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.

Determining menstrual cycle phase: An empirical examination of methodologies and recommendations for improvement in behavioral and brain sciences.

The recent decade has brought an exciting proliferation of behavioral, psychological and neuroscientific research involving the menstrual cycle. However, the reliability and validity of many popular methodologies for determining menstrual cycle phase lack empirical examination. These under-investigated methods include: (1) predicting menstrual cycle phase using self-report information only (e.g., "count" methods), (2) utilizing ovarian hormone ranges to determine menstrual cycle phase, and (3) using ovarian hormone changes from limited measurements (e.g., two time points) to determine menstrual cycle phase. In the current study, we examine the accuracy of these methods for menstrual cycle phase determination using 35-day within-person assessments of circulating ovarian hormones from 96 females across the menstrual cycle. Findings indicate that all three common methods are error-prone, resulting in phases being incorrectly determined for many participants, with Cohen's kappa estimates ranging from -0.13 to 0.53 indicating disagreement to only moderate agreement depending on the comparison. Such methodological challenges are surmountable through careful study design, more frequent hormone assays (when possible), and utilization of sophisticated statistical methods. With increased methodological rigor in behavioral, psychological and neuroscientific research, the field will be poised to detect biobehavioral correlates of ovarian hormone fluctuations for the betterment of the mental health and wellbeing of millions of females.

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.

A neurocognitive account of attentional control theory: how does trait anxiety affect the brain's attentional networks?

Attentional control theory (ACT) was proposed to account for trait anxiety's effects on cognitive performance. According to ACT, impaired processing efficiency in high anxiety is mediated through inefficient executive processes that are needed for effective attentional control. Here we review the central assumptions and predictions of ACT within the context of more recent empirical evidence from neuroimaging studies. We then attempt to provide an account of ACT within a framework of the relevant cognitive processes and their associated neural mechanisms and networks, particularly the fronto-parietal, cingular-opercula, and default mode networks. Future research directions, including whether a neuroscience-informed model of ACT can provide a platform for novel neurocognitive intervention for anxiety, are also discussed.

Targeting cognitive control to reduce anxiety in very young children: A proof of concept study.

OBJECTIVE: Underdeveloped cognitive control (CC)-the capacity to flexibly adjust to changing environments-may predispose some children to early onset anxiety disorders and represents a promising intervention target. The current study established and pilot-tested "Camp Kidpower"-a novel group-based, interactive CC training intervention-and assessed its impacts on behavioral and neurophysiological indices of CC among preschool children with elevated anxiety symptoms. METHODS: Forty-four anxious children (4-6 years) were enrolled in Camp Kidpower, delivered in four sessions over 10 days. Before and after camp, children's capacity for CC was measured using well-validated, non-trained behavioral tasks and error-related negativity (ERN). Child anxiety symptoms were measured by parent report on the Spence Preschool Anxiety Scale. RESULTS: Thirty-two children completed the study, as defined by completion of pre- and follow-up assessments and at least three camp sessions. From baseline to after camp, performance on behavioral tests of CC improved, ERN amplitude increased, and anxiety symptoms decreased. CONCLUSION: Results provide initial evidence that play-based cognitive training targeted to behavioral and brain markers of CC reduces anxiety in preschoolers.

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.

Conducting EEG research in clinically anxious preschoolers: A pilot study and preliminary recommendations.

Electroencephalography (EEG) data collection can be challenging in preschoolers with anxiety who are often debilitated by fear of the unknown. Thus, we iteratively refined techniques for EEG collection in three cohorts of children with anxiety enrolled in our study of a novel intervention. Techniques involved directing child attention away from the EEG setup (Cohort 1, N = 18), open discussion of equipment and processes during setup (Cohort 2, N = 21), and a preparatory EEG-exposure session prior to data collection (Cohort 3, N = 6). Children (N = 45, 4-7 years) attempted a Time 1 EEG before intervention, and those who completed intervention (N = 28) were invited to a Time 2 EEG. The percentages who provided analyzable EEGs were assessed by cohort. Cohort 3 provided more Time 1 EEGs (83.3%) than Cohorts 1 or 2 (66.7% each), suggesting that the preparatory session supported first-time EEG collection. More children provided Time 2 EEG data across successive cohorts (Cohort 1: 66.7%, Cohort 2: 82%, Cohort 3: 100%), suggesting that more open communication facilitated repeat EEG collection. Ultimately, increased EEG exposure and child-friendly communication about procedures improved data acquisition in this sample of clinically anxious preschoolers. Detailed study procedures are shared to support future EEG research in young children with anxiety.

Startle to neutral, not negative stimuli: A neurophysiological correlate of behavioral inhibition in young children.

A putative biomarker of anxiety risk, the startle response is typically enhanced by negative compared to neutral emotion modulation in adults, but remains understudied in children. To determine the extent to which neutral, negative, and positively valenced emotional conditions modulate startle response in early life, a child-friendly film paradigm was used to vary emotion across these conditions during startle induction in sixty-four 4- to 7-year-old children. Association of emotion-modulated startle with parent-reported anxiety symptom severity and child behavioral inhibition, a risk factor for anxiety problems, were assessed. Analyses revealed no difference in startle magnitude during negative compared to neutral film clips. By contrast, startle during both negative and neutral conditions was greater than startle during the positive condition. Larger startle magnitude during the neutral condition associated with higher levels of child behavioral inhibition (BI). These results are consistent with possible immaturity of startle response in young children, and suggest that startle amplitude in more emotionally ambiguous, neutral conditions could serve as an early biomarker for anxiety risk.

Conducting Event-Related Potential (ERP) Research with Young Children: A Review of Components, Special Considerations and Recommendations for Research on Cognition and Emotion.

There has been an unprecedented increase in the number of research studies employing event-related potential (ERP) techniques to examine dynamic and rapidly-occurring neural processes with children during the preschool and early childhood years. Despite this, there has been little discussion of the methodological and procedural differences that exist for studies of young children versus older children and adults. That is, reviewers, editors, and consumers of this work often expect developmental studies to simply apply adult techniques and procedures to younger samples. Procedurally, this creates unrealistic expectations for research paradigms, data collection, and data reduction and analyses. Scientifically, this leads to inappropriate measures and methods that hinder drawing conclusions and advancing theory. Based on ERP work with preschoolers and young children from 10 laboratories across North America, we present a summary of the most common ERP components under study in the area of emotion and cognition in young children along with 13 realistic expectations for data collection and loss, laboratory procedures and paradigms, data processing, ERP averaging, and typical challenges for conducting this type of work. This work is intended to supplement previous guidelines for work with adults and offer insights to aid researchers, reviewers, and editors in the design and evaluation of developmental research using ERPs. Here we make recommendations for researchers who plan to conduct or who are conducting ERP studies in children between ages 2 and 12, focusing on studies of toddlers and preschoolers. Recommendations are based on both data and our cumulative experience and include guidelines for laboratory setup, equipment and recording settings, task design, and data processing.

Intelligence and Neurophysiological Markers of Error Monitoring Relate to Children's Intellectual Humility.

This study explored developmental and individual differences in intellectual humility (IH) among 127 children ages 6-8. IH was operationalized as children's assessment of their knowledge and willingness to delegate scientific questions to experts. Children completed measures of IH, theory of mind, motivational framework, and intelligence, and neurophysiological measures indexing early (error-related negativity [ERN]) and later (error positivity [Pe]) error-monitoring processes related to cognitive control. Children's knowledge self-assessment correlated with question delegation, and older children showed greater IH than younger children. Greater IH was associated with higher intelligence but not with social cognition or motivational framework. ERN related to self-assessment, whereas Pe related to question delegation. Thus, children show separable epistemic and social components of IH that may differentially contribute to metacognition and learning.

Using person-specific neural networks to characterize heterogeneity in eating disorders: Illustrative links between emotional eating and ovarian hormones.

OBJECTIVE: Emotional eating has been linked to ovarian hormone functioning, but no studies to-date have considered the role of brain function. This knowledge gap may stem from methodological challenges: Data are heterogeneous, violating assumptions of homogeneity made by between-subjects analyses. The primary aim of this paper is to describe an innovative within-subjects analysis that models heterogeneity and has potential for filling knowledge gaps in eating disorder research. We illustrate its utility in an application to pilot neuroimaging, hormone, and emotional eating data across the menstrual cycle. METHOD: Group iterative multiple model estimation (GIMME) is a person-specific network approach for estimating sample-, subgroup-, and individual-level connections between brain regions. To illustrate its potential for eating disorder research, we apply it to pilot data from 10 female twins (N = 5 pairs) discordant for emotional eating and/or anxiety, who provided two resting state fMRI scans and hormone assays. We then demonstrate how the multimodal data can be linked in multilevel models. RESULTS: GIMME generated person-specific neural networks that contained connections common across the sample, shared between co-twins, and unique to individuals. Illustrative analyses revealed positive relations between hormones and default mode connectivity strength for control twins, but no relations for their co-twins who engage in emotional eating or who had anxiety. DISCUSSION: This paper showcases the value of person-specific neuroimaging network analysis and its multimodal associations in the study of heterogeneous biopsychosocial phenomena, such as eating behavior.

Playing with fire: effects of negative mood induction and working memory on vocabulary acquisition.

We investigated the impact of emotions on learning vocabulary in an unfamiliar language to better understand affective influences in foreign language acquisition. Seventy native English speakers learned new vocabulary in either a negative or a neutral emotional state. Participants also completed two sets of working memory tasks to examine the potential mediating role of working memory. Results revealed that participants exposed to negative stimuli exhibited difficulty in retrieving and correctly pairing English words with Indonesian words, as reflected in a lower performance on the prompted recall tests and the free recall measure. Emotional induction did not change working memory scores from pre to post manipulation. This suggests working memory could not explain the reduced vocabulary learning in the negative group. We argue that negative mood can adversely affect language learning by suppressing aspects of native-language processing and impeding form-meaning mapping with second language words.

The color of anxiety: neurobehavioral evidence for distraction by perceptually salient stimuli in anxiety.

Anxiety is reliably associated with an attentional bias favoring threatening information which is thought to be a key mechanism in the etiology and maintenance of anxious pathology. However, whether and how anxiety is related to attentional capture at a more basic level (i.e., in the absence of threat) is less well understood. To address this gap in the literature, we examined the association between anxiety and attentional capture in the context of visually salient, yet affectively neutral, stimuli. Specifically, we used a visual search task in which participants were required to locate a target while ignoring a salient distractor stimulus. A total of 122 undergraduates-half of whom were assigned to a state-anxiety induction-completed this task while event-related potentials were recorded and also completed self-report measures of trait and state anxiety. The results revealed that trait anxiety, but not state anxiety, was associated with impaired attentional control in the presence of a salient distractor. That is, behavioral slowing and the N2pc event-related potential-a neural measure of attentional selection-were enhanced for trait-anxious participants when the distractor was proximate to the target and required controlled attention in order to inhibit it. These findings extend previous work by providing evidence from multiple levels of analysis that attentional aberrations in anxiety reflect broad deficits in inhibiting distracting stimuli and are not limited to threat-relevant contexts.

The roles of interoceptive sensitivity and metacognitive interoception in panic.

BACKGROUND: Interoception refers to the ability to sense body signals. Two interoceptive dimensions have been recently proposed: (a) interoceptive sensitivity (IS) -objective accuracy in detecting internal bodily sensations (e.g., heartbeat, breathing)-; and (b) metacognitive interoception (MI) -explicit beliefs and worries about one's own interoceptive sensitivity and internal sensations. Current models of panic assume a possible influence of interoception on the development of panic attacks. Hypervigilance to body symptoms is one of the most characteristic manifestations of panic disorders. Some explanations propose that patients have abnormal IS, whereas other accounts suggest that misinterpretations or catastrophic beliefs play a pivotal role in the development of their psychopathology. Our goal was to evaluate these theoretical proposals by examining whether patients differed from controls in IS, MI, or both. Twenty-one anxiety disorders patients with panic attacks and 13 healthy controls completed a behavioral measure of IS motor heartbeat detection (HBD) and two questionnaires measuring MI. FINDINGS: Patients did not differ from controls in IS. However, significant differences were found in MI measures. Patients presented increased worries in their beliefs about somatic sensations compared to controls. These results reflect a discrepancy between direct body sensing (IS) and reflexive thoughts about body states (MI). CONCLUSION: Our findings support the idea that hypervigilance to body symptoms is not necessarily a bottom-up dispositional tendency (where patients are hypersensitive about bodily signals), but rather a metacognitive process related to threatening beliefs about body/somatic sensations.

Combining neural and behavioral indicators in the assessment of internalizing psychopathology in children and adolescents.

Anxiety and mood disorders are among the most prevalent mental health problems affecting our youth. We propose that assessment and treatment efforts in this area can benefit from a focus on developmentally sensitive neurobehavioral trait constructs, that is, individual difference constructs with direct referents in both neurobiology and behavior across the lifespan. This approach dovetails with the National Institute of Mental Health's Research Domain Criteria initiative, which aims to improve classification and treatment of psychopathology by delineating dimensions of functioning that transcend measurement domains and traditional diagnostic categories. We highlight two neurobehavioral dimensions with clear relevance for understanding internalizing problems at differing ages: (a) defensive reactivity and (b) cognitive control. Individual differences in defensive reactivity are posited to reflect variations in sensitivity of the brain's negative valence systems, whereas differences in cognitive control are theorized to reflect variations in neural systems dedicated to regulating behavior and affect. Focusing on these target constructs, we illustrate a psychoneurometric approach to assessment of internalizing psychopathology entailing use of neural, self-report, and behavioral indicators. We address the feasibility of the psychoneurometric approach for clinical application and present results from a pilot study demonstrating expected associations for neural, parent-report, and behavioral measures of defensive reactivity and cognitive control with internalizing symptoms in preschoolers. Together, our conceptual and empirical analyses highlight the promise of multimethod, dimensional assessment of internalizing psychopathology in the lab and in the clinic.

Depression self-labeling in U.S. college students: Associations with perceived control and coping strategies.

BACKGROUND: Research on mental illness labeling has demonstrated that self-labeling (identifying with a mental illness label, e.g., "I have depression") is associated with internalized stigma, maladaptive responses to that stigma, and lower quality of life. However, research has not yet examined the link between self-labeling and how individuals cope with emotional distress. It is important to understand this relationship because adaptive and maladaptive methods of coping can lead to positive and negative mental illness outcomes. METHODS: This cross-sectional study examined the link between depression self-labeling, depression symptoms, and three constructs related to depression self-management (perceived control over depression, cognitive emotion regulation strategies, and help-seeking beliefs) in a large (N = 1423) sample of U.S. college students. RESULTS: Approximately one-fifth of students (22.2 %) self-labeled as having depression, while 39.0 % were estimated to meet diagnostic criteria for MDD. After controlling for depression symptom severity, self-labeling was associated with lower levels of perceived control over depression (p = .002), more catastrophizing (p = .013), less perspective taking, refocusing, reappraisal, and planning (ps < 0.05), and more positive help-seeking attitudes towards medication (p < .001) but not therapy. LIMITATIONS: Results are non-causal and may not generalize to non-college populations. CONCLUSIONS: Self-labeling may inform how individuals cope with emotional distress, with the potential for positive and negative effects on clinical outcomes. This is consistent with well-established research on self-labeling with regards to stigma, but extends this research in important new directions.

Remotely administered non-deceptive placebos reduce COVID-related stress, anxiety, and depression.

Research suggests that placebos administered without deception (i.e. non-deceptive placebos) may provide an effective and low-effort intervention to manage stress and improve mental health. However, whether non-deceptive placebos administered remotely online can manage distress for people at risk for developing high levels of affective symptoms remains unclear. Volunteers experiencing prolonged stress from the COVID-19 pandemic were recruited into a randomized controlled trial to examine the efficacy of a non-deceptive placebo intervention administered remotely online on affective outcomes. COVID-related stress, overall stress, anxiety, and depression were assessed at baseline, midpoint, and endpoint. Compared with the control group, participants in the non-deceptive placebo group reported significant reductions from baseline in all primary affective outcomes after 2 weeks. Additionally, participants in the non-deceptive placebo group found the intervention feasible, acceptable, and appropriate for the context. Non-deceptive placebos, even when administered remotely online, offer an alternative and effective way to help people manage prolonged stress. Future large-scale studies are needed to determine if non-deceptive placebos can be effective across different prolonged stress situations and for clinical populations.

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.

Ovarian hormones reduce the negative association between worry and cognitive control: A combined neural and behavioral investigation.

BACKGROUND: Increased reactivity to response conflict and errors, processes governed by the dorsal anterior cingulate cortex (dACC), have both been implicated in anxiety. Anxiety is also more common in females than males. Importantly, natural changes in ovarian hormones levels are related to fluctuations in anxiety symptoms in healthy and clinical populations, and ovarian hormones likely modulate prefrontal cortex structure and function. No studies, however, have examined the role of fluctuating ovarian hormones in the association between anxiety and cognitive control across the menstrual cycle. METHODS: In this multimodal proof-of-concept study, naturally cycling females (N = 30 twins from 14 complete twin pairs and 2 participants whose co-twin was not in the final sample; age 18-29) provided saliva samples to assay for estradiol and progesterone and completed the Penn State Worry Questionnaire for 35 consecutive days. At two time points, during projected pre-ovulatory and post-ovulatory phases, they also completed the Flanker task while undergoing functional magnetic resonance imaging to probe cognitive control-related dACC activity. Multilevel modeling was used to examine within- and between-person effects of hormones and worry on cognitive-control indices. RESULTS: On days when estradiol and progesterone were low relative to a female's own average (i.e., within-subjects effect), worry was associated with greater flanker interference. In females with higher estradiol and progesterone levels compared to other females (i.e., between-subject effects), worry was associated with less error-related dACC activity, irrespective of the day that dACC activity was assessed. CONCLUSION: Findings suggest a protective effect of ovarian hormones on the link between worry and cognitive control. Associations between worry and conflict-monitoring were sensitive to daily hormonal fluctuations (within-person states), whereas associations between worry and error-monitoring were sensitive to mean hormone levels (between-person traits), suggesting that ovarian hormones are critical to consider in studies examining associations between anxiety and cognitive control in females.

Flanker task parameters are related to the strength of association between the ERN and anxiety: a meta-analysis.

The error-related negativity (ERN)-an index of error monitoring-is associated with anxiety symptomatology. Although recent work suggests associations between the ERN and anxiety are relatively modest, little attention has been paid to how variation in task parameters may influence the strength of ERN-anxiety associations. To close this gap, the current meta-analysis assesses the possible influence of task parameter variation in the Flanker task-the most commonly used task to elicit the ERN-on observed ERN-anxiety associations. Here, we leveraged an existing open database of published/unpublished ERN-anxiety effect sizes, supplementing this database by further coding for variation in stimulus type (letter vs. arrow), response type (one-handed vs. two-handed), and block-level feedback (with vs. without). We then performed meta-regression analyses to assess whether variation in these Flanker task parameters moderated the effect size of ERN-anxiety associations. No evidence for an effect of stimulus type was identified. However, both response type and block-level feedback significantly moderated the magnitude of ERN-anxiety associations. Specifically, studies employing either a two-handed (vs. one-handed) task, or those with (vs. without) block-level feedback exhibited more than a two-fold increase in the estimated ERN-anxiety effect size. Thus, accounting for common variation in task parameters may at least partially explain apparent inconsistencies in the literature regarding the magnitude of ERN-anxiety associations. At a practical level, these data can inform the design of studies seeking to maximize ERN-anxiety associations. At a theoretical level, the results also inform testable hypotheses regarding the exact nature of the association between the ERN and anxiety.