低频重复经颅磁刺激对青少年抑郁症患者注意网络影响的磁共振研究

Adolescent major depressive disorder (MDD) is a recurrent and potentially life-threatening illness, affecting as much as 8% of the adolescent population. It is estimated that at least 40% of adolescents with MDD do not show an adequate clinical response to antidepressant. Accordingly, there is increasing interest in developing new treatments for adolescent MDD such as repetitive transcranial magnetic stimulation (rTMS). The use of rTMS as a therapeutic treatment for MDD in adults was approved by the US Food and Drug Administration (FDA) in October of 2008 and safety guildlines for its use have since been established. We are hopeful there will be increased interest in rTMS for adolescent MDD trials particularly in light of evidence suggesting younger subjects with MDD respond better to the treatment than older subjects depression. High-frequency rTMS stimulation of the left dorsolateral prefrontal cortex (DLPFC) may lower the seizure threshold for adolescent MDD. Instead, low-frequency rTMS stimulation of the right DLPFC is chosen which is considered to be relatively safe during treatment of adolescent MDD. Low-frequency rTMS was introduced as a promising new treatment option for adolescent MDD and showed beneficial effects in some studies.A previous study demonstrated that the abnormalities of functional connectivity exist in the attentional network of adolescent depression. We suppose that low-frequency rTMS applied over the right DLPFC results in changes of neuralactivity of attention network, and these brain network activity changes may be one of the potential mechanisms of rTMS. More recently, with the development of the resting state fMRI and diffusion tensor imaging (DTI) technology, the magnetie resonance imaging seems to be a good tool for us to study on brain network connections in MDD. In this study, we analyse the effects of the rTMS treatment on attention network through different view as measured with fMRI and DTI, like the regional brain activity intensity, functional connection among the brain regions, and structure connection of brain regions. The effect of six-week of low-frequency rTMS stimulation of the right DLPFC on attention network in first-episode adolescent MDD was explored, and relative analysis was taken over the comparison on depression symptoms and executive function before and after rTMS treatment, which would derive the possible neural mechanisms of rTMS and further enhance the understanding of neurobiological mechanisms on adolescent MDD.

青少年抑郁症患病率约8%，严重危害青少年心理健康。目前至少40%青少年患者对抗抑郁药疗效欠佳，因此开展新的治疗技术，并探讨相关治疗机理有重要意义。FDA已批准重复经颅磁刺激（rTMS）可用于成人抑郁症治疗。高频刺激可能会降低青少年癫痫阈值，低频刺激更安全。既往研究提示低频rTMS对青少年抑郁治疗有效，青少年抑郁患者注意网络存在异常。我们推测，低频rTMS刺激青少年抑郁症右侧背外侧前额叶（DLPFC）调节异常的注意网络可能是潜在的作用机制之一。本研究以首发青少年抑郁患者为研究对象，运用fMRI和DTI技术，从注意网络的局部脑活动强度、脑区之间的的功能连接，以及脑区之间的结构连接等不同角度进行分析，探讨6周低频rTMS刺激首发青少年抑郁患者右侧DLPFC前后注意网络的变化，并与治疗前后抑郁症状、执行功能变化进行相关分析，揭示rTMS可能的神经作用机制，并加深对青少年抑郁症神经生物机制的了解。

抑郁症是一种常见的严重损害人类健康的情感性精神障碍。与成年期抑郁相比，青少年抑郁共病率(如物质滥用)及自杀风险更高,并且至少40%青少年抑郁患者对抗抑郁药疗效欠佳。因此在青少年抑郁患者中开展新的治疗技术如重复经颅磁刺激(rTMS)并探讨相关作用机理有重要意义。既往的研究和我们的前期工作提示低频rTMS对青少年患者抑郁症状及执行功能有一定的改善作用，然而rTMS的作用机制尚不清楚。有研究表明，青少年抑郁患者注意网络存在异常，因此我们推测，低频rTMS刺激青少年抑郁症患者右侧背外侧前额叶（DLPFC）调节异常的注意网络功能是否是潜在的作用机制之一。本项目研究了低频rTMS刺激首发未服药青少年抑郁症患者右侧DLPFC治疗前后注意网络和认知控制网络功能连接改变，同时结合临床量表和神经心理学评定，进一步探讨治疗前后脑网络的变化与抑郁症状、执行功能变化的关系。研究结果显示：（1）基线时发现青少年抑郁症患者在持续操作测验（CPT）、连线测验(TMT)、Stroop色词测试(SCWT)中表现较正常对照差，表明青少年抑郁症患者认知功能中注意, 信息处理速度和抑制功能受损。（2）基线时与正常对照相比，青少年抑郁症患者注意网络左侧顶内沟与左侧距状沟的功能连接减低，右侧顶内沟与左侧额中回的功能连接减低。右侧顶内沟与左侧额中回功能连接与注意功能呈正相关。青少年抑郁症患者认知控制网络中双侧背外侧前额叶与颞叶、顶叶、额叶及边缘系统的功能连接减弱。左侧背外侧前额叶皮质与右侧额下回的功能连接与疾病严重程度相关，右侧背外侧前额叶皮质与双侧扣带回中部的功能连接与执行功能相关。（3）经6周低频rTMS刺激右侧DLPFC治疗，与接受假性刺激的患者相比，接受真性rTMS治疗的患者在第六周时临床症状缓解更显著（P<0.05)。（4）接受真性rTMS治疗的患者在第六周时在持续操作测验2（CPT2）中表现较基线改善明显（P<0.05)，假性组无明显改变，表明接受真性rTMS治疗的患者注意功能较假性刺激组改善明显。（5）治疗后与正常对照相比青少年抑郁患者注意网络功能连接减低仍存在，治疗前后功能连接强度未发现统计学差异。本项目初步阐明了青少年抑郁症患者注意网络和认知控制网络的特点以及与临床特征和执行功能的关系，为了解rTMS治疗青少年抑郁症的临床疗效及可能的神经网络机制提供了重要的科学证据。