系不良反应;而非典型抗精神病药尽管临床效应谱更广,锥体外系不良反应有所减少,但仍伴随其他不良反应,因此,迫切需要寻找和开发更为安全有效的药物。该文综述了典型和非典型抗精神分裂症药物的优势与问题及研发趋势。     

首发未用药精神分裂症病人壳核及伏隔核静息态功能连接的研究

目的 采用基于兴趣区相关性的方法研究首发未用药精神分裂症（SCH）病人壳核和伏隔核的静息态功能连接。 方法 纳入首发未用药SCH病人25例和健康对照32例,均行静息态功能MRI检查和临床功能评估（包括韦氏记忆量表第3版空间广度测验、连线测试、简易视觉空间记忆测验-修订版、阳性与阴性症状量表）。在Matlab平台上使用脑成像数据处理和分析工具对2组的静息态功能MRI数据进行预处理,分别选取双侧壳核和伏隔核为兴趣区与全脑其他体素时间序列进行Pearson相关分析,获得的功能连接值采用两样本t检验比较组间差异。最后,在病人组中提取2组间存在差异脑区的功能连接系数,与4种临床功能评估结果进行偏相关分析。结果 与健康对照组相比,病人组右侧壳核与左侧舌回、右侧伏隔核与下丘脑/右侧海马旁回、左侧伏隔核与下丘脑的功能连接均减弱（体素水平 P<0.001,高斯随机场理论校正,簇水平P<0.05）。病人组右侧伏隔核-下丘脑/右侧海马旁回连接系数与韦氏记忆量表第3版空间广度测验评分呈正相关（r=0.533, P=0.009）。 结论 首发未用药SCH病人右侧壳核、双侧伏隔核分别存在功能失连接表现,可能是病人存在认知障碍的原因之一。     

利培酮与氯氮平治疗精神分裂症阴性症状临床对照分析

目的 以氯氮平作对照研究利境酮对精神分裂症阴性症状的疗效。方法 利培酮，氯氮平治疗４０例以阴性症状为主型的精神分裂症病人，以阴性症状评定量表（ＳＡＮＳ）得分结果评定疗效；以副反应量表（ＴＥＳＳ）得分情况评价治疗中出现的副反应。结果 两组在治疗前后ＳＡＮＳ总分相比均显著降低（Ｐ〈０．０５）；ＴＥＳＳ总分，利培酮组明显低于氯氮平组（Ｐ〈０．０１）。结论 提示利培酮是一种对精神分裂症阴必平平有较好疗效且     

抗精神病药物所致便秘的原因分析及护理干预

目的：探讨住院精神分裂症患者服用抗精神病药物所致便秘的原因分析及护理干预。方法对2015年1月～2015年12月住院的112名精神分裂症患者服用抗精神病药物是否引起便秘进行统计分析。结果各类抗精神病药物均能引起便秘,最高达27％,最低达3％。结论便秘与使用抗精神病药物具有明显的相关性,是抗精神病药物的常见不良反应。     

Decreased functional connectivity of the amygdala in Alzheimer's disease revealed by resting-state fMRI

Alzheimer's disease (AD), the most common cause of dementia, is thought to be a progressive neurodegenerative disease that is clinically characterised by a decline of memory and other cognitive functions. Mild cognitive impairment (MCI) is considered to be the prodromal stage of AD. However, the relationship between AD and MCI and the development process remains unclear. The amygdala is one of the most vulnerable structures in the early stages of AD. To our knowledge, this is the first report on the alteration of the functional connectivity of the amygdala in AD and MCI subjects. We hypothesised that the amygdala-cortical loop is impaired in AD and that these alterations relate to the disease severity. In our study, we used resting-state functional MRIs to investigate the altered amygdala connectivity patterns in 35 AD patients, 27 MCI patients and 27 age- and gender-matched normal controls (NC). Compared with the NC, the decreased functional connectivity found in the AD patients was mainly located between the amygdala and the regions that are included in the default mode, context conditioning and extinction networks. Importantly, the decreased functional connectivity between the amygdala and some of the identified regions was positively correlated with MMSE, which indicated that the cognitive function impairment is related to an altered functional connectivity pattern     

基于格兰杰因果的精神分裂感觉门控P50脑网络研究

目的从多通道脑电的功能连接角度,研究精神分裂患者在感觉门控状态下的脑网络连接特性。方法采集10例精神分裂症患者和10例正常受试者的听觉条件测试范式下的脑电数据,利用基于频域格兰杰因果分析的定向传递函数计算各导联间的因果连接矩阵,构建出各频段的功能网络。计算每位受试者的信息流增益并运用图论的方法比较了两组间的差异。结果在high-beta和gamma频段,精神分裂组的DTF_(mean)显著高于对照组(P0.001),精神分裂组的聚类系数显著高于对照组(high-beta,P0.001;gamma,P0.01),精神分裂组的全局效率显著高于对照组(P0.001),精神分裂组的信息流增益与对照组相比存在差异。结论精神分裂患者在感觉门控过程中因果网络在high-beta和gamma频段存在着过连接现象,表明脑区间的连接出现异常。     

Abnormal amygdala connectivity in patients with primary insomnia: evidence from resting state fMRI

Background

Neurobiological mechanisms underlying insomnia are poorly understood. Previous findings indicated that dysfunction of the emotional circuit might contribute to the neurobiological mechanisms underlying insomnia. The present study will test this hypothesis by examining alterations in functional connectivity of the amygdala in patients with primary insomnia (PI).

Methods

Resting-state functional connectivity analysis was used to examine the temporal correlation between the amygdala and whole-brain regions in 10 medication-naive PI patients and 10 age- and sex-matched healthy controls. Additionally, the relationship between the abnormal functional connectivity and insomnia severity was investigated.

Results

We found decreased functional connectivity mainly between the amygdala and insula, striatum and thalamus, and increased functional connectivity mainly between the amygdala and premotor cortex, sensorimotor cortex in PI patients as compared to healthy controls. The connectivity of the amygdala with the premotor cortex in PI patients showed significant positive correlation with the total score of the Pittsburgh Sleep Quality Index (PSQI).

Conclusions

The decreased functional connectivity between the amygdala and insula, striatum, and thalamus suggests that dysfunction in the emotional circuit might contribute to the neurobiological mechanisms underlying PI. The increased functional connectivity of the amygdala with the premotor and sensorimotor cortex demonstrates a compensatory mechanism to overcome the negative effects of sleep deficits and maintain the psychomotor performances in PI patients.     

Abschiedsbrief auf dem Körper nach genitaler Selbstbeschädigung

The case of suicide of a 29-year-old schizophrenic male who hanged himself in an atypical manner following partial circumcision is described and discussed. This was probably in the context of a long-lasting but currently acute exacerbated hebephrenic schizophrenia with hallucinatory-delusional symptoms. At autopsy, apart from the signs of atypical hanging, sentences and fragments of sentences resembling those of a suicide note were found written with a felt-tip pen and also superficially scratched on the skin over the entire body. The sentences were on the subject of suicide in a delusional form and were thus considered as having been written in close chronological connection with death. The unusual findings are presented and discussed as a supplement to the current literature.     

Fatal thromboembolism following physical restraint in a patient with schizophrenia

Fatal thromboembolism during physical restraint in patients suffering from psychotic disorders is a very rare occurrence. In the case we present here, the criteria used in forensic pathology for the age determination of venous thrombi are applied to a case of pulmonary embolism in a patient suffering from schizophrenia who died after physical restraint. The possible association between conventional antipsychotic drugs and deep venous thrombosis, followed by pulmonary embolism, in a man with no predisposing risk factors, as well as the question concerning the appropriateness of medical care, are discussed.