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多巴胺受体激动剂对轻度帕金森病患者序列工作记忆的影响
Alternative TitleThe Effect of Dopamine Receptor Agonists in Sequential Working Memory in mild Parkinson’s Disease
张冠宇
Contributor叶铮
2021-06
Abstract在十几秒到几十秒的时间内对序列信息进行保持和更新在日常生活中至关重要,即序列工作记忆。帕金森病(Parkinson’s disease,PD)作为常见的中老年人神经退行性疾病,不仅是运动障碍病,还会出现认知障碍等非运动症状。前人研究发现,PD 患者在序列工作记忆中的信息操作过程上出现损伤,而非在信息保持上。本研究将结合神经心理评估、神经影像和药物干预等研究手段,探究帕金森患者序列工作记忆中信息操作的神经机制。 研究一探究PD 患者序列工作记忆损伤的特点,包括实验1a 和实验1b。在实验1a 中,48 名新发未用药的PD 患者和50 名健康对照者完成了数字顺背测验和数字序背测验。在数字顺背测验中,被试需要按照原有顺序回忆数字,而在数字序背测验中,被试需要按照从小到大的顺序回忆数字。数字序背测验和数字顺背测验的对比强调了数字信息的操作过程(排序)。与健康对照者相比,PD 患者在数字序背测验中的得分显著降低,在数字顺背测验中的得分没有显著差异。对错误回答进行分类发现,在数字序背测验中,PD 患者比健康对照者产生更多的移位错误;在移位错误中,PD 患者又比健康对照者产生更多的前移错误。这说明PD 患者在序列排序中更倾向于过早地回忆某个项目。此外,PD 患者的移位错误发生率与日常生活中非运动症状严重程度成正比。在实验1b 中,结合功能磁共振成像技术,47 名新发未用药的PD 患者和47 名健康对照者完成了计算机化的数字序背任务。任务要求他们按照从小到大的顺序记忆数字。在“单纯回忆”条件中,数字是按照从小到大的顺序呈现的,被试只需要按照原有顺序记住它们。在“排序且回忆”条件中,数字是完全打乱呈现的,被试需要按照从小到大的顺序重新排列数字并记住它们。与健康对照者相比,PD 患者在序列工作记忆任务中的准确率显著降低,反应时间显著增长。PD 患者的排序代价(排序且回忆条件与单纯回忆条件的正确率/反应时差异)与日常生活中非运动症状的严重程度成正比。实验发现,“排序且回忆”条件比“单纯回忆”条件激活水平更高的脑区有后顶叶皮层,前额叶皮层,前运动皮层,丘脑底核(subthalamic nucleus,STN),丘脑,尾状核和小脑,而负激活水平更高的脑区有内侧前额叶皮层和后扣带回皮层(默认网络)。与单纯回忆条件相比,PD患者排序且回忆条件下的STN 和背外侧前额叶(dorsolateral prefrontal cortex,dlPFC)激活水平比健康对照者更高,而且STN 激活水平或功能连接只能预测单纯回忆条件的正确率,无法预测排序相关的正确率变化。说明STN 功能障碍可以预测轻度PD 患者序列工作记忆缺陷。 研究二探索多巴胺能药物对序列工作记忆行为及相关大脑活动的影响,包括实验2a 和实验2b。在实验2a 中,40 名轻度PD 患者和40 名健康对照者完成了计算机化的数字序背任务。在实验1b 的基础上,本实验结合鼠标追踪技术,分离了实际运动之前的认知过程以及运动准备过程的认知层面和实际运动的执行过程,记录了思考时间、排序时间、移动时间和移动轨迹曲线下的面积。实验发现,PD 患者比健康对照者的思考时间更长,移动时间更长,移动轨迹更受限。单纯回忆条件下的思考时间与左旋多巴的每日用药剂量呈负相关。排序时间与多巴胺D2/3 受体激动剂的每日用药剂量呈负相关。实验说明,在PD 患者中,刺激多巴胺D1 和D2/3 受体可能分别加快对序列信息的保持和操作。在实验2b 中,21 名新发PD 患者在服药前和持续用药4-6 周后都完成了与实验1b相同的计算机化的数字序背任务。与服药前相比,服用多巴胺D2/3 受体激动剂(普拉克索)后运动症状得到明显改善,数字序背任务的正确率明显提高,并且,排序且回忆条件下默认网络的负激活水平更高。患者存在较大的个体差异:运动症状改善得越明显,默认网络(尤其是楔前叶)负激活水平越高的PD 患者,在排序且回忆条件下的正确率提高得越多。说明多巴胺D2/3 受体激动剂可能是通过增强默认网络的负激活水平来提高排序正确率的。 综上所述,本研究发现在轻度PD 患者中,序列工作记忆的操作和更新已经受损,表现在数字排序测验得分低,数字序背任务正确率低。受损程度与非运动症状严重程度成正比。在宏观脑活动水平上,序列工作记忆与基底节和前额叶的功能障碍有关,表现为STN 与dlPFC 的激活水平更高。从临床干预的角度,多巴胺D2/3 受体激动剂可能通过增强默认网络的负激活水平来提高PD 患者序列工作记忆任务表现。
Other AbstractThe ability to maintain and manipulate sequential information in a short period of time is crucial in our daily life, namely sequential working memory. As a common neurodegenerative disease in elderly adults, Parkinson's disease (PD) has motor symptoms as well as non-motor symptoms such as cognitive impairment. Previous studies found that PD patients were impaired in information manipulation in sequential working memory, even when information maintenance is well preserved. This study is aimed to investigate the neural mechanism of information manipulation in sequential working memory in PD patients, using neuropsychological tests, neuroimaging, and pharmacological intervention. Study 1 demonstrated the characteristics of PD patients’ deficits in sequential working memory (Experiment 1a and Experiment 1b). In Experiment 1a, 48 newly diagnosed and untreated PD patients and 50 healthy controls completed the digit span forward and adaptive digit ordering tests. Participants were asked to recall the digits in the original and ascending order in these two neuropsychological tests, respectively. The contrast between the digit span forward and digit ordering tests emphasizes the manipulation of sequences (ordering). PD patients scored lower than healthy controls in the adaptive digit ordering test, but not in the digit span forward test. We classified the error responses into different types. In the adaptive digit ordering test, PD patients produced more transposition errors than healthy controls particularly anticipation errors. It suggests that PD patients are more likely to recall items too early in sequential ordering. In PD patients, the rate of transposition errors positively correlated with the severity of non-motor symptoms in daily life. In Experiment 1b, 47 newly diagnosed and untreated PD patients and 47 healthy controls completed a computerized digit ordering task during functional magnetic resonance imaging (fMRI) scanning. They were asked to memorize the digits in ascending order. In “pure recall” trials, the digits were presented in ascending order and there was no need to reorder them. In “reorder & recall” trials, the digits were randomized and participants had to reorder them. PD patients performed worse than healthy controls with lower accuracy and longer response times. In PD patients, ordering-related accuracy/reaction time cost (reorder & recall vs pure recall) positively correlated with the severity of non-motor symptoms in daily life. Regional activations were greater for “reorder & recall” than “pure recall” trials in the posterior parietal cortex, prefrontal cortex, premotor cortex, subthalamic nucleus, thalamus, caudate nucleus and cerebellum. Regional deactivations were greater for “pure recall” than “reorder & recall” trials in the medial prefrontal cortex and posterior cingulate cortex (default mode network). Compared with “pure recall” trials, the subthalamic nucleus and dorsolateral prefrontal cortex were more activated in “reorder & recall” trials in PD patients than healthy controls. The accuracy of “pure recall” trials could be predicted by the functional connectivity of subthalamic nucleus. However, ordering-related accuracy change (reorder & recall vs pure recall) could not be predicted by the activation or functional connectivity of subthalamic nucleus. It suggests that the dysfunction of subthalamic nucleus may be the neural markers of sequential working memory deficits in mild PD. Study 2 investigated the effects of dopaminergic drugs on behavior and related brain activities of sequential working memory (Experiment 2a and Experiment 2b). In Experiment 2a, 40 patients with mild PD and 40 healthy controls completed a computerized digit ordering task. The task used in Experiment 2a was combined with the mouse tracking technique to separate the cognitive processes and cognitive aspects of motor programming before the actual movement and the execution processes of the actual movement. The initiation time, ordering time, movement time, and area under the movement trajectory curve were estimated. PD patients showed longer initiation time, longer movement time, and more constrained movement trajectories than healthy controls. The initiation time of “pure recall” trials negatively correlated with the daily exposure to actual levodopa dose. The ordering time negatively correlated with levodopa equivalent dose for dopamine D2/3 receptor agonists. It suggests that stimulating dopamine D1 and D2/3 receptors might speed up the maintenance and manipulation of sequences, respectively. In Experiment 2b, 21 newly diagnosed and untreated PD patients completed the computerized digit ordering task combined with fMRI before and after 4-6 weeks of medical therapy with a selective D2/3 receptor agonist (pramipexole). After taking pramipexole, the severity of motor symptom of PD patients was decreased and task accuracy was improved, in addition, the deactivation in the default mode network was greater in “reorder & recall” trials. There are significant individual differences that patients with more improved motor symptom and more deactivated default mode network (particularly precuneus) showed higher accuracy improvement in “reorder & recall” trials. It suggests that dopamine D2/3 receptor agonist may improve the ordering accuracy by hyper-deactivation of the default mode network. In conclusion, this study found that the manipulation of sequences was impaired even in mild PD patients with lower score and accuracy in digit ordering test/task. The impairment positively correlated with the severity of non-motor symptoms in daily life. At brain level, it correlated with the hyper-activity of subthalamic nucleus and dorsolateral prefrontal cortex. After treating with pramipexole, the patients’ task performances were enhanced. It may due to hyper-deactivation of the default mode network.
Keyword序列工作记忆 帕金森病 多巴胺D2/3 受体 前额叶 丘脑底核
Subtype博士
Language中文
Degree Name理学博士
Degree Discipline基础心理学
Degree Grantor中国科学院心理研究所
Place of Conferral中国科学院心理研究所
Document Type学位论文
Identifierhttp://ir.psych.ac.cn/handle/311026/39549
Collection认知与发展心理学研究室
Recommended Citation
GB/T 7714
张冠宇. 多巴胺受体激动剂对轻度帕金森病患者序列工作记忆的影响[D]. 中国科学院心理研究所. 中国科学院心理研究所,2021.
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