Trinity College Institute of Neuroscience and School of Psychology, Trinity College Dublin, Dublin, Ireland.
PLoS One. 2011;6(9):e24126. doi: 10.1371/journal.pone.0024126. Epub 2011 Sep 8.
Rising life expectancies coupled with an increasing awareness of age-related cognitive decline have led to the unwarranted use of psychopharmaceuticals, including acetylcholinesterase inhibitors (AChEIs), by significant numbers of healthy older individuals. This trend has developed despite very limited data regarding the effectiveness of such drugs on non-clinical groups and recent work indicates that AChEIs can have negative cognitive effects in healthy populations. For the first time, we use a combination of EEG and simultaneous EEG/fMRI to examine the effects of a commonly prescribed AChEI (donepezil) on cognition in healthy older participants. The short- and long-term impact of donepezil was assessed using two double-blind, placebo-controlled trials. In both cases, we utilised cognitive (paired associates learning (CPAL)) and electrophysiological measures (resting EEG power) that have demonstrated high-sensitivity to age-related cognitive decline. Experiment 1 tested the effects of 5 mg/per day dosage on cognitive and EEG markers at 6-hour, 2-week and 4-week follow-ups. In experiment 2, the same markers were further scrutinised using simultaneous EEG/fMRI after a single 5 mg dose. Experiment 1 found significant negative effects of donepezil on CPAL and resting Alpha and Beta band power. Experiment 2 replicated these results and found additional drug-related increases in the Delta band. EEG/fMRI analyses revealed that these oscillatory differences were associated with activity differences in the left hippocampus (Delta), right frontal-parietal network (Alpha), and default-mode network (Beta). We demonstrate the utility of simple cognitive and EEG measures in evaluating drug responses after acute and chronic donepezil administration. The presentation of previously established markers of age-related cognitive decline indicates that AChEIs can impair cognitive function in healthy older individuals. To our knowledge this is the first study to identify the precise neuroanatomical origins of EEG drug markers using simultaneous EEG/fMRI. The results of this study may be useful for evaluating novel drugs for cognitive enhancement.
随着预期寿命的延长和人们对与年龄相关的认知能力下降的认识不断提高，相当数量的健康老年人不恰当地使用了精神药物，包括乙酰胆碱酯酶抑制剂（AChEIs）。尽管关于此类药物对非临床人群的有效性的数据非常有限，而且最近的研究表明 AChEIs 会对健康人群产生负面影响，但这种趋势仍在发展。我们首次使用 EEG 和同时进行的 EEG/fMRI 来检查一种常用的 AChEI（多奈哌齐）对健康老年人认知的影响。使用两项双盲、安慰剂对照试验评估了多奈哌齐的短期和长期影响。在这两种情况下，我们都利用了对与年龄相关的认知能力下降具有高敏感性的认知（成对关联学习（CPAL））和电生理测量（静息 EEG 功率）。实验 1 测试了每天 5 毫克剂量在 6 小时、2 周和 4 周随访时对认知和 EEG 标志物的影响。在实验 2 中，在单次 5 毫克剂量后，使用同时进行的 EEG/fMRI 进一步检查了相同的标志物。实验 1 发现多奈哌齐对 CPAL 和静息 Alpha 和 Beta 波段功率有显著的负面影响。实验 2 复制了这些结果，并发现 Delta 波段的药物相关增加。EEG/fMRI 分析表明，这些振荡差异与左海马（Delta）、右侧额顶网络（Alpha）和默认模式网络（Beta）的活动差异有关。我们证明了简单的认知和 EEG 测量在评估急性和慢性多奈哌齐给药后的药物反应中的效用。以前建立的与年龄相关的认知能力下降的标志物的呈现表明，AChEIs 可以损害健康老年人的认知功能。据我们所知，这是首次使用同时进行的 EEG/fMRI 来确定 EEG 药物标志物的确切神经解剖起源的研究。这项研究的结果可能有助于评估用于认知增强的新型药物。
