Shanmugan Sheila, Satterthwaite Theodore D, Sammel Mary D, Cao Wen, Ruparel Kosha, Gur Ruben C, Epperson C Neill, Loughead James
Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Penn PROMOTES Research on Sex and Gender in Health, University of Pennsylvania, Philadelphia, PA, USA.
Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Psychoneuroendocrinology. 2017 Oct;84:197-205. doi: 10.1016/j.psyneuen.2017.07.239. Epub 2017 Jul 14.
During the menopause transition, women are at increased risk of subjective symptoms of executive dysfunction. Evidence from animal and human participant studies suggests adverse childhood experiences (ACE) may be a risk factor for executive complaints during this hormonal transition. Preclinical literature indicates early life adversity effects on serotonin function may play a role in this increased susceptibility. However, the mechanisms underlying this increase in vulnerability in human participants remain relatively unknown. Here we examined the impact of ACE and tryptophan depletion (TD), a paradigm used to lower central serotonin levels, on functional network connectivity in discovery and replication datasets. We hypothesized that ACE would be associated with decreased within-network connectivity. We predicted that TD would further lower connectivity in women with high levels of early adversity, but have no effect in women with low levels of early adversity. Forty women underwent two functional imaging sequences at two time points (141 total scans) in a double-blind, placebo controlled, crossover study. The effects of ACE and TD were evaluated using generalized estimating equations (GEE). As predicted, ACE was associated with lower within-network connectivity. While TD had no effect on connectivity in the low ACE group, TD increased connectivity in the high ACE group. The robust effect of ACE remained significant in the replication dataset, though the ACE×TD interaction did not. Together, these results suggest that early life adversity has lasting impacts on large-scale functional networks underlying executive function. Alterations in functional network connectivity may be one mechanism by which early life adversity increases the risk of cognitive disorders during menopause.
在更年期过渡期间，女性出现执行功能障碍主观症状的风险增加。来自动物和人类参与者研究的证据表明，童年不良经历（ACE）可能是这一激素过渡期间执行功能障碍主诉的一个风险因素。临床前文献表明，早年逆境对血清素功能的影响可能在这种易感性增加中起作用。然而，人类参与者中这种易感性增加的潜在机制仍然相对不明。在此，我们在发现和复制数据集中研究了ACE和色氨酸耗竭（TD，一种用于降低中枢血清素水平的范式）对功能网络连通性的影响。我们假设ACE将与网络内连通性降低相关。我们预测TD会进一步降低早年逆境水平高的女性的连通性，但对早年逆境水平低的女性没有影响。在一项双盲、安慰剂对照、交叉研究中，40名女性在两个时间点接受了两个功能成像序列（共141次扫描）。使用广义估计方程（GEE）评估ACE和TD的影响。如预测的那样，ACE与较低的网络内连通性相关。虽然TD对低ACE组的连通性没有影响，但TD增加了高ACE组的连通性。ACE的强大效应在复制数据集中仍然显著，尽管ACE×TD交互作用不显著。总之，这些结果表明，早年逆境对执行功能背后的大规模功能网络有持久影响。功能网络连通性的改变可能是早年逆境增加更年期认知障碍风险的一种机制。
