Dopamine-Related Disruption of Functional Topography of Striatal Connections in Unmedicated Patients With Schizophrenia.
Dopamine-Related Disruption of Functional Topography of Striatal Connections in Unmedicated Patients With Schizophrenia.
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DOI：
10.1001/jamapsychiatry.2016.0178
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发表时间：
2016-08-01
期刊：
影响因子：
25.8
通讯作者：
Abi-Dargham A
中科院分区：
文献类型：
--
作者：
Horga G;Cassidy CM;Xu X;Moore H;Slifstein M;Van Snellenberg JX;Abi-Dargham A
尽管纹状体多巴胺在精神病中的作用已明确，但目前的观点普遍认为，皮质功能障碍可能是精神病性症状出现的必要条件。纹状体 - 皮质连接的拓扑结构对于高阶信息的门控和整合至关重要，因此，多巴胺失调对这种拓扑结构的破坏可能导致精神分裂症中的皮质功能障碍。然而，这一假设仍需使用多变量方法进行检验，以确定纹状体连接的整体模式，且要排除抗多巴胺能药物的混杂影响。
为了确定未用药的精神分裂症患者纹状体各亚区之间的大脑连接模式是否异常，以及这种异常是否与精神病性症状和纹状体外多巴胺能传递有关。
在这项多模态的病例对照研究中，我们获取了18名未用药的精神分裂症患者和24名匹配的健康对照者的静息态功能磁共振成像（fMRI）数据。其中一部分人（分别为12名患者和17名对照者）在使用安非他明前后接受了使用多巴胺D2受体放射性示踪剂[11C]FLB457的正电子发射断层扫描（PET）成像。数据采集时间为2011年6月16日至2014年2月25日。
（1）纹状体各亚区之间纹状体连接模式的组间差异（通过多变量逻辑回归评估），以及多变量纹状体连接模式（2）与纹状体外基线D2受体结合潜能及其在安非他明作用后的变化（BPND和ΔBPND）之间的关系，以及（3）与用阳性和阴性症状量表（PANSS）评估的阳性症状严重程度之间的关系。
患者表现出纹状体连接模式异常，包括尾状核与一组分布的联合皮质区域的连接异常（p = 0.0036）。在患者中，与对照组中发现的纹状体连接多变量模式的偏差越大，与阳性症状越严重呈特异性相关（p = 0.0021）。纹状体连接也与皮质和纹状体外皮质下区域的基线BPND相关（p = 0.0116，经邦费罗尼校正），但与ΔBPND无关。
通过对纹状体 - 皮质连接进行多模态的回路层面探究，我们首次证明在未用药的精神分裂症患者中这些连接的功能拓扑结构整体受到破坏。这些发现表明，纹状体 - 皮质连接异常可能是多巴胺失调对精神病性症状病理生理学影响的基础。
Despite the well-established role of striatal dopamine in psychosis, current views generally agree that cortical dysfunction is likely necessary for the emergence of psychotic symptoms. The topographical organization of striatal-cortical connections is central to gating and integration of higher-order information, so a disruption of such topography via dysregulated dopamine could lead to cortical dysfunction in schizophrenia. However, this hypothesis remains to be tested using multivariate methods ascertaining the global pattern of striatal connectivity and without the confounding effects of anti-dopaminergic medication. To determine whether the pattern of brain connectivity across striatal subregions is abnormal in unmedicated patients with schizophrenia, and whether this abnormality relates to psychotic symptoms and extrastriatal dopaminergic transmission. In this multimodal, case-control study, we obtained resting-state functional Magnetic Resonance Imaging (fMRI) data in 18 unmedicated patients with schizophrenia and 24 matched healthy controls. A subset of these (12 and 17, respectively) underwent Positron Emission Tomographic (PET) imaging with the dopamine D2-receptor radiotracer [11C]FLB457, before and after amphetamine. Data were acquired between June 16, 2011, and February 25, 2014. (1) Group differences in the striatal connectivity pattern (assessed via multivariable logistic regression) across striatal subregions, and the relationship between the multivariate striatal connectivity pattern (2) with extrastriatal baseline D2-receptor binding potential and its change following amphetamine (BPND and ΔBPND), and (3) with severity of positive symptoms evaluated with the PANSS scale. Patients exhibited an abnormal pattern of striatal connectivity, which included abnormal caudate connections with a distributed set of associative cortex regions (p=0.0036). In patients, more deviation from the multivariate pattern of striatal connectivity found in controls correlated specifically with more severe positive symptoms (p=0.0021). Striatal connectivity also correlated with baseline BPND across cortical and extrastriatal subcortical regions (p=0.0116, Bonferroni-corrected) but not with ΔBPND. Using a multimodal, circuit-level interrogation of striatal-cortical connections, we provide a first demonstration that the functional topography of these connections is globally disrupted in unmedicated patients with schizophrenia. These findings suggest that striatal-cortical dysconnectivity may underlie the effects of dopamine dysregulation on the pathophysiology of psychotic symptoms.