健康与遗传心理学研究室知识库

    阴性症状被视为精神分裂症的核心缺损，持续性是阴性症状的重要特征。持续性阴性症状的概念提出主要用于界定临床性持续半年以上的阴性症状，它同时考察阴性症状的严重程度，持续性及性质，对阴性症状的考察比较全面。目前持续性阴性症状的标准是基于传统的阴性症状评估工具，但是随着对阴性症状理解的加深，己经发展出新一代的阴性症状评估工具。因此，发展基于新一代阴性症状评估工具的持续性阴性症状的标准是非常必要的。另外一方面，目前对于阴性症状脑机制的探讨较多，但是由于对阴性症状的界定方法不同，评估工具不同，造成很多不一致的研究结果。所以，从持续性阴性症状的角度出发，基于新一代评估工具来系统探讨其脑结构与脑功能的异常，可以为阴性症状脑机制的研究提供新的证据。
    本研究主要从两方面展开对精神分裂症持续性阴性症状的研究:一是从持续性阴性症状的临床评估角度出发，探讨新一代的阴性症状评估工具(Clinical Assessment工nterview for Negative Symptoms,  CA工NS)在评估持续性阴性症状时的标准;另一个方面是从多模态的脑影像学角度出发，探讨持续性阴性症状的灰质缺损，白质纤维束缺损以及功能连接异常，寻找特异于持续性阴性症状的脑结构与脑功能的异常。
    研究一针对CA工NS对持续性阴性症状的行为分类做出探讨，共纳入206例精神分裂症患者，进行了为期6个月的追踪随访，分别在基线，三个月，六个月时进行评估。采用持续性阴性症状的SANS (Scale for Assessment of Negative Symptoms)分类方法区分持续性阴性症状(57例)与非持续性阴性症状(149例)。采用ROC曲线(Receiver Operating Characteristic Curve)分析计算CA工NS及其分量表，PANSS-N(the Negative Symptoms Scale of Positive And Negative Syndrome Scale)的界值及其对应的敏感度与特异度及其曲线下面积。结果发现CA工NS在区分持续性阴性症状与非持续性阴性症状时的界值是25分，而PANSS-N 是16分，MAP (Motivation And Pleasure)量表分是17分，EXP (Expression)是5分。CA工NS总分及MAP分AUC (Area Under the Curve)在0. 9以上，具有很好的诊断效度;EXP分及PANSS-N的AUC在0. 8-0. 9之间，具有较好的诊断效度。总的来说，CA工NS是一种很好的诊断工具，优于传统的阴性症状评估工具。
    研究二主要主要从脑成像角度系统探讨持续性阴性症状的脑结构变化。首先采用Activation likelihood estimation (ALE)分析方法对既往与持续性阴性症状相关的研究文献行综述，寻找出与持续性阴性症状相关的灰质缺损脑区，结果显示与持续性阴性症相关的灰质缺损的脑区主要包括:双侧内侧前额叶，左侧中央前回，左侧额中回，左侧尾状核，双侧海马旁回，左侧前扣带回，丘脑，脑岛，以及缺损最明显的左侧尾状核。其后，我们采用实证研究，纳入共90例被试，分别完成Magnetic Resonance工malting (MR工)扫描，其中采用CA工NS的标准区分出持续性阴性症状组26例，非持续性阴性症状组31例，健康对照组33例，采用Voxel Based  Morphometry (VBM)进行分析，比较三组之间灰质缺损的差异。结果显示:持续性阴性症状组与非持续性阴性症状组之间的灰质缺损不存在显著性差异，但是分别与健康对照组相比，持续性阴性症状组表现出更多脑区更严重的灰质缺损，这些脑区主要集中在右侧岛盖额下回，左侧顶下缘角回，右侧扣带回，左侧颗中回，右侧梭状回，海马旁回，左侧岛盖部额下回，丘脑以及左侧舌回。进一步的相关分析，我们发现病人组中与阴性症状各因子均显著相关的脑区是左侧扣带回。综合两部分的研究，我们发现精神分裂症持续性阴性症状的灰质缺损主要集中在前额叶及边缘系统的相关脑区，尤其是海马旁回，丘脑及扣带回等。
    研究三采用弥散张量成像的方式探讨持续性阴性症状白质纤维束的缺损，纳入研究的持续性阴性症状组26例，非持续性阴性症状组31例，健康对照组33例。对于持续性阴性症状的区分采用的是研究一中的基于CA工NS的最新标准。三组(持续性阴性症状组，非持续性阴性症状组，健康对照组)被试存在差异的纤维束主要包括:脐服体膝部及体部，宵窿，双侧内囊后肢，双侧前放射冠，左侧后放射冠，双侧丘脑后辐射，双侧终纹等，其中健康对照组FA (Fractional Anisotropy)值显著高于持续性阴性症状组及非持续性阴性症状组。持续性阴性症状组与健康对照组差异的白质纤维束主要包括:脐服体体部，宵窿，前后放射冠及双侧终纹;非持续性阴性症状组与健康对照组差异的白质纤维束主要表现在双侧丘脑后放射冠，右侧内囊，左侧终纹等。持续性阴性症状组与非持续性阴性症状组之间不存在显著差异。进一步的相关分析结果显示，宵窿的FA值与快感缺乏得分呈显著负相关。从上述结果我们可以看出额叶一纹状体环路间的白质纤维束异常与持续性阴性症状相关，宵窿是是关键部分。
    研究四则采用静息态磁共振成像技术探讨持续性阴性症状功能连接的异常，基于CA工NS分类标准的持续性阴性症状组26例，非持续性阴性症状组31例，健康对照组33例。非持续性阴性症状组与健康对照组之间的差异主要表现在:右侧岛盖部额下回到右侧中央前回及左侧的补充运动区的功能连接，左侧的顶下缘角回到右侧丘脑之间的功能连接，以及右侧的中央前回与右侧丘脑之间的功能连接。持续性阴性症状组与健康对照组之间的差异主要表现在:左侧的顶下缘角回到右侧的额中回的功能连接，右侧的颗中回与右侧丘脑之间的功能连接，右侧海马到右侧中央前回之间的功能连接，以及右侧丘脑到颗中回之间的功能连接。持续性阴性症状组与非持续性阴性症状组之间的功能连接的差异主要集中在左侧顶下缘角回与右侧颗中回之间的功能连接，以及右侧扣带回与右侧海马旁回之间的功能连接。进一步的相关分析结果显示，右侧岛盖部额下回到右侧丘脑之间的功能连接与快感缺乏得分显著正相关。综上，额一颗一顶环路，额叶一纹状体环路的功能连接异常似乎更加特异于持续性阴性症状。
    总的来说，对于持续性阴性症状的区分，以工NS是很好的诊断工具，诊断效度优于传统的阴性症状评估工具。从对基于CA工NS分类出的持续性阴性症状的脑结构与脑功能的研究来看，我们发现前额叶，丘脑，尾状核，海马，海马旁回，前后扣带回等脑区及其之间的连接，无论是结构层面还是功能层面在持续性阴性症状的病理过程中均起到关键作用。其中，前额叶一纹状体环路及其相关脑区似乎更加特异于持续性阴性症状。

    Negative symptoms, a major contributing factor to poor functional outcomes in patients with schizophrenia, are often more persistent than positive symptoms. The construct of Persistent Negative Symptoms (PNS) has been put forward to describe negative symptoms that are enduring, trait-like features of psychotic disorders that are resistant to currently available treatment. The presence of PNS affects a large number of clinical patients with schizophrenia. However, the current diagnostic criteria for PNS are not based on the latest re-conceptualization of negative symptom assessment such as the Clinical Assessment Interview for Negative Symptoms (CAWS). Deriving PNS proxy from such a new rating scale is critically important for clinical trials and the use of these new measures to identi勿more clinically homogeneous subgroups.
    Moreover, it is still not fully clear for the altered brain structural and functional connectivity associated with patients with PNS.    The present study aimed to address these issues with the use of the newly developed and validated CAINS in patients with PNS and to examine the associated altered brain structural and functional connectivity observed in these patients. In Study 1，a total of 206 patients with schizophrenia were recruited and divided into the PNS group (n=57) and the Non-PNS group (n=149) using the conventional PNS criteria developed using the SANS. To determine which PNS cut-offs should be established with the CAWS, Receiver Operating Characteristic (ROC) curve analysis was evaluated for the CAWS subscales and total scores in the PNS and Non-PNS groups. The findings showed that PNS cutoffs of CAWS total scores, Motivation and Pleasure (MAP) subscale score and Expression (EXP) subscale score were 25, 17, and 5, respectively. Area Under the Curve (AUC) indicated excellent discrimination of the PNS and Non-PNS groups using the cut-score for the total scale. The discrimination for MAP was better than EXP. The Positive Predictive Value (PPV) and Negative Predictive Value (NPV) of the MAP subscale were 81.54% and 97.16%. These findings suggest that the PNS cut-scores derived for the CAWS are comparable to existing scales. The proxy tool offers a novel means of identifying PNS patients in clinical trials using a next-generation scale that overcomes methodological and conceptual limitations of older scales.
    In Study 2, we firstly conducted an Activation Likelihood Estimation (ALE) meta-analysis to quantitatively examine brain grey matter reduction in schizophrenia patients with PNS. A total of 12 voxel-based morphometry (VBM) studies were included in ALE meta-analysis using more stringent criterion of PNS. Significant grey matter reduction in the PNS group relative to controls was observed in the left caudate nucleus, the left precentral region, the left middle frontal region, the bilateral parahippocampal region, the left anterior cingulate region, the bilateral medial frontal gyrus, the thalamus and the insula. In the second part of Study 2, we recruited 26 patients with PNS, 31 with non-PNS, and 33 healthy controls to undertake the MRI scans and T1 imaging. VBM analysis showed that there was no significant grey matter reduction found between PNS group and non-PNS group. However, comparing to healthy controls, PNS group showed much more grey matter reduction, especially at the prefrontal regions. We also found that the grey matter reduction in the left cingular gyrus were associated with the severity of negative symptoms in both groups of patients with PNS and non-PNS. Taken together, these findings suggested that the grey matter reduction of PNS were mainly located in the prefrontal cortex and subcortical regions, such as the parahippocampal gyrus, thalamus and cingulate gyrus……