个体化精准靶点 rTMS治疗难治性抑郁症动机性快感缺失及脑网络机制研究

Motivational anhedonia is core symptom of treatment resistant depression (TRD). However, the mechanism is unclear and the specific pointed therapy is absent. Based on previous neuroimaging and brain injury study, we hypothesized that the OFC and sgACC is related to motivational anhedonia experience. NAcc is responsible for hedonic seeking. DLPFC integrate information to make motivatonal behavior. OFC and sgACC showed excessive top-down inhibitory effect on NAcc, while the bottom-up driving effect of NAcc to DLPFC was decreased. Firstly, we confirm that motivational anhedonia is important pathogenesis of TRD and the brain network hypothesis according to behavioral and brain network difference between TRD, remitted and health control groups. Secondly, we verify that the left DLPFC is optimal excitatory target of rTMS for motivational anhedonia by comparising therapeutic effect and brain network modification before and after rTMS treatment targeting on DLPFC subregion with individualized accurate positioning. Lastly, we explore that the OFC is the optimal inhibitory target of rTMS for motivational anhedonia by comparing the therepeutic efficacy and brain network modification before and after the rTMS treatment targeting on OFC subregion with individualized accurate positioning. It is important to understand the mechanism of TRD and provide experimental and theoretical evidence of rTMS application in TRD treatment.

动机性快感缺失是难治性抑郁症（TRD）核心症状，但机制不清，缺乏针对性治疗。基于影像学研究结果，提出脑网络假说：眶额叶（OFC）和前扣带回膝部（sgACC）与动机性快感缺失体验有关，伏隔核（NAcc）负责动机性快感寻求，背外侧前额叶（DLPFC）整合信息并作出动机行为。OFC和sgACC至NAcc top-down环路增强，NAcc至DLPFC bottom-up环路减弱。本课题比较TRD、治疗缓解与健康对照组之间行为和影像学差异，探索动机性快感缺失是TRD发病机制，验证脑网络假说；比较个体化精准定位左侧DLPFC rTMS治疗前后临床疗效和脑网络改变，验证左侧DLPFC是rTMS治疗TRD动机性快感缺失有效兴奋靶点；比较个体化精准定位OFC rTMS治疗前后临床疗效和脑网络改变，提出OFC是rTMS治疗TRD动机性快感缺失有效抑制靶点。研究对理解TRD发病机制及rTMS治疗有重要意义。

动机性快感缺失是难治性抑郁症的核心临床症状，但神经机制不清楚，更缺乏发有针对性的治疗方法。基于脑影像研究结果，提出脑网络假设：OFC与动机性快感缺失体验有关，NAcc负责动机性快感寻求，DLPFC整合信息并作出动机性行为。处于top-down上游的OFC对NAcc抑制作用增强。处于bottom-up下游的NAcc至DLPFC的驱动作用减弱。rTMS是治疗难治性抑郁症的理想选择。但仍需解决靶点精确定位和有效靶点选择问题。本研究拟选取难治性抑郁症、重度抑郁症、抑郁症缓解期病人和健康对照组，验证动机性快感缺失是难治性抑郁症的重要发病机制，验证其脑网络假设。选取抑郁症快感缺失患者，观察左侧DLPFC定位方法rTMS对快感缺失症状的疗效和脑网络改变，进一步确定rTMS治疗的个体化精准定位方法是治疗抑郁症动机性快感缺失的有效兴奋性靶点。同时针对OFC靶点采用高精度tDCS技术对抑郁症快感缺失患者和高快感缺失特质正常人进行干预研究，探讨靶点为OFC的tDCS刺激对动机性快感缺失脑网络的调控作用及与临床症状改善的关系，为治疗快感缺失症状选择更有效的刺激靶点和刺激技术提供依据。本研究对理解抑郁症的神经机制有重要的理论意义，也为rTMS和tDCS技术的临床应用提供理论和实验依据。研究发现，以与伏隔核最强功能连接的右侧背外侧前额叶为刺激靶点，结果发现经过15天的rTMS的干预后，真刺激组的患者动机性快感缺失显著改善，假刺激组变化不显著。真刺激干预后动机相关ERP成分cue-N2 和cue-P3出现明显正走向。且cue-N2波幅与TEPS动机性快感缺失量表有显著相关。干预前奖赏与中性条件下的cue-N2差异波可以显著预测动机性快感缺失改善效果。