PDF(Pubmed)
Abstract：
Impaired response inhibition is commonly present in individuals with attention-deficit/hyperactivity disorder (ADHD) and their unaffected relatives, suggesting impaired response inhibition as a candidate endophenotype in ADHD. Therefore, we explored whether behavioral and neural correlates of response inhibition are related to polygenic risk scores for ADHD (PRS-ADHD). We obtained functional magnetic resonance imaging of neural activity and behavioral measures during a stop-signal task in the NeuroIMAGE cohort, where inattention and hyperactivity-impulsivity symptoms were assessed with the Conners Parent Rating Scales. Our sample consisted of 178 ADHD cases, 103 unaffected siblings, and 173 controls (total N = 454; 8-29 years), for whom genome-wide genotyping was available. PRS-ADHD was constructed using the PRSice-2 software. We found PRS-ADHD to be associated with ADHD symptom severity, a slower and more variable response to Go-stimuli, and altered brain activation during response inhibition in several regions of the bilateral fronto-striatal network. Mean reaction time and intra-individual reaction time variability mediated the association of PRS-ADHD with ADHD symptoms (total, inattention, hyperactivity-impulsivity), and activity in the left temporal pole and anterior parahippocampal gyrus during failed inhibition mediated the relationship of PRS-ADHD with hyperactivity-impulsivity. Our findings indicate that PRS-ADHD are related to ADHD severity on a spectrum of clinical, sub-threshold, and normal levels; more importantly, we show a shared genetic etiology of ADHD and behavioral and neural correlates of response inhibition. Given the modest sample size of our study, future studies with higher power are warranted to explore mediation effects, suggesting that genetic liability to ADHD may adversely affect attention regulation on the behavioral level and point to a possible response inhibition-related mechanistic pathway from PRS-ADHD to hyperactivity-impulsivity.
摘要：
受损的反应抑制通常存在于患有注意力缺陷/多动障碍（ADHD）的个体及其未受影响的亲属中。提示反应抑制受损作为ADHD的候选内表型。因此,我们探讨了反应抑制的行为和神经相关性是否与ADHD的多基因风险评分(PRS-ADHD)相关.我们在NeuroIMAGE队列的停止信号任务中获得了神经活动和行为测量的功能磁共振成像，其中注意力不集中和多动冲动症状用Conners父母评定量表进行评估。我们的样本包括178例ADHD病例，103个未受影响的兄弟姐妹，和173名对照（总N=454；8-29年），可进行全基因组基因分型的人。使用PRSice-2软件构建PRS-ADHD。我们发现PRS-ADHD与ADHD症状严重程度有关，对围棋刺激的反应更慢、更多变，并在双侧前纹状体网络的几个区域的反应抑制期间改变了大脑激活。平均反应时间和个体内反应时间变异性介导了PRS-ADHD与ADHD症状的关联（总，注意力不集中,多动-冲动)，抑制失败期间左颞极和海马前回的活动介导了PRS-ADHD与多动冲动的关系。我们的研究结果表明，PRS-ADHD与临床上的ADHD严重程度有关，次阈值，和正常水平；更重要的是，我们显示了ADHD的共同遗传病因与反应抑制的行为和神经相关。鉴于我们研究的样本量适中，未来有更高权力的研究有必要探索调解效果，提示ADHD的遗传倾向可能对行为水平的注意力调节产生不利影响,并指出从PRS-ADHD到多动-冲动的可能的应答抑制相关机制途径.
