Estradiol and the Catechol-o-methyltransferase Gene Interact to Predict Working Memory Performance: A Replication and Extension.

Decades of evidence across taxa have established the importance of dopamine (DA) signaling in the pFC for successful working memory performance. Genetic and hormonal factors can shape individual differences in prefrontal DA tone. The catechol-o-methyltransferase (COMT) gene regulates basal prefrontal DA, and the sex hormone 17ß-estradiol potentiates DA release. E. Jacobs and M. D'Esposito [Estrogen shapes dopamine-dependent cognitive processes: Implications for women's health. Journal of Neuroscience, 31, 5286-5293, 2011] investigated the moderating role of estradiol on cognition using the COMT gene and COMT enzymatic activity as a proxy for pFC DA tone. They found that increases in 17ß-estradiol within women at two time points during the menstrual cycle influenced working memory performance in a COMT-dependent manner. Here, we aimed to replicate and extend the behavioral findings of Jacobs and D'Esposito by employing an intensive repeated-measures design across a full menstrual cycle. Our results replicated the original investigation. Within-person increases in estradiol were associated with improved performance on 2-back lure trials for participants with low basal levels of DA (Val/Val carriers). The association was in the opposite direction for participants with higher basal levels of DA (Met/Met carriers). Our findings support the role of estrogen in DA-related cognitive functions and further highlight the need to consider gonadal hormones in cognitive science research.

Benefits of adaptive cognitive training on cognitive abilities in women treated for primary breast cancer: Findings from a 1-year randomised control trial intervention.

OBJECTIVE: While adaptive cognitive training is beneficial for women with a breast cancer diagnosis, transfer effects of training benefits on perceived and objective measures of cognition are not substantiated. We investigated the transfer effects of online adaptive cognitive training (dual n-back training) on subjective and objective cognitive markers in a longitudinal design. METHODS: Women with a primary diagnosis of breast cancer completed 12 sessions of adaptive cognitive training or active control training over 2 weeks. Objective assessments of working memory capacity (WMC), as well as performance on a response inhibition task, were taken while electrophysiological measures were recorded. Self-reported measures of cognitive and emotional health were collected pre-training, post-training, 6-month, and at 1-year follow-up times. RESULTS: Adaptive cognitive training resulted in greater WMC on the Change Detection Task and improved cognitive efficiency on the Flanker task together with improvements in perceived cognitive ability and depression at 1-year post-training. CONCLUSIONS: Adaptive cognitive training can improve cognitive abilities with implications for long-term cognitive health in survivorship.

Investigating interactive effects of worry and the catechol-o-methyltransferase gene (COMT) on working memory performance.

Extant research indicates that worry is associated with reduced working memory. It remains unclear, however, what mechanisms contribute to impaired performance in worriers. Critically, dopamine in the prefrontal cortex heavily influences the stability of mental representations during working memory tasks, yet no research has probed its role in associations between worry and working memory. To address this gap, the current study was designed to examine the moderating role of dopamine on the association between worry and working memory, using the catechol-o-methyltransferase (COMT) gene as a proxy for basal levels of dopamine. Across four assessments, we examined within- and between-person variation in worry and its interactive effects with COMT to predict working memory performance. Within-person variation in worry interacted with COMT to predict accuracy, such that higher worry across time predicted less accuracy for homozygous Val carriers but not Met carriers. Our findings demonstrate that basal dopamine plays an important role in how increases in worry across time for an individual negatively impact working memory performance.

Errors elicit frontoparietal theta-gamma coupling that is modulated by endogenous estradiol levels.

Cognitive control-related error monitoring is intimately involved in behavioral adaptation, learning, and individual differences in a variety of psychological traits and disorders. Accumulating evidence suggests that a focus on women's health and ovarian hormones is critical to the study of such cognitive brain functions. Here we sought to identify a novel index of error monitoring using a time-frequency based phase amplitude coupling (t-f PAC) measure and examine its modulation by endogenous levels of estradiol in females. Forty-three healthy, naturally cycling young adult females completed a flanker task while continuous electroencephalogram was recorded on four occasions across the menstrual cycle. Results revealed significant error-related t-f PAC between theta phase generated in fronto-central areas and gamma amplitude generated in parietal-occipital areas. Moreover, this error-related theta-gamma coupling was enhanced by endogenous levels of estradiol both within females across the cycle as well as between females with higher levels of average circulating estradiol. While the role of frontal midline theta in error processing is well documented, this paper extends the extant literature by illustrating that error monitoring involves the coordination between multiple distributed systems with the slow midline theta activity modulating the power of gamma-band oscillatory activity in parietal regions. They further show enhancement of inter-regional coupling by endogenous estradiol levels, consistent with research indicating modulation of cognitive control neural functions by the endocrine system in females. Together, this work identifies a novel neurophysiological marker of cognitive control-related error monitoring in females that has implications for neuroscience and women's health.

Examining a window of vulnerability for affective symptoms in the mid-luteal phase of the menstrual cycle.

Particular phases of the menstrual cycle may exacerbate affective symptoms for females with a diagnosed mental health disorder. However, there are mixed findings regarding whether affective symptoms change across the menstrual cycle in females without a clinical diagnosis. The window of vulnerability model proposes that natural increases in ovarian hormones in the mid-luteal phase of the menstrual cycle lead to systematic changes in brain networks associated with affective processing. Consequently, the model posits that females may experience stress more intensely and remember negative events more readily in the mid-luteal phase, increasing their risk for higher affective symptoms. Using a 35-day longitudinal study design, we tested the window of vulnerability model in a non-clinical sample. We tracked naturally cycling females' daily stress and three types of affective symptoms: anxious apprehension, anxious arousal, and anhedonic depression. Using multilevel modeling, we simultaneously modeled within- and between-person associations among stress and menstrual phase for each affective symptom. We found increased anhedonic depression in the mid-luteal phase but not anxious apprehension or anxious arousal. Moreover, we detected a positive association between within- and between-person stress and anxious apprehension and anhedonic depression, but not anxious arousal. These associations were not stronger in the mid-luteal phase. Overall, we provide weak evidence for a window of vulnerability for affective symptoms in the mid-luteal phase of the menstrual cycle. Our findings suggest that stress is a better predictor of fluctuations in affective symptoms than the menstrual cycle. Moreover, our findings highlight the importance of measuring multiple negative affective symptoms because they may be differentially related to stress and the menstrual cycle.

Hormonal contraceptive use moderates the association between worry and error-related brain activity.

Uncovering mechanisms that can help explain the experience and impact of anxiety in women is important for improving etiological models and treatments to meet the needs of unique individuals. An enlarged error-related negativity (ERN) - an electrophysiological marker of cognitive control-related error monitoring- represents one indicator of neural processes more strongly related to anxiety in women than men. In this study, we further examined this association in women by testing the moderating effect of hormonal contraceptive (HC) use on the relationship between worry - i.e., a transdiagnostic cognitive dimension of anxiety - and the ERN. Results revealed that HCs moderated the worry-ERN association. Specifically, we found a significant and large relationship between worry and enlarged ERN in women using HCs, which was smaller and nonsignificant in naturally cycling women (i.e., those not using HCs). These findings suggest that the interplay among HC use, error-related cognitive control, and worry represents a novel mechanism for better characterizing the expression and impact of worry in women.

An electrophysiological investigation on the emotion regulatory mechanisms of brief open monitoring meditation in novice non-meditators.

Despite a growing literature supporting the salutary effects of mindfulness meditation on emotion regulation, the underlying mechanisms linking neural and subjective changes occurring during the actual practice of meditation with emotion regulatory effects observed after meditation remains virtually unexplored. The current study sought to address this gap in knowledge by testing the hypothesis that adoption of internally-directed focused attention, indexed by increased alpha and theta spectral power, during brief open monitoring (OM) mindfulness meditation predicts reduced emotional reactivity, as measured by the late positive potential (LPP). Results revealed that the OM meditation did not produce demonstrable differences in alpha and theta power but did increase self-reported sleepiness relative to controls. Follow-up analyses showed that sleepiness uniquely moderated the effect of meditation on the LPP, such that less sleepiness during meditation, but not the control audio, corresponded to smaller LPPs to negative images. Change in theta, but not alpha power, between meditation and rest was positively correlated with the LPP even after controlling for sleepiness. Although the primary hypothesis was unsupported, the findings demonstrate that phenomenological and neural changes occurring during OM meditation may modulate its subsequent "off-the-cushion" effects on emotional reactivity.