Hernaus Dennis, Casales Santa Marta Ma, Offermann Jan Stefan, Van Amelsvoort Thérèse
University of Maryland School of Medicine, Department of Psychiatry; Maryland Psychiatric Research Center, MD, USA.
Department of Psychiatry and Neuropsychology, South Limburg Mental Health Research and Teaching Network, EURON, School for Mental Health and NeuroScience MHeNS Maastricht University, Maastricht, The Netherlands.
Eur Neuropsychopharmacol. 2017 Apr;27(4):399-410. doi: 10.1016/j.euroneuro.2017.02.004. Epub 2017 Mar 11.
Experimental animal work has demonstrated that dopamine and noradrenaline play an essential role in modulating prefrontal cortex-mediated networks underlying working memory performance. Studies of functional connectivity have been instrumental in extending such notions to humans but, so far, have almost exclusively focussed on pharmacological agents with a predominant dopaminergic mechanism of action. Here, we investigate the effect of a single dose of atomoxetine 60mg, a noradrenaline transporter inhibitor, on working memory performance and associated functional connectivity during an n-back task in 19 healthy male volunteers. Atomoxetine increased functional connectivity between right anterior insula and dorsolateral prefrontal cortex, precentral gyrus, posterior parietal cortex and precuneus during the high-working memory load condition of the n-back task. Increased atomoxetine-induced insula-dorsolateral prefrontal cortex functional connectivity during this condition correlated with decreased reaction time variability and was furthermore predicted by working memory capacity. These results show for the first time that noradrenaline transporter blockade-induced increases in cortical catecholamines accentuate fronto-parietal working memory-related network integrity. The observation of significant inter-subject variability in response to atomoxetine has implications for inverted-U frameworks of dopamine and noradrenaline function, which could be useful to predict drug effects in clinical disorders with variable treatment response.
实验动物研究表明,多巴胺和去甲肾上腺素在调节前额叶皮层介导的工作记忆表现相关网络中起着至关重要的作用。功能连接性研究有助于将这些概念扩展到人类,但到目前为止,几乎完全集中在具有主要多巴胺能作用机制的药物上。在此,我们研究了单剂量60毫克托莫西汀(一种去甲肾上腺素转运体抑制剂)对19名健康男性志愿者在n-back任务期间的工作记忆表现及相关功能连接性的影响。在n-back任务的高工作记忆负荷条件下,托莫西汀增加了右侧前岛叶与背外侧前额叶皮层、中央前回、顶叶后皮层和楔前叶之间的功能连接性。在此条件下,托莫西汀诱导的岛叶-背外侧前额叶皮层功能连接性增加与反应时间变异性降低相关,并且工作记忆容量可对其进行预测。这些结果首次表明,去甲肾上腺素转运体阻断引起的皮质儿茶酚胺增加会增强额顶叶与工作记忆相关的网络完整性。观察到托莫西汀反应存在显著的个体间差异,这对多巴胺和去甲肾上腺素功能的倒U型框架具有启示意义,这可能有助于预测在治疗反应多变的临床疾病中的药物效果。
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