Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
Department of Basic Medical Sciences, Neuroscience and Sense Organs, Università degli Studi di Bari "Aldo Moro," Bari, Italy3Biomarkers and Clinical Imaging, Hoffmann-La Roche, Basel, Switzerland.
JAMA Psychiatry. 2016 Jun 1;73(6):598-605. doi: 10.1001/jamapsychiatry.2016.0161.
Although deficits in emotional processing are prominent in schizophrenia, it has been difficult to identify neural mechanisms related to the genetic risk for this highly heritable illness. Prior studies have not found consistent regional activation or connectivity alterations in first-degree relatives compared with healthy controls, suggesting that a more comprehensive search for connectomic biomarkers is warranted.
To identify a potential systems-level intermediate phenotype linked to emotion processing in schizophrenia and to examine the psychological association, task specificity, test-retest reliability, and clinical validity of the identified phenotype.
DESIGN, SETTING, AND PARTICIPATIONS: The study was performed in university research hospitals from June 1, 2008, through December 31, 2013. We examined 58 unaffected first-degree relatives of patients with schizophrenia and 94 healthy controls with an emotional face-matching functional magnetic resonance imaging paradigm. Test-retest reliability was analyzed with an independent sample of 26 healthy participants. A clinical association study was performed in 31 patients with schizophrenia and 45 healthy controls. Data analysis was performed from January 1 to September 30, 2014.
Conventional amygdala activity and seeded connectivity measures, graph-based global and local network connectivity measures, Spearman rank correlation, intraclass correlation, and gray matter volumes.
Among the 152 volunteers included in the relative-control sample, 58 were unaffected first-degree relatives of patients with schizophrenia (mean [SD] age, 33.29 [12.56]; 38 were women), and 94 were healthy controls without a first-degree relative with mental illness (mean [SD] age, 32.69 [10.09] years; 55 were women). A graph-theoretical connectivity approach identified significantly decreased connectivity in a subnetwork that primarily included the limbic cortex, visual cortex, and subcortex during emotional face processing (cluster-level P corrected for familywise error = .006) in relatives compared with controls. The connectivity of the same subnetwork was significantly decreased in patients with schizophrenia (F = 6.29, P = .01). Furthermore, we found that this subnetwork connectivity measure was negatively correlated with trait anxiety scores (P = .04), test-retest reliable (intraclass correlation coefficient = 0.57), specific to emotional face processing (F = 17.97, P < .001), and independent of gray matter volumes of the identified brain areas (F = 1.84, P = .18). Replicating previous results, no significant group differences were found in face-related amygdala activation and amygdala-anterior cingulate cortex connectivity (P corrected for familywise error =.37 and .11, respectively).
Our results indicate that altered connectivity in a visual-limbic subnetwork during emotional face processing may be a functional connectomic intermediate phenotype for schizophrenia. The phenotype is reliable, task specific, related to trait anxiety, and associated with manifest illness. These data encourage the further investigation of this phenotype in clinical and pharmacologic studies.
尽管精神分裂症患者存在明显的情绪处理缺陷，但很难确定与这种高度遗传疾病相关的神经机制。先前的研究并未发现一级亲属与健康对照组相比存在一致的区域激活或连接改变，这表明更全面地寻找连接组生物标志物是合理的。
确定与精神分裂症情绪处理相关的潜在系统水平中间表型，并检查所确定表型的心理关联、任务特异性、测试-重测可靠性和临床有效性。
设计、地点和参与者：该研究于 2008 年 6 月 1 日至 2013 年 12 月 31 日在大学研究医院进行。我们使用情绪面孔匹配功能磁共振成像范式检查了 58 名未受影响的精神分裂症患者的一级亲属和 94 名健康对照者。使用独立的 26 名健康参与者样本分析了测试-重测可靠性。对 31 名精神分裂症患者和 45 名健康对照者进行了临床关联研究。数据分析于 2014 年 1 月 1 日至 9 月 30 日进行。
常规杏仁核活性和种子连接测量、基于图的全局和局部网络连接测量、Spearman 秩相关、组内相关和灰质体积。
在包括亲属-对照样本在内的 152 名志愿者中，58 名为精神分裂症患者的未受影响的一级亲属（平均[标准差]年龄，33.29[12.56]岁；38 名为女性），94 名为无一级亲属患有精神疾病的健康对照者（平均[标准差]年龄，32.69[10.09]岁；55 名为女性）。与对照组相比，在情绪面孔处理过程中，一个主要包括边缘皮层、视觉皮层和皮质下区域的子网络的连接明显降低（簇级经家族性错误校正的 P 值=0.006）。在精神分裂症患者中，同样的网络连接也显著降低（F=6.29，P=0.01）。此外，我们发现该子网连接测量值与特质焦虑评分呈负相关（P=0.04），具有测试-重测可靠性（组内相关系数=0.57），专门针对情绪面孔处理（F=17.97，P<0.001），并且与所确定的大脑区域的灰质体积无关（F=1.84，P=0.18）。复制先前的结果，在与面孔相关的杏仁核激活和杏仁核-前扣带回皮层连接方面，未发现组间存在显著差异（经家族性错误校正的 P 值分别为 0.37 和 0.11）。
我们的结果表明，情绪面孔处理过程中视觉-边缘子网的连接改变可能是精神分裂症的功能连接组中间表型。该表型可靠、任务特异性、与特质焦虑相关，并与显性疾病相关。这些数据鼓励在临床和药物研究中进一步研究该表型。
