Central Institute of Mental Health Mannheim, University of Heidelberg, Medical Faculty Mannheim, Mannheim, Germany.
Department of Psychiatry and Psychotherapy, Charité-University Medicine Berlin, Campus Mitte, Berlin, Germany.
JAMA Psychiatry. 2014 May;71(5):531-9. doi: 10.1001/jamapsychiatry.2014.9.
Attenuated ventral striatal response during reward anticipation is a core feature of schizophrenia that is seen in prodromal, drug-naive, and chronic schizophrenic patients. Schizophrenia is highly heritable, raising the possibility that this phenotype is related to the genetic risk for the disorder.
To examine a large sample of healthy first-degree relatives of schizophrenic patients and compare their neural responses to reward anticipation with those of carefully matched controls without a family psychiatric history. To further support the utility of this phenotype, we studied its test-retest reliability, its potential brain structural contributions, and the effects of a protective missense variant in neuregulin 1 (NRG1) linked to schizophrenia by meta-analysis (ie, rs10503929).
DESIGN, SETTING, AND PARTICIPANTS: Examination of a well-established monetary reward anticipation paradigm during functional magnetic resonance imaging at a university hospital; voxel-based morphometry; test-retest reliability analysis of striatal activations in an independent sample of 25 healthy participants scanned twice with the same task; and imaging genetics analysis of the control group. A total of 54 healthy first-degree relatives of schizophrenic patients and 80 controls matched for demographic, psychological, clinical, and task performance characteristics were studied.
Blood oxygen level-dependent response during reward anticipation, analysis of intraclass correlations of functional contrasts, and associations between striatal gray matter volume and NRG1 genotype.
Compared with controls, healthy first-degree relatives showed a highly significant decrease in ventral striatal activation during reward anticipation (familywise error-corrected P < .03 for multiple comparisons across the whole brain). Supplemental analyses confirmed that the identified systems-level functional phenotype is reliable (with intraclass correlation coefficients of 0.59-0.73), independent of local gray matter volume (with no corresponding group differences and no correlation to function, and with all uncorrected P values >.05), and affected by the NRG1 genotype (higher striatal responses in controls with the protective rs10503929 C allele; familywise error-corrected P < .03 for ventral striatal response).
Healthy first-degree relatives of schizophrenic patients show altered striatal activation during reward anticipation in a directionality and localization consistent with prior patient findings. This provides evidence for a functional neural system mechanism related to familial risk. The phenotype can be assessed reliably, is independent of alterations in striatal structure, and is influenced by a schizophrenia candidate gene variant in NRG1. These data encourage us to further investigate the genetic and molecular contributions to this phenotype.
在奖励预期期间，腹侧纹状体反应的减弱是精神分裂症的一个核心特征，在前驱期、未经药物治疗和慢性精神分裂症患者中均可观察到。精神分裂症的遗传性很强，这表明这种表型与该疾病的遗传风险有关。
检查大量精神分裂症患者的一级亲属，并将其对奖励预期的神经反应与经过精心匹配的无家族精神病史对照者进行比较。为了进一步支持这种表型的效用，我们研究了其测试-再测试可靠性、潜在的大脑结构贡献，以及通过荟萃分析（即 rs10503929）与精神分裂症相关的神经调节蛋白 1（NRG1）的保护性错义变体的影响。
设计、环境和参与者：在大学医院进行功能磁共振成像检查时，对一个成熟的货币奖励预期范式进行检查；基于体素的形态测量学；在一个由 25 名健康参与者组成的独立样本中，使用相同的任务进行两次扫描，对纹状体激活进行测试-再测试可靠性分析；以及对对照组进行影像遗传学分析。共研究了 54 名精神分裂症患者的一级亲属和 80 名在人口统计学、心理、临床和任务表现方面相匹配的对照者。
奖励预期期间血氧水平依赖反应、功能对比的组内相关系数分析，以及纹状体灰质体积与 NRG1 基因型之间的关系。
与对照组相比，健康的一级亲属在奖励预期期间表现出腹侧纹状体激活的显著降低（全脑多重比较的错误发现率校正 P<0.03）。补充分析证实，所确定的系统水平功能表型是可靠的（组内相关系数为 0.59-0.73），独立于局部灰质体积（无组间差异，与功能无关，且所有未校正的 P 值均>0.05），并受 NRG1 基因型的影响（携带保护性 rs10503929 C 等位基因的对照组纹状体反应较高；腹侧纹状体反应的错误发现率校正 P<0.03）。
精神分裂症患者的一级亲属在奖励预期期间表现出纹状体激活的改变，其方向性和定位与先前的患者研究一致。这为与家族风险相关的功能性神经系统机制提供了证据。该表型可以可靠地评估，独立于纹状体结构的改变，并且受 NRG1 中精神分裂症候选基因变异的影响。这些数据鼓励我们进一步研究该表型的遗传和分子贡献。
