PDSII是什么意思Childhood maltreatment history and attention bias variability in healthy adult women： role of inflammation and the BDNF Val66Met genotype

The main findings can be summarized as follows. In healthy adult women, a history of childhood emotional abuse was significantly associated with ABV whereas none of the maltreatment types was associated with attention bias. Proinflammatory activity as indicated by serum hsTNF-α levels was significantly associated with greater ABV. The BDNF Val66Met polymorphism was associated with ABV in the manner that ABV significantly increased with increasing numbers of the Met allele. We further observed a significant genotype-by-emotional abuse interaction for ABV, such that Met allele carriers with childhood emotional abuse exhibited even greater ABV while this interactive effect was absent in Val/Val homozygotes.

This is the first study, to our knowledge, to examine the association between childhood maltreatment and ABV in a nonclinical population. Our finding of the significant association between childhood emotional abuse and greater ABV is in line with the evidence for PTSD patients^{20,21,25,28,29}. On the other hand, there was no association between childhood maltreatment and attention bias. This seems to be plausible, considering that previous findings of attention bias in trauma-related conditions have been mixed such that attention bias toward threat^{9,13,14,19,79}, away from threat^{16,17,18,22,23,24}, and no bias^15,20,21 have all been reported. In this study of childhood maltreatment, the absence of association for attention bias, together with the significant relationship between emotional abuse and ABV, suggests that the fluctuation in attention bias towards and away from emotional stimuli over time, rather than constant bias in only one direction, better reflects the emotional attention dysfunction associated with childhood (emotional) trauma. In addition, the observed trend-level correlation between ABV and attention ability suggests that ABV can be partially, albeit not totally, accounted for by general attention ability; this result may suggest both validity and uniqueness of this index.

Although not included in our hypothesis, the tripartite correlations between childhood emotional abuse, ABV, and depression led us to further investigate this association using mediation analysis. The result indicated that depressive symptoms could to some extent mediate the relationship between childhood emotional abuse and ABV. This mediation is plausible, considering that childhood abuse increases the risk of depression^2,4 and that depression is associated with biased attention to emotional information³⁶. In line with our finding, attention control training, a treatment shown to improve ABV in PTSD patients^28,80, has been found to ameliorate not only PTSD symptoms but also depressive symptoms^28,80,81. Taken together, it is conceivable that depression can be partly involved in the trauma-related ABV and its treatment mechanism.

Biological factors may underlie the association between childhood trauma and persistent dysregulation in emotional attention. An increasing body of research has demonstrated that childhood maltreatment leaves a lasting impact on stress-related biological systems including the hypothalamic–pituitary–adrenal axis and the inflammatory system⁸². It is proposed that the early trauma-associated alterations in these systems can increase the vulnerability to various psychiatric disorders such as depression and PTSD, as these disorders are also associated with dysregulated glucocorticoid signaling and increased proinflammatory activities^83,84. In this study, we, therefore, examined the three proinflammatory markers in relation to childhood maltreatment and attention bias indices. The results indicated that increased peripheral inflammation as indexed by serum hsTNF-α levels was significantly associated with greater ABV; however, hsTNF-α levels (and the other inflammatory markers) were not significantly correlated with childhood maltreatment. Although the latter result was not what we hypothesized, these results together suggest that TNF-α may be involved in ABV, possibly independently of childhood trauma. It may be that some other psychosocial factors than childhood maltreatment predominantly contributed to the variation in hsTNF-α levels, given that our nonclinical individuals had overall low levels of childhood maltreatment. Although we can only speculate on the reason for the specific association of ABV with hsTNF-α but not with hsCRP or IL-6, this might be related to the fact that TNF-α is a cytokine while CRP is an acute-phase protein. More specifically, studies show that proinflammatory cytokines such as TNF-α and interleukins can have detrimental effects on cognitive function⁸⁵ and that circulating cytokines in the periphery can affect the brain such as through the blood–brain barrier⁸⁶; while the effects of acute-phase proteins on the brain are less clear. IL-6 is also a cytokine, but it can have anti-inflammatory properties as well as proinflammatory ones⁸⁷, which might explain the absence of a clear association with ABV.

Our results on the BDNF Val66Met polymorphism suggest that the Met allele dose-dependently increases ABV and that this effect can at least partly be accounted for by its interaction with childhood emotional abuse. These findings accord with the evidence that the Met allele relates to attention bias^56,57 and that this SNP interacts with childhood trauma to affect cognitive bias and brain morphology^54,88. Supporting this, a functional neuroimaging study demonstrates that this SNP predicts amygdala and anterior hippocampus responses to emotional faces in anxious and depressed adolescents⁸⁹. From a broader perspective, the present finding adds to the growing literature on gene–environment interaction for the development of psychopathology. It may also be worth noting that the minor Met allele frequency in our sample was 0.38, which is similar to the frequency of 0.41 reported in a representative genome variation database of Japanese individuals⁹⁰. In contrast, the frequency of this allele is reported to be ~0.15–0.20 among many other populations such as Europeans, according to the Genome Aggregation Database (gnomAD). This relatively higher Met allele frequency in the present sample enabled us to examine its dose-dependent effect, without combining the Val/Met and Met/Met genotypes into a single group. The present analysis where all the three genotype groups were distinguished also accords with the evidence from animal studies demonstrating a dosage effect of the Met allele⁹¹. On the other hand, our finding warrants further investigations in other ethnic groups since there may be some ethnicity-specific effects of the Met allele⁹¹.

Several limitations need to be considered when interpreting our findings. First, as the cognitive assessment and inflammatory measurement were derived from cross-sectional data at a single time point, their temporal relationships or long-term trajectories remain speculative. Second, as we only included female participants, it is unknown whether the present findings might be specific to women or common to both sexes. The main reason for the focus on female patients was that this study built on our previous studies of childhood maltreatment, cognitive function, memory bias, inflammation, and the BDNF Val66Met polymorphism in women with PTSD^61,92,93,94. In addition, it was necessary to consider potential sex differences in this study, given the evidence for differential psychobiological impacts of childhood maltreatment between sexes⁹⁵ and for sexually dimorphic effects of the BDNF Val66Met polymorphism⁴⁹. Third, while we calculated ABV by using the bins of trial, some recent studies have used the moving average method to calculate it^25,29. Although the latter method may be more sensitive in assessing ABV than the former, both calculation methods measure the same concept (i.e., ABV). In addition, the fact that a significant association was found between childhood emotional abuse and ABV in the present study suggests that ABV obtained by using bins is a sufficiently sensitive index that reflects the effect of childhood maltreatment. Still, it is possible that future studies could benefit from adopting the moving average method to calculate ABV. Fourth, we used a retrospective measure (i.e., the CTQ) to assess childhood maltreatment, which might have biased the results. Finally, this study targeted nonclinical individuals, and therefore its clinical significance remains relatively unclear. Relatedly, the exclusion of participants with psychiatric symptoms may have potentially restricted the range of the association between childhood maltreatment and attention bias/ABV. Indeed, the vast majority of our participants did not report any childhood experience of physical abuse or sexual abuse, suggesting that the nonsignificant results for physical/sexual abuse may be attributable to the very small number of individuals with a history of these two types of maltreatment; while this relatively low frequency of childhood physical/sexual abuse (compared to the other types of maltreatment) among the general population is in agreement with previous reports from Japan in which CTQ was used^96,97. The low maltreatment frequency may have contributed to the lower internal consistency values (i.e., between 0.5 and 0.6) for physical/sexual abuse in our sample as compared to the high values (i.e., between 0.8 and 0.9) for emotional abuse/neglect. The internal consistency value for physical neglect was even lower, which would be attributable not only to the low frequency of this type of maltreatment in our sample but also to the generally lower internal consistency value of this subscale relative to the other four CTQ subscales as reported in previous studies targeting various populations^98,99. Still, however, it is also possible that childhood emotional abuse more markedly influences ABV than do other types of maltreatment, considering that ABV reflects dysfunctional emotional attention processing. Meanwhile, the frequency of emotional neglect was relatively high in our sample, but this maltreatment type was not significantly associated with ABV. Although the reason for these discrepant results between emotional abuse and emotional neglect for ABV is not clear, the former might have a greater (or more direct) influence on this attentional function than the latter.

In summary, this study shows that childhood emotional abuse is associated with greater ABV in healthy adult women, suggesting that the early-life adversity can have a long-term negative impact on emotional attention control. In terms of biological mechanisms, our findings indicate that increased inflammation as indexed by the elevated blood hsTNF-α level may be involved in ABV, possibly independently of childhood maltreatment. Findings further suggest that the relationship between childhood emotional abuse and ABV could be moderated by the BDNF Val66Met polymorphism in the manner that increasing numbers of Met alleles lead to greater ABV by interacting with the emotional abuse. Future studies that examine the association between early-life adversity and ABV among clinical populations, as well as those that investigate the underlying mechanisms, are needed. Efforts will also need to be directed at developing treatments/interventions that target ABV for subclinical and psychiatrically ill individuals.