【作者】 王凯；

【导师】 李斐；

【作者基本信息】 上海交通大学 ， 儿科学， 2019， 博士

【摘要】 孤独症谱系障碍(ASD)和注意缺陷多动障碍(ADHD)的症状经常共同发生。DSM-IV指出ASD诊断是ADHD诊断的排除标准,从而限制了对这种常见临床共现的研究。DSM-5在其修订的诊断标准中认识到这种共现的频率,并首次允许ASD与ADHD的共病诊断。虽然既往大多数研究已经分别单独描绘了ASD和ADHD的发展轨迹,但是关于它们同时发生的情况知之甚少,其潜在的神经机制更是不甚明了。本课题分四部分,基于多模态神经影像数据研究ASD共患ADHD患者的脑功能及结构灰质体积的异常模式,探索潜在神经生物学机制。1.探索ASD共患ADHD患者的静息态脑网络的异常连接模式。使用公开数据库孤独症脑成像数据交换数据集(Autism Brain Imaging Data Exchange II,ABIDE＿Ⅱ)(N=339:ASD＿co ADHD=79,ASD＿non ADHD=83,TD=177)的静息态功能核磁共振数据,研究发现ASD＿co ADHD患者与ASD＿non ADHD患者相比,其默认网络(DMN)内的功能连通性降低,而DMN与躯体运动网络之间的功能连通性增强。其中,DMN内部功能连接强度与整个ASD患者样本中以及ASD＿co ADHD患者样本中的孤独症特征程度呈现负性相关。因此,默认网络(DMN)的功能障碍是ASD和ADHD共同发生的核心特征。2.探索ASD共患ADHD患者脑结构灰质体积的异常模式。我们使用ABIDE＿Ⅱ数据库结构核磁共振影像数据在站点内严格匹配年龄、性别后(N=135:ASD＿co ADHD=45,ASD＿non ADHD=45,TD=45),结果发现ASD＿co ADHD患者隶属于默认网络(DMN)的右侧前扣带皮层(ACC)和隶属于躯体运动网络的左侧中央前回灰质体积的增加,证明除了功能连接的异常外,默认网络和躯体运动网络内的皮层灰质体积亦存在异常,进一步证明默认网络及躯体运动网络的异常是ASD和ADHD共同发生的核心脑网络。3.利用基于中国汉族儿童的单站点数据探索和验证中国ASD合并ADHD行为表型患儿脑结构灰质体积的异常模式。采用上海交通大学附属新华医院收集的ASD患儿大脑结构核磁共振数据,根据长处与困难问卷(SDQ)和中文版注意缺陷多动障碍SNAP-Ⅳ评定量表(父母版)将样本分组(N=101:ASD＿co ADHD=40,ASD＿non ADHD=40,TD=21),结果发现中国汉族ASD合并ADHD行为表型患儿的默认网络脑区(左侧额叶上回)灰质体积及躯体运动网络脑区(右颞叶上回、中回、中央后回及左小脑)灰质体积异于单纯ASD患儿;在疾病组内,右侧颞叶团块的灰质体积与患儿年龄呈现显著负相关,进一步提示默认网络和躯体运动网络是区分ASD合并ADHD症状患儿与单纯ASD患儿关键神经网络。4.最后,我们综述了关于孤独症默认网络的研究。综上,大脑多模态核磁影像数据的结果均提示默认网络和躯体运动网络是ASD和ADHD共同发生的关键核心网络,我们的结果支持临床表型(ASD+ADHD)的存在,为临床后期该类患者集中训练、神经调节或药物治疗方法提供关键靶点。更多还原

【Abstract】 Symptoms of autism spectrum disorder(ASD)and attention deficit hyperactivity disorder(ADHD)often occur together.DSM-IV pointed out that ASD diagnosis was the exclusion criteria for ADHD,limiting the study of this common clinical cooccurrence.DSM-5 recognized this co-occurrence frequency in its revised diagnostic criteria and allowed comorbid diagnosis of ASD and ADHD for the first time.Although most studies to date have documented the separated developmental trajectories of ASD and ADHD,little was known about their simultaneous occurrence,and the underlying neural mechanisms were even less clear.Our project would be divided into three parts to explore the potential neurobiological mechanism of brain network and structure in ASD patients with ADHD Comorbidity using multi-modal neuroimaging data.1.This part aim to explore the characteristics of functional connectivity in the resting brain network and between networks in patients with ASD comorbid ADHD.Using resting functional magnetic resonance data from Autism Brain Imaging Data Exchange II(ABIDE＿II)(N=339: ASD＿co ADHD=79,ASD＿non ADHD=83,TD=177),we found that the functional connectivity in default network(DMN)of ASD patients with ADHD was decreased and the functional connectivity between DMN and Somatomotor network was increased.The decrease of functional connectivity in the default network(DMN)was negatively correlated with the degree of autism characteristics in the whole sample of ASD patients and those with ASD and ADHD.Therefore,the dysfunction of default network(DMN)is the core feature of the co-occurrence of ASD and ADHD.2.This part aim to further explore the characteristic changes of gray matter volume in patients with ASD comorbid ADHD.After using the ABIDE＿II database structure T1 data to strictly match the gender and age within each site(N=135: ASD＿co ADHD=45,ASD＿non ADHD=45,TD=45),it was found that increased grey matter volume of the right anterior cingulate cortex(ACC)and the left precentral gyrus,separately belonging to the default network(DMN)and the Somatomotor network,which proved that besides the abnormal functional connections(FC),the volume of gray matter in the default network(DMN)and Somatomotor network were also abnormal,further proving that the abnormality of default network and Somatomotor network is the core brain network of the co-occurrence of ASD and ADHD.3.Using single-site data to explore the abnormal characteristics of gray matter volume the co-occurrence of ASD and ADHD.The brain structure magnetic resonance imaging(s MRI)of children with ASD collected by Xinhua Hospital affiliated to Shanghai Jiaotong University were grouped according to the Chinese version of the SNAP-IV Rating Scale for Parental Deficit Hyperactivity Disorder(parent version)(N=101: ASD＿co ADHD=40),ASD＿non ADHD=40,TD=21),the results found that the Chinese Han ASD combined with ADHD children’s DMN(left frontal lobe)gray matter volume and Somatomotor network(right inferior and middle temporal gyrus,the postcentral gyrus and left cerebellum)gray matter volume were damaged,although the specific location of gray matter volume change was different from that of European and American Caucasians,the gray matter volume of the right temporal lobe cluster was significantly negatively correlated with the age of the children in the disease group,further suggesting the DMN and Somatomotor network were the key neural networks for distinguishing children with the cooccurrence of ASD and ADHD from simple ASD children.In summary,the results of multimodal brain MRI data suggest that the default network and Somatomotor network are the key core networks for the co-occurrence of ASD and ADHD.Our results supported the existence of a clinically combined phenotype(ASD+ ADHD).It provided a key target for focused training,neuromodulation or pharmacotherapeutic approaches.更多还原