Chau C M Y, Cepeda I L, Devlin A M, Weinberg J, Grunau R E
Developmental Neurosciences and Child Health, Child & Family Research Institute, Vancouver, BC, Canada; Pediatrics, University of British Columbia, Vancouver, BC, Canada.
Cellular & Physiological Sciences, University of British Columbia, Vancouver, BC, Canada.
Neuroscience. 2017 Feb 7;342:188-199. doi: 10.1016/j.neuroscience.2015.08.044. Epub 2015 Aug 28.
Early stress in the form of repetitive neonatal pain, in infants born very preterm, is associated with long-term dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and with poorer cognitive performance. Brain-derived neurotrophic factor (BDNF) which is important in synaptic plasticity and cognitive functions is reduced by stress. Therefore the BDNF Val66Met variant, which affects secretion of BDNF, may interact with early exposure to pain-related stress in children born very preterm, to differentially affect HPA regulation that in turn may be associated with altered cognitive performance. The aims of this study were to investigate whether in children born very preterm, the BDNF Val66Met variant modulates the association between neonatal pain-related stress and cortisol levels at age 7years, and if cortisol levels were related to cognitive function. Furthermore, we examined whether these relationships were sex-specific. Using a longitudinal cohort design, N=90 children born very preterm (24-32weeks gestation) were followed from birth to age 7years. Cortisol was assayed from hair as an index of cumulative stress and from saliva to measure reactivity to a cognitive challenge. BDNF Val66Met variant was genotyped at 7years using real-time polymerase chain reaction (PCR). Using generalized linear modeling, in boys with the Met allele, greater neonatal pain-related stress (adjusted for clinical risk factors) predicted lower hair cortisol (p=0.006) and higher reactivity salivary cortisol (p=0.002). In both boys and girls with the Met allele, higher salivary cortisol reactivity was correlated with lower IQ (r=-0.60; p=0.001) and poorer visual-motor integration (r=-0.48; p=0.008). Our findings show associations between lower BDNF availability (presence of the Met allele) and vulnerability to neonatal pain/stress in boys, but not girls. This exploratory study suggests new directions for research into possible mechanisms underlying how neonatal pain/stress is related to cognitive performance in children born very preterm.
对于极早产儿而言，重复性新生儿疼痛这种早期应激形式与下丘脑-垂体-肾上腺（HPA）轴的长期失调以及较差的认知表现相关。在突触可塑性和认知功能中起重要作用的脑源性神经营养因子（BDNF）会因应激而减少。因此，影响BDNF分泌的BDNF Val66Met变异体可能与极早产儿早期暴露于疼痛相关应激相互作用，从而对HPA调节产生不同影响，而这反过来可能与认知表现改变有关。本研究的目的是调查在极早产儿中，BDNF Val66Met变异体是否调节新生儿疼痛相关应激与7岁时皮质醇水平之间的关联，以及皮质醇水平是否与认知功能相关。此外，我们还研究了这些关系是否存在性别特异性。采用纵向队列设计，对90名极早产儿（孕周24 - 32周）从出生随访至7岁。通过检测头发中的皮质醇作为累积应激指标，检测唾液中的皮质醇以测量对认知挑战的反应性。在7岁时使用实时聚合酶链反应（PCR）对BDNF Val66Met变异体进行基因分型。使用广义线性模型，在携带Met等位基因的男孩中，更高的新生儿疼痛相关应激（经临床风险因素校正）预示着更低的头发皮质醇水平（p = 0.006）和更高的唾液皮质醇反应性（p = 0.002）。在携带Met等位基因的男孩和女孩中，更高的唾液皮质醇反应性均与更低的智商（r = -0.60；p = 0.001）和更差的视动整合能力（r = -0.48；p = 0.008）相关。我们的研究结果表明，BDNF可用性降低（存在Met等位基因）与男孩而非女孩的新生儿疼痛/应激易感性之间存在关联。这项探索性研究为极早产儿中新生儿疼痛/应激与认知表现之间潜在机制的研究提供了新的方向。
