Abnormal fMRI response of the dorsolateral prefrontal cortex in cognitively intact siblings of patients with schizophrenia
Abnormal fMRI response of the dorsolateral prefrontal cortex in cognitively intact siblings of patients with schizophrenia
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DOI：
10.1176/appi.ajp.160.4.709
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发表时间：
2003-04-01
影响因子：
17.7
通讯作者：
Weinberger, DR
中科院分区：
文献类型：
--
作者：
Callicott, JH;Egan, MF;Weinberger, DR
目的：神经生物学中间表型的确定可能会加快在诸如精神分裂症等复杂精神疾病中寻找易感基因的进程。早期的家族研究表明，执行认知和工作记忆方面的缺陷可能与精神分裂症的遗传易感性有关，但这种行为表型的生物学基础尚未确定。
方法：作者在执行N - back工作记忆任务期间使用功能性磁共振成像（fMRI）来评估精神分裂症患者的非精神分裂症、认知完整的兄弟姐妹的与工作记忆相关的皮质生理情况。他们将23名精神分裂症患者的未患病兄弟姐妹与18名匹配的对照受试者进行比较。作为一项有计划的重复实验，他们又研究了另外25名未患病兄弟姐妹和15名对照受试者。
结果：在两个队列中，工作记忆表现没有组间差异。然而，两组兄弟姐妹在右侧背外侧前额叶皮质都表现出过度的生理反应，这在性质上与早期对精神分裂症患者的fMRI研究结果相似。
结论：这些fMRI数据提供了直接证据，表明在精神分裂症遗传风险较高的个体中，即使没有明显的认知异常，背外侧前额叶皮质功能也存在原发性生理异常。这种过度的fMRI反应意味着在前额叶内在回路层面上对记忆信息的处理效率低下，这与早期在精神分裂症患者中的发现相似。这些数据预测，导致前额叶信息处理效率低下的等位基因的遗传会增加患精神分裂症的风险。
Objective: The identification of neurobiological intermediate phenotypes may hasten the search for susceptibility genes in complex psychiatric disorders such as schizophrenia. Earlier family studies have suggested that deficits in executive cognition and working memory may be related to genetic susceptibility for schizophrenia, but the biological basis for this behavioral phenotype has not been identified.Method: The authors used functional magnetic resonance imaging (fMRI) during performance of the N-back working memory task to assess working memory-related cortical physiology in nonschizophrenic, cognitively intact siblings of patients with schizophrenia. They compared 23 unaffected siblings of schizophrenic patients to 18 matched comparison subjects. As a planned replication, they studied another 25 unaffected siblings and 15 comparison subjects.Results: In both cohorts, there were no group differences in working memory performance. Nevertheless, both groups of siblings showed an exaggerated physiological response in the right dorsolateral prefrontal cortex that was qualitatively similar to results of earlier fMRI studies of patients with schizophrenia.Conclusions: These fMRI data provide direct evidence of a primary physiological abnormality in dorsolateral prefrontal cortex function in individuals at greater genetic risk for schizophrenia, even in the absence of a manifest cognitive abnormality. This exaggerated fMRI response implicates inefficient processing of memory information at the level of intrinsic prefrontal circuitry, similar to earlier findings in patients with schizophrenia. These data predict that inheritance of alleles that contribute to inefficient prefrontal information processing will increase risk for schizophrenia.