DNA methylation of Vesicular Glutamate Transporters in the mesocorticolimbic brain following early-life stress and adult ethanol exposure-an explorative study.

DNA methylation and gene expression can be altered by early life stress (ELS) and/or ethanol consumption. The present study aimed to investigate whether DNA methylation of the Vesicular Glutamate Transporters (Vglut)1-3 is related to previously observed Vglut1-3 transcriptional differences in the ventral tegmental area (VTA), nucleus accumbens (Acb), dorsal striatum (dStr) and medial prefrontal cortex (mPFC) of adult rats exposed to ELS, modelled by maternal separation, and voluntary ethanol consumption. Targeted next-generation bisulfite sequencing was performed to identify the methylation levels on 61 5'-cytosine-phosphate-guanosine-3' sites (CpGs) in potential regulatory regions of Vglut1, 53 for Vglut2, and 51 for Vglut3. In the VTA, ELS in ethanol-drinking rats was associated with Vglut1-2 CpG-specific hypomethylation, whereas bidirectional Vglut2 methylation differences at single CpGs were associated with ELS alone. Exposure to both ELS and ethanol, in the Acb, was associated with lower promoter and higher intronic Vglut3 methylation; and in the dStr, with higher and lower methylation in 26% and 43% of the analyzed Vglut1 CpGs, respectively. In the mPFC, lower Vglut2 methylation was observed upon exposure to ELS or ethanol. The present findings suggest Vglut1-3 CpG-specific methylation signatures of ELS and ethanol drinking, underlying previously reported Vglut1-3 transcriptional differences in the mesocorticolimbic brain.

Memory and language impairments are associated with anxiety disorder severity in childhood.

Introduction Children with anxiety disorders have been suggested to possess deficits in verbal fluency, shifting and attention, with inconsistent results regarding working memory and its subcomponents. This study extends previous findings by analyzing the performance of children with anxiety disorders in a wide range of neuropsychological functions. Methods We evaluated 54 children with a primary diagnosis of an anxiety disorder according to diagnostic criteria from the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) using subtests of a neuropsychological battery. The severity of anxiety disorders was assessed using the Pediatric Anxiety Rating Scale (PARS). We calculated the frequency of neuropsychological impairments (-1.5 standard deviation of the normative sample). Comparisons between groups were performed based on the severity of anxiety symptoms, as well as in the presence of one vs. more diagnoses of anxiety disorder. Results We found higher impairment in visuospatial working memory (23.1%), semantic memory (27.8%), oral language (35.4%) and word writing (44.4%) in anxious children. Moreover, children with higher anxiety severity presented lower performance in visuospatial working memory, inferential processing, word reading, writing comprehension, copied writing, and semantic verbal fluency (d = 0.49 to 0.96 [Cohen's d]). The higher the number of anxiety diagnoses, the lower the performance in episodic memory and oral and written language (d = 0.56 to 0.77). Conclusion Our data suggested the presence of memory (visuospatial working memory and semantic memory) and language deficits (oral and writing) in some children with an anxiety disorder. Severity and number of anxiety diagnoses were associated with lower performance in memory and language domains in childhood.

Memory and language impairments are associated with anxiety disorder severity in childhood

Abstract Introduction Children with anxiety disorders have been suggested to possess deficits in verbal fluency, shifting and attention, with inconsistent results regarding working memory and its subcomponents. This study extends previous findings by analyzing the performance of children with anxiety disorders in a wide range of neuropsychological functions. Methods We evaluated 54 children with a primary diagnosis of an anxiety disorder according to diagnostic criteria from the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) using subtests of a neuropsychological battery. The severity of anxiety disorders was assessed using the Pediatric Anxiety Rating Scale (PARS). We calculated the frequency of neuropsychological impairments (-1.5 standard deviation of the normative sample). Comparisons between groups were performed based on the severity of anxiety symptoms, as well as in the presence of one vs. more diagnoses of anxiety disorder. Results We found higher impairment in visuospatial working memory (23.1%), semantic memory (27.8%), oral language (35.4%) and word writing (44.4%) in anxious children. Moreover, children with higher anxiety severity presented lower performance in visuospatial working memory, inferential processing, word reading, writing comprehension, copied writing, and semantic verbal fluency (d = 0.49 to 0.96 [Cohen's d]). The higher the number of anxiety diagnoses, the lower the performance in episodic memory and oral and written language (d = 0.56 to 0.77). Conclusion Our data suggested the presence of memory (visuospatial working memory and semantic memory) and language deficits (oral and writing) in some children with an anxiety disorder. Severity and number of anxiety diagnoses were associated with lower performance in memory and language domains in childhood.

Adverse caregiving in infancy blunts neural processing of the mother.

The roots of psychopathology frequently take shape during infancy in the context of parent-infant interactions and adversity. Yet, neurobiological mechanisms linking these processes during infancy remain elusive. Here, using responses to attachment figures among infants who experienced adversity as a benchmark, we assessed rat pup cortical local field potentials (LFPs) and behaviors exposed to adversity in response to maternal rough and nurturing handling by examining its impact on pup separation-reunion with the mother. We show that during adversity, pup cortical LFP dynamic range decreased during nurturing maternal behaviors, but was minimally impacted by rough handling. During reunion, adversity-experiencing pups showed aberrant interactions with mother and blunted cortical LFP. Blocking pup stress hormone during either adversity or reunion restored typical behavior, LFP power, and cross-frequency coupling. This translational approach suggests adversity-rearing produces a stress-induced aberrant neurobehavioral processing of the mother, which can be used as an early biomarker of later-life pathology.

Hypothalamus-pituitary-adrenal axis imbalance and inflammation contribute to sex differences in separation- and restraint-induced depression.

Whether social contact contributes to the underlying mechanisms of depression and the observed sex differences is unclear. In this study, we subjected young male and female mice to separation- and restraint-induced stress for 4 weeks and assessed behaviors, neurotransmitter levels, hormones, and inflammatory cytokines. Results showed that, compared with controls, male mice exposed to stress displayed significant decreases in body weight and sucrose preference after 1 week. In the fourth week, they exhibited a higher degree of anxiety (open field test) and depressive-like behavior (forced swim test). Moreover, the males showed significant decreases in monoamine neurotransmitters, including norepinephrine and dopamine in striatum, and an increase in pro-inflammatory cytokines, such as tumor necrosis factor α and interleukin 1ß in serum. In contrast, females showed persistent loss of weight during stress and displayed significant decreases in sucrose preference after stress. Importantly, the females but not males showed activation of the hypothalamus-pituitary-adrenal (HPA) axis, with significantly higher levels adrenocorticotropic hormone. Additionally, mRNA level of c-fos and AVP showed there was significant interaction between stress and sex. Finally, we conclude that an imbalance of the HPA axis and inflammation might be important contributors to sex differences in separation/restraint-induced depressive behavior and that changes might be mediated by c-fos and AVP.

A neurobiological framework of separation anxiety and related phenotypes.

In the DSM-5, separation anxiety disorder (SAD) is newly classified in the chapter on anxiety, renewing research efforts into its etiology. In this narrative review, we summarize the current literature on the genetic, endocrine, physiological, neural and neuropsychological underpinnings of SAD per se, SAD in the context of panic disorder, separation anxiety symptoms, and related intermediate phenotypes. SAD aggregates in families and has a heritability of ~43%. Variants in the oxytocin receptor, serotonin transporter, opioid receptor µ1, dopamine D4 receptor and translocator protein genes have all been associated with SAD. Dysregulation of the hypothalamus-pituitary-adrenal axis, dysfunctional cortico-limbic interaction and biased cognitive processing seem to constitute further neurobiological markers of separation anxiety. Hypersensitivity to carbon dioxide appears to be an endophenotype shared by SAD, panic disorder and anxiety sensitivity. The identification of biological risk markers and its multi-level integration hold great promise regarding the prediction of SAD risk, maintenance and course, and in the future may allow for the selection of indicated preventive and innovative, personalized therapeutic interventions.

Separation Anxiety Symptom Profiles and Parental Accommodation Across Pediatric Anxiety Disorders.

Parental accommodation refers to ways in which caregivers modify their behavior to decrease child distress in the short-term. Accommodation is prevalent among anxious youth and related to decreased treatment and functional outcomes. Although separation anxiety disorder (SAD) is associated with increased accommodation, SAD is not a predictor of treatment response, suggesting that a diagnosis of SAD alone may not be enough to clarify the relationship between accommodation and separation anxiety symptoms within a clinical context. Participants were youth with a primary anxiety disorder (N = 186; aged 7-17) enrolled in an outpatient anxiety clinic. Latent class analysis was used to extract profiles from parent-reported SAD symptoms using the Anxiety Disorders Interview Schedule for DSM-IV/5. Profiles were compared on pre-treatment accommodation. Low, moderate, and interfering SAD classes emerged. Interfering SAD was associated with high accommodation. Results help to clarify the association between SAD and accommodation and has implications for personalized intervention.

Adult Separation Anxiety Disorder Symptomology as a Risk Factor for Thin-Ideal Internalization: The Role of Self-Concept Clarity.

The study of when and how individuals compare themselves against standards has been an enduring focus for clinical and social psychology researchers in efforts to facilitate well-being and health. Our study focused on internalization of the societal thin-ideal standard for feminine attractiveness, a construct that has proven to be very important in women's psychological health. Although multiple adverse consequences of thin-ideal internalization have been documented, the understanding of variability in the extent of thin-ideal internalization across women (e.g., why do some women strongly internalize thin-ideal standards when others do not?) is much less well developed. This research was conducted to explore the role of adult separation anxiety disorder (ASAD) symptomology and conceptions of the self in young women's propensity to internalize the thin-ideal attractiveness standard. Results show that elevated ASAD symptoms are associated with greater thin-ideal internalization. A structural equations model demonstrates the reason for this association; young women with higher ASAD symptomology exhibit lower self-concept clarity, which drives greater thin-ideal internalization. This research makes novel practical and conceptual contributions by (a) delineating a new risk factor for the development of thin-ideal internalization, (b) highlighting a previously undocumented vulnerability of women who experience ASAD symptoms, and (c) documenting the relationship between ASAD and lower self-concept clarity. Implications for mental health practitioners are discussed.

The Moderating Role of Sleep in the Relationship Between Social Isolation and Internalising Problems in Early Adolescence.

Social isolation may be a unique risk factor for depression and anxiety in early adolescence. However, optimal sleep may protect adolescents from the emotional sequela of social isolation. The present study aimed to investigate whether sleep moderates the relationship between social isolation and symptoms of anxiety and depression in early adolescence. Five hundred and twenty eight early adolescents (M = 11.18 years, SD = 0.56, range 10-12 years, 51% male) completed online questionnaires assessing social isolation, sleep duration, daytime sleepiness and symptoms of generalised anxiety, social anxiety, separation anxiety and depression. Sleep duration moderated the effect of social isolation on symptoms of generalised anxiety, social anxiety and depression, but not separation anxiety. Daytime sleepiness emerged as an additional sleep-related risk factor in the relationship between social isolation and depressive symptoms. Therefore, sleep may be an important modifiable risk or protective factor to target, in the prevention of depression and anxiety in adolescence.

Exercise attenuates maternal separation-induced mood disorder-like behaviors by enhancing mitochondrial functions and neuroplasticity in the dorsal raphe.

Loss of the mother-infant relationship during early childhood affects infant development and is known to increase the infant's vulnerability to neuropsychiatric disorders throughout life. Serotonin deficits and mitochondrial dysfunction in the dorsal raphe may underlie mood disorders such as anxiety and depression. Exercise is known to have a positive effect on brain function. In this study, we investigated the effect of exercise on mitochondrial function, apoptosis, and serotonin levels in the dorsal raphe as well as behavioral changes in cases of maternal separation. Exposure to the stress of maternal separation resulted in mitochondrial dysfunction in the dorsal raphe, including impaired Ca2+ homeostasis, an increase in reactive oxygen species such as H2O2, and a decrease in the O2 respiration rate. Exposure to maternal separation stress also decreased tryptophan hydroxylase and 5-hydroxytryptamine positive cells and increased apoptosis, anxiety, and depression. The impairments in mitochondrial function, apoptosis, and serotonin in the dorsal raphe, as well as anxiety and depression, were all improved by exercise. Exercise might alter mitochondrial function, serotonin levels, and the rate of apoptosis in the dorsal raphe. Therefore, exercise might be an important non-pharmacological intervention for the prevention and treatment of the adverse effects of maternal separation.

Anxiety-associated and separation distress-associated behaviours in Angelman syndrome.

BACKGROUND: Anxiety is considered a 'frequent' feature in the clinical criteria for Angelman syndrome; however, the nature and severity of anxiety symptoms have not been well characterised in this population. Anxiety behaviours, especially in response to separation from a preferred caregiver, have been described clinically but have not yet been explored empirically. METHOD: This study used a combination of standardised and clinician-derived survey items to assess the frequency, nature and severity of behaviours associated with anxiety and separation distress in 100 individuals with Angelman syndrome. Family (e.g. income and maternal education) and individual (e.g. age, sex, genetic subtype, sleep difficulties and aggressive behaviours) variables were also gathered to assess possible predictors of higher anxiety levels. Approximately half of the sample was seen in clinic and assessed with standardised measures of development and daily functioning, allowing for an additional exploration of the association between anxiety symptoms and extent of cognitive impairment. RESULTS: Anxiety concerns were reported in 40% of the sample, almost 70% were reported to have a preferred caregiver and over half displayed distress when separated from that caregiver. Individuals with the deletion subtype and individuals who are younger were less likely to have anxiety behaviours. Sleep difficulties and aggressive behaviour consistently significantly predicted total anxiety, the latter suggesting a need for future studies to tease apart differences between anxiety and aggression or anger in this population. CONCLUSIONS: Anxiety concerns, especially separation distress, are common in individuals with Angelman syndrome and represent an area of unmet need for this population.

The Impact of Early Life Stress on Anxiety Symptoms in Late Adulthood.

Early life stress (ELS) may increase the risk of anxiety throughout the life course. Whether this effect extends to late adulthood is poorly known. In our study comprising 1872 participants from the Helsinki Birth Cohort Study born in 1934-1944, we investigated the association of various forms of ELS and their accumulation with self-reported anxiety symptoms at the age of 65-77 years. Data on childhood socioeconomic status and separation from parents were based on national registers for all participants. Information on self-reported emotional and physical trauma, parental divorce, and death of a family member in childhood was obtained from 1277 participants. We found that experiencing emotional trauma, physical trauma, and low socioeconomic status in childhood were associated with increased anxiety symptoms in late adulthood [B = 0.44 (95% CI = 0.31-0.58); B = 0.33 (95% CI = 0.20-0.46); B = 0.10 (95% CI = 0.01-0.19), respectively]. These associations remained significant even after controlling for other forms of ELS. Accumulation of early life stress also increased the levels of late-adulthood anxiety symptoms and the risk of anxiety regarded as clinically significant. Screening for potentially stressful childhood experiences in elderly populations may help identifying individuals with increased anxiety symptoms and planning preventive and therapeutic interventions for those exposed to ELS.

Infant Attachment Insecurity and Baseline Physiological Activity and Physiological Reactivity to Interpersonal Stress: A Meta-Analytic Review.

This meta-analytic review (k = 5-10; N = 258-895) examined links between attachment insecurity and physiological activity at baseline and in response to interpersonal stress elicited by separation-reunion procedures in the early life course (1-5 years). Insecurity was trivially, nonsignificantly associated with baseline physiological activity (heart rate [HR]: g = -.06; respiratory sinus arrhythmia [RSA]: g = -.06; cortisol: g = .01) and nonsignificantly associated with physiological reactivity to separation from parents (HR: g = -.001; RSA: g = .24). However, insecurity was moderately associated with heightened RSA (g = .26) and cortisol (g = .27) reactivity upon reunion with parents. Findings provide insight into the biobehavioral organization of attachment, suggesting that early insecurity is associated with heightened physiological reactivity to interpersonal stress.

Acute maternal separation potentiates the gene expression and corticosterone response induced by inflammation.

Maternal care is crucial for infants and profoundly affects their responses to different kinds of stressors. Here, we examined how maternal separation affects inflammatory gene expression and the corticosterone response to an acute immune challenge induced by lipopolysaccharide (LPS; 40 µg/kg ip) in mouse pups, 8-9 days old. Maternal separation initially attenuated LPS-induced hypothalamic pro-inflammatory gene expression, but later, at 3 h after immune challenge, robustly augmented such gene expression and increased serum corticosterone levels. Providing the pups with a warm and soft object prevented the separation-induced augmented hypothalamic-pituitary-adrenal (HPA)-axis response. It also prevented the potentiated induction of some, but not all, inflammatory genes to a similar extent as did the dam. Our results show that maternal separation potentiates the inflammatory response and the resulting HPA-axis activation, which may have detrimental effects if separation is prolonged or repeated.

A randomized interventional study to promote milk secretion during mother-baby separation based on the health belief model: A consort compliant.

BACKGROUND: Breast milk is the most important nutrition for premature babies, but mothers of premature infants have difficulty in initiating and sustaining lactation. Breastfeeding infants who are separated with mothers have decreased morbidity. Nevertheless, such decrease is limited due to insufficient milk supply resulting from mother-baby separation during lac. OBJECTIVE: To evaluate the effect of intervention methods based on the health belief model on promoting the secretion of milk among mothers who were separated with their babies. METHODS: In this prospective, randomized controlled clinical trial, we enrolled 260 separation mothers between September 26, 2016 and March 7, 2017, in a 3rd-grade women and children hospital of Chengdu. The mothers all had cesarean delivery and were randomized into 2 groups: the intervention group (educated by investigators based on the health belief) and the control group (routinely educated by obstetric nurses). Data on the onset of lactation and the milk volume during 3 days postpartum were collected. The breast swelling rate within 3 days postpartum and the exclusive breastfeeding rate at 42 days postpartum were compared. The psychologic scores of separation maternal in both groups were assessed with State-Trait Anxiety Inventory at the 3rd day postpartum. RESULTS: Compared with the control group, the intervention group had significantly earlier lactation time (P < .01), significantly larger milk volume (P < .01) during 24, 24 to 48, and 48 to 72 hours, and significantly lower psychologic scores (P < .01) at the 3rd-day postpartum.The onset of lactation among mothers who initiated milk expression within 1 hour after childbirth were earlier than those who initiated milk expression between 1 and 6 hours (P < .01); the milk volume within 24-hour postpartum did not differ significantly between the 2 groups (P > .05). However, the milk volume of the early-expression group (<1 hour) was significantly higher than that of the late-expression group (1-6 hours) during 24 to 48 and 48 to72 hours (P < .05).The breast swelling rate of separation mothers within 3 days postpartum in the intervention group was lower than that in the control group (P < .05). The exclusive breastfeeding rate of mothers in the intervention group was significantly higher than that in the control group (59% vs 35%; P < .01) at 42 days postpartum. CONCLUSION: Nursing intervention based on the health belief model can stimulate milk secretion in mothers who were separated with their babies.

Insulin sensitivity, leptin, adiponectin, resistin, and testosterone in adult male and female rats after maternal-neonatal separation and environmental stress.

Care of premature infants often requires parental and caregiver separation, particularly during hypoxic and hypothermic episodes. We have established a neonatal rat model of human prematurity involving maternal-neonatal separation and hypoxia with spontaneous hypothermia prevented by external heat. Adults previously exposed to these neonatal stressors show a sex difference in the insulin and glucose response to arginine stimulation suggesting a state of insulin resistance. The current study used this cohort of adult rats to evaluate insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR)], plasma adipokines (reflecting insulin resistance states), and testosterone. The major findings were that daily maternal-neonatal separation led to an increase in body weight and HOMA-IR in adult male and female rats and increased plasma leptin in adult male rats only; neither prior neonatal hypoxia (without or with body temperature control) nor neonatal hypothermia altered subsequent adult HOMA-IR or plasma adiponectin. Adult male-female differences in plasma leptin were lost with prior exposure to neonatal hypoxia or hypothermia; male-female differences in resistin were lost in the adults that were exposed to hypoxia and spontaneous hypothermia as neonates. Exposure of neonates to daily hypoxia without spontaneous hypothermia led to a decrease in plasma testosterone in adult male rats. We conclude that neonatal stressors result in subsequent adult sex-dependent increases in insulin resistance and adipokines and that our rat model of prematurity with hypoxia without hypothermia alters adult testosterone dynamics.

Paneth Cell Defects Induce Microbiota Dysbiosis in Mice and Promote Visceral Hypersensitivity.

BACKGROUND & AIMS: Separation of newborn rats from their mothers induces visceral hypersensitivity and impaired epithelial secretory cell lineages when they are adults. Little is known about the mechanisms by which maternal separation causes visceral hypersensitivity or its relationship with defects in epithelial secretory cell lineages. METHODS: We performed studies with C3H/HeN mice separated from their mothers as newborns and mice genetically engineered (Sox9flox/flox-vil-cre on C57BL/6 background) to have deficiencies in Paneth cells. Paneth cell deficiency was assessed by lysozyme staining of ileum tissues and lysozyme activity in fecal samples. When mice were 50 days old, their abdominal response to colorectal distension was assessed by electromyography. Fecal samples were collected and microbiota were analyzed using Gut Low-Density Array quantitative polymerase chain reaction. RESULTS: Mice with maternal separation developed visceral hypersensitivity and defects in Paneth cells, as reported from rats, compared with mice without maternal separation. Sox9flox/flox-vil-Cre mice also had increased visceral hypersensitivity compared with control littermate Sox9flox/flox mice. Fecal samples from mice with maternal separation and from Sox9flox/flox-vil-cre mice had evidence for intestinal dysbiosis of the microbiota, characterized by expansion of Escherichia coli. Daily gavage of conventional C3H/HeN adult mice with 109 commensal E coli induced visceral hypersensitivity. Conversely, daily oral administration of lysozyme prevented expansion of E coli during maternal separation and visceral hypersensitivity. CONCLUSIONS: Mice with defects in Paneth cells (induced by maternal separation or genetically engineered) have intestinal expansion of E coli leading to visceral hypersensitivity. These findings provide evidence that Paneth cell function and intestinal dysbiosis are involved in visceral sensitivity.

Infant stranger fear trajectories predict anxious behaviors and diurnal cortisol rhythm during childhood.

Although a robust literature has linked stable, high levels of fear across childhood to increased risk for anxiety problems, less is known about alternative pathways to anxiety. We tested two putatively normative developmental pathways of early fearfulness for their distinct associations with behavioral (anxiety-related behaviors and symptoms) and biological (diurnal cortisol) markers of anxiety risk in middle childhood in a community-based sample (n = 107). Steeper increases in fear from 6 to 36 months predicted more parent-reported anxiety symptoms at age 8 years. In addition, children who exhibited steep increases in fear during infancy were overrepresented among children with diagnoses of separation anxiety disorder at age 8 years. Finally, we showed that steeper increases in fearfulness in infancy predicted flatter slopes of diurnal cortisol at age 8 years for girls. Thus, differences in stranger fear across infancy may indicate varying degrees of risk for anxious behaviors in later childhood.

Sensitivity to carbon dioxide and translational studies of anxiety disorders.

Heightened concentrations of CO2 in inhaled air provoke temporary acidification of the brain, followed by compensatory hyperventilation and increased arousal/anxiety. These responses are likely to map a basic, latent general alarm/avoidance system that is largely shared across mammals, and are sources of individual differences. By showing paroxysmal respiratory and emotional responses to CO2 challenges, humans with panic and separation anxiety disorders lie at one extreme of the distribution for CO2 sensitivity. This is also a developmental trait, sensitive to interference with parental cares. By sharing CO2 sensitivity with humans, rodents constitute a valuable resource to model panic and separation anxiety in the laboratory. Advantages of modeling CO2 sensitivity in rodents include non-inferential measurements (e.g. respiratory readouts) as proxies for human conditions, unbiased investigation of gene-environment interplays, and flexible availability of tissues for mechanistic studies. Data in humans and animals such as those reported in this issue of Neuroscience begin to reveal that CO2-driven behavioral responses stem from anatomo-physiological systems that are relatively separated from those subserving general dispositions to anxiety. This supports the notion that sensitivity to suffocative stimuli and ensuing human panic are significantly independent from trait/cognitive anxiety, and corroborates newer conceptualizations that distinguish between fear and anxiety circuitries.

Associations between Disorder-Specific Symptoms of Anxiety and Error-Monitoring Brain Activity in Young Children.

Anxiety disorders are among the earliest emerging disorders and most common mental health problem across the lifespan. A common characteristic of individuals with anxiety is poor attentional and cognitive control. Therefore, researchers are interested in how cognitive functioning relates to anxiety in young children. In particular, research has demonstrated associations between anxiety and electrophysiological markers of cognitive control skills such as the error-related negativity (ERN). The nature of the anxiety-ERN relationship is not well understood, however. The purpose of the present study was to examine: 1) the association between the ERN and diagnostically-defined symptoms of different anxiety disorders; and 2) the extent to which disorder-specific symptoms of anxiety moderated the association between ERN and behavioral performance on a Go/No-Go task in a sample of 139 children 5-8 years of age (70 females and 69 males). Results suggest that more separation anxiety disorder (SAD) symptoms are associated with a smaller ΔERN, even after controlling for other anxiety disorder symptoms. Children with more SAD symptoms showed higher error rates and failed to exhibit the expected association between ΔERN and behavioral performance, suggesting ineffective error-monitoring in young children with SAD problems.