N-Methyl-D-Aspartate Receptor Antagonist Effects on Prefrontal Cortical Connectivity Better Model Early Than Chronic Schizophrenia
N-Methyl-D-Aspartate Receptor Antagonist Effects on Prefrontal Cortical Connectivity Better Model Early Than Chronic Schizophrenia
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DOI：
10.1016/j.biopsych.2014.07.022
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发表时间：
2015-03-15
影响因子：
10.6
通讯作者：
Krystal, John H.
中科院分区：
文献类型：
--
作者：
Anticevic, Alan;Corlett, Philip R.;Krystal, John H.
背景：前额皮质（PFC）功能与精神分裂症的发病和进展有关。然而，随着疾病的发展，PFC功能改变背后的神经机制知之甚少。最近的药理学研究表明，谷氨酸功能障碍可能导致功能连接增加。然而，精神分裂症的药理学模型忽略了疾病进展对PFC功能的影响。本研究比较了n -甲基- d -天冬氨酸谷氨酸受体（NMDAR）拮抗剂对精神分裂症健康志愿者PFC功能连接的影响。方法：首先，我们以数据驱动的方式测试了氯胺酮对健康志愿者PFC功能连通性的影响（n = 19）。接下来，我们将健康受试者（n = 96）与三个临床组进行比较：精神分裂症高危个体（n = 21），精神分裂症病程早期患者（n = 28）和慢性疾病患者（n = 20）。在独立分析中，我们使用数据驱动的全球大脑连接技术来识别功能连接障碍，该技术仅限于PFC。结果：结果显示，服用氯胺酮的健康志愿者PFC超连通性较强（Cohen’s d = 1.46），与精神分裂症和EC-SCZ高危人群相似。与EC-SCZ患者相比，慢性疾病患者未发现超连通性。结果首次证明氯胺酮对PFC功能连接的影响类似于早期病程，而不是慢性精神分裂症。结论：结果表明，NMDAR拮抗剂治疗与精神分裂症相关的前额叶连接障碍具有疾病阶段特异性相关性。这一发现对疾病进展的神经生物学和NMDAR拮抗剂在精神分裂症治疗药物开发中的广泛使用具有重要意义。
BACKGROUND: Prefrontal cortex (PFC) function contributes to schizophrenia onset and progression. However, little is known about neural mechanisms behind PFC functional alterations along illness stages. Recent pharmacologic studies indicate that glutamate dysfunction may produce increased functional connectivity. However, pharmacologic models of schizophrenia overlook effects of illness progression on PFC function. This study compared N-methyl-D-aspartate glutamate receptor (NMDAR) antagonist effects in healthy volunteers with stages of schizophrenia with respect to PFC functional connectivity.METHODS: First, we tested ketamine effects on PFC functional connectivity in healthy volunteers in a data-driven way (n = 19). Next, we compared healthy subjects (n = 96) with three clinical groups: individuals at high risk for schizophrenia (n = 21), people early in their course of schizophrenia (EC-SCZ) (n = 28), and patients with chronic illness (n = 20). Across independent analyses, we used data-driven global brain connectivity techniques restricted to PFC to identify functional dysconnectivity.RESULTS: Results revealed robust PFC hyperconnectivity in healthy volunteers administered ketamine (Cohen's d = 1.46), resembling individuals at high risk for schizophrenia and EC-SCZ. Hyperconnectivity was not found in patients with chronic illness relative to EC-SCZ patients. Results provide the first evidence that ketamine effects on PFC functional connectivity resemble early course but not chronic schizophrenia.CONCLUSIONS: Results suggest an illness phase-specific relevance of NMDAR antagonist administration for prefrontal dysconnectivity associated with schizophrenia. This finding has implications for the neurobiology of illness progression and for the widespread use of NMDAR antagonists in the development of therapeutics for schizophrenia.