Anxiety is a leading cause of disability worldwide and is two times more prevalent in female than male populations. Importantly, anxiety is associated with reduced prefrontal cortex (PFC) function in areas critical for cognitive processes such as working memory. Attentional Control Theory (ACT) suggests that worry, a core cognitive feature of anxiety, places an additional load on working memory resources, thereby leading to cognitive impairments and enhanced effort to maintain performance. Ample evidence supports that worry is associated with impaired working memory performance. However, fewer studies have clarified the association between worry and working memory-related neural function. Preclinical models have proposed that anxiety may interact with dopamine and estradiol to influence lateral prefrontal cortex function, a region critical for working memory. However, no study has examined their interactive effects in humans. This project aims to address this gap by examining dopamine and estradiol’s effects on the relationship between worry and oscillatory neural activity (i.e., theta-gamma coupling; TGC) involved in working memory function in a female sample. The study aims are to (1) establish the relationship between worry and TGC; (2) examine the role of tonic dopamine (measured by the COMT gene) in the association between worry and TGC; and (3) examine whether estradiol moderated the association between worry and TGC. I hypothesized two plausible directions for the association between worry and TGC based on previous literature. Research suggests that those with chronic psychiatric conditions evidence less TGC compared to controls due to reduced prefrontal cortex function (i.e., hypoactivation hypothesis). Alternatively, aligned with the predictions of ACT, it is plausible that worry may be related to enhanced TGC indicating exaggerated neural activity to maintain favorable performance (i.e., processing inefficiency hypothesis). For the second aim, I predicted that lower dopamine levels would strengthen the association between worry and TGC, irrespective of the direction of the association. Lastly, I expected the association between worry and TGC to be enhanced when estradiol is low. The sample consisted of 135 female participants who completed a verbal working memory task (N-back) up to four times in-person. Saliva samples on the day of N-back completion were used to assay for estradiol concentrations and extract COMT gene polymorphisms (rs4680). Worry was within- and between-person centered to examine the role of within-person changes in worry over time and between-person differences in worry averaged across a whole menstrual cycle. TGC was computed on correct trials of the N-back task. I found evidence for both the hypoactivation and processing inefficiency hypotheses on two-back lure trials – trials that were of moderate difficulty. Specifically, within-person increases in worry were associated with reduced TGC for those with high average symptoms of worry. In contrast, within-person increases in worry were associated with increased TGC for those with low average levels of worry. I also found that increases in within-person worry were associated with enhanced TGC for Val/Val carriers (those with less tonic dopamine), whereas there was no association for Met/Met carriers. Further, this association was enhanced for Val carriers when estradiol was high. The findings demonstrate that the association between within-person increases in worry and TGC may depend on the amount of worry one experiences on average and tonic dopamine levels. This study further highlights the utility of incorporating dopaminergic neurotransmission in our understanding of worry-related cognitive impairments.
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