Meyer Bernhard M, Huemer Julia, Rabl Ulrich, Boubela Roland N, Kalcher Klaudius, Berger Andreas, Banaschewski Tobias, Barker Gareth, Bokde Arun, Büchel Christian, Conrod Patricia, Desrivières Sylvane, Flor Herta, Frouin Vincent, Gallinat Jurgen, Garavan Hugh, Heinz Andreas, Ittermann Bernd, Jia Tianye, Lathrop Mark, Martinot Jean-Luc, Nees Frauke, Rietschel Marcella, Smolka Michael N, Bartova Lucie, Popovic Ana, Scharinger Christian, Sitte Harald H, Steiner Hans, Friedrich Max H, Kasper Siegfried, Perkmann Thomas, Praschak-Rieder Nicole, Haslacher Helmuth, Esterbauer Harald, Moser Ewald, Schumann Gunter, Pezawas Lukas
Department of Psychiatry and Psychotherapy, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
Department of Child and Adolescent Psychiatry, Medical University of Vienna, Vienna, Austria.
Brain Struct Funct. 2016 Jan;221(1):103-14. doi: 10.1007/s00429-014-0895-5. Epub 2014 Oct 16.
Prefrontal dopamine levels are relatively increased in adolescence compared to adulthood. Genetic variation of COMT (COMT Val158Met) results in lower enzymatic activity and higher dopamine availability in Met carriers. Given the dramatic changes of synaptic dopamine during adolescence, it has been suggested that effects of COMT Val158Met genotypes might have oppositional effects in adolescents and adults. The present study aims to identify such oppositional COMT Val158Met effects in adolescents and adults in prefrontal brain networks at rest. Resting state functional connectivity data were collected from cross-sectional and multicenter study sites involving 106 healthy young adults (mean age 24 ± 2.6 years), gender matched to 106 randomly chosen 14-year-olds. We selected the anterior medial prefrontal cortex (amPFC) as seed due to its important role as nexus of the executive control and default mode network. We observed a significant age-dependent reversal of COMT Val158Met effects on resting state functional connectivity between amPFC and ventrolateral as well as dorsolateral prefrontal cortex, and parahippocampal gyrus. Val homozygous adults exhibited increased and adolescents decreased connectivity compared to Met homozygotes for all reported regions. Network analyses underscored the importance of the parahippocampal gyrus as mediator of observed effects. Results of this study demonstrate that adolescent and adult resting state networks are dose-dependently and diametrically affected by COMT genotypes following a hypothetical model of dopamine function that follows an inverted U-shaped curve. This study might provide cues for the understanding of disease onset or dopaminergic treatment mechanisms in major neuropsychiatric disorders such as schizophrenia and attention deficit hyperactivity disorder.
与成年期相比，青春期前额叶多巴胺水平相对升高。儿茶酚-O-甲基转移酶（COMT Val158Met）的基因变异导致Met携带者的酶活性降低和多巴胺可用性增加。鉴于青春期突触多巴胺的剧烈变化，有人提出COMT Val158Met基因型的影响在青少年和成年人中可能具有相反的作用。本研究旨在确定在静息状态下青少年和成年人前额叶脑网络中这种相反的COMT Val158Met效应。静息态功能连接数据来自一项横断面多中心研究，该研究纳入了106名健康的年轻成年人（平均年龄24±2.6岁），性别匹配106名随机选择的14岁青少年。由于前内侧前额叶皮质（amPFC）作为执行控制和默认模式网络的枢纽发挥着重要作用，我们选择其作为种子区域。我们观察到，COMT Val158Met对amPFC与腹外侧以及背外侧前额叶皮质和海马旁回之间静息态功能连接的影响存在显著的年龄依赖性逆转。对于所有报告的区域，与Met纯合子相比，Val纯合子成年人的连接性增加，而青少年的连接性降低。网络分析强调了海马旁回作为观察到的效应的中介的重要性。本研究结果表明，青少年和成年人的静息态网络受到COMT基因型的剂量依赖性和截然相反的影响，遵循一种假设的多巴胺功能模型，该模型呈倒U形曲线。这项研究可能为理解精神分裂症和注意力缺陷多动障碍等主要神经精神疾病的发病机制或多巴胺能治疗机制提供线索。
