哌甲酯治疗注意缺陷多动障碍儿童缓解机制的多模态磁共振研究

Attention deficit/hyperactivity disorder (ADHD) is highly prevalent among children and adolescents and often associated with poor long-term outcomes in adulthood. It is thus a serious public health problem. Methylphenidate (MPH) is recommended as a first-line medication for ADHD in many countries, but the individual treatment response varies . Some patients present good response to MPH with minimal or no symptoms left and optimal functioning (remission) after treatment, while others are poor responders. However, little is known regarding the neural mechanisms underlining heterogeneous responsiveness to MPH. In this prospective, open-label and naturalistic observation study, we plan to use multimodal magnetic resonance imaging (MRI) technology to explore the neural mechanisms of remission in children with ADHD treated with MPH. The baseline multimodal MRI scans of 100 drug-native children with ADHD and 50 normal controls would be collected first. Patients with ADHD are then to be administered osmotic release oral system MPH (OROS-MPH) for 8 weeks. At the end of the 8th week , the response to OROS-MPH would be established and accordingly, the ADHD patients would be subdivided into remission and non-remission groups. The baseline structural and functional brain features of the remission group, which may act as good predictors of treatment response to MPH in ADHD, would be identified. The after-treatment MRI acquisition would be performed afterwards on a subsample of 25 remission ADHD, 25 non-remission ADHD and 25 normal control respectively. The brain structural and functional alterations related with remission in the remission group would be identified by both self-controlled (before and after MPH treatment) and group-wise comparison of MRI data, which would hence reveal the neural mechanisms of MPH treatment related remission in ADHD. We would also focus on the relationships between the structural and functional brain alterations in the cingulo-frontal-parietal cognitive-attention network and the improvement of symptoms in the remission group. The results of this study would contribute to our understanding of the pathophysiology of ADHD, add to the empirical evidences for targeted therapy of ADHD and have a great impact on the improvement of outcome of ADHD.

注意缺陷多动障碍（ADHD）患病率高，结局不良，是重大的公共卫生问题。多国指南均推荐哌甲酯为治疗ADHD的一线药物。但该药个体反应差异大，疗效缓解者，症状基本消失，功能恢复，但部分患者未达缓解。影响哌甲酯治疗缓解的脑机制尚不清楚。本研究采用前瞻性设计，使用多模态磁共振成像（MRI）技术，收集未治疗的100例ADHD和50例对照儿童的MRI数据，经8周哌甲酯缓释片治疗后，根据疗效，将ADHD分为缓解和未缓解组，寻找缓解组特征性的脑结构及功能异常，探讨预测缓解的脑影像学标记；对缓解、未缓解和对照组各25例儿童再次收集MRI数据，通过治疗前后自身对照及组间比较，发现与症状缓解相关的脑结构及功能变化，揭示哌甲酯治疗缓解的脑神经机制，并重点探讨前扣带回-额-顶认知注意网络结构和功能异常及变化在缓解机制中的作用。本研究对深入理解ADHD的神经病理机制，进一步开展靶向治疗，提高疗效，改善预后具有重要意。

注意缺陷多动障碍（ADHD）的一线治疗药物包括哌甲酯及托莫西汀，但个体对于药物的反应差异大，部分患者可达缓解，症状基本消失，部分患者未缓解。目前药物治疗缓解的机制尚不清楚，寻找药物治疗的缓解机制以及预测药物疗效的指标有利于对ADHD进行精准治疗。本研究收集200例未用药的ADHD及50例正常对照儿童的基线资料，并收集75例随访12周的ADHD患者（服用哌甲酯22例，服用托莫西汀27例，未用药26例）的资料。对基线及既往随访资料的分析发现，ADHD存在脑结构共变网络、脑岛、杏仁核及其亚区的功能连接、脑白质发育的对称性等方面的异常，ADHD感觉-运动皮层的与全脑的功能连接水平低于正常儿童，哌甲酯及认知行为训练可以使ADHD的异常脑功能趋于正常化。对于本研究随访数据的初步分析发现，基线状态下感觉-运动皮层及内侧前额叶的功能连接状况分别与托莫西汀治疗三个月后的注意缺陷症状和多动冲动症状改善相关，基线状态下感觉-运动皮层的功能连接缺陷越明显，三个月后的注意缺陷症状改善越好；基线状态下内侧前额叶的功能缺陷越轻，三个月后多动、冲动症状改善越显著。本研究后继分析将从前期发现的脑结构、脑功能等异常的指标中寻找预测药物缓解机制的特征指标，研究结果对于临床用药选择有指导意义，特别是起效慢（3-6周）的托莫西汀，可以更有利于ADHD的精准治疗，节约医疗资源。