Schizophrenie als Diskonnektionssyndrom

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.     

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.     

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.     

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.     

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.     

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.     

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、...     

Cognitive Impairment and Basal Ganglia Functional Connectivity in Vascular Parkinsonism

BACKGROUND AND PURPOSE:Patients with vascular parkinsonism have higher cognitive decline and more basal ganglia lesions. We aimed to evaluate the relationship of cognitive impairment with functional connectivity between the basal ganglia and cingulate cortex in vascular parkinsonism.MATERIALS AND METHODS:Thirty patients (8 with vascular parkinsonism and 22 with Parkinson disease) and 23 controls were enrolled. The Mattis Dementia Rating Scale and the Stroop Task were used to assess cognitive decline. MR imaging examinations included T1-MPRAGE, FLAIR, and resting-state fMRI sequences. MPRAGE was segmented to obtain basal ganglia and cingulate cortex volumes. FLAIR was segmented to obtain white matter hyperintensity lesion volume. Resting-state fMRI sequences were used to compare basal ganglia functional connectivity with the cingulate cortex between patients and controls.RESULTS:Patients with vascular parkinsonism exhibited impaired attention, resistance to interference, and inhibitory control and an increased number of errors on the Stroop Task. They also had higher caudate nucleus and white matter hyperintensity lesion volumes, which were positively correlated (ρ = 0.75, P < .0001). Caudate nucleus functional connectivity with the perigenual anterior cingulate cortex was increased in patients with vascular parkinsonism compared with controls and patients with Parkinson disease, and it was positively correlated with the caudate nucleus volume (ρ = 0.44, P = .016). Caudate nucleus functional connectivity with the posterior cingulate cortex was decreased in patients with vascular parkinsonism compared with controls and negatively correlated with the number of errors on the Stroop test (ρ = −0.51, P = .0003).CONCLUSIONS:In patients with vascular parkinsonism, cognitive decline could be related to changes of caudate nucleus functional connectivity with the cingulate cortex at resting-state, which may be induced by ischemia-related remodelling.

Brain lesions related to small-vessel disease may affect the white matter and basal ganglia and can lead to parkinsonism features.¹ Vascular parkinsonism (VP) has thus emerged as a secondary parkinsonism subtype that occurs in 3.2/100,000 individuals per year and 2 times more frequently in men than in women.² Clinically, patients with VP more frequently present with lower body parkinsonism, urinary incontinence, and abnormal pyramidal response.³ Compared with age-matched patients with Parkinson disease (PD) and healthy controls, they also have significantly higher cognitive decline with impaired attention and resistance to interference and reduced inhibitory control.⁴ Regarding brain morphology, patients with VP are characterized by more frequent basal ganglia lesions^5–7 compared with patients with PD and controls. Because attention, resistance to interference, and inhibitory control were related to cingulate cortex function, we hypothesized that basal ganglia functional connectivity with the cingulate cortex could be modified in patients with VP.Resting-state fMRI (rsfMRI) provides information regarding the functional connectivity of brain structures. This relies on temporal correlation of activity estimated by measuring the blood oxygen level-dependent (BOLD) signal. Seed-driven functional connectivity MR imaging allows determining correlation coefficients between the time course of a seed ROI and the time course of others voxels (seed-to-voxel analysis) or determining correlations between each pair of seed areas (ROI-to-ROI analysis).We thus aimed to determine whether alteration of basal ganglia functional connectivity with the cingulate cortex could be involved in the cognitive impairment of patients with VP compared with those with PD and healthy controls by using both seed-to-voxel and ROI-to-ROI analyses of rsfMRI sequences.     

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.     

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.     

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。     

Changes in thalamus connectivity in mild cognitive impairment: evidence from resting state fMRI

Purpose

The subcortical region such as thalamus was believed to have close relationship with many cerebral cortexes which made it especially interesting in the study of functional connectivity. Here, we used resting state functional MRI (fMRI) to examine changes in thalamus connectivity in mild cognitive impairment (MCI), which presented a neuro-disconnection syndrome.

Materials and methods

Data from 14 patients and 14 healthy age-matched controls were analyzed. Thalamus connectivity was investigated by examination of the correlation between low frequency fMRI signal fluctuations in the thalamus and those in all other brain regions.

Results

We found that functional connectivity between the left thalamus and a set of regions was decreased in MCI; these regions are: bilateral cuneus, middle occipital gyrus (MOG), superior frontal gyrus (SFG), medial prefrontal cortex (MPFC), precuneus, inferior frontal gyrus (IFG) and precentral gyrus (PreCG). There are also some regions showed reduced connectivity to right thalamus; these regions are bilateral cuneus, MOG, fusiform gyrus (FG), MPFC, paracentral lobe (PCL), precuneus, superior parietal lobe (SPL) and IFG. We also found increased functional connectivity between the left thalamus and the right thalamus in MCI.

Conclusion

The decreased connectivity between the thalamus and the other brain regions might indicate reduced integrity of thalamus-related cortical networks in MCI. Furthermore, the increased connectivity between the left and right thalamus suggest compensation for the loss of cognitive function. Briefly, impairment and compensation of thalamus connectivity coexist in the MCI patients.     

Functional connectivity and microstructural white matter changes in phenocopy frontotemporal dementia

Objectives

Phenocopy frontotemporal dementia (phFTD) is a rare and poorly understood clinical syndrome. PhFTD shows core behavioural variant FTD (bvFTD) symptoms without associated cognitive deficits and brain abnormalities on conventional MRI and without progression. In contrast to phFTD, functional connectivity and white matter (WM) microstructural abnormalities have been observed in bvFTD. We hypothesise that phFTD belongs to the same disease spectrum as bvFTD and investigated whether functional connectivity and microstructural WM changes similar to bvFTD are present in phFTD.

Methods

Seven phFTD patients without progression or alternative psychiatric diagnosis, 12 bvFTD patients and 17 controls underwent resting state functional MRI (rs-fMRI) and diffusion tensor imaging (DTI). Default mode network (DMN) connectivity and WM measures were compared between groups.

Results

PhFTD showed subtly increased DMN connectivity and subtle microstructural changes in frontal WM tracts. BvFTD showed abnormalities in similar regions as phFTD, but had lower increased DMN connectivity and more extensive microstructural WM changes.

Conclusions

Our findings can be interpreted as neuropathological changes in phFTD and are in support of the hypothesis that phFTD and bvFTD may belong to the same disease spectrum. Advanced MRI techniques, objectively identifying brain abnormalities, would therefore be potentially suited to improve the diagnosis of phFTD.

Key points

? PhFTD shows brain abnormalities that are similar to bvFTD. ? PhFTD shows increased functional connectivity in the parietal default mode network. ? PhFTD shows microstructural white matter abnormalities in the frontal lobe. ? We hypothesise phFTD and bvFTD may belong to the same disease spectrum.

     

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。     

Age-related early/late variations of functional connectivity across the human lifespan

Purpose

Many questions remain regarding how the brain develops, matures, and ages across the lifespan. The functional connectivity networks in the resting-state brain can reflect many of the characteristic changes in the brain that are associated with increasing age. Functional connectivity has been shown to be time-dependent over the course of a lifespan and even over the course of minutes. The lifespan strategies of all cognitive networks and how dynamic functional connectivity is associated with age are unclear.

Methods

In this paper, studies employing both linear and quadratic models to define new specific lifespan strategies, including early/late increase/decrease models, were conducted to explore the lifespan functional changes. A large data sample was retrieved from the publicly available data from the Nathan Kline Institute (N?=?149 and ages 9–85). Both static and dynamic functional connectivity indexes were calculated including the static functional connectivity, the mean of the dynamic functional connectivity and variations in dynamic functional connectivity.

Results

The between-network connectivity results revealed early increases in the default-mode (DF) and cingulo-opercular network (CO)-associated network connectivities and a late increase in the fronto-parietal (FP)-associated network connectivity. These results depicted various lifespan strategies for different development stages and different cognitive networks across the lifespan. Additionally, the static FC and mean dynamic FC exhibited consistent results, and their variation exhibited a constant decrease with age across the entire age range.

Conclusion

These results (FDR-corrected p value?<?0.05) suggest that the early/late variations in lifespan strategies could reflect an association between varied and complex circumstances and brain development.