Cader S, Palace J, Matthews P M
Centre for Functional Magnetic Resonance Imaging of the Brain, University of Oxford, UK.
J Psychopharmacol. 2009 Aug;23(6):686-96. doi: 10.1177/0269881108093271. Epub 2008 Jul 17.
The aim of this study is to define mechanisms underlying the pharmacological effects of brain cholinesterase inhibition on cognitive function in patients with multiple sclerosis (MS). Both a Stroop task and an N-back task were used to probe the changes in brain activity using functional magnetic resonance imaging (fMRI) in a single (investigator)-blind, crossover treatment design studying 15 patients with multiple sclerosis (12 relapsing remitting, 3 secondary progressive) taking rivastigmine (4.5 mg po bid) and domperidone (10 mg po qd) or domperidone alone. Administration of rivastigmine increased Stroop functional magnetic resonance imaging activation in the right inferior frontal gyrus for the Stroop task (P < 0.05, corrected). Incremental functional magnetic resonance imaging activation with progressively greater N-back task difficulty was enhanced by rivastigmine in prefrontal and parietal cortical regions (P < 0.01, ANOVA). Functional connectivity analysis of the N-back functional magnetic resonance imaging data based on correlations between pair-wise interregional activations showed increased connectivity between left to right prefrontal, anterior cingulate to left prefrontal and right parietal to right prefrontal regions with rivastigmine (P < 0.05, corrected). Although there were no statistically significant changes in the neuropsychological task performance with rivastigmine in this small study, 11 of 15 patients showed improvements, whereas only 4 of 15 patients showed decline in performance (P = 0.07). With regard to the previous data, these findings suggest different patterns of brain response to lower dose acute and higher dose chronic administration of rivastigmine in patients with multiple sclerosis. They showed that rivastigmine enhances the prefrontal function and alters the functional connectivity associated with cognition. We interpret this as evidence for greater efficiency of brain information transfer that should increase confidence in a potentially beneficial clinical therapeutic effect.
本研究的目的是确定脑胆碱酯酶抑制对多发性硬化症（MS）患者认知功能产生药理作用的潜在机制。在一项单盲（研究者）、交叉治疗设计中，使用Stroop任务和N-回溯任务，通过功能磁共振成像（fMRI）探究脑活动的变化，该研究纳入了15例多发性硬化症患者（12例复发缓解型，3例继发进展型），他们服用卡巴拉汀（口服，4.5毫克，每日两次）和多潘立酮（口服，10毫克，每日一次）或仅服用多潘立酮。服用卡巴拉汀可增加Stroop任务中右侧额下回的Stroop功能磁共振成像激活（P < 0.05，校正后）。在额叶前部和顶叶皮质区域，随着N-回溯任务难度的逐渐增加，卡巴拉汀增强了功能磁共振成像激活的增量（P < 0.01，方差分析）。基于成对区域间激活之间的相关性对N-回溯功能磁共振成像数据进行功能连接性分析显示，服用卡巴拉汀后，左前额叶与右前额叶、前扣带回与左前额叶以及右顶叶与右前额叶区域之间的连接性增加（P < 0.05，校正后）。尽管在这项小型研究中，服用卡巴拉汀后神经心理学任务表现没有统计学上的显著变化，但15例患者中有11例表现有所改善，而15例患者中只有4例表现下降（P = 0.07）。结合之前的数据，这些发现表明，多发性硬化症患者对低剂量急性和高剂量慢性服用卡巴拉汀的脑反应模式不同。结果显示，卡巴拉汀可增强前额叶功能并改变与认知相关的功能连接性。我们将此解释为脑信息传递效率提高的证据，这应该会增加对潜在有益临床治疗效果的信心。
